Novel fused heterocyclic-carbonylhydrazone dinitrile compound and its use

Abstract

The present invention relates to a novel fused heterocyclic-carbonylhydrazone dinitrile compound and application thereof.

Description

Technical Field

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

[0002] Tau protein (tau (τ) protein) is a microtubule-associated protein (MAP) primarily expressed in nerve cell axons. It has a molecular weight of 50,000 to 70,000, acts to stabilize microtubules, and exhibits molecular diversity through phosphorylation. In humans, tau protein forms six isoforms through the insertion of 29 or 58 amino acid residues at the N-terminus and the alternative splicing of three or four repeating structures (called microtubule-binding domains) at the C-terminus of the mRNA.

[0003] In healthy neurons, tau stabilizes microtubules by promoting axonal growth and neuronal polarization. When pathologically hyperphosphorylated, tau dissociates from microtubules, forming insoluble aggregates. Furthermore, a structural framework that induces tau aggregation has been proposed, and evidence has been provided that insoluble filaments are formed from 10 soluble monomers, which are then combined into high-dimensional structures called neurofibrillary tangles (NFTs). Full-length human tau protein contains a microtubule-binding domain composed of four repetitive conserved sequences. Within these repetitive sequences, positively charged residues play a crucial role in binding to highly negatively charged microtubules (each αβ-tubulin dimer has 20 to 30 electrons). Tau's binding affinity for microtubules is also actively regulated by tau phosphorylation, which induces a dynamic rearrangement of the microtubule network. When tau is abnormally hyperphosphorylated, the equilibrium of this dynamic rearrangement is disrupted, and its affinity for microtubules rapidly decreases.

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

[0005] Therefore, although it is known that hyperphosphorylation and / or aggregation of tau protein leads to various neurodegenerative diseases, including Alzheimer's disease and tauopathies, the specific mechanisms of how these abnormal tau species lead to changes in signaling pathways and trigger neurotoxicity have not been demonstrated, and there are no effective treatments or therapeutic agents available to treat these diseases. Summary of the Invention

[0006] Technical issues

[0007] The present inventors have made great efforts to develop novel small molecule compounds capable of inhibiting tau protein aggregation and / or hyperphosphorylation. As a result, the present inventors have discovered a series of novel fused heterocyclic-carbonylhydrazone dinitrile compounds that can effectively inhibit tau protein aggregation at effective concentrations without exhibiting cytotoxicity, thereby completing the present invention.

[0008] Technical Solution

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

[0010] [Formula 1]

[0011]

[0012] In the above formula 1,

[0013] X1 to X3 are each independently N or C(H);

[0014] Y1 and Y2 are each independently N(R4), C(H), O or S;

[0015] n is 0 or 1;

[0016] Forming an aromatic or non-aromatic fused heterocyclic ring or

[0017] R1 is hydrogen, C 1-6 Alkyl or C 1-6 alkylcarbonyl;

[0018] R2 and R3 are each independently hydrogen, C 1-6 Alkyl, halogen, cyano, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkylaminocarbonyl, or di(C 1-6 alkyl)aminocarbonyl; and

[0019] R4 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 0-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl-C 0-6 Alkyl, 5- or 6-membered heterocyclic-C 0-6 Alkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl,

[0020] wherein the 5- or 6-membered heterocyclic ring, C 6-10 Aryl and 5- to 10-membered heteroaryl are unsubstituted or replaced by C 1-6 Alkoxy or C 1-6 Alkoxycarbonyl substitution.

[0021] Another object of the present invention is to provide a method for preparing the above compound.

[0022] Another object of the present invention is to provide a composition for inhibiting tau protein aggregation, which comprises the above compound as an active ingredient.

[0023] Another object of the present invention is to provide a composition for inhibiting hyperphosphorylation of tau protein, which comprises the above compound as an active ingredient.

[0024] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases caused by tau protein aggregation or hyperphosphorylation, which comprises the above-mentioned compound as an active ingredient.

[0025] Another object of the present invention is to provide a method for preventing or treating diseases caused by tau protein aggregation or hyperphosphorylation, which comprises administering the above-mentioned pharmaceutical composition to a subject in need thereof.

[0026] Beneficial effects

[0027] The novel fused heterocyclic-carbon hydrazone dinitrile compound of the present invention can effectively inhibit tau protein aggregation and / or hyperphosphorylation, and thus can be effectively used to prevent or treat diseases caused thereby, such as Alzheimer's disease and various tauopathies. DETAILED DESCRIPTION

[0028] The first aspect of the present invention provides a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof:

[0029] [Formula 1]

[0030]

[0031] In the above formula 1,

[0032] X1 to X3 are each independently N or C(H);

[0033] Y1 and Y2 are each independently N(R4), C(H), O or S;

[0034] n is 0 or 1;

[0035] Forming an aromatic or non-aromatic fused heterocyclic ring or

[0036] R1 is hydrogen, C 1-6 Alkyl or C 1-6 alkylcarbonyl;

[0037] R2 and R3 are each independently hydrogen, C 1-6 Alkyl, halogen, cyano, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, C 1-6 Alkylaminocarbonyl or di(C 1-6 alkyl)aminocarbonyl; and

[0038] R4 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 0-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl-C 0-6 Alkyl, 5- or 6-membered heterocyclic-C 0-6 Alkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl,

[0039] wherein the 5- or 6-membered heterocyclic ring, C 6-10 Aryl and 5- to 10-membered heteroaryl are unsubstituted or replaced by C 1-6 Alkoxy or C 1-6 Alkoxycarbonyl substitution.

[0040] For example, in the compounds of the present invention,

[0041] R1 is hydrogen, C 1-6 Alkyl or C 1-6 alkylcarbonyl;

[0042] R2 is hydrogen, halogen, C 1-6 Alkyl or C 1-6 alkoxy;

[0043] R3 is hydrogen or C 1-6 alkyl; and

[0044] R4 is hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl-C 0-6 Alkyl or C 6-10 Aryl, but not limited thereto.

[0045] Specifically, in the compounds of the present invention,

[0046] R1 is hydrogen, methyl or acetyl;

[0047] R2 is hydrogen, chlorine, fluorine, methyl or methoxy;

[0048] R3 is hydrogen or methyl; and

[0049] R4 is hydrogen, methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl or phenyl, but is not limited thereto.

[0050] For example, the compound of the present invention may be a compound represented by the following Formula 2:

[0051] [Formula 2]

[0052]

[0053] In the above formula 2,

[0054] One of Y1 and Y2 is CH, and the other is NR4;

[0055] Connecting with CH is Connecting with NR4 is

[0056] R3 is hydrogen or methyl; and

[0057] R4 is hydrogen, methyl or isopropyl.

[0058] Alternatively, the compound of the present invention may be a compound represented by the following formula 3:

[0059] [Formula 3]

[0060]

[0061] In the above formula 3,

[0062] X3 is C(H) or N;

[0063] R1 is hydrogen, methyl or acetyl;

[0064] R2 is hydrogen, chloro, fluoro, methyl or methoxy; and

[0065] R 4′ and R 4″ Each is independently hydrogen, methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl or phenyl.

[0066] In addition, the compound of the present invention may be a compound represented by the following formula 4:

[0067] [Formula 4]

[0068]

[0069] In the above formula 4,

[0070] Y1 is S or O; and

[0071] R4 is hydrogen, methyl, isopropyl or difluoromethyl.

[0072] More specifically, the compound represented by Formula 1 may be:

[0073] 1. (1-Oxo-1,2-dihydroisoquinolin-7-yl) carbonyl dicarbonitrile,

[0074] 2. (2-Methyl-1-oxo-1,2-dihydroisoquinolin-7-yl) carbonyl dicarbonitrile,

[0075] 3. (2-Isopropyl-1-oxo-1,2-dihydroisoquinolin-7-yl) carbonyl dicarbonitrile,

[0076] 4. (1-Oxo-1,2-dihydroisoquinolin-5-yl) carbonyl dicarbonitrile,

[0077] 5. (2-Methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonyl dicarbonitrile,

[0078] 6. (2-Isopropyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonyl dicarbonitrile,

[0079] 7. (2,3-Dimethyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonyl dicarbonitrile,

[0080] 8. (2-Oxo-1,2-dihydroquinolin-6-yl)carbonyl dicarbonitrile,

[0081] 9. (6-Fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile,

[0082] 10. (6-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile,

[0083] 11. (7-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile,

[0084] 12. (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile,

[0085] 13. (2-Oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonyl dicarbonitrile,

[0086] 14. (3-Methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbazone dinitrile,

[0087] 15. (2-Oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonyl dicarbonitrile,

[0088] 16. (3-Methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbazone dinitrile,

[0089] 17. (1-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile,

[0090] 18. (3-Isopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbazone dinitrile,

[0091] 19. (3-(Difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbazone dinitrile,

[0092] 20. (3-Isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonyl dicarbonitrile,

[0093] 21. (3-(Difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbazone dinitrile,

[0094] 22. (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile,

[0095] 23. (1,3-Diisopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile,

[0096] 24. (1,3-bis(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile,

[0097] 25. (1-Methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonyl dicarbonitrile,

[0098] 26. (4-Methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonyl dicarbonitrile,

[0099] 27. (1,4-Dimethyl-2-oxo-1,2-dihydroquinolin-6-yl)carbazone dinitrile,

[0100] 28. (3-Methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonyl dicarbonitrile,

[0101] 29. (3-Isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbazone dinitrile,

[0102] 30. (3-(Difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonyl dicarbonitrile,

[0103] 31. (1,3,6-Trimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile,

[0104] 32. (6-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile,

[0105] 33. (7-Methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile,

[0106] 34. (1,3-Diisopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile,

[0107] 35. (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile,

[0108] 36. (3-Isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile,

[0109] 37. (3-(Difluoromethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile,

[0110] 38. (1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile,

[0111] 39. (3-(Difluoromethyl)-1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile,

[0112] 40. (1-Cyclopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone-dicarbonitrile, 41. (1-Cyclopropyl-3-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone-dicarbonitrile,

[0113] 42. (1-Cyclopropyl-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dicarbonitrile,

[0114] 43. (3-(Difluoromethyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile,

[0115] 44. (1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile,

[0116] 45. (1-Isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile,

[0117] 46. (1-(Difluoromethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile,

[0118] 47. (3-Methyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile,

[0119] 48. (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile,

[0120] 49. (3-Ethyl-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile,

[0121] 50. (1-(Difluoromethyl)-3-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile,

[0122] 51. (3-cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile,

[0123] 52. (3-cyclopropyl-1-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile,

[0124] 53. (3-cyclopropyl-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile,

[0125] 54. (3-Isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile,

[0126] 55. (1-ethyl-3-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile,

[0127] 56. (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)(methyl)carbazone-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonylcarbonitrile, or

[0128] 57. Acetyl (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazole-5-yl) carbonyl dicarbonitrile, but not limited thereto.

[0129] Furthermore, these compounds may be compounds represented by the chemical formulas shown in Table 1 below.

[0130] Table 1

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138] At the same time, the compounds of the present invention may exist in the form of pharmaceutically acceptable salts. As salts, acid salts formed from pharmaceutically acceptable free acids are useful. As used herein, the term "pharmaceutically acceptable salt" refers to any organic or inorganic addition salt of a compound represented by Formulas 1 to 4 that is relatively non-toxic and harmless to the patient, and the side effects caused by the salt do not impair the beneficial effects of the compound.

[0139] Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an aqueous solution of an excess of acid and precipitating the solution with a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. An aqueous solution of the compound and an acid or alcohol (e.g., ethylene glycol monoethyl ether) in equal molar amounts is heated, and the mixture can be evaporated and dried subsequently, or the precipitated salt can be filtered with suction.

[0140] In this case, an organic acid or an inorganic acid can be used as a free acid. Hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as an inorganic acid. Methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used as an organic acid. However, the present invention is not limited thereto.

[0141] In addition, a base can be used to prepare a pharmaceutically acceptable metal salt. Alkali metal salts or alkaline earth metal salts are obtained by the following method: the compound is dissolved in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, the insoluble compound salt is filtered, and the filtrate is evaporated and dried. In this case, sodium salts, potassium salts or calcium salts are prepared as metal salts suitable for pharmaceutical use, but the present invention is not limited thereto. In addition, the corresponding silver salt can be obtained by the following method: an alkali metal or alkaline earth metal salt is reacted with a suitable silver salt (e.g., silver nitrate).

[0142] Unless otherwise indicated, pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in compounds of Formulas 1 to 4. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of hydroxyl groups, and other pharmaceutically acceptable salts of amino groups may include hydrobromide, sulfate, bisulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate, and p-toluenesulfonate. These pharmaceutically acceptable salts can be prepared by methods for preparing salts known in the art.

[0143] As the salt of the compound of Formulae 1 to 4 of the present invention, any salt can be used without limitation as a pharmaceutically acceptable salt as long as it exhibits pharmacological activity equivalent to that of the compound of Formulae 1 to 4, for example, it inhibits tau protein aggregation and / or hyperphosphorylation.

[0144] In addition, the compounds represented by Formulas 1 to 4 according to the present invention include, but are not limited to, pharmaceutically acceptable salts thereof, and solvates, such as possible hydrates that can be prepared therefrom, and all possible stereoisomers. Solvates and stereoisomers of the compounds represented by Formulas 1 to 4 can be prepared from the compounds represented by Formulas 1 to 4 using any method known in the art.

[0145] In addition, the compounds represented by Formulas 1 to 4 according to the present invention can be prepared in crystalline or amorphous form, and if prepared in crystalline form, can be optionally hydrated or solvated. In the present invention, stoichiometric hydrates of compounds represented by Formulas 1 to 4, and compounds containing different amounts of water are provided. Solvates of compounds represented by Formulas 1 to 4 according to the present invention include stoichiometric solvates and non-stoichiometric solvates.

[0146] A second aspect of the present invention provides a method for preparing the compound of formula 1.

[0147] For example, the compounds of the present invention can be prepared by a process comprising the following steps:

[0148] In the first step, a compound having a reactive amine group at one end represented by the following formula 5 is reacted with sodium nitrite and malononitrile in the presence of an acid to form an imine bond; and

[0149] Optionally, in the second step, when R1 is a substituent other than hydrogen, an R1 substituent is introduced into the product obtained in the previous step.

[0150] [Formula 5]

[0151]

[0152] In the above formula 5,

[0153] X1 to X3, Y1, Y2, n, R2 and R3 are as defined above, and

[0154] When Y1 and Y2 are N(H), N(H) may be protected by a tert-butoxycarbonyl group.

[0155] In this regard, when the N(H) groups of Y1 and Y2 are protected by a tert-butoxycarbonyl group, the method may further include a deprotection step after the reaction.

[0156] Specifically, the first step of the method can be performed through a series of processes, including the following steps:

[0157] 1-1) Dissolve the compound of formula 5 and sodium nitrite in C 1-4 a lower alcohol solvent, and adding an aqueous acid solution thereto at a temperature of -5°C to 5°C to form a diazonium salt,

[0158] 1-2) adding malononitrile to the reaction solution containing the diazonium salt obtained in step 1-1) and reacting at a temperature of 15° C. to 40° C., and

[0159] 1-3) An aqueous base solution is added to the reaction solution of step 1-2) to neutralize the reaction solution, but the present invention is not limited thereto.

[0160] For example, the first step can be performed by performing the reaction of step 1-1) at a low temperature of about 0° C. for 2 minutes to 1 hour using a 1M hydrochloric acid solution, and then performing the reaction of step 1-2) at room temperature for 2 minutes to 1 hour, but is not limited thereto.

[0161] For example, the second step can be performed by reacting the carbonyl dinitrile compound obtained in the previous step (wherein R1 is unsubstituted) with a halogenated derivative of R1 in an organic solvent. Specifically, when R1 is C 1-6 When R1 is C alkyl, the second step can be performed by dissolving the carbonyl dinitrile compound obtained in the previous step (wherein R1 is unsubstituted) in an organic solvent such as DMF, and adding a halogenated alkane such as iodide corresponding to R1 to the reaction solution, and reacting at a temperature of 50°C to 70°C, wherein the reaction solution may further contain potassium tert-butoxide. However, the present invention is not limited thereto. Specifically, when R1 is C 1-6 When the carbonyl group is an alkylcarbonyl group, the second step can be performed by dissolving the carbonyl dinitrile compound (wherein R1 is unsubstituted) obtained in the previous step in a lower alcohol such as methanol, followed by reaction with a base such as potassium hydroxide and solidification to obtain a product, and reacting the product with C in the presence of triethylamine. 1–6 The alkylcarbonyl group is reacted with a corresponding halogenated alkylcarbonyl group such as acetyl chloride in an organic solvent such as acetonitrile. However, the present invention is not limited thereto.

[0162] For example, the compound of formula 5 used to prepare the compound of the present invention can be prepared from a compound represented by one of the following formulas 5-a to 5-c:

[0163] [Formula 5-a]

[0164]

[0165] [Formula 5-b]

[0166]

[0167] [Formula 5-c]

[0168]

[0169] In Formula 5-b, each of the two R4 can be selected from the series of substituents defined above, and the two R4 can be the same, or one R4 can be different from the other R4.

[0170] Specifically, the method of the present invention may further include the following step: before the first step, reducing the nitro group of the compound represented by one of Formulae 5-a to 5-c to an amine group.

[0171] For example, the reduction can be performed by reacting in an organic solvent such as 1,4-dioxane or methanol in the presence of a Pd / C catalyst, reacting with AcOH in the presence of Fe, or reacting with ammonium chloride in the presence of Fe, but is not limited thereto.

[0172] Specifically, the compound represented by formula 5-a can be prepared by the following steps: reacting its precursor (wherein one of Y1 and Y2 is CH and the other is O) with an amino compound NH2R4 in a state dissolved in an organic solvent so that the O site is replaced by NR4, but the compound is not limited thereto. For example, the reaction can be carried out in the following manner: stirring the precursor and ammonia or R4-substituted amine at a temperature of 70°C to 130°C in an organic solvent such as THF or methanol for 30 minutes to 5 hours, but is not limited thereto. In this regard, microwaves can be used for stirring, but are not limited thereto.

