RU2826002C1 - Novel compounds of condensed heterocyclyl-carbohydrazonoyl dicyanides and use thereof - Google Patents

Abstract

FIELD: chemistry; pharmaceutics.

SUBSTANCE: group of inventions relates to pharmaceutical chemistry and includes derivatives of condensed heterocyclyl-carbohydrazonoyl dicyanides of formula 1, pharmaceutically acceptable salts thereof, method of producing said compounds and pharmaceutical compositions based on said compounds. In formula 1, X₁ - X₃ each independently represents N or C(H); Y₁ and Y₂ each independently represents N(R₄), C(H), O or S, and at least one of Y₁ and Y₂ is N (R₄); n is 0 or 1; is or to form an aromatic or non-aromatic fused heterocyclic ring; R₁ is hydrogen, C_1-6 alkyl or C_1-6 alkylcarbonyl; R₂ and R₃ each independently represents hydrogen, C_1-6alkyl, halogen or C_1-6 alkoxy; and R₄ is hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_3-6 cycloalkyl-C_0-6 alkyl or C_6-10 aryl.

EFFECT: compounds of formula 1, which inhibit tau protein aggregation.

20 cl, 5 tbl, 65 ex

Description

Field of technology

The present invention relates to new condensed heterocyclyl carbonohydrazonoyl dicyanide compounds and their use.

Prior art

Tau protein (tau (τ) protein), a microtubule-associated protein (MAP) primarily expressed in axons of nerve cells with a molecular weight of 50,000 to 70,000, serves to stabilize microtubules and exhibits molecular diversity through phosphorylation. In humans, tau protein is formed into six isoforms by insertion of 29 or 58 amino acid residues at the N-terminus and alternative splicing of mRNA from 3 or 4 repeating structures (called the microtubule-binding domain) at the C-terminus.

In healthy nerves, tau protein stabilizes microtubules, promoting axon growth and nerve cell polarization. When pathologically hyperphosphorylated, tau protein dissociates from microtubules, resulting in insoluble aggregation. Furthermore, a structural backbone inducing tau protein aggregation has been proposed, and evidence has been presented that insoluble filaments are formed from 10 soluble monomers and that these filaments are bundled into high-dimensional structures called neurofibrillary tangles (NFTs). Full-length human tau protein contains a microtubule-binding domain consisting of four repeating conserved sequences. Among these repeating sequences, positively charged residues play an important role in binding to highly negatively charged microtubules (20 to 30 electrons per αβ-tubulin dimer). Tau microtubule binding affinity is also actively regulated by tau phosphorylation, and this phosphorylation causes dynamic rearrangement of microtubule networks. When tau is abnormally overphosphorylated, the balance of this dynamic rearrangement is disrupted and affinity for microtubules rapidly declines.

Hyperphosphorylation and/or aggregation of tau proteins cause abnormal accumulation of these tau proteins in nerve cells, which is indicated as a cause of various neurodegenerative diseases, etc. Tau protein aggregates are mainly found in the cell bodies and dendrites of nerve cells, and these tau protein aggregates are called neurofibrillary tangles (NFTs) and neuropil threads. Study of the microstructures of neurofibrillary tangles (NFTs) shows that such microstructures consist of paired helical filaments (NFTs), in which tau proteins are entangled in the form of thin threads, aggregated and hyperphosphorylated, unlike normal tau protein. The phenomenon of abnormal tau protein aggregation also manifests itself in tauopathy. In this case, although the exact role of tau protein aggregation in the development of tauopathy is not known, this tau protein aggregation phenomenon appears to be similar to the aggregation phenomenon characteristic of common neurodegenerative diseases.

Thus, although hyperphosphorylation and/or aggregation of tau protein is known to cause various neurodegenerative diseases including Alzheimer's disease and tauopathy, the specific mechanism by which these abnormal tau types cause changes in the signaling pathway and induce neurotoxicity has not yet been confirmed, and there are no effective treatments or therapeutic agents for these diseases.

Disclosure of invention

Technical task

As a result of intensive efforts to develop new small molecule compounds capable of inhibiting the aggregation and/or hyperphosphorylation of tau protein, the present inventors have found that a series of new fused heterocyclyl carbohydrazonoyl dicyanide compounds effectively inhibit tau protein aggregation without exhibiting cytotoxicity at effective concentrations, thereby completing the present invention.

Technical solution

The object of the present invention is to provide a compound represented by formula 1 below or a pharmaceutically acceptable salt thereof:

[Formula 1]

in formula 1 above:

X ₁ - X ₃ each independently represents N or C(H);

Y ₁ and Y ₂ each independently represent N(R ₄ ), C(H), O or S;

n is 0 or 1;

represents or with the formation of an aromatic or non-aromatic condensed heterocyclic ring;

R ₁ is hydrogen, C _1-6 alkyl or C _1-6 alkylcarbonyl;

R ₂ and R ₃ are each independently hydrogen, C _1-6 alkyl, halogen, cyano, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, di(C _1-6 alkyl)amino, C _1-6 alkylaminocarbonyl, or di(C _1-6 alkyl)aminocarbonyl; and

R ₄ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl-C _0-6 alkyl, 5- or 6-membered heterocycle-C _0-6 alkyl, C _6-10 aryl or 5-10-membered heteroaryl,

wherein said 5- or 6-membered heterocycle, C _1-10 aryl and 5-10-membered heteroaryl are unsubstituted or substituted with C _1-6 alkoxy or C _1-6 alkoxycarbonyl.

Another object of the present invention is to provide a method for producing the compound described above.

Another object of the present invention is to provide a composition for inhibiting tau protein aggregation comprising the compound described above as an active ingredient.

Another object of the present invention is to provide a composition for inhibiting hyperphosphorylation of tau protein, comprising the compound described above as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease caused by aggregation or hyperphosphorylation of tau protein, comprising the compound described above as an active ingredient.

Another object of the present invention is to provide a method for preventing or treating a disease caused by aggregation or hyperphosphorylation of tau protein, comprising administering to a subject in need thereof the pharmaceutical composition described above.

Beneficial effects

The novel fused heterocyclyl carbonohydrazonoyl dicyanide compounds of the present invention can effectively inhibit the aggregation and/or hyperphosphorylation of tau protein and thus can be effectively used for the prevention or treatment of diseases caused thereby, such as Alzheimer's disease and various tauopathies.

The best mode of carrying out the invention

In a first aspect of the present invention there is provided a compound represented by formula 1 below, or a pharmaceutically acceptable salt thereof:

[Formula 1]

in formula 1 above:

X ₁ - X ₃ each independently represents N or C(H);

Y ₁ and Y ₂ each independently represent N(R ₄ ), C(H), O or S;

n is 0 or 1;

represents or with the formation of an aromatic or non-aromatic condensed heterocyclic ring;

R ₁ is hydrogen, C _1-6 alkyl or C _1-6 alkylcarbonyl;

R ₂ and R ₃ are each independently hydrogen, C _1-6 alkyl, halogen, cyano, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, di(C _1-6 alkyl)amino, C _1-6 alkylaminocarbonyl, or di(C _1-6 alkyl)aminocarbonyl; and

R ₄ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy-C _0-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl-C _0-6 alkyl, 5- or 6-membered heterocycle-C _0-6 alkyl, C _6-60 aryl or 5-10-membered heteroaryl,

wherein said 5- or 6-membered heterocycle, C _6-10 aryl and 5-10-membered heteroaryl are unsubstituted or substituted with C _1-6 alkoxy or C _1-6 alkoxycarbonyl.

For example, in the compound of the present invention:

R ₁ is hydrogen, C _1-6 alkyl or C _1-6 alkylcarbonyl;

R ₂ is hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

R ₃ is hydrogen or C _1-6 alkyl; and

R ₄ is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl-C _0-6 alkyl, or C _1-10 aryl, without limitation.

In particular, in the compound of the present invention:

R ₁ is hydrogen, methyl or acetyl;

R ₂ represents hydrogen, chlorine, fluorine, methyl or methoxy;

R ₃ is hydrogen or methyl; and

R ₄ is hydrogen, methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl or phenyl, but is not limited thereto.