[0173] In addition, the precursor of the compound represented by the above formula 5-a (wherein one of Y1 and Y2 is CH and the other is O) can be optionally prepared by the following steps: cyclization between a nitrobenzoic acid derivative and N, N-dimethylformamide dimethyl acetal or acetal acetone, but is not limited thereto. For example, the cyclization can be carried out in the following manner: reaction with N, N-dimethylformamide dimethyl acetal in a DMF solvent, or reaction with acetal acetone in tert-butanol in the presence of Cu. The reaction can be carried out at a temperature of 100° C. to 130° C. for 2 to 24 hours under stirring, but is not limited thereto. In this regard, microwave stirring can be used, but is not limited thereto.

[0174] Specifically, in the method of the present invention, the compound represented by the above formula 5-b or 5-c can be optionally prepared by further performing the following steps: introducing an R4 substituent by reacting a precursor compound containing R4 with an active halide. For example, the reaction with DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and an R4-halide or an R4-sodium haloacetate can be carried out in a DMF solvent at room temperature with stirring for 6 to 24 hours, but is not limited thereto.

[0175] In addition, in the method of the present invention, the compound represented by the above formula 5-b can be prepared by cyclization between unsubstituted or R2-substituted 1,2-diaminonitrophenyl and carbonyldiimidazole (CDI). For example, the reaction can be carried out at room temperature for 6 to 24 hours using DMF solvent, but is not limited thereto.

[0176] For example, purchased commercially available compounds can be used as reactants and intermediates used in each step of the method of the present invention, or the reactants and intermediates used in each step can be synthesized individually or in combination using commercially available compounds through reactions known in the art, but the present invention is not limited thereto.

[0177] In addition, if necessary, the method may further include a process of separating and / or purifying the product after each reaction, and these processes can be performed using various methods well known in the art.

[0178] The third aspect of the present invention is to provide a composition for inhibiting tau protein aggregation, which comprises the compound of the present invention as an active ingredient.

[0179] The fourth aspect of the present invention is to provide a composition for inhibiting the hyperphosphorylation of tau protein, which comprises the compound of the present invention as an active ingredient.

[0180] The fifth aspect of the present invention is to provide a pharmaceutical composition for preventing or treating diseases caused by tau protein aggregation or hyperphosphorylation, which comprises the compound of the present invention as an active ingredient.

[0181] The sixth aspect of the present invention is to provide a method for preventing or treating diseases caused by tau protein aggregation or hyperphosphorylation, which comprises administering the compound of the present invention to a subject in need thereof.

[0182] In a specific embodiment of the present invention, a total of 57 compounds numbered 1 to 57 and represented by Formula 1 were newly synthesized, and their effects of inhibiting tau protein aggregation and hyperphosphorylation were confirmed. In addition, in order to confirm the possibility of use as a pharmaceutical composition, it was confirmed that these compounds have no cytotoxicity.

[0183] As used herein, the term "prevention" refers to any action that inhibits or delays the occurrence, spread and recurrence of diseases induced by tau protein aggregation or hyperphosphorylation by administering the pharmaceutical composition of the present invention, and the term "treatment" refers to any action that improves or beneficially changes the symptoms of the disease by administering the pharmaceutical composition of the present invention.

[0184] As described above, since the compounds of the present invention not only inhibit tau protein aggregation or hyperphosphorylation but are also non-toxic to cells, pharmaceutical compositions containing the compounds as active ingredients can be used to prevent or treat diseases caused by tau protein aggregation or hyperphosphorylation. Diseases caused by tau protein aggregation or hyperphosphorylation for which the pharmaceutical compositions of the present invention can be applied include Alzheimer's disease, Parkinson's disease, vascular dementia, acute stroke, trauma, cerebrovascular disease, cerebral and spinal cord trauma, spinal cord trauma, peripheral neuropathy, retinopathy, glaucoma, or tauopathy. Non-limiting examples of tauopathies can 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 associated with chromosome 17, Lytico-bodig disease (Guam Parkinsonism-dementia complex), ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, pantothenate kinase-related neurodegeneration, lipofuscinosis, post-traumatic stress disorder, and traumatic brain injury.

[0185] For example, compositions of the present invention can further include pharmaceutically acceptable carrier, diluent or excipient, can be mixed with various forms and use according to the general method of every kind of use purpose, for example oral formulations, for example powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol, and the injection medicine of sterile injection solution, and can be orally administered or can use by various approaches, comprise intravenous, intraperitoneal, subcutaneous, rectal and topical.The example of the suitable carrier, excipient or diluent comprising in said composition can comprise lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talcum, magnesium stearate and mineral oil.Composition of the present invention can further include filler, antiaggregant, lubricant, wetting agent, flavoring, emulsifying agent, preservative etc.

[0186] Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations are prepared by mixing one or more excipients such as starch, calcium carbonate, sucrose, lactose and gelatin with the composition. In addition to simple excipients, lubricants such as magnesium stearate or talc can also be used.

[0187] Examples of oral liquid preparations include suspensions, oral solutions, emulsions, syrups, etc., which may include various excipients such as wetting agents, sweeteners, aromatics, and preservatives in addition to water and liquid paraffin commonly used as simple diluents.

[0188] Preparations for parenteral administration include aseptic aqueous solvents, non-aqueous solvents, suspending agents, emulsifying agents, lyophilized preparations and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate etc. can be used as non-aqueous solvents or suspending agents. Witepsol, polyethylene glycol (macrogol), twin 61, cocoa butter, laurel oil, glycerol gelatin etc. can be used as the matrix of suppository. Meanwhile, injection may include conventional additives such as solubilizing agents, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.

[0189] The preparation can be prepared by conventional mixing, granulation or coating methods and can contain about 0.1wt% to 75wt%, preferably about 0.1wt% to 50wt% of the active ingredient. A unit preparation for a mammal weighing about 50kg to 70kg contains about 10mg to 200mg of the active ingredient.

[0190] In this case, the compositions of the present invention are used in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease and not cause side effects with a reasonable benefit / risk ratio that is applicable to medical treatment, and the level of an effective amount can be determined based on the patient's health, disease type, severity, drug activity, drug sensitivity, method of administration, time of administration, route of administration, excretion rate, treatment cycle, factors including the combined or concurrently used medicine, and other factors well known in the medical field. The compositions of the present invention can be used as a separate therapeutic agent or in combination with other therapeutic agents, can be used sequentially or simultaneously with conventional therapeutic agents, and can be used in single or multiple doses. Taking all of the above factors into account, it is important to administer the minimum amount that can obtain maximum effect without side effects, which can be easily determined by those skilled in the art.

[0191] For example, since the dosage can be increased or decreased depending on the administration route, severity of the disease, gender, body weight, age, etc., the dosage does not limit the scope of the present invention in any way.

[0192] The preferred dose of the compounds of this invention is according to the condition and body weight of the patient, the severity of the disease, the form of the medicine and the approach and the duration of administration, but can be suitably selected by those skilled in the art. However, in order to achieve the desired effect, the compound of the present invention can be used in an amount of 0.0001mg / kg to 100mg / kg (body weight) every day, preferably 0.001mg / kg to 100mg / kg (body weight). The compound can be used once a day or several times a day in divided doses by oral or parenteral route.

[0193] The seventh aspect of the present invention is to provide a method for preventing or treating diseases caused by tau protein aggregation or hyperphosphorylation, which comprises administering the pharmaceutical composition of the present invention to a subject in need thereof.

[0194] As used herein, the term "subject" refers to any animal, including, in addition to humans, monkeys, cattle, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rabbits, and guinea pigs, that has or may have a disease caused by tau protein aggregation or hyperphosphorylation. By administering the pharmaceutical composition of the present invention to a subject, the disease can be effectively prevented or treated. In addition, since the pharmaceutical composition of the present invention exhibits a therapeutic effect by inhibiting tau protein aggregation or hyperphosphorylation, a synergistic effect can be exhibited by administering the composition in combination with a conventional therapeutic agent.

[0195] As used herein, the term "administer" refers to providing a predetermined substance to a patient by any suitable method, and the route of administration of the composition of the present invention can be any conventional route, as long as the substance can reach the target tissue. The composition can be administered by intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration or rectal administration, but the present invention is not limited thereto. In addition, the pharmaceutical composition of the present invention can be administered by any device capable of moving the active substance to the target cell. Preferred administration and preparations include intravenous injection of drugs, subcutaneous injection of drugs, intradermal injection of drugs, intramuscular injection of drugs and drip medicine. Injectable medicines can be prepared using aqueous solvents such as physiological saline solution or Ringer's solution, or non-aqueous solvents such as vegetable oils, higher fatty acid esters (e.g., ethyl oleate) or alcohols (e.g., ethanol, benzyl alcohol, propylene glycol or glycerol), and may include pharmaceutical carriers such as stabilizers for preventing denaturation (e.g., ascorbic acid, sodium bisulfite, sodium metabisulfite, BHA, tocopherol or EDTA), emulsifiers, buffers for pH control, or preservatives for inhibiting the growth of microorganisms (e.g., phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol or benzyl alcohol).

[0196] Modes for Carrying Out the Invention

[0197] Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. However, these Examples and Experimental Examples are merely illustrations of the present invention, and the scope of the present invention is not limited to these Examples and Experimental Examples.

[0198] Example 1: Preparation of (1-oxo-1,2-dihydroisoquinolin-7-yl)carbonyl dinitrile (Compound 1)

[0199] Step 1-1: Preparation of 7-nitroisoquinolin-1(2H)-one

[0200] A 2.0 M ammonia solution (3.4 mL, 6.80 mmol) was added to 7-nitro-1H-isochromen-1-one (130 mg, 0.68 mmol) to obtain a reaction mixture, which was stirred in a microwave at 80° C. for 2 hours. After completion of the reaction, the reaction product was solidified with distilled water and filtered to obtain 73 mg (yield: 56%) of the title compound.

[0201] 1 H NMR (400MHz, DMSO-d6) δ11.76 (s, 1H), 8.90 (d, J = 2.5Hz, 1H), 8.44 (dd, J = 8.8Hz, 2.5Hz, 1H), 7.91 (d, J = 8.7Hz, 1H), 7.46 (d, J = 7.1Hz, 1H), 6.73 (d, J = 7.1Hz, 1H).

[0202] Step 1-2: Preparation of 7-aminoisoquinolin-1(2H)-one

[0203] 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 a hydrogen atmosphere for 4 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 27 mg (yield: 46%) of the title compound.

[0204] 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),7.40–7.20(m,2H),6.97(dd,J=8.4Hz,2.5Hz,1H),6.80(dd,J=7.0Hz,5.5Hz,1H),6.34(d,J=7.0Hz,1H),5.47(s,2H).

[0205] Step 1-3: Preparation of (1-oxo-1,2-dihydroisoquinolin-7-yl)carbonyl dicarbonitrile

[0206] Under a nitrogen atmosphere, 7-aminoisoquinolin-1(2H)-one (20 mg, 0.12 mmol) and sodium nitrite (13 mg, 0.19 mmol) obtained in step 1-2 were dissolved in ethanol, and 1.0 M aqueous hydrochloric acid solution (0.4 mL, 0.37 mmol) was added thereto 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 the reaction mixture was stirred at room temperature for 10 minutes. The pH of the reaction mixture was adjusted to 6.0 using aqueous sodium hydroxide solution, and then stirred at room temperature for another hour. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 20 mg (yield: 67%) of the title compound.

[0207] 1 H NMR (400MHz, DMSO-d6) δ13.22(s,1H),11.33(d,J=5.7Hz,1H),8.24(d,J=2.4Hz,1H),7.81(dd,J =8.7Hz, 2.4Hz, 1H), 7.72 (d, J = 8.7Hz, 1H), 7.16 (dd, J = 7.1Hz, 5.8Hz, 1H), 6.56 (d, J = 7.0Hz, 1H).

[0208] Example 2: Preparation of (2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbonyl dinitrile (Compound 2)

[0209] Step 2-1: Preparation of 7-nitro-1H-isochromen-1-one

[0210] 2-Methyl-5-nitrobenzoic acid (500 mg, 2.76 mmol) was dissolved in dimethylformamide (DMF, 10 mL), and N,N-dimethylformamide dimethyl acetal (1.10 mL, 8.23 mmol) was added thereto, and the reaction mixture was stirred at 115 ° C for 12 hours. After the reaction was completed, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 65 mg (yield: 12%) of the title compound.

[0211] 1H NMR (400MHz, DMSO-d6) δ 8.79 (d, J = 2.5 Hz, 1H), 8.61 ( dd, J = 8.6 Hz, 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).

[0212] Step 2-2: Preparation of 2-methyl-7-nitroisoquinolin-1(2H)-one

[0213] 1.0 M methylamine (10.5 mL, 20.93 mmol) was added to 7-nitro-1H-isochromene-1-one (200 mg, 1.05 mmol) obtained in step 2-1, and the reaction mixture was stirred at 120 ° C for 12 hours. After the reaction was completed, the reaction product was extracted with distilled water and dichloromethane to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 126 mg (yield: 59%) of the title compound.

[0214] 1 H NMR(400MHz,DMSO-d6)δ8.90(d,J=2.5Hz,1H),8.43(dd,J=8.8Hz,2.5Hz,1H),7 .89(d,J=8.8Hz,1H),7.75(d,J=7.3Hz,1H),6.78(d,J=7.3Hz,1H),3.55(s,3H).

[0215] Step 2-3: Preparation of 7-amino-2-methylisoquinolin-1(2H)-one

[0216] In the same manner as in Step 1-2 of Example 1 above, except that 2-methyl-7-nitroisoquinolin-1(2H)-one (100 mg, 0.49 mmol) obtained in Step 2-2 above was used instead of 7-nitroisoquinolin-1(2H)-one, 49 mg (yield: 57%) of the title compound was obtained.

[0217] 1 H NMR (400MHz, DMSO-d6) δ7.36–7.29(m,2H),7.08(d,J=7.2Hz,1H),6.97(dd,J=8.4Hz,2.5Hz,1H),6.40(d,J=7.2Hz,1H),5.51(s,2H),3.44(s,3H).

[0218] Step 2-4: Preparation of (2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbonyl dicarbonitrile

[0219] In the same manner as in Steps 1-3 of Example 1 above, except that 7-amino-2-methylisoquinolin-1(2H)-one (40 mg, 0.23 mmol) obtained in Step 2-3 above was used instead of 7-aminoisoquinolin-1(2H)-one, 49 mg (yield: 85%) of the title compound was obtained.

[0220] 1 H NMR (400MHz, DMSO-d6) δ13.25 (s, 1H), 8.28 (d, J = 2.4Hz, 1H), 7.81 (dd, J = 8.7Hz, 2.4Hz ,1H),7.72(d,J=8.7Hz,1H),7.46(d,J=7.3Hz,1H),6.63(d,J=7.3Hz,1H),3.52(s,3H).

[0221] Example 3: Preparation of (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbonyl dinitrile (Compound 3)

[0222] Step 3-1: Preparation of 2-isopropyl-7-nitroisoquinolin-1(2H)-one

[0223] 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 above, and the reaction mixture was stirred at 80°C in a microwave for 12 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, solidified with diethyl ether and hexane, and filtered to obtain 20 mg (yield: 54%) of the title compound.

[0224] 1 H NMR (400 MHz, CHLOROFORM-d) δ 9.31 (d, J = 2.4 Hz, 1H), 8.41 (dd, J = 8.7 Hz, 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).

[0225] Step 3-2: Preparation of 7-amino-2-isopropylisoquinolin-1(2H)-one

[0226] In the same manner as in Step 1-2 of Example 1 above, except that 2-isopropyl-7-nitroisoquinolin-1(2H)-one (70 mg, 0.30 mmol) obtained in Step 3-1 above was used instead of 7-nitroisoquinolin-1(2H)-one, 54 mg (yield: 89%) of the title compound was obtained.

[0227] 1 H NMR (400MHz, DMSO-d6) δ9.31(d,J=2.4Hz,1H),8.41(dd,J=8.7Hz,2.4Hz,1H),7.62(d,J=8.7Hz, 1H), 7.34 (d, J = 7.6Hz, 1H), 6.62 (d, J = 7.5Hz, 1H), 5.38 (p, J = 6.8Hz, 1H), 1.42 (d, J = 6.8Hz, 6H).

[0228] Step 3-3: Preparation of (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbonyl dicarbonitrile

[0229] The title compound (30 mg, 72%) was obtained 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.

[0230] 1 H NMR (400MHz, DMSO-d6) δ13.25(s,1H),8.30(d,J=2.3Hz,1H),7.81(dd,J=8.7Hz,2.3Hz,1H),7.72(d,J= 8.7Hz, 1H), 7.52 (d, J = 7.5Hz, 1H), 6.69 (d, J = 7.5Hz, 1H), 5.19 (p, J = 6.8Hz, 1H), 1.33 (d, J = 6.8Hz, 6H).

[0231] Example 4: Preparation of (1-oxo-1,2-dihydroisoquinolin-5-yl)carbonyl dinitrile (Compound 4)

[0232] Step 4-1: Preparation of 5-nitro-1H-isochromen-1-one

[0233] The title compound (88 mg, yield: 42%) was obtained in the same manner as in Step 2-1 of Example 2 above, except that 2-methyl-3-nitrobenzoic acid (200 mg, 1.10 mmol) was used instead of 2-methyl-5-nitrobenzoic acid.

[0234] 1 H NMR (400 MHz, chloroform-d) δ 8.69–8.61 (m, 1H), 8.49 (dd, J = 8.1 Hz, 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).

[0235] Step 4-2: Preparation of 5-nitroisoquinolin-1(2H)-one

[0236] In the same manner as in Step 1-1 of Example 1 above, except that 5-nitro-1H-isochromen-1-one (100 mg, 0.52 mmol) obtained in Step 4-1 above was used instead of 7-nitro-1H-isochromen-1-one, 45 mg (yield: 45%) of the title compound was obtained.

[0237] 1 H NMR (400MHz, DMSO-d6) δ11.75 (s, 1H), 8.58 (d, J = 8.0Hz, 1H), 8.46 (dd, J = 7.9Hz, 1.4Hz, 1H), 7.67 (t, J = 8.0Hz, 1H), 7.45 (d, J = 7.6Hz, 1H), 6.97 (d, J = 7.6Hz, 1H).