For example, the compound of the present invention may be a compound represented by formula 2 below:

[Formula 2]

in formula 2 above:

one of Y ₁ and Y ₂ is CH and the other is NR ₄ ;

when connected with SN it represents A when associated with NR ₄ it represents

R ₃ is hydrogen or methyl; and

R ₄ is hydrogen, methyl or isopropyl.

Alternatively, the compound of the present invention may be a compound represented by formula 3 below:

[Formula 3]

in formula 3 above:

X ₃ represents C(H) or N;

R ₁ is hydrogen, methyl or acetyl;

R ₂ is hydrogen, chlorine, fluorine, methyl or methoxy; and

R _4' and R _4'' each independently represent hydrogen, methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl or phenyl.

In addition, the compound of the present invention may be a compound represented by formula 4 below:

[Formula 4]

in formula 4 above:

Y ₁ represents S or O; and

R ₄ is hydrogen, methyl, isopropyl or difluoromethyl.

More specifically, the compound represented by formula 1 may be

by yourself:

1) (1-oxo-1,2-dihydroisoquinolin-7-yl)carbonohydrazonoyl dicyanide,

2) (2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbonohydrazonoyl dicyanide,

3) (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbonohydrazonoyl dicyanide,

4) (1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide,

5) (2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide,

6) (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide,

7) (2,3-dimethyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide,

8) (2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide,

9) (6-fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carboxylic acid,

10) (6-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carboxymethyl cyanide,

11) (7-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carboxylic acid,

12) (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide,

13) (2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

14) (3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

15) (2-oxo-2,3-dihydrobenzo[d|oxazol-6-yl)carbonohydrazonoyl dicyanide,

16) (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide,

17) (1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide,

18) (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

19) (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

20) (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide,

21) (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide,

22) (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide,

23) (1,3-Diisopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide,

24) (1,3-bis(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide,

25) (1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide,

26) (4-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide,

27) (1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl icyanide,

28) (3-methyl-2-oxo-2,3-Dihydrobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide,

29) (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide,

30) (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide,

31) (1,3,6-trimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide,

32) (6-methoxy-1,3-Dimethyl-2-oxo-2,3-Dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide,

33) (7-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide,

34) (1,3-Diisopropyl-2-oxo-2,3-Dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide,

35) (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide,

36) (3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide,

37) (3-(difluoromethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide,

38) (1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d|imidazol-5-yl)carbonohydrazonoyl dicyanide,

39) (3-(difluoromethyl)-1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide,

40) (1-cyclopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide,

41) (1-cyclopropyl-3-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide,

42) (1-cyclopropyl-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide,

43) (3-(difluoromethyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide,

44) (1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carboxylic acid,

45) (1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide,

46) (1-(difluoromethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide,

47) (3-methyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide,

48) (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide,

49) (3-ethyl-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide,

50) (1-(difluoromethyl)-3-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide,

51) (3-cyutopropyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide,

52) (3-cyclopropyl-1-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide,

53) (3-cyclopropyl-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6 -yl)carbonohydrazonoyl dicyanide,

54) (3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide,

55) (1-ethyl-3-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide,

56) (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)(methyl)carbonohydrazonoyl dicyanide or

57) acetyl (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, without limitation.

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

In this case, the compounds of the present invention may exist in the form of a pharmaceutically acceptable salt. As a salt, an acid salt formed by a pharmaceutically acceptable free acid is useful. The term "pharmaceutically acceptable salt" used herein refers to any organic or inorganic acid addition salt of the compounds represented by formulas 1-4, which is relatively non-toxic and harmless to patients, and the side effects caused by this salt do not worsen the beneficial effects of this compound.

An acid addition salt is prepared in a conventional manner, for example by dissolving the compound in an excess of an aqueous acid solution and precipitating this solution using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and the acid or alcohol (e.g. glycol monoethyl ether) in water are heated and then the mixture is evaporated and dried, or the precipitated salt is filtered by suction.

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

In addition, a pharmaceutically acceptable metal salt can be obtained using a base. An alkali metal salt or an alkaline earth metal salt is obtained by dissolving a compound in an excess amount of an alkali metal hydroxide solution or an alkaline earth metal hydroxide, filtering off the insoluble salt of the compound, and then evaporating and drying the filtrate. In this case, obtaining a sodium, potassium or calcium salt as a metal salt is suitable for pharmaceutical use, but the present invention is not limited thereto. In addition, a corresponding silver salt can be obtained by reacting an alkali metal salt or an alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compounds of formulas 1-4, unless otherwise indicated. 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, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and para-toluenesulfonate (tosylate). These pharmaceutically acceptable salts can be prepared by methods for preparing salts known in the art.

As salts of the compounds of formulas 1-4 of the present invention, any salt can be used without limitation as a pharmaceutically acceptable salt, provided that it exhibits a pharmacological activity equivalent to the compounds of formulas 1-4, for example, it inhibits the aggregation and/or hyperphosphorylation of tau protein.

In addition, the compounds represented by formulas 1-4 of the present invention include, without limitation, their pharmaceutically acceptable salts, as well as solvates, such as possible hydrates, which can be obtained from them, and all possible stereoisomers. Solvates and stereoisomers of the compounds represented by formulas 1-4 can be obtained from the compounds represented by formulas 1-4 using any method known in the art.

Moreover, the compounds represented by formulas 1-4 of the present invention can be obtained in crystalline or amorphous form, and can be optionally hydrated or solvated if obtained in crystalline form. The present invention can provide compounds containing various amounts of water, as well as stoichiometric hydrates of the compounds represented by formulas 1-4. Solvates of the compounds represented by formulas 1-4 of the present invention include both stoichiometric solvates and non-stoichiometric solvates.

In a second aspect of the present invention, a method for preparing a compound of formula 1 is provided.

For example, a compound of the present invention can be prepared by a method comprising:

a first step of reacting a compound represented by formula 5 below, comprising a reactive amino group at one end, with sodium nitrite and malononitrile in the presence of an acid to form an imine bond; and

possibly a second step of introducing a substituent Ri into the product obtained in the previous step, when Ri is a substituent other than hydrogen:

[Formula 5]

in formula 5 above:

X ₁ - X ₃ , Y ₁ , Y ₂ , n, R ₂ and R ₃ are as defined above, and

when Y ₁ and Y ₂ are N(H), then N(H) can be protected by tert-butoxycarbonyl.

In this regard, when N(H) in Y ₁ and Y ₂ is protected with tert-butoxycarbonyl, said method may further include a deprotection step after the reaction.

In particular, the first stage of the method can be performed as a series of processes, including the stages:

1-1) dissolving the compound of formula 5 and sodium nitrite in a solvent C _1-4 lower alcohol and adding to it an aqueous solution of acid at a temperature from -5°C to 5°C to form a diazonium salt,

1-2) adding malononitrile to the reaction solution comprising the diazonium salt obtained in step 1-1), and carrying out the reaction at a temperature of 15°C to 40°C, and

1-3) neutralization of the reaction solution from step 1-2) by adding to it an aqueous solution of a base, without limitation thereto.

For example, the first step may be carried out by performing the reaction of step 1-1) at a low temperature of about 0°C for 2 minutes to 1 hour using a 1 M hydrochloric acid solution, and then performing the reaction of step 1-2) at room temperature for 2 minutes to 1 hour, without being limited thereto.

For example, the second step can be carried out by reacting the carbonohydrazonoyl dicyanide compound obtained in the previous step in which R ₁ is not substituted with a halogenated derivative of R ₁ in an organic solvent. In particular, when R ₁ is C _1-6 alkyl, the second step can be carried out by dissolving the carbonohydrazonoyl dicyanide compound obtained in the previous step in which R ₁ is not substituted in an organic solvent such as DMF and adding a haloalkane such as an alkane iodide corresponding to R ₁ to the reaction solution and carrying out the reaction at a temperature of 50°C to 70°C, wherein the reaction solution may further include potassium tert-butoxide. However, the present invention is not limited thereto. In particular, when R ₁ is C _1-6 alkylcarbonyl, the second step can be carried out by dissolving the carbonohydrazonoyl dicyanide of the compound obtained in the previous step in which R ₁ is not substituted 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 this product with a halogenated alkylcarbonyl such as acetyl chloride corresponding to the C _1-6 alkylcarbonyl in an organic solvent such as acetonitrile in the presence of triethylamine. However, the present invention is not limited to this.