[0238] Step 4-3: Preparation of 5-amino-2-isoquinolin-1(2H)-one

[0239] In the same manner as in Step 1-2 of Example 1 above, except that 5-nitroisoquinolin-1(2H)-one (50 mg, 0.26 mmol) obtained in Step 4-2 above was used instead of 7-nitroisoquinolin-1(2H)-one, 18 mg (yield: 42%) of the title compound was obtained.

[0240] 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),7.39(d,J=7.9Hz,1H),7.14(t,J=7.8Hz,1H),7.02(d d, J=7.4Hz, 4.8Hz, 1H), 6.86 (dd, J=7.7Hz, 1.2Hz, 1H), 6.67 (d, J=7.4Hz, 1H), 5.61 (s, 2H).

[0241] Step 4-4: Preparation of (1-oxo-1,2-dihydroisoquinolin-5-yl)carbonyl dicarbonitrile

[0242] 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, 6 mg (yield: 38%) of the title compound was obtained in the same manner as in steps 1-3 of the above-mentioned Example 1.

[0243] 1H NMR (400MHz, DMSO-d6) δ11.42(s,1H),8.10(d,J=7.9Hz,1H),7.69(dd,J=7.8Hz,1.3 Hz, 1H), 7.50 (t, J = 7.9Hz, 1H), 7.27 (dd, J = 7.3Hz, 5.8Hz, 1H), 6.82 (d, J = 7.4Hz, 1H).

[0244] Example 5: Preparation of (2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonyl dinitrile (Compound 5)

[0245] Step 5-1: Preparation of 2-methyl-5-nitroisoquinolin-1(2H)-one

[0246] In the same manner as in Step 2-2 of Example 2 above, except using 5-nitro-1H-isochromen-1-one (74 mg, 0.39 mmol) instead of 7-nitro-1H-isochromen-1-one, 37 mg (yield: 47%) of the title compound was obtained.

[0247] 1 H NMR (400MHz, DMSO-d6) δ8.61(d,J=7.9Hz,1H),8.47(dd,J=7.9Hz,1.3Hz,1H),7.74( d, J=7.8Hz, 1H), 7.68 (t, J=8.0Hz, 1H), 7.03 (dd, J=7.7Hz, 0.8Hz, 1H), 3.55 (s, 3H).

[0248] Step 5-2: Preparation of 5-amino-2-methylisoquinolin-1(2H)-one

[0249] In the same manner as in Step 1-2 of Example 1 above, 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, 30 mg (yield: 69%) of the title compound was obtained.

[0250] 1 H NMR (400MHz, DMSO-d6) δ7.42(d,J=7.9Hz,1H),7.32(d,J=7.5Hz,1H),7.16(t,J=7.8Hz ,1H),6.84(dd,J=7.8Hz,1.2Hz,1H),6.73(d,J=7.6Hz,1H),5.64(s,2H),3.46(s,3H).

[0251] Step 5-3: Preparation of (2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonyl dicarbonitrile

[0252] 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, the title compound (31 mg, yield: 86%) was obtained in the same manner as in step 1-3 of the above-mentioned Example 1.

[0253] 1 H NMR (400 MHz, CHLOROFORM-d) δ 9.87 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 7.81 (dd, J = 8.0 Hz, 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).

[0254] Example 6: Preparation of (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonyl dinitrile (Compound 6)

[0255] Step 6-1: Preparation of 2-isopropyl-5-nitroisoquinolin-1(2H)-one

[0256] In the same manner as in Step 3-1 of Example 3 above, except using 5-nitro-1H-isochromen-1-one (30 mg, 0.16 mmol) instead of 7-nitro-1H-isochromen-1-one, 11 mg (yield: 30%) of the title compound was obtained.

[0257] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.80 (dd, J = 8.0 Hz, 1.4 Hz, 1H), 8.40 (dd, J = 8.0 Hz, 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).

[0258] Step 6-2: Preparation of 5-amino-2-isopropylisoquinolin-1(2H)-one

[0259] In the same manner as in Step 1-2 of Example 1 above, except that 2-isopropyl-5-nitroisoquinolin-1(2H)-one (40 mg, 0.17 mmol) obtained in Step 6-1 above was used instead of 7-nitroisoquinolin-1(2H)-one, 34 mg (yield: 99%) of the title compound was obtained.

[0260] 1H NMR (400MHz, chloroform-d) δ7.92(d,J=8.1Hz,1H),7.29(d,J=7.9Hz,1H),7.13(d,J=7.7Hz,1H),6.94(dd, J=7.6Hz,1.2Hz,1H),6.55–6.42(m,1H),5.40(p,J=6.9Hz,1H),3.95(s,2H),1.38(d,J=6.9Hz,6H).

[0261] Step 6-3: Preparation of (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonyl dicarbonitrile

[0262] 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, the title compound (22 mg, yield: 79%) was obtained in the same manner as in step 1-3 of the above-mentioned Example 1.

[0263] 1 H NMR(400MHz, DMSO-d6)δ8.14(d,J=8.0Hz,1H),7.72–7.58(m,2H),7.51(t,J=7 .9Hz, 1H), 6.96 (d, J = 7.8Hz, 1H), 5.18 (p, J = 6.8Hz, 1H), 1.34 (d, J = 6.8Hz, 6H).

[0264] Example 7: Preparation of (2,3-dimethyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonyl dinitrile (Compound 7)

[0265] Step 7-1: 3-Methyl-5-nitro-1 H -Preparation of isochromen-1-one

[0266] Acetylacetone (1.04mL, 10.16mmol), copper (13mg, 0.20mmol), potassium tert-butoxide (456mg, 4.06mmol) and tert-butanol (10mL) were added to 2-bromo-3-nitrobenzoic acid (500mg, 2.03mmol), and the reaction mixture was stirred in a microwave at 110 ° C for 5 hours. After the reaction was completed, the reaction mixture was acidified by adding aqueous hydrochloric acid to the reaction mixture, and the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 68mg (yield: 16%) of the title compound.

[0267] 1H NMR (400 MHz, CHLOROFORM-d) δ 8.58 (dt, J = 7.8 Hz, 1.1 Hz, 1H), 8.44 (dd, J = 8.2 Hz, 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).

[0268] Step 7-2: Preparation of 2,3-dimethyl-5-nitroisoquinolin-1(2H)-one

[0269] In the same manner as in Step 2-2 of Example 2 above, 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, 56 mg (yield: 88%) of the title compound was obtained.

[0270] 1 H NMR (400MHz, DMSO-d6) δ8.26 (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).

[0271] Step 7-3: Preparation of 5-amino-2,3-dimethylisoquinolin-1(2H)-one

[0272] In the same manner as in Step 1-2 of Example 1 above, 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, 13 mg (yield: 29%) of the title compound was obtained.

[0273] 1 H NMR (400MHz, DMSO-d6) δ7.38 (d, J=7.9Hz, 1H), 7.08 (t, J=7.8Hz, 1H), 6.81 (dd, J= 7.7Hz, 1.2Hz, 1H), 6.64 (s, 1H), 5.51 (s, 2H), 3.48 (s, 3H), 2.39 (d, J = 1.0Hz, 3H).

[0274] Step 7-4: Preparation of (2,3-dimethyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonyl dicarbonitrile

[0275] In the same manner as in Step 1-3 of Example 1 above, 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, 13 mg (yield: 92%) of the title compound was obtained.

[0276] 1 H NMR (400MHz, DMSO-d6) δ8.11(d,J=8.0Hz,1H),7.65(dd,J=7.8Hz,1.3Hz,1H),7.44(t,J=7.9Hz,1H),6.78(s,1H),3.54(s,3H),2.47(s,3H).

[0277] Example 8: Preparation of (2-oxo-1,2-dihydroquinolin-6-yl)carbonyl dinitrile (Compound 8)

[0278] Step 8-1: Preparation of 6-aminoisoquinolin-2(1H)-one

[0279] The title compound (34 mg, 13% yield) was obtained in the same manner as in Step 1-2 of Example 1 above, except that 6-nitroisoquinolin-2(1H)-one (300 mg, 1.58 mmol) was used instead of 7-nitroisoquinolin-1(2H)-one.

[0280] 1 H NMR (400MHz, DMSO-d6) δ11.36 (s, 1H), 7.66 (d, J = 9.5Hz, 1H), 7.02 (s, 1H), 6.83 (d d, J=8.7Hz, 2.5Hz, 1H), 6.71 (d, J=2.5Hz, 1H), 6.36 (d, J=9.5Hz, 1H), 4.98 (s, 2H).

[0281] Step 8-2: Preparation of (2-oxo-1,2-dihydroisoquinolin-6-yl)carbonyl dicarbonitrile

[0282] In the same manner as in Step 1-3 of Example 1 above, 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, 17 mg (yield: 59%) of the title compound was obtained.

[0283] 1 H NMR (400MHz, DMSO-d6) δ13.13(s,1H),11.87(s,1H),7.97(d,J=9.6Hz,1H),7.74(s ,1H),7.66(dd,J=8.9Hz,2.4Hz,1H),7.34(d,J=8.9Hz,1H),6.55(d,J=9.6Hz,1H).

[0284] Example 9: Preparation of (6-fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dinitrile (Compound 9)

[0285] Step 9-1: Preparation of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one

[0286] Under a nitrogen atmosphere, 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 stirred at room temperature for 12 hours. After the reaction was completed, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 512 mg (yield: 89%) of the title compound.

[0287] 1 H NMR (400 MHz, acetone-d6) 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).

[0288] Step 9-2: Preparation of 5-fluoro-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one

[0289] Under a nitrogen atmosphere, 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, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.02 mL, 6.84 mmol) and iodomethane (0.42 mL, 6.84 mmol) were added thereto, and the reaction mixture was stirred at room temperature for 1 to 5 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 328 mg (yield: 64%) of the title compound.

[0290] 1 H NMR (400 MHz, acetone-d6) 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).

[0291] Step 9-3: Preparation of 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

[0292] Under a nitrogen atmosphere, 5-fluoro-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one (250 mg, 1.11 mmol) and iron (496 mg, 8.88 mmol) obtained in step 9-2 were dissolved in acetic acid, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 190 mg (yield: 88%) of the title compound.

[0293] 1 H NMR (400 MHz, acetone-d6) 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).

[0294] Step 9-4: (6-fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1 H -Benzo[ d ]imidazol-5-yl)carbonyl dihydrazine Preparation of nitrile

[0295] Under a nitrogen atmosphere, 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 solution (0.2 mL) were dissolved in distilled water, and sodium nitrite (65 mg, 0.77 mmol) was added thereto 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 reaction mixture was stirred at room temperature for 11 hours. After the reaction was completed, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 28 mg (yield: 20%) of the title compound.

[0296] 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).

[0297] Example 10: Preparation of (6-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dinitrile (Compound 10)

[0298] Step 10-1: Preparation of 5-chloro-6-nitro-1H-benzo[d]imidazol-2(3H)-one

[0299] The title compound (882 mg, 77% yield) was obtained 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.

[0300] 1 H NMR (400 MHz, acetone-d6) δ 10.30 (s, 1H), 10.19 (s, 1H), 7.71 (s, 1H), 7.26 (s, 1H).

[0301] Step 10-2: Preparation of 5-chloro-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one

[0302] In the same manner as in Step 9-2 of Example 9 above, 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, 410 mg (yield: 73%) of the title compound was obtained.

[0303] 1 H NMR (400 MHz, acetone-d6) δ 7.83 (s, 1H), 7.41 (s, 1H), 3.48 (s, 3H), 3.47 (s, 3H).

[0304] Step 10-3: 5-amino-6-chloro-1,3-dimethyl-1 H -Benzo[ d ]imidazole-2(3 H Preparation of )-ketone

[0305] In the same manner as in Step 9-3 of Example 9 above, 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, 190 mg (yield: 88%) of the title compound was obtained.

[0306] 1 H NMR (400 MHz, acetone-d6) 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).

[0307] Step 10-4: (6-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone Preparation of dinitrile

[0308] In the same manner as in Step 9-4 of Example 9 above, except that 5-amino-6-chloro-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, 28 mg (yield: 20%) of the title compound was obtained.

[0309] 1 H NMR (400MHz, DMSO-d6) δ7.39(s,1H),7.30(s,1H),3.34(s,3H),3.33(s,3H).

[0310] Example 11: Preparation of (7-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dinitrile (Compound 11)

[0311] Step 11-1: Preparation of 4-chloro-6-nitro-1H-benzo[d]imidazol-2(3H)-one

[0312] The title compound (720 mg, yield: 63%) was obtained in the same manner as in Step 9-1 of Example 9 above, 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.

[0313] 1 H NMR (400 MHz, acetone-d6) 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).

[0314] Step 11-2: 4-chloro-1,3-dimethyl-6-nitro-1 H -Benzo[ d ]imidazole-2(3 H Preparation of )-ketone

[0315] In the same manner as in Step 9-2 of Example 9 above, 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, 412 mg (yield: 73%) of the title compound was obtained.

[0316] 1 H NMR (400 MHz, acetone-d6) 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).

[0317] Step 11-3: Preparation of 6-amino-4-chloro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

[0318] In the same manner as in Step 9-3 of Example 9 above, 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, 154 mg (yield: 71%) of the title compound was obtained.

[0319] 1 H NMR (400 MHz, acetone-d6) 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).

[0320] Step 11-4: (7-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone Preparation of dinitrile

[0321] In the same manner as in Step 9-4 of Example 9 above, 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, 42 mg (yield: 41%) of the title compound was obtained.

[0322] 1 H NMR (400MHz, DMSO-d6) δ7.20 (s, 2H), 3.58 (s, 3H).

[0323] Example 12: Preparation of (1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dinitrile (Compound 12)

[0324] Step 12-1: Preparation of 6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0325] Under a nitrogen atmosphere, 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 stirred at 80°C for 8 hours. After completion of the reaction, the reaction product was filtered through acetonitrile to obtain 570 mg (yield: 81%) of the title compound.

[0326] 1H NMR (400 MHz, acetone-d6) 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).

[0327] Step 12-2: 1,3-dimethyl-6-nitro-1 H -imidazo[4,5- b ]pyridine-2(3 H Preparation of )-ketone

[0328] In the same manner as in Step 9-2 of Example 9 above, 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, 351 mg (yield: 76%) of the title compound was obtained.

[0329] 1 H NMR (400 MHz, acetone-d6) 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).

[0330] Step 12-3: Preparation of 6-amino-1,3-dimethyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0331] 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 completion of the reaction, the reaction product was filtered with methanol, and the filtrate was concentrated to obtain 241 mg (yield: 94%) of the title compound.

[0332] 1 H NMR (400 MHz, acetone-d6) 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).

[0333] Step 12-4: (1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbazone Preparation of dinitrile

[0334] In the same manner as in Step 9-4 of Example 9 above, 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, 100 mg (yield: 47%) of the title compound was obtained.

[0335] 1 H NMR (400 MHz, acetone-d6) 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).

[0336] Example 13: Preparation of (2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonyl dicarbonitrile (Compound 13)

[0337] Step 13-1: 6-aminobenzo[ d ]thiazole-2(3 H Preparation of )-ketone

[0338] Under a nitrogen atmosphere, 6-nitrobenzo[d]thiazol-2(3H)-one (200 mg, 1.02 mmol) was dissolved in ethanol / water, to which 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 hour. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 83 mg (yield: 49%) of the title compound.

[0339] 1 H NMR (400MHz, DMSO-d6) δ 11.34 (s, 1H), 6.79 (d, J = 8.4Hz, 1H), 6.69 (d, J = 2.2Hz, 1H), 6.51 (dd, J = 8.5Hz, 2.3Hz, 1H), 4.95 (s, 2H).

[0340] Step 13-2: Preparation of (2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonyl dicarbonitrile

[0341] In the same manner as in Step 9-4 of Example 9 above, 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 mixed solution of ethanol and water in a ratio of 1:3 was used as the solvent, 34 mg (yield: 47%) of the title compound was obtained.

[0342] 1 H NMR (400MHz, DMSO-d6) δ 11.96 (s, 1H), 7.68 (s, 1H), 7.39 (d, J = 8.8Hz, 1H), 7.13 (d, J = 8.6Hz, 1H).

[0343] Example 14: Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonyl dicarbonitrile (Compound 14)

[0344] Step 14-1: Preparation of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one

[0345] Except for using 6-nitrobenzo[d]thiazol-2(3H)-one (100 mg, 0.48 mmol) instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one, the title compound (68 mg, 64% yield) was obtained in the same manner as in Step 9-2 of Example 9 above.

[0346] 1 H NMR (400 MHz, acetone-d6) δ 8.61 (d, J = 2.4 Hz, 1H), 8.31 (dd, J = 8.9 Hz, 2.4 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 3.58 (s, 3H).

[0347] Step 14-2: Preparation of 6-amino-3-methylbenzo[d]thiazol-2(3H)-one

[0348] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 79 mg (yield: 91%) of the title compound was obtained.

[0349] 1 H NMR (400 MHz, acetone-d6) δ 6.95 (d, J = 8.5 Hz, 1H), 6.87 (d, J = 2.3 Hz, 1H), 6.72 (dd, J = 8.5 Hz, 2.3 Hz, 1H), 4.62 (s, 2H), 3.35 (s, 3H).

[0350] Step 14-3: Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonyl dicarbonitrileIn the same manner as in Step 9-4 of Example 9 above, except that 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one was replaced with 6-amino-3-methylbenzo[d]thiazol-2(3H)-one obtained in Step 14-2, and a mixed solution of ethanol and water in a ratio of 1:3 was used as the solvent, 94 mg (yield: 83%) of the title compound was obtained.

[0351] 1 H NMR (400MHz, DMSO-d6) δ7.81 (d, J = 2.2 Hz, 1H), 7.51 (dd, J = 8.8 Hz, 2.3 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 3.41 (s, 3H).

[0352] Example 15: Preparation of (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonyl dinitrile (Compound 15)

[0353] Step 15-1: Preparation of 6-aminobenzo[d]oxazol-2(3H)-one

[0354] Except for using 6-nitrobenzo[d]oxazol-2(3H)-one instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one, the title compound (131 mg, yield: 78%) was obtained in the same manner as in Step 14-2 of Example 14 above.