For example, the compound of formula 5 used in the preparation of the compound of the present invention can be prepared from a compound represented by one of formulas 5-a to 5-c below:

[Formula 5-a]

In formula 5-b, each of the two R ₄ may be selected from the variety of substituents defined above, and both R ₄ may be the same, or one R 4 may be different from the other R ₄ .

In particular, the method of the present invention may further comprise, before the first step, a step of reducing the nitro group of the compound represented by one of the formulae 5-a to 5-c to an amino group.

For example, the reduction can be carried out by reaction in an organic solvent such as 1,4-dioxane or methanol in the presence of a Pd/C catalyst, by reaction with AcOH in the presence of Fe, or by reaction with ammonium chloride in the presence of Fe, without being limited thereto.

Specifically, the compound represented by the formula 5-a can be produced by reacting its precursor in which one of Y ₁ and Y ₂ is CH and the other is O with an amine-based compound NH ₂ R ₄ in a state of dissolution in an organic solvent so as to replace the O site with an NR4 group, but the compound is not limited thereto. For example, the reaction can be carried out by stirring the precursor and ammonia or a Bd-substituted amine in an organic solvent such as THF or methanol at a temperature of 70°C to 130°C for 30 minutes to 5 hours, but is not limited thereto. In this regard, a microwave oven can be used for stirring, but is not limited thereto.

In addition, a precursor of the compound represented by the above formula 5-a, in which one of Y ₁ and Y ₂ is CH and the other is O, can be obtained, optionally, by cyclization between a nitrobenzoic acid derivative and N,N-dimethylformamide dimethyl acetal or acetone acetal, but not limited thereto. For example, the cyclization can be carried out by reaction with N,N-dimethylformamide dimethyl acetal in a DMF solvent or reaction with acetone acetal in tert-butyl alcohol 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 with stirring, but not limited thereto. In this regard, a microwave oven can be used for stirring, but not limited thereto.

In particular, in the method of the present invention, the compound represented by the formula 5-b or 5-c above can be obtained, optionally, by further carrying out the step of introducing the substituent R ₄ by reaction with a precursor of the compound including R ₄ and a reactive halide. For example, the reaction with DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and R ₄ -halide or R ₄ -sodium haloacetate can be carried out in a DMF solvent under stirring at room temperature for 6 to 24 hours, but is not limited thereto.

In addition, in the method of the present invention, the compound represented by the formula 5-b above can be obtained by cyclization between unsubstituted or R ₂ -substituted 1,2-diaminnitrophenyl and carbonyldiimidazole (CDI). For example, the reaction can be carried out using a DMF solvent at room temperature for 6 to 24 hours, without being limited thereto.

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

In addition, if necessary, the method may further include processes for isolating and/or purifying the product after each reaction, and these processes can be carried out using various methods well known in the art.

A third aspect of the present invention is to provide a composition for inhibiting tau protein aggregation comprising the compound of the present invention as an active ingredient.

A fourth aspect of the present invention is to provide a composition for inhibiting tau protein hyperphosphorylation comprising a compound of the present invention as an active ingredient.

The fifth aspect of the present invention is to provide a pharmaceutical composition for preventing or treating a disease caused by aggregation or hyperphosphorylation of tau protein, comprising the compound of the present invention as an active ingredient.

A sixth aspect of the present invention is to provide a method for preventing or treating a disease caused by aggregation or hyperphosphorylation of tau protein, comprising administering a compound of the present invention to a subject in need thereof.

In specific embodiments of the present invention, a total of 57 compounds numbered from 1 to 57 and represented by formula 1 were newly synthesized and their effect on inhibiting the aggregation and hyperphosphorylation of tau protein was confirmed. Moreover, to confirm the possibility of use as a pharmaceutical composition, it was confirmed that these compounds do not exhibit cytotoxicity.

As used herein, the term "prevention" refers to any action that inhibits or delays the onset, spread, and recurrence of a disease caused by tau protein aggregation or hyperphosphorylation upon administration of the pharmaceutical composition of the present invention, and the term "treatment" refers to any action in which the symptoms of a disease are improved or beneficially modified upon administration of the pharmaceutical composition of the present invention.