[0355] 1 H NMR (400 MHz, acetone-d6) δ 6.83 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 2.1 Hz, 1H), 6.49 (dd, J = 8.3 Hz, 2.1 Hz, 1H), 4.60 (s, 2H).

[0356] Step 15-2: Preparation of (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonyl dicarbonitrile

[0357] In the same manner as in Step 9-4 of Example 9 above, except that 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one was replaced with 6-aminobenzo[d]oxazol-2(3H)-one obtained in Step 15-1 and a mixed solution of ethanol and water in a ratio of 1:3 was used as the solvent, 115 mg (yield: 76%) of the title compound was obtained.

[0358] 1 H NMR (400MHz, DMSO-d6) δ 11.77 (s, 1H), 7.40 (d, J = 2.0Hz, 1H), 7.30 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.13 (d, J = 8.4Hz, 1H).

[0359] Example 16: Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonyl dinitrile (Compound 16)

[0360] Step 16-1: Preparation of 3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one

[0361] Except for using 6-nitrobenzo[d]oxazol-2(3H)-one instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one, the title compound (282 mg, 87% yield) was obtained in the same manner as in Step 9-2 of Example 9 above.

[0362] 1 H NMR (400 MHz, acetone-d6) δ 6.87 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 2.1 Hz, 1H), 6.55 (dd, J = 8.3 Hz, 2.1 Hz, 1H), 4.64 (s, 2H), 3.32 (s, 3H).

[0363] Step 16-2: Preparation of 6-amino-3-methylbenzo[d]oxazol-2(3H)-one

[0364] In the same manner as in Step 14-2 of Example 14 above, except that 3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one obtained in Step 16-1 was used instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one, 111 mg (yield: 88%) of the title compound was obtained.

[0365] 1 H NMR (400 MHz, acetone-d6) δ 6.95 (d, J = 8.5 Hz, 1H), 6.87 (d, J = 2.3 Hz, 1H), 6.72 (dd, J = 8.5 Hz, 2.3 Hz, 1H), 4.62 (s, 2H), 3.35 (s, 3H).

[0366] Step 16-3: Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonyl dicarbonitrile

[0367] In the same manner as in Step 9-4 of Example 9 above, except that 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one was replaced with 6-amino-3-methylbenzo[d]oxazol-2(3H)-one obtained in Step 16-2 and a mixed solution of ethanol and water in a ratio of 1:3 was used as the solvent, 107 mg (yield: 73%) of the title compound was obtained.

[0368] 1H NMR (400MHz, DMSO-d6) δ7.43 (d, J = 2.0 Hz, 1H), 7.36 (dd, J = 8.5 Hz, 2.0 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 3.34 (s, 3H).

[0369] Example 17: Preparation of (1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile (Compound 17)

[0370] Step 17-1: Preparation of N-methyl-2,4-dinitroaniline

[0371] Under a nitrogen atmosphere, 1-chloro-2,4-dinitrobenzene (3 g, 14.81 mmol) was dissolved in THF, 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, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was solidified with diethyl ether and filtered to obtain 2.81 g (yield: 96%) of the title compound.

[0372] 1 H NMR (400 MHz, acetone-d6) 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).

[0373] Step 17-2: N 1 Preparation of methyl-4-nitrobenzene-1,2-diamine

[0374] After dissolving N-methyl-2,4-dinitroaniline (300 mg, 1.52 mmol) obtained in step 17-1 in methanol, sodium sulfide (356 mg, 4.57 mmol) and sodium bicarbonate (384 mg, 4.57 mmol) dissolved in distilled water were added thereto, and the reaction mixture was stirred at 80 ° C under a nitrogen atmosphere for 8 hours. After the reaction was completed, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was solidified with diethyl ether and filtered to obtain 193 mg (yield: 76%) of the title compound.

[0375] 1H NMR (400 MHz, acetone-d6) δ 7.68 (dd, J = 8.8 Hz, 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).

[0376] Step 17-3: Preparation of 1-methyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0377] The N obtained in step 17-2 1 1-Methyl-4-nitrobenzene-1,2-diamine (900 mg, 5.38 mmol) was dissolved in DMF, and CDI (2.56 g, 16.15 mmol) was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 15 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was solidified with diethyl ether and filtered to obtain 568 mg (yield: 55%) of the title compound.

[0378] 1 H NMR (400 MHz, acetone-d6) δ 10.27 (s, 1H), 8.10 (dd, J = 8.6 Hz, 2.2 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 3.47 (s, 3H).

[0379] Step 17-4: Preparation of 5-amino-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0380] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 306 mg (yield: 91%) of the title compound was obtained.

[0381] 1 H NMR (400 MHz, acetone-d6) 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 Hz, 2.0 Hz, 1H), 4.31 (s, 2H), 3.23 (s, 3H).

[0382] Step 17-5: Preparation of (1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile

[0383] In the same manner as in Step 9-4 of Example 9 above, except that 5-amino-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (250 mg, 1.53 mmol) obtained in Step 17-4 was used instead of 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one, and a mixed solution of ethanol and water in a ratio of 1:3 was used as the solvent, 62 mg (yield: 17%) of the title compound was obtained.

[0384] 1 H NMR (400MHz, DMSO-d6) δ13.01 (s, 1H), 10.99 (s, 1H), 7.19 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.12–7.10 (m, 2H), 3.27 (s, 3H).

[0385] Example 18: Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonyl dicarbonitrile (Compound 18)

[0386] Step 18-1: Preparation of 3-isopropyl-6-nitrobenzo[d]thiazol-2(3H)-one

[0387] In the same manner as in Step 9-2 of Example 9 above, except using 6-nitrobenzo[d]thiazol-2(3H)-one instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one and 2-iodopropane instead of iodomethane, 162 mg (yield: 44%) of the title compound was obtained.

[0388] 1 H NMR (400 MHz, acetone-d6) δ 8.59 (d, J = 2.4 Hz), 8.26 (dd, J = 9.2 Hz, 2.4 Hz), 7.67 (d, J = 9.2 Hz), 4.97–4.90 (m, 1 H), 1.61 (d, J = 6.8 Hz, 6 H).

[0389] Step 18-2: Preparation of 6-amino-3-isopropylbenzo[d]thiazol-2(3H)-one

[0390] In the same manner as in Step 14-2 of Example 14 above, 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, 112 mg (yield: 85%) of the title compound was obtained.

[0391] 1H NMR (400 MHz, acetone-d6) δ 7.13 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 6.71 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 4.76–4.69 (m, 1H), 4.64 (s, 2H), 1.53 (d, J = 6.8 Hz, 6H).

[0392] Step 18-3: Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonyl dicarbonitrile

[0393] In the same manner as in Step 9-4 of Example 9 above, 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 mixed solution of ethanol and water in a ratio of 1:3 was used as the solvent, 109 mg (yield: 80%) of the title compound was obtained.

[0394] 1 H NMR (400MHz, DMSO-d6) δ7.79 (d, J = 2.4Hz, 1H), 7.55 (d, J = 9.2Hz, 1H), 7.49 (d, J = 2.4Hz, 1H), 4.81–4.74 (m, 1H), 1.50 (d, J = 7.2Hz, 6H).

[0395] Example 19: Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonyl dicarbonitrile (Compound 19)

[0396] Step 19-1: Preparation of 3-(difluoromethyl)-6-nitrobenzo[d]thiazol-2(3H)-one

[0397] 6-Nitrobenzo[d]thiazol-2(3H)-one (300 mg, 1.53 mmol) was dissolved in DMF under a nitrogen atmosphere. 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 completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was solidified with methanol and filtered to obtain 176 mg (yield: 47%) of the title compound.

[0398] 1 H NMR (400 MHz, acetone-d6) δ 8.76 (d, J = 2.4 Hz, 1H), 8.38 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.75 (t, J = 57.2 Hz, 1H).

[0399] Step 19-2: Preparation of 6-amino-3-(difluoromethyl)benzo[d]thiazol-2(3H)-one

[0400] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 125 mg (yield: 95%) of the title compound was obtained.

[0401] 1 H NMR (400 MHz, acetone-d6) 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 Hz, 2.2 Hz, 1H), 4.89 (s, 2H).

[0402] Step 19-3: Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonyl dicarbonitrile Preparation

[0403] In the same manner as in Step 9-4 of Example 9 above, except that 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one was replaced with 6-amino-3-(difluoromethyl)benzo[d]thiazol-2(3H)-one obtained in Step 19-2 and a mixed solution of ethanol and water in a ratio of 1:3 was used as the solvent, 85 mg (yield: 63%) of the title compound was obtained.

[0404] 1 H NMR (400MHz, DMSO-d6) δ7.90 (s, 1H), 7.82 (t, J = 56.8Hz, 1H), 7.53 (s, 2H).

[0405] Example 20: Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonyl dicarbonitrile (Compound 20)

[0406] Step 20-1: Preparation of 3-isopropyl-6-nitrobenzo[d]oxazol-2(3H)-one

[0407] In the same manner as in Step 9-2 of Example 9 above, except using 6-nitrobenzo[d]oxazol-2(3H)-one instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one and 2-iodopropane instead of iodomethane, 201 mg (yield: 54%) of the title compound was obtained.

[0408] 1H NMR (400 MHz, acetone-d6) δ 8.23 (dd, J = 8.8 Hz, 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).

[0409] Step 20-2: Preparation of 6-amino-3-isopropylbenzo[d]oxazol-2(3H)-one

[0410] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 124 mg (yield: 85%) of the title compound was obtained.

[0411] 1 H NMR (400 MHz, acetone-d6) δ 7.00 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 2.0 Hz, 1H), 6.51 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 4.62 (s, 2H), 4.48–4.41 (m, 1H), 1.48 (d, J = 6.8 Hz, 6H).

[0412] Step 20-3: Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonyl dicarbonitrile

[0413] In the same manner as in Step 9-4 of Example 9 above, 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 mixed solution of ethanol and water in a ratio of 1:3 was used as the solvent, 99 mg (yield: 59%) of the title compound was obtained.

[0414] 1 H NMR (400MHz, DMSO-d6) δ7.47–7.43(m,2H),7.33(dd,J=8.8Hz,2.0Hz,1H),4.51–4.44(m,1H),1.46(d,J=6.8Hz,6H).

[0415] Example 21: Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonyl dicarbonitrile (Compound 21)

[0416] Step 21-1: Preparation of 3-(difluoromethyl)-6-nitrobenzo[d]oxazol-2(3H)-one

[0417] Except for using 6-nitrobenzo[d]oxazol-2(3H)-one (300 mg, 1.67 mmol) instead of 6-nitrobenzo[d]thiazol-2(3H)-one, the title compound (144 mg, yield: 38%) was obtained in the same manner as in Step 19-1 of Example 19 above.

[0418] 1 H NMR (400 MHz, acetone-d6) δ 8.34–8.30 (m, 2H), 7.68 (d, J = 8.8 Hz, 1H), 7.65 (t, J = 57.6 Hz, 1H).

[0419] Step 21-2: Preparation of 6-amino-3-(difluoromethyl)benzo[d]oxazol-2(3H)-one

[0420] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 110 mg (yield: 98%) of the title compound was obtained.

[0421] 1 H NMR (400 MHz, acetone-d6) 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 Hz, 2.0 Hz, 1H) 4.91 (s, 2H).

[0422] Step 21-3: Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonyl dicarbonitrile Preparation

[0423] In the same manner as in Step 9-4 of Example 9 above, except that 5-amino-6-fluoro-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one was replaced with 6-amino-3-(difluoromethyl)benzo[d]oxazol-2(3H)-one obtained in Step 21-2, and a mixed solution of ethanol and water in a ratio of 1:3 was used as the solvent, 85 mg (yield: 63%) of the title compound was obtained.

[0424] 1 H NMR (400MHz, DMSO-d6) δ7.73 (t, J = 57.2Hz, 1H), 7.52 (d, J = 1.2Hz, 1H), 7.45–7.40 (m, 2H).

[0425] Example 22: Preparation of (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile (Compound 22)

[0426] Step 22-1: Preparation of 1,3-dimethyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[0427] Except for using 5-nitro-1H-benzo[d]imidazol-2(3H)-one instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one, 207 mg (yield: 64%) of the title compound was obtained in the same manner as in Step 9-2 of Example 9 above.

[0428] 1 H NMR (400 MHz, acetone-d6) δ 8.09 (dd, J = 8.6 Hz, 2.2 Hz), 7.98 (d, J = 2.0 Hz), 7.30 (d, J = 8.4 Hz), 3.51 (s, 3H), 3.48 (s, 3H).

[0429] Step 22-2: Preparation of 5-amino-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

[0430] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 105 mg (yield: 82%) of the title compound was obtained.

[0431] 1 H NMR (400 MHz, acetone-d6) 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).

[0432] Step 22-3: (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile preparation

[0433] In the same manner as in Step 9-4 of Example 9 above, except that 5-amino-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 mixed solution of ethanol and water in a ratio of 1:3 was used as the solvent, 11 mg (yield: 8%) of the title compound was obtained.

[0434] 1 H NMR (400 MHz, acetone-d6) δ 7.18–7.14 (m, 2H), 6.97 (d, J = 8.0 Hz, 1H), 3.37 (s, 3H), 3.35 (s, 3H).

[0435] Example 23: Preparation of (1,3-diisopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dinitrile (Compound 23)

[0436] Step 23-1: Preparation of 1,3-diisopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[0437] In the same manner as in Step 9-2 of Example 9 above, 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 iodomethane, 204 mg (yield: 46%) of the title compound was obtained.

[0438] 1 H NMR (400 MHz, acetone-d6) 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).

[0439] Step 23-2: Preparation of 5-amino-1,3-diisopropyl-1H-benzo[d]imidazol-2(3H)-one

[0440] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 118 mg (yield: 89%) of the title compound was obtained.

[0441] 1 H NMR (400 MHz, acetone-d6) δ 6.92 (d, J = 8.0 Hz, 1H), 6.64 (d, J = 2.0 Hz, 1H), 6.37 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 4.62–4.54 (m, 2H), 4.33 (s, 2H), 1.46–1.43 (m, 12H).

[0442] Step 23-3: (1,3-Diisopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile Preparation

[0443] In the same manner as in Step 9-4 of Example 9 above, except that 5-amino-1,3-diisopropyl-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 mixed solution of ethanol and water in a ratio of 1:3 was used as the solvent, 12 mg (yield: 10%) of the title compound was obtained.

[0444] 1H NMR (400MHz, DMSO-d6) δ7.22–7.20(m,2H),7.04(dd,J=8.8Hz,1.6Hz,1H),4.61–4.55(m,2H),1.44–1.42(m,12H).

[0445] Example 24: Preparation of (1,3-bis(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile (Compound 24)

[0446] Step 24-1: Preparation of 1,3-bis(difluoromethyl)-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[0447] Except for using 5-nitro-1H-benzo[d]imidazol-2(3H)-one instead of 6-nitrobenzo[d]thiazol-2(3H)-one, the title compound (179 mg, 38% yield) was obtained in the same manner as in Step 19-1 of Example 19 above.

[0448] 1 H NMR (400 MHz, acetone-d6) δ 8.33 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.83–7.53 (m, 2H).

[0449] Step 24-2: Preparation of 5-amino-1,3-bis(difluoromethyl)-1H-benzo[d]imidazol-2(3H)-one

[0450] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 69 mg (yield: 96%) of the title compound was obtained.

[0451] 1 H NMR (400 MHz, acetone-d6) 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 Hz, 2.2 Hz, 1H), 4.90 (s, 2H).

[0452] Step 24-3: (1,3-bis(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone Preparation of dinitrile

[0453] In the same manner as in Step 9-4 of Example 9 above, except that 5-amino-1,3-bis(difluoromethyl)-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 mixed solution of ethanol and water in a ratio of 1:3 was used as the solvent, 45 mg (yield: 58%) of the title compound was obtained.

[0454] 1 H NMR (400MHz, DMSO-d6) δ7.93–7.61(m,2H),7.56(s,1H),7.49–7.42(m,2H).

[0455] Example 25: Preparation of (1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonyl dicarbonitrile (Compound 25)

[0456] Step 25-1: Preparation of 1-methyl-6-nitroquinolin-2(1H)-one

[0457] The title compound (123 mg, 38% yield) was obtained in the same manner as in Step 9-2 of Example 9 above, except that 6-nitroquinolin-2(1H)-one was used instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one.

[0458] 1 H NMR(400MHz,DMSO-d6)δ8.74(d,J=2.7Hz,1H),8.40(dd,J=9.4Hz,2.7Hz,1H),8 .15(d,J=9.5Hz,1H),7.73(d,J=9.3Hz,1H),6.80(d,J=9.5Hz,1H),3.67(s,3H).

[0459] Step 25-2: Preparation of 6-amino-1-methylquinolin-2(1H)-one

[0460] In the same manner as in Step 13-2 of Example 13 above, 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 solvents, 56 mg (yield: 59%) of the title compound was obtained.

[0461] 1H NMR (400MHz, DMSO-d6) δ7.66(d,J=9.4Hz,1H),7.25(d,J=8.9Hz,1H),6.94(dd,J=8.9H z, 2.7Hz, 1H), 6.78 (d, J = 2.6Hz, 1H), 6.48 (d, J = 9.4Hz, 1H), 5.09 (s, 2H), 3.53 (s, 3H).

[0462] Step 25-3: Preparation of (1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonyl dicarbonitrile

[0463] Except that 6-amino-1-methylquinolin-2(1H)-one obtained in step 25-2 was used instead of 7-aminoisoquinolin-1(2H)-one, 55 mg (yield: 77%) of the title compound was obtained in the same manner as in step 1-3 of the above-mentioned Example 1.

[0464] 1 H NMR (400MHz, DMSO-d6) δ13.16(s,1H),7.98(d,J=9.5Hz,1H),7.79(d,J=2.5Hz,1H),7. 74 (dd, J=9.1Hz, 2.6Hz, 1H), 7.59 (d, J=9.1Hz, 1H), 6.66 (d, J=9.5Hz, 1H), 3.61 (s, 3H).

[0465] Example 26: Preparation of (4-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonyl dicarbonitrile (Compound 26)

[0466] Step 26-1: 4-Methyl-6-nitroquinoline-2(1 H Preparation of )-ketone

[0467] 4-Methylquinolin-2(1H)-one (1 g, 6.28 mmol) was dissolved in sulfuric acid (4 mL), and a 65% mixed solution of nitric acid (0.5 mL) and sulfuric acid (0.5 mL) was added, and the reaction mixture was stirred at 0°C for 2 hours. After the reaction was completed, distilled water (30 mL) was added, and the reaction mixture was stirred at 0°C and filtered to obtain 1.08 g (yield: 84%) of the title compound.

[0468] 1 H NMR (400MHz, DMSO-d6) δ 12.18 (s, 1H), 8.51 (d, J = 2.6 Hz, 1H), 8.35 (dd, J = 9.0 Hz, 2.5 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 6.58 (s, 1H).

[0469] Step 26-2: Preparation of 6-amino-4-methylquinolin-2(1H)-one

[0470] In the same manner as in Step 13-2 of Example 13 above, 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 solvents, 47 mg (yield: 37%) of the title compound was obtained.

[0471] 1 H NMR (400MHz, DMSO-d6) δ11.22(s,1H),7.04(d,J=8.5Hz,1H),6.87–6.78(m,2H),6.28(s,1H),5.00(s,2H),2.31(s,3H).

[0472] Step 26-3: Preparation of (4-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbazone dinitrile

[0473] Except that 6-amino-4-methylquinolin-2(1H)-one obtained in step 26-2 was used instead of 7-aminoisoquinolin-1(2H)-one, 48 mg (yield: 83%) of the title compound was obtained in the same manner as in step 1-3 of the above-mentioned Example 1.

[0474] 1 H NMR (400MHz, DMSO-d6) δ13.13(s,1H),11.73(s,1H),7.78(d,J=2.4Hz,1H),7. 66(dd,J=8.9Hz,2.4Hz,1H),7.34(d,J=8.9Hz,1H),6.47(s,1H),2.41(s,3H).

[0475] Example 27: Preparation of (1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonyl dinitrile (Compound 27)

[0476] Step 27-1: Preparation of 1,4-dimethyl-6-nitroquinolin-2(1H)-one

[0477] Except for using 4-methyl-6-nitroquinolin-2(1H)-one instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one, the title compound (206 mg, 38% yield) was obtained in the same manner as in Step 9-2 of Example 9 above.

[0478] 1 H NMR (400MHz, DMSO-d6) δ8.55(d,J=2.6Hz,1H),8.42(ddd,J=9.3Hz,2.6Hz,1.1Hz,1H),7.73(dd,J=9.4Hz,1.1Hz,1H),6.72(s,1H),3.65(s,3H),2.53(s,3H).

[0479] Step 27-2: Preparation of 6-amino-1,4-dimethylquinolin-2(1H)-one

[0480] In the same manner as in Step 13-2 of Example 13 above, 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 solvents, 33 mg (yield: 19%) of the title compound was obtained.

[0481] 1 H NMR (400MHz, DMSO-d6) δ7.25(d,J=8.9Hz,1H),6.94(dd,J=8.9Hz,2.5Hz,1H),6.89(d,J=2.5Hz,1H),6.42(s,1H),5.10(s,2H),3.52(s,3H),2.32(s,3H).

[0482] Step 27-3: Preparation of (1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonyl dicarbonitrile

[0483] Except that 6-amino-1,4-dimethylquinolin-2(1H)-one obtained in step 27-2 was used instead of 7-aminoisoquinolin-1(2H)-one, 55 mg (yield: 77%) of the title compound was obtained in the same manner as in step 1-3 of the above-mentioned Example 1.

[0484] 1 H NMR (400MHz, DMSO-d6) δ13.14(s,1H),7.82(d,J=2.5Hz,1H),7.73(dd,J=9.2 Hz, 2.5Hz, 1H), 7.58 (d, J = 9.2Hz, 1H), 6.59 (s, 1H), 3.59 (s, 3H), 2.42 (s, 3H).

[0485] Example 28: Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonyl dicarbonitrile (Compound 28)

[0486] Step 28-1: Preparation of 3-methyl-5-nitrobenzo[d]oxazol-2(3H)-one

[0487] Except for using 5-nitrobenzo[d]dioxol-2(3H)-one instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one, the title compound (226 mg, yield: 70%) was obtained in the same manner as in Step 9-2 of Example 9 above.

[0488] 1H NMR (400MHz, DMSO-d6) δ8.21 (d, J = 2.3 Hz, 1H), 8.10 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 3.43 (s, 3H).

[0489] Step 28-2: Preparation of 5-amino-3-methylbenzo[d]oxazol-2(3H)-one

[0490] In the same manner as in Step 1-2 of Example 1 above, 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, 150 mg (yield: 88%) of the title compound was obtained.

[0491] 1 H NMR (400MHz, DMSO-d6) δ6.95 (d, J = 8.5 Hz, 1H), 6.37 (d, J = 2.2 Hz, 1H), 6.28 (dd, J = 8.5 Hz, 2.2 Hz, 1H), 5.07 (s, 2H), 3.23 (s, 3H).

[0492] Step 28-3: Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonyl dicarbonitrile

[0493] Except for using 5-amino-3-methylbenzo[d]oxazol-2(3H)-one obtained in step 28-2 instead of 7-aminoisoquinolin-1(2H)-one, the title compound (73 mg, yield: 38%) was obtained in the same manner as in steps 1-3 of the above-mentioned Example 1.

[0494] 1 H NMR (400MHz, DMSO-d6) δ13.11(s,1H),7.36(d,J=8.6Hz,1H),7.32(d,J=2.1Hz,1H),7.24(dd,J=8.6Hz,2.2Hz,1H).

[0495] Example 29: Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonyl dicarbonitrile (Compound 29)

[0496] Step 29-1: Preparation of 3-isopropyl-5-nitrobenzo[d]oxazol-2(3H)-one

[0497] The title compound (94 mg, yield: 25%) was obtained in the same manner as in Step 28-1 of Example 28 above, except that 2-iodopropane was used instead of iodomethane.

[0498] 1H NMR (400MHz, DMSO-d6) δ 8.22 (d, J = 2.3 Hz, 1H), 8.10 ( dd, J = 8.8 Hz, 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).

[0499] Step 29-2: Preparation of 5-amino-3-isopropylbenzo[d]oxazol-2(3H)-one

[0500] In the same manner as in Step 1-2 of Example 1 above, 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, 48 mg (yield: 61%) of the title compound was obtained.

[0501] 1 H NMR (400MHz, DMSO-d6) δ6.96 (d, J=8.4Hz, 1H), 6.57 (d, J=2.2Hz, 1H), 6.28 (dd, J= 8.4Hz, 2.2Hz, 1H), 5.01 (s, 2H), 4.37 (hept, J = 6.9Hz, 1H), 1.42 (d, J = 7.1Hz, 6H).

[0502] Step 29-3: (3-isopropyl-2-oxo-2,3-dihydrobenzo[ d Preparation of oxazol-5-yl) carbonyl dinitrile

[0503] Except for using 5-amino-3-isopropylbenzo[d]oxazol-2(3H)-one obtained in step 29-2 instead of 7-aminoisoquinolin-1(2H)-one, the title compound (9 mg, yield: 15%) was obtained in the same manner as in steps 1-3 of the above-mentioned Example 1.

[0504] 1 H NMR (400MHz, DMSO-d6) δ13.00(s,1H),7.46(d,J=2.1Hz,1H),7.38(d,J=8.7Hz,1H ), 7.24 (dd, J = 8.7Hz, 2.2Hz, 1H), 4.51 (hept, J = 6.9Hz, 1H), 1.46 (d, J = 6.9Hz, 6H).

[0505] Example 30: Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonyl dicarbonitrile (Compound 30)

[0506] Step 30-1: Preparation of 3-(difluoromethyl)-5-nitrobenzo[d]oxazol-2(3H)-one

[0507] The title compound (104 mg, yield: 27%) was obtained in the same manner as in Step 28-1 of Example 28, except that sodium 2-chloro-2,2-difluoroacetate was used instead of iodomethane.

[0508] 1 H NMR (400MHz, DMSO-d6) δ9.05 (s, 1H), 8.71 (s, 1H), 8.38 (dd, J = 9.0Hz, 2.3Hz, 1H), 8.06 (d, J = 9.0Hz, 1H).

[0509] Step 30-2: Preparation of 5-amino-3-(difluoromethyl)benzo[d]oxazol-2(3H)-one

[0510] The title compound was obtained in the same manner as in Step 1-2 of Example 1 above, 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, and was used in the next step without additional purification.

[0511] Step 30-3: Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonyl dicarbonitrile Preparation

[0512] In the same manner as in Step 1-3 of Example 1 above, 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, 30 mg (yield: 22%) of the title compound was obtained.

[0513] 1 H NMR (400MHz, DMSO-d6) δ13.13 (s, 1H), 8.80 (s, 1H), 7.85–7.81 (m, 2H), 7.59 (dd, J = 9.0Hz, 2.1Hz, 1H).

[0514] Example 31: Preparation of (1,3,6-trimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dinitrile (Compound 31)

[0515] Step 31-1: Preparation of 5-methyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one

[0516] The title compound (67 mg, 29% yield) was obtained 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.

[0517] 1H NMR (400MHz, DMSO-d6) δ11.25(s,1H),11.00(s,1H),7.59(s,1H),6.96(s,1H),2.55(s,3H).

[0518] Step 31-2: Preparation of 1,3,5-trimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one

[0519] In the same manner as in Step 9-2 of Example 9 above, 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, 268 mg (yield: 78%) of the title compound was obtained.

[0520] 1 H NMR (400MHz, DMSO-d6) δ7.91 (s, 1H), 7.26 (s, 1H), 3.37 (d, J = 5.5Hz, 6H), 2.60 (s, 3H).

[0521] Step 31-3: Preparation of 5-amino-1,3,6-trimethyl-1H-benzo[d]imidazol-2(3H)-one

[0522] In the same manner as in Step 1-2 of Example 1 above, 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, 169 mg (yield: 78%) of the title compound was obtained.

[0523] 1 H NMR (400MHz, DMSO-d6) δ6.73 (s, 1H), 6.41 (s, 1H), 4.55 (s, 2H), 3.20 (d, J = 5.0Hz, 6H), 2.09 (s, 3H).

[0524] Step 31-4: (1,3,6-trimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile Preparation

[0525] Except that 5-amino-1,3,6-trimethyl-6-nitro-1H-benzo[d]imidazol-one obtained in step 31-2 was used instead of 7-aminoisoquinolin-1(2H)-one, 20 mg (yield: 10%) of the title compound was obtained in the same manner as in step 1-3 of the above-mentioned Example 1.

[0526] 1 H NMR (400MHz, DMSO-d6) δ 12.26 (s, 1H), 7.14 (s, 1H), 7.05 (s, 1H), 3.31 (d, J = 2.7Hz, 6H), 2.38 (s, 3H).

[0527] Example 32: Preparation of (6-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dinitrile (Compound 32)

[0528] Step 32-1: Preparation of 5-methoxy-6-nitro-1H-benzo[d]imidazol-2(3H)-one

[0529] The title compound (336 mg, yield: 98%) was obtained in the same manner as in Step 9-1 of Example 9 above, except that 4-methoxy-5-nitrobenzene-1,2-diamine was used instead of 4-fluoro-5-nitrobenzene-1,2-diamine.

[0530] 1 H NMR (400MHz, DMSO-d6) δ11.26(s,1H),10.86(s,1H),7.48(s,1H),6.81(s,1H),3.90(s,3H).

[0531] Step 32-2: Preparation of 5-methoxy-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one

[0532] In the same manner as in Step 9-2 of Example 9 above, 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, 224 mg (yield: 66%) of the title compound was obtained.

[0533] 1 H NMR (400MHz, DMSO-d6) δ7.81(s,1H),7.19(s,1H),3.95(s,3H),3.39(s,3H),3.34(s,3H).

[0534] Step 32-3: Preparation of 5-amino-6-methoxy-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

[0535] In the same manner as in Step 1-2 of Example 1 above, 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, 78 mg (yield: 44%) of the title compound was obtained.

[0536] 1 H NMR (400MHz, DMSO-d6) δ6.78(s,1H),6.47(s,1H),4.45(s,2H),3.78(s,3H),3.25(s,3H),3.20(s,3H).

[0537] Step 32-4: (6-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl Preparation of hydrazoyl dinitrile

[0538] Except for using 5-amino-6-methoxy-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-one obtained in step 32-2 instead of 7-aminoisoquinolin-1(2H)-one, the title compound (37 mg, yield: 54%) was obtained in the same manner as in steps 1-3 of the above-mentioned Example 1.

[0539] 1 H NMR (400MHz, DMSO-d6) δ11.75(s,1H),7.21(s,1H),7.12(s,1H),3.94(s,3H),3.34(s,3H),3.31(s,3H).

[0540] Example 33: Preparation of (7-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dinitrile (Compound 33)

[0541] Step 33-1: Preparation of 4-methoxy-6-nitro-1H-benzo[d]imidazol-2(3H)-one

[0542] The title compound (509 mg, 89% yield) was obtained 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.

[0543] 1 H NMR (400MHz, DMSO-d6) δ 11.57 (s, 1H), 11.15 (s, 1H), 7.57 (d, J = 2.0Hz, 1H), 7.48 (d, J = 2.0Hz, 1H), 3.96 (s, 3H).

[0544] Step 33-2: Preparation of 4-methoxy-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one

[0545] In the same manner as in Step 9-2 of Example 9 above, 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, 119 mg (yield: 70%) of the title compound was obtained.

[0546] 1 H NMR (400MHz, DMSO-d6) δ7.83 (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).

[0547] Step 33-3: Preparation of 6-amino-4-methoxy-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

[0548] In the same manner as in Step 1-2 of Example 1 above, 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, 15 mg (yield: 16%) of the title compound was obtained.

[0549] 1 H NMR (400MHz, DMSO-d6) δ6.04(d,J=1.7Hz,1H),5.97(d,J=1.7Hz,1H),4.85(s,2H),3.76(s,3H),3.38(s,3H),3.17(s,2H).

[0550] Step 33-4: (7-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl Preparation of hydrazoyl dinitrile

[0551] In the same manner as in Step 1-3 of Example 1 above, 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, 20 mg (yield: 30%) of the title compound was obtained.

[0552] 1 H NMR (400MHz, DMSO-d6) δ13.00(s,1H),6.96(d,J=1.8Hz,1H),6.91(d,J=1.8Hz,1H),3.87(s,3H),3.48(s,3H),3.30(s,3H).

[0553] Example 34: Preparation of (1,3-diisopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile (Compound 34)

[0554] Step 34-1: Preparation of 1,3-diisopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0555] In the same manner as in Step 9-2 of Example 9 above, except using 6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one instead of 5-fluoro-6-nitro-1H-benzo[d]imidazol-2(3H)-one and 2-iodopropane instead of iodomethane, 387 mg (yield: 30%) of the title compound was obtained.

[0556] 1H NMR (400MHz, DMSO-d6) δ 8.94 (d, J = 2.3Hz, 1H), 8.32 (d, J = 2.3Hz, 1H), 4.72 (dhept, J = 16.6Hz, 6.9Hz, 2H), 1.50 (dd, J = 16.1Hz, 6.9Hz, 12H).

[0557] Step 34-2: Preparation of 6-amino-1,3-diisopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0558] In the same manner as in Step 28-2 of Example 28 above, 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, 162 mg (yield: 42%) of the title compound was obtained.

[0559] 1 H NMR (400MHz, DMSO-d6) δ7.37(d,J=2.2Hz,1H),6.92(d,J=2.2Hz,1H),4.84(s,2H),4.61–4.48(m,J=7.0Hz,2H),1.41(dd,J=19.6Hz,6.9Hz,12H).

[0560] Step 34-3: Preparation of 6-amino-1,3-diisopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0561] Except for using 6-amino-1,3-diisopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one obtained in step 34-2 instead of 7-aminoisoquinolin-1(2H)-one, the title compound (43 mg, yield: 27%) was obtained in the same manner as in step 1-3 of the above-mentioned Example 1.

[0562] 1 H NMR (400MHz, DMSO-d6) δ 8.13 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 4.64 (dp, J = 11.5 Hz, 6.9 Hz, 2H), 1.46 (dd, J = 19.8 Hz, 6.9 Hz, 12H).

[0563] Example 35: Preparation of (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile (Compound 35)

[0564] Step 35-1: Preparation of 3-ethyl-1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[0565] 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 thereto, and the reaction mixture was then cooled to 0°C. Ethyl iodide (0.156 mL, 1.94 mmol) was slowly added thereto, and the reaction mixture was slowly heated to room temperature and stirred at room temperature for 17 hours. After the reaction was completed, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was solidified with ether and filtered to obtain 133.5 mg (yield: 77%) of the title compound.

[0566] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.11 (dd, J = 8.7 Hz, 2.2 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 3.49 (s, 3H).

[0567] Step 35-2: Preparation of 5-amino-3-ethyl-1-methyl-1H-benzo[d]imidazol-2(3H)-one

[0568] In the same manner as in Step 1-2 of Example 1 above, 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, 74.7 mg (yield: 68%) of the title compound was obtained.

[0569] 1 H NMR (400MHz, DMSO-d6) δ6.79(d,J=8.3Hz,1H),6.40(d,J=2.1Hz,1H),6.31(dd,J=8.2H z, 2.1Hz, 1H), 4.76 (s, 2H), 3.74 (q, J = 7.2Hz, 2H), 3.21 (s, 3H), 1.16 (t, J = 7.2Hz, 3H).

[0570] Step 35-3: (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dihydrazone Preparation of nitrile

[0571] In the same manner as in Step 1-3 of Example 1 above, 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, 60.9 mg (yield: 58%) of the title compound was obtained.

[0572] 1H NMR (400MHz, DMSO-d6) δ13.04(s,1H),7.30(d,J=2.0Hz,1H),7.23(dd,J=8.4Hz,2.0Hz ,1H),7.18(d,J=8.4Hz,1H),3.88(q,J=7.2Hz,2H),3.32(s,3H),1.20(t,J=7.2Hz,3H).

[0573] Example 36: Preparation of (3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile (Compound 36)

[0574] Step 36-1: Preparation of 3-isopropyl-1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[0575] 135.9 mg (yield: 55%) of the title compound was obtained in the same manner as in Step 9-2 of Example 9 above, 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 iodomethane.

[0576] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (dd, J = 8.7 Hz, 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).

[0577] Step 36-2: Preparation of 5-amino-3-isopropyl-1-methyl-1H-benzo[d]imidazol-2(3H)-one

[0578] 114.2 mg (yield: 100%) of the title compound was obtained in the same manner as in Step 1-2 of Example 1 above, 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.

[0579] 1 H NMR (400MHz, DMSO-d6) δ6.78(d,J=8.2Hz,1H),6.56(d,J=2.0Hz,1H),6.30(dd,J=8.3Hz ,2.0Hz,1H),4.73(s,2H),4.49(hept,J=7.0Hz,1H),3.19(s,3H),1.39(d,J=7.0Hz,6H).

[0580] Step 36-3: (3-Isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone Preparation of dinitrile

[0581] Except for using 5-amino-3-isopropyl-1-methyl-1H-benzo[d]imidazol-2(3H)-one obtained in step 36-2 instead of 7-aminoisoquinolin-1(2H)-one, the title compound (15.2 mg, yield: 9%) was obtained in the same manner as in steps 1-3 of the above-mentioned Example 1.

[0582] 1 H NMR (400MHz, DMSO-d6) δ12.96(s,1H),7.42(d,J=1.9Hz,1H),7.22(dd,J=8.5Hz,1.9Hz,1 H), 7.17 (d, J = 8.5Hz, 1H), 4.61 (hept, J = 7.0Hz, 1H), 3.30 (s, 3H), 1.44 (d, J = 6.9Hz, 6H).

[0583] Example 37: Preparation of (3-(difluoromethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile (Compound 37)

[0584] Step 37-1: Preparation of 3-difluoromethyl-1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[0585] Under a nitrogen atmosphere, 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one (100 mg, 0.52 mmol) was dissolved in DMF. Sodium 2-chloro-2,2-difluoroacetate (157.9 mg, 1.04 mmol) and potassium carbonate (143.1 mg, 1.04 mmol) were added. 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 obtain 58.5 mg (yield: 46%) of the title compound.

[0586] 1 H NMR (400MHz, DMSO-d6) δ8.23 (dd, J = 8.8Hz, 2.2Hz, 1H), 8.05 (d, J = 2.2Hz, 1H), 7.81 (t, J = 57.5Hz, 1H), 7.52 (d, J = 8.8Hz, 1H), 3.41 (s, 3H).

[0587] Step 37-2: Preparation of 5-amino-3-difluoromethyl-1-methyl-1H-benzo[d]imidazol-2(3H)-one

[0588] In the same manner as in Step 1-2 of Example 1 above, 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, 56.1 mg (yield: 72%) of the title compound was obtained.

[0589] 1 H NMR (400MHz, DMSO-d6) δ7.56 (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 Hz, 2.1 Hz, 1H), 5.03 (s, 2H), 3.24 (s, 3H).

[0590] Step 37-3: (3-Difluoromethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone Preparation of acyl dinitrile

[0591] In the same manner as in Step 1-3 of Example 1 above, 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, 53.2 mg (yield: 71%) of the title compound was obtained.

[0592] 1 H NMR (400 MHz, acetone-d6) 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 Hz, 2.1 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 3.42 (s, 3H).

[0593] Example 38: Preparation of (1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile (Compound 38)

[0594] Step 38-1: Preparation of N-ethyl-2,4-dinitroaniline

[0595] 1.95 g (yield: 93%) of the title compound was obtained in the same manner as in Step 17-1 of Example 17 above, except that ethylamine was used instead of methylamine.

[0596] 1H NMR (400 MHz, CHLOROFORM-d) δ 9.13 (d, J = 2.7 Hz, 1H), 8.49 (s, 1H), 8.27 (ddd, J = 9.5 Hz, 2.7 Hz, 0.8 Hz, 1H), 6.92 (d, J = 9.5 Hz, 1H), 3.48 (qd, J = 7.2 Hz, 5.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H).

[0597] Step 38-2:N 1 Preparation of 4-ethyl-nitrobenzene-1,2-diamine

[0598] 1.46 g (yield: 88%) of the title compound was obtained 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.

[0599] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.83 (dd, J = 8.9 Hz, 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).

[0600] Step 38-3: Preparation of 1-ethyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[0601] 1.57 g (yield: 95%) of the title compound was obtained in the same manner as in Step 9-1 of Example 9 above, 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.

[0602] 1 H NMR (400MHz, DMSO-d6) δ11.42 (s, 1H), 8.01 (dd, J=8.7Hz, 2.3Hz, 1H), 7.75 (d, J= 2.3Hz, 1H), 7.36 (d, J = 8.7Hz, 1H), 3.90 (q, J = 7.2Hz, 2H), 1.21 (t, J = 7.2Hz, 3H).

[0603] Step 38-4: Preparation of 1-ethyl-3-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[0604] In the same manner as in Step 9-1 of Example 9 above, 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 iodomethane was used instead of iodoethane, 172.0 mg (yield: 80%) of the title compound was obtained.

[0605] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.11 (dd, J = 8.7 Hz, 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).

[0606] Step 38-5: Preparation of 5-amino-1-ethyl-3-methyl-H-benzo[d]imidazol-2(3H)-one

[0607] In the same manner as in Step 1-2 of Example 1 above, 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, 117.6 mg (yield: 80%) of the title compound was obtained.

[0608] 1 H NMR (400MHz, DMSO-d6) δ6.82(d,J=8.2Hz,1H),6.35(d,J=2.1Hz,1H),6.30(dd,J=8.2H z, 2.1Hz, 1H), 4.78 (s, 2H), 3.75 (q, J = 7.1Hz, 2H), 3.20 (s, 3H), 1.15 (t, J = 7.1Hz, 3H).

[0609] Step 38-6: (1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazolidine dihydrogen Preparation of nitrile

[0610] 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, 10.8 mg (yield: 6%) of the title compound was obtained in the same manner as in steps 1-3 of the above-mentioned Example 1.

[0611] 1 H NMR (400MHz, DMSO-d6) δ13.07 (s, 1H), 7.26–7.22 (m, 3H), 3.86 (q, J = 7.2Hz, 2H), 1.20 (t, J = 7.1Hz, 3H).

[0612] Example 39: Preparation of (3-(difluoromethyl)-1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile (Compound 39)

[0613] Step 39-1: Preparation of 3-difluoromethyl-1-ethyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[0614] 133.0 mg (yield: 42%) of the title compound was obtained in the same manner as in Step 37-1 of the above-mentioned 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.

[0615] 1 H NMR(400MHz, DMSO-d6)δ8.22(dd,J=8.8Hz,2.2Hz,1H),8.06(d,J=2.2Hz,1H),7.81(t ,J=57.5Hz,1H),7.60(d,J=8.9Hz,1H),3.97(q,J=7.2Hz,2H),1.26(t,J=7.2Hz,3H).

[0616] Step 39-2: Preparation of 5-amino-3-difluoromethyl-1-ethyl-1H-benzo[d]imidazol-2(3H)-one

[0617] In the same manner as in Step 1-2 of Example 1 above, 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, 88.2 mg (yield: 75%) of the title compound was obtained.

[0618] 1 H NMR (400MHz, DMSO-d6) δ7.56(t,J=58.3Hz,1H),6.97(d,J=8.4Hz,1H),6.65(d,J=2.0Hz,1H ), 6.44 (dd, J = 8.4Hz, 2.1Hz, 1H), 5.03 (s, 2H), 3.77 (q, J = 7.2Hz, 2H), 1.19 (t, J = 7.2Hz, 3H).

[0619] Step 39-3: (3-Difluoromethyl-1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone Preparation of acyl dinitrile

[0620] Except for using 5-amino-3-difluoromethyl-1-ethyl-1H-benzo[d]imidazol-2(3H)-one obtained in step 39-2 instead of 7-aminoisoquinolin-1(2H)-one, the title compound (64.7 mg, yield: 56%) was obtained in the same manner as in steps 1-3 of the above-mentioned Example 1.

[0621] 1 H NMR (400 MHz, acetone-d6) 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 Hz, 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).

[0622] Example 40: Preparation of (1-cyclopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile (Compound 40)

[0623] Step 40-1: Preparation of N-cyclopropyl-2,4-dinitroaniline

[0624] 179.9 mg (yield: 81%) of the title compound was obtained in the same manner as in Step 17-1 of Example 17 above, except that cyclopropylamine was used instead of methylamine.

[0625] 1 H NMR (400MHz, chloroform-d) δ9.13 (d, J=2.6Hz, 1H), 8.56 (s, 1H), 8.31 (ddd, J=9.5Hz, 2.6Hz, 0.7Hz, 1H), 7. 40(d,J=9.5Hz,1H),2.70(tdt,J=6.8Hz,3.8Hz,1.8Hz,1H),1.12–0.98(m,2H),0.82–0.67(m,2H).

[0626] Step 40-2:N 1 Preparation of cyclopropyl-4-nitrobenzene-1,2-diamine

[0627] 1.69 g (yield: 89%) of the title compound was obtained 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.

[0628] 1 H NMR (400MHz, chloroform-d) δ7.85 (ddd, J=8.9Hz, 2.5Hz, 0.6Hz, 1H), 7.61 (d, J=2.5Hz, 1H), 6.98 (d, J=8.9Hz, 1H) ,4.66(s,1H),3.29(s,2H),2.53(ttd,J=6.7Hz,3.6Hz,1.3Hz,1H),0.93–0.82(m,2H),0.63–0.55(m,2H).

[0629] Step 40-3: Preparation of 1-cyclopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[0630] 1.83 g (yield: 96%) of the title compound was obtained in the same manner as in Step 9-1 of Example 9 above, 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.

[0631] 1 H NMR (400MHz, DMSO-d6) δ11.30(s,1H),8.01(dd,J=8.7Hz,2.3Hz,1H),7.71(d,J=2.3Hz,1H), 7.32(d,J=8.7Hz,1H),2.93(tt,J=7.0Hz,3.7Hz,1H),1.09–1.01(m,2H),0.93–0.85(m,2H).

[0632] Step 40-4: Preparation of 1-cyclopropyl-3-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[0633] In the same manner as in Step 35-1 of Example 35 above, except that 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one was replaced with 1-cyclopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in Step 40-3, and iodomethane was replaced with iodoethane, 186.6 mg (yield: 87%) of the title compound was obtained.

[0634] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (ddd, J = 8.6 Hz, 2.3 Hz, 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 Hz, 4.1 Hz, 3.1 Hz, 1H), 1.22–1.11 (m, 2H), 1.07–0.98 (m, 2H).

[0635] Step 40-5: Preparation of 5-amino-1-cyclopropyl-3-methyl-H-benzo[d]imidazol-2(3H)-one

[0636] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 41.6 mg (yield: 75%) of the title compound was obtained.

[0637] 1H NMR (400 MHz, CHLOROFORM-d) δ 6.96 (d, J = 8.2 Hz, 1H), 6.44 (dd, J = 8.2 Hz, 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).

[0638] Step 40-6: (1-cyclopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone Preparation of dinitrile

[0639] 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, 29.9 mg (yield: 52%) of the title compound was obtained in the same manner as in steps 1-3 of the above-mentioned Example 1.

[0640] 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 Hz, 2.1 Hz, 1H), 3.41 (s, 3H), 2.89 (tt, J = 7.0 Hz, 3.7 Hz, 1H), 1.17–1.09 (m, 2H), 1.01 (tt, J = 5.3 Hz, 3.7 Hz, 2H).

[0641] Example 41: Preparation of (1-cyclopropyl-3-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile (Compound 41)

[0642] Step 41-1: Preparation of 1-cyclopropyl-3-ethyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[0643] In the same manner as in Step 35-1 of Example 35 above, except that 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one was replaced with 1-cyclopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in Step 40-3, 159.9 mg (yield: 70%) of the title compound was obtained.

[0644] 1H NMR (400MHz, DMSO-d6) δ8.09(d,J=2.2Hz,1H),8.07(dd,J=8.6Hz,2.3Hz,1H),7.38(d,J=8.6Hz,1H),3.94(q ,J=7.1Hz,2H),2.98(tt,J=7.1Hz,3.7Hz,1H),1.21(t,J=7.2Hz,3H),1.12–1.03(m,2H),0.95–0.86(m,2H).

[0645] Step 41-2: Preparation of 5-amino-1-cyclopropyl-3-ethyl-H-benzo[d]imidazol-2(3H)-one

[0646] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 83.2 mg (yield: 61%) of the title compound was obtained.

[0647] 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.96 (d, J = 8.2 Hz, 1H), 6.43 (dd, J = 8.2 Hz, 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).

[0648] Step 41-3: (1-cyclopropyl-3-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone Preparation of dinitrile

[0649] In the same manner as in Step 1-3 of Example 1 above, 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, 53.6 mg (yield: 49%) of the title compound was obtained.

[0650] 1 H NMR (400MHz, DMSO-d6) δ13.04(s,1H),7.52–7.06(m,3H),3.83(q,J=7.2Hz,2H),2.89(tt,J= 7.0Hz, 3.7Hz, 1H), 1.18 (t, J=7.2Hz, 3H), 1.02 (td, J=7.3Hz, 5.0Hz, 2H), 0.92–0.82 (m, 2H).

[0651] Example 42: Preparation of (1-cyclopropyl-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile (Compound 42)

[0652] Step 42-1: Preparation of 1-cyclopropyl-3-isopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[0653] In the same manner as in Step 35-1 of Example 35 above, except that 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one was replaced with 1-cyclopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in Step 40-3, and isopropyl iodide was replaced with iodoethane, 207.5 mg (yield: 69%) of the title compound was obtained.

[0654] 1 H NMR (400MHz, DMSO-d6) δ8.17(d,J=2.3Hz,1H),8.03(dd,J=8.8Hz,2.2Hz,1H),7.51(d,J=8.8Hz,1H),5.27(hept,J= 6.2Hz, 1H), 3.18 (tt, J = 7.1Hz, 3.7Hz, 1H), 1.43 (d, J = 6.2Hz, 6H), 1.13 (td, J = 7.4Hz, 5.2Hz, 2H), 0.98–0.90 (m, 2H).

[0655] Step 42-2: Preparation of 5-amino-1-cyclopropyl-3-isopropyl-H-benzo[d]imidazol-2(3H)-one

[0656] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 114.5 mg (yield: 62%) of the title compound was obtained.

[0657] 1 H NMR (400MHz, chloroform-d) δ6.97(d,J=8.2Hz,1H),6.52(d,J=2.1Hz,1H),6.43(dd,J=8.2Hz,2.1Hz,1H),4 .65(hept,J=7.0Hz,1H),3.56(s,2H),2.84–2.71(m,1H),1.48(d,J=7.0Hz,6H),1.07–0.94(m,4H).

[0658] Step 42-3: (1-cyclopropyl-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone Preparation of acyl dinitrile

[0659] Except for using 5-amino-1-cyclopropyl-3-isopropyl-1H-benzo[d]imidazol-2(3H)-one obtained in step 42-2 instead of 7-aminoisoquinolin-1(2H)-one, the title compound (39.8 mg, yield: 26%) was obtained in the same manner as in steps 1-3 of the above-mentioned Example 1.

[0660] 1 H NMR (400MHz, DMSO-d6) δ12.96(s,1H),7.39(d,J=1.3Hz,1H),7.22(d,J=1.2Hz,2H),4.58(hept,J=6.9Hz,1 H), 2.87 (tt, J = 7.0Hz, 3.6Hz, 1H), 1.42 (d, J = 6.9Hz, 6H), 1.01 (td, J = 7.2Hz, 5.0Hz, 2H), 0.90–0.82 (m, 2H).

[0661] Example 43: Preparation of (3-(difluoromethyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile (Compound 43)

[0662] Step 43-1: Preparation of N-isopropyl-2,4-dinitroaniline

[0663] 2.02 g (yield: 90%) of the title compound was obtained in the same manner as in Step 17-1 of Example 17 above, except that isopropylamine was used instead of methylamine.

[0664] 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 Hz, 2.7 Hz, 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).

[0665] Step 43-2:N 1 Preparation of Isopropyl-4-nitrobenzene-1,2-diamine

[0666] 1.08 g (yield: 62%) of the title compound was obtained in the same manner as in Step 17-2 of Example 17 above, except that N-isopropyl-2,4-dinitroaniline obtained in Step 43-1 was used instead of N-methyl-2,4-dinitroaniline and a mixed solution of methanol and water in a ratio of 1:1 was used as the solvent.

[0667] 1H NMR (400MHz, chloroform-d) δ7.84 (dd, J=8.9Hz, 2.6Hz, 1H), 7.63 (d, J=2.6Hz, 1H), 6.55 (d, J=9. 0Hz, 1H), 4.20 (s, 1H), 3.82–3.63 (m, J = 6.3Hz, 1H), 3.29 (s, 2H), 1.29 (d, J = 6.3Hz, 6H).

[0668] Step 43-3: Preparation of 1-isopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[0669] 1.15 g (yield: 94%) of the title compound was obtained in the same manner as in Step 9-1 of Example 9 above, 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.

[0670] 1 H NMR (400MHz, DMSO-d6) δ11.42 (s, 1H), 7.96 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.74 (d, J = 2 .3Hz, 1H), 7.47 (d, J = 8.8Hz, 1H), 4.63 (hept, J = 6.9Hz, 1H), 1.46 (d, J = 7.0Hz, 6H).

[0671] Step 43-4: Preparation of 3-difluoromethyl-1-isopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[0672] In the same manner as in Step 37-1 of Example 37 above, except that 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one was replaced with 1-isopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one obtained in Step 43-3, 89.3 mg (yield: 29%) of the title compound was obtained.

[0673] 1 H NMR (400MHz, DMSO-d6) δ8.17 (dd, J=8.9Hz, 2.3Hz, 1H), 8.05 (d, J=2.3Hz, 1H), 7.79 (t, J=57.6Hz, 1H), 7.69 (d, J=8.9Hz, 1H), 4.68 (hept, J=6.9Hz, 1H), 1.49 (d, J=6.9Hz, 6H).

[0674] Step 43-5: Preparation of 5-amino-3-difluoromethyl-1-ethyl-H-benzo[d]imidazol-2(3H)-one

[0675] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 67.2 mg (yield: 84%) of the title compound was obtained.

[0676] 1 H NMR (400MHz, DMSO-d6) δ7.53(t,J=58.4Hz,1H),7.07(d,J=8.5Hz,1H),6.65(d,J=2.1Hz,1H), 6.42 (dd, J=8.5Hz, 2.1Hz, 1H), 5.03 (s, 2H), 4.49 (hept, J=6.9Hz, 1H), 1.41 (d, J=6.9Hz, 6H).

[0677] Step 43-6: (1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dihydrogen Preparation of nitrile

[0678] In the same manner as in Steps 1-3 of Example 1 above, 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, 53.6 mg (yield: 60%) of the title compound was obtained.

[0679] 1 H NMR(400MHz,DMSO-d6)δ13.10(s,1H),7.69(t,J=57.8Hz,1H),7.53–7.44(m,2H ), 7.35 (dd, J = 8.8Hz, 2.1Hz, 1H), 4.59 (p, J = 6.9Hz, 1H), 1.46 (d, J = 7.0Hz, 6H).

[0680] Example 44: Preparation of (1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dinitrile (Compound 44)

[0681] Step 44-1: Preparation of N-methyl-3,5-dinitropyridin-2-amine

[0682] 1.62 g (yield: 83%) of the title compound was obtained in the same manner as in Step 17-1 of Example 17 above, except that 2-chloro-3,5-dinitropyridine was used instead of 1-chloro-2,4-dinitrobenzene.

[0683] 1H NMR (400 MHz, acetone-d6) 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).

[0684] Step 44-2:N 1 Preparation of methyl-5-nitropyridine-2,3-diamine

[0685] 1.14 g (yield: 83%) of the title compound was obtained in the same manner as in Step 17-2 of Example 17 above, except that N-methyl-3,5-dinitropyridin-2-amine obtained in Step 44-1 was used instead of N-methyl-2,4-dinitroaniline.

[0686] 1 H NMR (400MHz, DMSO-d6) 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).

[0687] Step 44-3: Preparation of 3-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0688] The title compound (669.7 mg, 53% yield) was obtained in the same manner as in Step 9-1 of Example 9 above, 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.

[0689] 1 H NMR (400MHz, DMSO-d6) δ 11.69 (s, 1H), 8.92 (d, J = 2.3Hz, 1H), 7.92 (d, J = 2.3Hz, 1H), 3.36 (s, 3H).

[0690] Step 44-4: Preparation of 1-ethyl-3-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0691] 148.8 mg (yield: 65%) of the title compound was obtained in the same manner as in Step 35-1 of Example 35 above, 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.

[0692] 1H 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).

[0693] Step 44-5: Preparation of 6-amino-1-ethyl-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0694] In the same manner as in Step 1-2 of Example 1 above, 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 as the solvent instead of dioxane, and the reaction was carried out at 40°C, 92.8 mg (yield: 74%) of the title compound was obtained.

[0695] 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).

[0696] Step 44-6: (1-cyclopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone Preparation of dinitrile

[0697] 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, 45.8 mg (yield: 31%) of the title compound was obtained in the same manner as in steps 1-3 of the above-mentioned Example 1.

[0698] 1 H NMR (400MHz, DMSO-d6) δ13.10 (s, 1H), 8.16 (d, J = 2.1Hz, 1H), 7.62 (d, J = 2.1Hz, 1H), 3.92 (q, J = 7.1Hz, 2H), 3.33 (s, 4H), 1.20 (t, J = 7.1Hz, 3H).

[0699] Example 45: Preparation of (1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile (Compound 45)

[0700] Step 45-1: Preparation of 1-isopropyl-3-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0701] In the same manner as in Step 35-1 of the above-mentioned 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, 98.5 mg (yield: 40%) of the title compound was obtained.

[0702] 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).

[0703] Step 45-2: Preparation of 6-amino-1-isopropyl-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0704] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 64.1 mg (yield: 81%) of the title compound was obtained.

[0705] 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).

[0706] Step 45-3: (1-Isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl) Preparation of carbonyl dinitrile

[0707] Except for using 5-amino-1-cyclopropyl-3-ethyl-1H-benzo[d]imidazol-2(3H)-one obtained in step 45-2 instead of 7-aminoisoquinolin-1(2H)-one, the title compound (8.6 mg, yield: 9%) was obtained in the same manner as in steps 1-3 of the above-mentioned Example 1.

[0708] 1 H NMR (400MHz, DMSO-d6) δ13.10 (s, 1H), 8.15 (d, J = 2.1Hz, 1H), 7.66 (d, J = 2.1Hz, 1H), 4.64 (hept, J = 6.9Hz, 1H), 3.32 (s, 3H), 1.44 (d, J = 6.9Hz, 6H).

[0709] Example 46: Preparation of (1-(difluoromethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile (Compound 46)

[0710] Step 46-1: Preparation of 1-difluoromethyl-3-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0711] In the same manner as in Step 37-1 of the above-mentioned 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, 58.5 mg (yield: 46%) of the title compound was obtained.

[0712] 1 H NMR (400MHz, DMSO-d6) δ9.11 (d, J = 2.3Hz, 1H), 8.25 (d, J = 2.3Hz, 1H), 7.87 (t, J = 57.4Hz, 1H), 3.40 (s, 3H).

[0713] Step 46-2: Preparation of 6-amino-1-difluoromethyl-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0714] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 121.1 mg (yield: 88%) of the title compound was obtained.

[0715] 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).

[0716] Step 46-3: (1-difluoromethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6- Preparation of (4-(2-aminoethyl)carbonyl)carbazone dinitrile

[0717] In the same manner as in Step 1-3 of Example 1 above, 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, 57.3 mg (yield: 81%) of the title compound was obtained.

[0718] 1H NMR (400MHz, DMSO-d6) δ8.29 (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).

[0719] Example 47: Preparation of (3-methyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile (Compound 47)

[0720] Step 47-1: Preparation of 3-methyl-6-nitro-1-phenyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0721] 3-Methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one (50 mg, 0.26 mmol), 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) obtained in step 44-3 of Example 44 were dissolved in DMSO, and iodinated benzene (28.7 mg, 0.26 mmol) dissolved in DMSO was slowly added thereto. The reaction mixture was heated to 130°C and stirred for 14 hours. After completion of the reaction, the reaction product was extracted with a saturated aqueous solution of ammonium chloride and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 36.6 mg (yield: 52%) of the title compound.

[0722] 1 H NMR (400MHz, DMSO-d6) δ9.05 (d, J = 2.3Hz, 1H), 7.88 (d, J = 2.3Hz, 1H), 7.63 (d, J = 5.7Hz, 4H), 7.58–7.47 (m, 1H), 3.50 (s, 3H).

[0723] Step 47-2: Preparation of 6-amino-3-methyl-1-phenyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0724] In the same manner as in Step 1-2 of Example 1 above, 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 as the solvent instead of dioxane, and the reaction was carried out at 60°C, 18.2 mg (yield: 34%) of the title compound was obtained.

[0725] 1H NMR (400MHz, DMSO-d6) δ7.61–7.49(m,4H),7.46(d,J=2.3Hz,1H),7.45–7.41(m,1H),6.73(d,J=2.2Hz,1H),4.96(s,2H),3.32(s,3H).

[0726] Step 47-3: (1-difluoromethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6- Preparation of 2-(2-aminoethyl)carbonylcarbazonyl dinitrile

[0727] In the same manner as in Step 1-3 of Example 1 above, 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, 14.0 mg (yield: 58%) of the title compound was obtained.

[0728] 1 H NMR (400 MHz, acetone-d6) 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 Hz, 2.2 Hz, 1H), 3.48 (s, 3H).

[0729] Example 48: Preparation of (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile (Compound 48)

[0730] Step 48-1: Preparation of N-ethyl-3,5-dinitropyridin-2-amine

[0731] 1.66 g (yield: 79%) of the title compound was obtained 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.

[0732] 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 Hz, 5.6 Hz, 2H), 1.37 (t, J = 7.3 Hz, 3H).

[0733] Step 48-2:N 1 Preparation of ethyl-5-nitropyridine-2,3-diamine

[0734] 1.15 g (yield: 80%) of the title compound was obtained in the same manner as in Step 17-2 of Example 17 above, 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 solution of methanol and water in a ratio of 1:1 was used as the solvent.

[0735] 1 H 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 Hz, 5.4 Hz, 2H), 3.30 (s, 2H), 1.31 (t, J = 7.2 Hz, 3H).

[0736] Step 48-3: Preparation of 3-ethyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0737] In the same manner as in Step 9-1 of Example 9 above, 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, 891.8 mg (yield: 68%) of the title compound was obtained.

[0738] 1 H NMR (400MHz, DMSO-d6) δ 11.69 (s, 1H), 8.93 (d, J = 2.4Hz, 1H), 7.93 (d, J = 2.3Hz, 1H), 3.92 (q, J = 7.2Hz, 2H), 1.27 (t, J = 7.2Hz, 3H).

[0739] Step 48-4: Preparation of 3-ethyl-1-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0740] In the same manner as in Step 35-1 of Example 35 above, 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 iodomethane was used instead of iodoethane, 127.8 mg (yield: 80%) of the title compound was obtained.

[0741] 1 H 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).

[0742] Step 48-5: Preparation of 6-amino-3-ethyl-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0743] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 94.8 mg (yield: 87%) of the title compound was obtained.

[0744] 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).

[0745] Step 48-6: (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl Preparation of hydrazoyl dinitrile

[0746] 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, 61.6 mg (yield: 46%) of the title compound was obtained in the same manner as in steps 1-3 of the above-mentioned Example 1.

[0747] 1 H NMR (400 MHz, acetone-d6) 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).

[0748] Example 49: Preparation of (3-ethyl-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile (Compound 49)

[0749] Step 49-1: Preparation of 3-ethyl-1-isopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0750] 108.3 mg (yield: 45%) of the title compound was obtained in the same manner as in Step 48-4 of Example 48, except that isopropyl iodide was used instead of iodomethane.

[0751] 1H 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).

[0752] Step 49-2: Preparation of 6-amino-3-ethyl-1-isopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0753] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 75.2 mg (yield: 82%) of the title compound was obtained.

[0754] 1 H 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).

[0755] Step 49-3: (3-ethyl-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl) Preparation of carbonyl dinitrile

[0756] In the same manner as in Step 1-3 of Example 1 above, 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, 43.5 mg (yield: 42%) of the title compound was obtained.

[0757] 1 H NMR (400 MHz, acetone-d6) 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).

[0758] Example 50: Preparation of (1-(difluoromethyl)-3-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile (Compound 50)

[0759] Step 50-1: Preparation of 1-difluoromethyl-3-ethyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0760] In the same manner as in Step 37-1 of the above-mentioned 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, 129.6 mg (yield: 70%) of the title compound was obtained.

[0761] 1 H NMR (400MHz, DMSO-d6) δ9.12 (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).

[0762] Step 50-2: Preparation of 6-amino-1-difluoromethyl-3-ethyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0763] 103.7 mg (yield: 90%) of the title compound was obtained in the same manner as in Step 1-2 of Example 1 above, 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.

[0764] 1 H NMR (400MHz, DMSO-d6) δ7.67(t,J=58.2Hz,1H),7.53(d,J=2.2Hz,1H),7.02(d,J=2.2Hz,1H),5.18(s,2H),3.81(q,J=7.2Hz,2H),1.23(t,J=7.2Hz,3H).

[0765] Step 50-3: (3-difluoromethyl-1-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6- Preparation of 2-(2-aminoethyl)carbonylcarbazonyl dinitrile

[0766] 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, 69.3 mg (yield: 80%) of the title compound was obtained in the same manner as in steps 1-3 of the above-mentioned Example 1.

[0767] 1H NMR (400MHz, DMSO-d6) 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).

[0768] Example 51: Preparation of (3-cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dinitrile (Compound 51)

[0769] Step 51-1: Preparation of N-cyclopropyl-3,5-dinitropyridin-2-amine

[0770] 1.99 g (yield: 90%) of the title compound was obtained 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.

[0771] 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 Hz, 7.1 Hz, 3.9 Hz, 1H), 1.11–0.97 (m, 2H), 0.80–0.64 (m, 2H).

[0772] Step 51-2: N 2 Preparation of cyclopropyl-5-nitropyridine-2,3-diamine

[0773] 1.33 g (yield: 78%) of the title compound was obtained in the same manner as in Step 17-2 of Example 17 above, except that N-cyclopropyl-3,5-dinitropyridine-2-amine obtained in Step 51-1 was used instead of N-methyl-2,4-dinitroaniline and a mixed solution of methanol and water in a ratio of 1:1 was used as the solvent.

[0774] 1 H NMR (400MHz, DMSO-d6) δ8.41(d,J=2.5Hz,1H),7.34(d,J=2.5Hz,1H),7.12(d,J=3.6Hz, 1H), 5.35 (s, 2H), 2.93 (tq, J = 7.3Hz, 3.8Hz, 1H), 0.84–0.71 (m, 2H), 0.57–0.45 (m, 2H).

[0775] Step 51-3: Preparation of 3-cyclopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0776] In addition to using the N obtained in step 51-2 21.16 g (yield: 77%) of the title compound was obtained in the same manner as in Step 9-1 of Example 9, except that 4-fluoro-5-nitrobenzene-1,2-diamine was used instead of cyclopropyl-5-nitropyridine-2,3-diamine.

[0777] 1 H NMR (400MHz, DMSO-d6) δ11.56(s,1H),8.91(d,J=2.4Hz,1H),7.88(d,J=2.4Hz,1H),3.07–2.92(m,1H),1.17–0.78(m,4H).

[0778] Step 51-4: Preparation of 3-cyclopropyl-1-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0779] In the same manner as in Step 35-1 of Example 35 above, 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 iodomethane was used instead of iodoethane, 172.0 mg (yield: 80%) of the title compound was obtained.

[0780] 1 H NMR (400MHz, DMSO-d6) δ8.95(d,J=2.3Hz,1H),8.31(d,J=2.3Hz,1H),3.40(s,3H),3.08–2.97(m,1H),1.11–0.99(m,4H).

[0781] Step 51-5: Preparation of 6-amino-3-cyclopropyl-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0782] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 89.3 mg (yield: 78%) of the title compound was obtained.

[0783] 1 H NMR (400MHz, DMSO-d6) δ7.37(d,J=2.3Hz,1H),6.69(d,J=2.3Hz,1H),4.92(s,2H),3.20(s,3H),2.86(tt,J=7.2Hz,3.5Hz,1H),1.04–0.85(m,4H).

[0784] Step 51-6: (3-cyclopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone Preparation of dinitrile

[0785] In the same manner as in Step 1-3 of Example 1 above, 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, 25.6 mg (yield: 20%) of the title compound was obtained.

[0786] 1 H NMR (400MHz, DMSO-d6) 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 Hz, 3.6 Hz, 1H), 0.99 (d, J = 7.5 Hz, 4H).

[0787] Example 52: Preparation of (3-cyclopropyl-1-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile (Compound 52)

[0788] Step 52-1: Preparation of 3-cyclopropyl-1-ethyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0789] 179.5 mg (yield: 79%) of the title compound was obtained in the same manner as in Step 35-1 of Example 35 above, 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.

[0790] 1 H NMR (400 MHz, DMSO-d6) 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 Hz, 4.1 Hz, 1H), 1.38 (t, J = 7.3 Hz, 3H), 1.29–1.09 (m, 4H).

[0791] Step 52-2: Preparation of 6-amino-3-cyclopropyl-1-ethyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0792] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 112.0 mg (yield: 71%) of the title compound was obtained.

[0793] 1H 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 Hz, 4.1 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H), 1.10 (dddt, J = 7.0 Hz, 4.5 Hz, 2.8 Hz, 1.2 Hz, 4H).

[0794] Step 52-3: (3-cyclopropyl-1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone Preparation of dinitrile

[0795] In the same manner as in Step 1-3 of Example 1 above, 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, 66.2 mg (yield: 44%) of the title compound was obtained.

[0796] 1 H NMR (400MHz, DMSO-d6) δ13.11(s,1H),8.16(d,J=2.2Hz,1H),7.58(d,J=2.2Hz,1H),3.88(q,J=7.1H z, 2H), 2.95 (td, J = 7.0Hz, 3.6Hz, 1H), 1.19 (t, J = 7.1Hz, 3H), 1.00 (ddt, J = 9.9Hz, 5.2Hz, 2.7Hz, 4H).

[0797] Example 53: Preparation of (3-cyclopropyl-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile (Compound 53)

[0798] Step 53-1: Preparation of 3-cyclopropyl-1-isopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0799] In the same manner as in Step 35-1 of Example 35 above, 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 iodoethane, 187.7 mg (yield: 76%) of the title compound was obtained.

[0800] 1H NMR (400 MHz, DMSO-d6) 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 Hz, 4.1 Hz, 1H), 1.56 (d, J = 7.1 Hz, 6H), 1.24–1.12 (m, 4H).

[0801] Step 53-2: Preparation of 6-amino-3-cyclopropyl-1-isopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0802] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 130.9 mg (yield: 79%) of the title compound was obtained.

[0803] 1 H NMR (400MHz, chloroform-d) δ7.58(d,J=2.3Hz,1H),6.75(d,J=2.3Hz,1H),4.69(hept,J=7.0Hz,1H),3.50(s,2H ), 2.92 (tt, J = 6.5Hz, 4.1Hz, 1H), 1.47 (d, J = 7.0Hz, 6H), 1.10 (dddd, J = 9.7Hz, 4.2Hz, 2.6Hz, 1.2Hz, 4H).

[0804] Step 53-3: (3-cyclopropyl-1-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone Preparation of acyl dinitrile

[0805] In the same manner as in Step 1-3 of Example 1 above, 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, 22.9 mg (yield: 34%) of the title compound was obtained.

[0806] 1 H NMR (400MHz, DMSO-d6) δ13.13(s,1H),8.14(d,J=2.1Hz,1H),7.62(d,J=2.2Hz,1H),4 .61(hept,J=6.9Hz,1H),3.03–2.79(m,1H),1.42(d,J=6.9Hz,6H),1.08–0.91(m,4H).

[0807] Example 54: Preparation of (3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile (Compound 54)

[0808] Step 54-1: Preparation of N-isopropyl-3,5-dinitropyridin-2-amine

[0809] 2.07 g (yield: 93%) of the title compound was obtained 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.

[0810] 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 Hz, 6.6 Hz, 1H), 1.37 (d, J = 6.5 Hz, 6H).

[0811] Step 54-2:N 2 Preparation of 5-isopropyl-2,3-nitropyridine-5-nitropyridine-2,3-diamine

[0812] 1.07 g (yield: 59%) of the title compound was obtained in the same manner as in Step 17-2 of Example 17 above, except that N-isopropyl-3,5-dinitropyridine-2-amine obtained in Step 54-1 was used instead of N-methyl-2,4-dinitroaniline and a mixed solution of methanol and water in a ratio of 1:1 was used as the solvent.

[0813] 1 H NMR (400MHz, DMSO-d6) δ8.37(d,J=2.5Hz,1H),7.32(d,J=2.6Hz,1H),6.74(d, J=7.2Hz,1H),5.41(s,2H),4.39–4.26(m,J=6.6Hz,1H),1.21(d,J=6.5Hz,6H).

[0814] Step 54-3: Preparation of 3-isopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0815] In addition to using the N obtained in step 54-2 2 1.08 g (yield: 91%) of the title compound was obtained in the same manner as in Step 9-1 of Example 9, except that 4-fluoro-5-nitrobenzene-1,2-diamine was replaced with 5-isopropyl-5-nitropyridine-2,3-diamine.

[0816] 1H NMR (400MHz, DMSO-d6) 8.91 (d, J = 2.4Hz, 1H), 7.91 (d, J = 2.4Hz, 1H), 4.69 (hept, J = 6.9Hz, 1H), 1.51 (d, J = 6.9Hz, 6H).

[0817] Step 54-4: Preparation of 3-isopropyl-1-methyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0818] In the same manner as in Step 35-1 of Example 35 above, 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 iodomethane was used instead of iodoethane, 143.5 mg (yield: 67%) of the title compound was obtained.

[0819] 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).

[0820] Step 54-5: Preparation of 6-amino-3-isopropyl-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0821] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 97.2 mg (yield: 78%) of the title compound was obtained.

[0822] 1 H NMR (400MHz, DMSO-d6) δ7.37 (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).

[0823] Step 54-6: (3-Isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone Preparation of dinitrile

[0824] In the same manner as in Step 1-3 of Example 1 above, 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, 103.5 mg (yield: 77%) of the title compound was obtained.

[0825] 1 H NMR (400MHz, DMSO-d6) δ 13.18 (s, 1H), 8.16 (d, J = 2.2Hz, 1H), 7.56 (d, J = 2.2Hz, 1H), 4.66 (hept, J = 6.9Hz, 1H), 3.35 (s, 3H), 1.49 (d, J = 6.9Hz, 6H).

[0826] Example 55: Preparation of (1-ethyl-3-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonyl dicarbonitrile (Compound 55)

[0827] Step 55-1: Preparation of 1-ethyl-3-isopropyl-6-nitro-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0828] In the same manner as in Step 35-1 of Example 35 above, 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, 194.1 mg (yield: 86%) of the title compound was obtained.

[0829] 1 H NMR (400MHz, chloroform-d) δ9.00 (d, J=2.3Hz, 1H), 7.92 (d, J=2.3Hz, 1H), 4.87 (hept, J= 6.9Hz, 1H), 3.98 (q, J = 7.2Hz, 2H), 1.61 (d, J = 6.9Hz, 6H), 1.39 (t, J = 7.3Hz, 3H).

[0830] Step 55-2: Preparation of 6-amino-1-ethyl-3-isopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

[0831] In the same manner as in Step 1-2 of Example 1 above, 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 the solvent, 27.4 mg (yield: 16%) of the title compound was obtained.

[0832] 1 H NMR (400MHz, DMSO-d6) δ7.37(d,J=2.2Hz,1H),6.77(d,J=2.3Hz,1H),4.88(s,2H),4.55( hept,J=6.9Hz,1H),3.75(q,J=7.2Hz,2H),1.44(d,J=6.9Hz,6H),1.17(t,J=7.2Hz,3H).

[0833] Step 55-3: (1-ethyl-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone Preparation of dinitrile

[0834] In the same manner as in Step 1-3 of Example 1 above, 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, 5.7 mg (yield: 15%) of the title compound was obtained.

[0835] 1 H NMR (400MHz, DMSO-d6) δ13.17(s,1H),8.16(d,J=2.2Hz,1H),7.61(d,J=2.2Hz,1H),4.6 5(h, J=7.0Hz, 1H), 3.90 (q, J=7.2Hz, 2H), 1.49 (d, J=6.9Hz, 6H), 1.21 (t, J=7.0Hz, 3H).

[0836] Example 56: Preparation of (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)(methyl)carbonyl dinitrile (Compound 56)

[0837] Under a nitrogen atmosphere, (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile (100 mg, 0.39 mmol) prepared in Example 22 was dissolved in dimethylformamide, potassium tert-butoxide (66 mg, 0.59 mmol) was added thereto at room temperature, and then iodomethane (122 μL, 1.97 mmol) was added thereto. The reaction mixture was stirred at 60°C for 4 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 41 mg (yield: 38%) of the title compound.

[0838] 1 H NMR (400MHz, DMSO-d6) δ7.48–7.15(m,3H), 4.10–3.84(m,3H), 3.35(s,6H).

[0839] Example 57: Preparation of acetyl (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazole-5-yl) carbonyl dinitrile (Compound 57)

[0840] (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonyl dicarbonitrile (150 mg, 0.59 mmol) and KOH (36 mg, 0.65 mmol) prepared in Example 22 were dissolved in methanol, and the solution was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed under reduced pressure and solidified with diethyl ether. The resulting solid (170 mg, 0.58 mmol) and triethylamine (40 μL, 0.29 mmol) were dissolved in acetonitrile, acetyl chloride (103 μL, 1.45 mmol) was added thereto, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, solidified with diethyl ether, and then filtered. The filtrate was further concentrated under reduced pressure and solidified with hexane to obtain 43 mg (yield: 25%) of the title compound.

[0841] 1 H NMR (400 MHz, chloroform-d) δ 7.07 (d, J = 8.5 Hz, 1H), 6.91 (dd, J = 8.2 Hz, 1.7 Hz, 1H), 6.77 (s, 1H), 3.46 (s, 3H), 3.42 (s, 3H), 2.61 (s, 3H).

[0842] [Preparation Example]

[0843] Meanwhile, the novel compound represented by Formula 1 according to the present invention can be formulated into various forms. The following examples exemplarily describe several methods for preparing formulations comprising the compound represented by Formula 1 according to the present invention as an active ingredient, and the present invention is not limited thereto.

[0844] Preparation Example 1: Preparation of tablets by direct compression

[0845] 5.0 mg of each active ingredient prepared in Examples 1-57 was sieved, mixed with 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate, and then compressed into tablets.

[0846] Preparation Example 2: Preparation of tablets by wet granulation

[0847] 5.0 mg of each active ingredient prepared in Examples 1-57 was sieved and mixed with 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg of polysorbate 80 was dissolved in purified water and added to the mixture in an appropriate amount, followed by atomization to obtain 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 into tablets.

[0848] Preparation Example 3: Preparation of powders and capsules

[0849] 5.0 mg of each active ingredient prepared in Examples 1-57 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 size 5 hard gelatin capsules using suitable equipment to prepare capsules.

[0850] Preparation Example 4: Preparation of Injectable Drugs

[0851] 100 mg of each active ingredient prepared in Examples 1-57 was mixed with 180 mg of mannitol, 26 mg of Na2HPO4·12H2O and 2974 mg of distilled water to prepare an injection.

[0852] Experimental Example 1: Selection of tau protein aggregation inhibitory substances using a cell model

[0853] In order to select new tau protein aggregation inhibitors, a tau-BiFC cell model was used, in which the formation of tau oligomers was easily observed in living cells. Tau-BiFC cells were divided equally into 384-well plates. The next day, each compound prepared according to Example 1-57 was treated with 1 μM, 3 μM, and 10 μM of each compound, together with Forskolin (treated at a concentration of 30 μM), which is a compound that induces tau protein aggregation by activating tau phosphorylase PKA. After 48 hours, the nuclei were stained with Hoechst (treated at a concentration of 2 μg / mL), and the BiFC fluorescence intensity was automatically measured using Operetta (PerkinElmer) to count the stained nuclei in each well of the entire well plate. The group treated only with forskolin, which induces tau protein aggregation, was set as a reference point for 100% tau protein aggregation status, and the following formula was used to confirm the effect of the compound: "BiFC fluorescence intensity of the compound synthesized according to an embodiment of the present invention / (fluorescence intensity of the control group treated only with forskolin, which induces tau protein aggregation - fluorescence intensity of the untreated control group) × 100". In addition, the degree of cytotoxicity induced by the newly synthesized compound was also measured, where 100% cell viability of the group treated only with forskolin was used as a reference, and the cytotoxicity value of each compound was calculated using the following formula: "(number of stained cell nuclei in the group treated with the compound / number of stained cell nuclei in the group treated with forskolin) × 100". Based on the treatment results, substances that inhibit intracellular tau protein aggregation were selected from a series of candidate groups that showed a tau protein aggregation inhibition rate of 70% or higher and a cell viability of 100% at a compound treatment concentration of 10 μM or higher.

[0854] Experimental Example 2: Confirmation of the concentration-dependent inhibitory effect of new compounds on tau protein aggregation In order to evaluate the dose-dependent tau protein aggregation inhibitory effect of the compounds selected according to Experimental Example 1 on tau protein aggregation, tau-BiFC cells were treated with the selected compounds at concentrations of 0.03 μM, 0.01 μM, 0.3 μM, 1 μM, 3 μM, 10 μM and 30 μM, and forskolin (treatment concentration of 30 μM, which is a tau protein aggregation-inducing substance). After 48 hours, the tau protein aggregation reaction and the degree of cytotoxicity were analyzed by observing the cell images. The IC of the compound was analyzed by nonlinear regression analysis using prism software (Graph Pad). 50 The calculation results of representative compounds are shown in Table 2 below.

[0855] Table 2

[0856]

[0857]

[0858]

[0859]

[0860] ND: Not determined

[0861] Experimental Example 3: Inhibitory effect of new compounds on CYP coenzyme activity

[0862] The inhibitory effects of the compounds prepared according to Examples 1 to 57 on CYP coenzyme activity were identified. Specifically, human liver microsomes (0.25 mg / mL), 0.1 M phosphate buffer solution (pH 7.4), a drug mixture containing substrates of five drug-metabolizing enzymes (50 μM phenacetin, 10 μM diclofenac, 100 μM S-mephenytoin, 5 μM dextromethorphan, and 2.5 μM midazolam), and the compounds at a concentration of 0 μM or 10 μM were mixed and pre-incubated at 37° C. for 5 minutes. Then, an NADPH generating system solution was added thereto, and the mixture was further incubated at 37° C. for 15 minutes. Afterwards, the reaction was terminated by adding an acetonitrile solution containing an internal standard substance (terfenadine) and centrifuged for 5 minutes (14,000 rpm, 4°C). The supernatant was then injected into an LC-MS / MS system for simultaneous analysis of metabolites of the substrate drug, thereby evaluating the inhibitory effect on drug metabolism.

[0863] The metabolites of each CYP coenzyme indicator drug produced by the reaction were analyzed using a Shimadzu Nexera XR system and a TSQ Vantage (Thermo). A Kinetex C18 (2.1 mm × 100 mm, 2.6 μm particle size; Phenomenex, USA) HPLC column was used, and the mobile phases were (A) distilled water containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid, with the gradient program shown in Table 3 applied thereto.

[0864] Table 3

[0865] Time (min) Flow rate (mL / min) ％A ％B 0 0.3 100 0 1.0 0.3 60 40 4.0 0.3 50 50 4.1 0.3 100 0 7.0 0.3 100 0

[0866] The metabolites produced were quantified using the multiple reaction monitoring (MRM) quantitative mode, and data were analyzed using Xcalibur (version 1.6.1). In order to indicate the inhibitory effect of the novel compounds prepared according to the embodiments of the present invention on CYP coenzyme activity, the CYP coenzyme activity (%) relative to the control group not treated with the compound is shown in Table 4 below.

[0867] Table 4

[0868]

[0869]

[0870]

[0871] Experimental Example 4: Identification of liver microsome stability induced by novel compounds

[0872] The stability of the compounds prepared according to Examples 1-57 on liver microsomes was confirmed. Specifically, four types of liver microsomes (human, dog, rat and mouse, each 0.25 mg / mL), 0.1 M phosphate buffer solution (pH 7.4) and each compound at a concentration of 1 μM were mixed and pre-incubated at 37°C for 5 minutes, and then an NADPH generating system solution was added thereto and further incubated at 37°C for 30 minutes. Thereafter, the reaction was terminated by adding an acetonitrile solution containing an internal standard substance (chloropropamide), and centrifuged for 5 minutes (14,000 rpm, 4°C), and the supernatant was then injected into an LC-MS / MS system for analysis of the substrate drug, thereby evaluating the metabolic stability of the eight compounds.

[0873] The amount of substrate remaining after the reaction was analyzed using a Shimadzu Nexera XR system and a TSQ Vantage (Thermo). A Kinetex XB-C18 HPLC column (2.1 mm × 100 mm, 2.6 μm particle size; Phenomenex, USA) was used, and the mobile phases consisted of (A) distilled water containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid. Data were analyzed using Xcalibur software (version 1.6.3) and Xcalibur (version 1.6.1). The calculated results are shown in Table 5 below.

[0874] Table 5

[0875]

[0876]

[0877]

[0878] The above description of the present invention is provided for illustrative purposes, and those skilled in the art will appreciate that various changes and modifications may be made without changing the technical concepts and basic features of the present invention. It is therefore apparent that the above embodiments are illustrative in all respects and do not limit the present invention. The various embodiments disclosed herein are not limiting, and the true scope and spirit are indicated by the appended claims. The present invention is limited only by the terms of the appended claims and the full scope of equivalents to which such claims are entitled.

Claims

1. A compound represented by the following formula 2 or a pharmaceutically acceptable salt thereof: [Formula 2] in, In the above formula 2, One of Y1 and Y2 is CH, and the other is NR4; Connecting with CH is Connecting with NR4 is R3 is hydrogen or methyl; and R4 is hydrogen, methyl or isopropyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: (1) (1-oxo-1,2-dihydroisoquinolin-7-yl) carbonyl dicarbonitrile, (2) (2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl) carbonyl dicarbonitrile, (3) (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-7-yl) carbonyl dicarbonitrile, (4) (1-oxo-1,2-dihydroisoquinolin-5-yl) carbonyl dicarbonitrile, (5) (2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl) carbonyl dicarbonitrile, (6) (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-5-yl) carbonyl dicarbonitrile, (7) (2,3-dimethyl-1-oxo-1,2-dihydroisoquinolin-5-yl) carbonyl dicarbonitrile, (8) (2-oxo-1,2-dihydroquinolin-6-yl) carbonyl dicarbonitrile, (25) (1-methyl-2-oxo-1,2-dihydroquinolin-6-yl) carbonyl dicarbonitrile, (26) (4-methyl-2-oxo-1,2-dihydroquinolin-6-yl) carbonyl dicarbonitrile, (27) (1,4-Dimethyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonyl dicarbonitrile.

3. A method for preparing the compound according to any one of claims 1 to 2, comprising: A step of reacting a compound having a reactive amine group at one end represented by the following Formula 5 with sodium nitrite and malononitrile in the presence of an acid to form an imine bond: [Formula 5] Among them, in the above formula 5, X1 to X3 are C(H); One of Y1 and Y2 is CH, and the other is NR4; Connecting with CH is Connecting with NR4 is n is 1; R2 is hydrogen; R3 is hydrogen or methyl; R4 is hydrogen, methyl or isopropyl; and When Y1 or Y2 is N(H), N(H) is protected by tert-butoxycarbonyl.

4. The method according to claim 3, wherein when the N(H) of Y1 or Y2 is protected by a tert-butoxycarbonyl group, the method further comprises a deprotection step after the reaction.

5. The method according to claim 3, wherein the first step is performed by a series of processes, comprising the following steps: 1-1) Dissolve the compound of formula 5 and sodium nitrite in C 1-4 a lower alcohol solvent, and adding an aqueous acid solution thereto at a temperature of -5°C to 5°C to form a diazonium salt, 1-2) adding malononitrile to the reaction solution containing the diazonium salt obtained in step 1-1) and reacting at a temperature of 15° C. to 40° C., and 1-3) An aqueous base solution is added to the reaction solution of step 1-2) to neutralize the reaction solution.

6. The method according to claim 3, wherein the compound of formula 5 is prepared from a compound represented by formula 5-a: [Formula 5-a] 7. The method according to claim 6, further comprising the steps of: Prior to the first step, the nitro group of the compound represented by Formula 5-a is reduced to an amine group.

8. The method according to claim 7, wherein the compound represented by the above formula 5-a is prepared by reacting a precursor of the compound, wherein one of Y1 and Y2 is CH and the other is O, with an amino compound NH2R4 in a state dissolved in an organic solvent to replace the O position with NR4.

9. The method according to claim 8, wherein the precursor of the compound represented by the above formula 5-a, wherein one of Y1 and Y2 is CH and the other is O, is optionally prepared by the following steps: cyclization between a nitrobenzoic acid derivative and N,N-dimethylformamide dimethyl acetal or acetal acetone. 10 . A composition for inhibiting tau protein aggregation, comprising the compound of claim 1 as an active ingredient.

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

12. A pharmaceutical composition for preventing or treating diseases caused by tau protein aggregation or hyperphosphorylation, comprising the compound of claim 1 as an active ingredient.

13. The pharmaceutical composition of claim 12, wherein the disease caused by tau protein aggregation or hyperphosphorylation is selected from the group consisting of Alzheimer's disease, Parkinson's disease, vascular dementia, acute stroke, trauma, cerebrovascular disease, peripheral neuropathy, retinopathy and glaucoma. The pharmaceutical composition according to claim 13 , wherein the trauma is cerebrospinal trauma or spinal cord trauma.

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

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