As described above, since the compound of the present invention not only inhibits the aggregation or hyperphosphorylation of tau protein but also does not exhibit toxicity to cells, a pharmaceutical composition containing this compound as an active ingredient can be used for the prevention or treatment of diseases caused by the aggregation or hyperphosphorylation of tau protein. The disease caused by the aggregation or hyperphosphorylation of tau protein for which the pharmaceutical composition of the present invention can be used for the treatment can be Alzheimer's disease, Parkinson's disease, vascular dementia, acute stroke, trauma, cerebrovascular disease, brain injury, spinal cord injury, peripheral neuropathy, retinopathy, glaucoma or tauopathy. Non-limiting examples of tauopathies may include chronic traumatic encephalopathy (CTE), primary age-related tauopathy, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, argyrophilic grain disease (AGD), frontotemporal dementia (FTD), chromosome 17-linked parkinsonism, lytico-bodig disease (Guam complex parkinsonism-dementia), ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, pantothenate kinase-associated neurodegeneration, lipofuscinosis, posttraumatic stress disorder, and traumatic brain injury.

For example, the composition of the present invention may further comprise a pharmaceutically acceptable carrier, diluent or excipient, can be manufactured and used in various forms such as oral forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, and injection preparations in the form of sterile injection solutions according to the general method for each purpose of use, and can be administered orally or can be administered by various routes including intravenous, intraperitoneal, subcutaneous, rectal and local administration. Examples of a suitable carrier, excipient or diluent included in this composition may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil. The composition of the present invention may further include a filler, an antiplatelet agent, a lubricant, a humectant, a flavoring agent, an emulsifier, a preservative and the like.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such a solid preparation is prepared by mixing one or more excipients such as starch, calcium carbonate, sucrose, lactose and gelatin with the composition. In this case, in addition to a simple excipient, a lubricant such as magnesium stearate or talc can be used.

As an example of the oral liquid preparation, a suspension, an internal solution, an emulsion, a syrup and the like can be given, and the oral liquid preparation may include various excipients such as a humectant, a sweetener, a flavoring agent and a preservative, in addition to water and liquid paraffin, which are usually used as a simple diluent.

The parenteral preparations include an aqueous solvent, a non-aqueous solvent, a suspending agent, an emulsifier, a lyophilized preparation, and a suppository which are sterilized. As the non-aqueous solvent or suspending agent, propylene glycol, polyethylene glycol, a vegetable oil such as olive oil, an injectable ester such as ethyl oleate, or the like can be used. As the suppository base, witepsol, macrogol, tween 61, cocoa butter, lauric oil, glycerogelatin, etc. can be used. Meanwhile, the injection preparations can include conventional additives such as a solubilizing agent, an isotonic agent, a suspending agent, an emulsifier, a stabilizer, and a preservative.

The composition can be prepared by a conventional mixing, granulating or coating method and can contain the active ingredient in an amount of from about 0.1 to 75% by weight, preferably from about 0.1% to 50% by weight. A standard composition for a mammal weighing from 50 to 70 kg contains from 10 to 200 mg of the active ingredient.

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

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

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

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

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

The term "administration" as used herein refers to providing a predetermined substance to a patient by any suitable route, and the route of administration of the composition of the present invention may be any general route, as long as the substance is capable of reaching the target tissue. The composition may 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 may be administered by any device capable of delivering the active substance to the target cell. Preferred routes of administration and compositions include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections and drip injections of drugs. Injectable preparations may be prepared using an aqueous solvent such as saline or Ringer's solution, or a non-aqueous solvent such as vegetable oil, a higher fatty acid ester (e.g., ethyl oleate), or an alcohol (e.g., ethanol, benzyl alcohol, propylene glycol, or glycerol), and may include a pharmaceutical carrier such as a stabilizing agent to prevent denaturation (e.g., ascorbic acid, sodium hydrogen sulfite, sodium metabisulfite, BHA, tocopherol, or EDTA), an emulsifier, a buffering agent to control pH, or a preservative to inhibit the growth of microorganisms (e.g., phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, or benzyl alcohol).

Implementation of the invention

Hereinafter, the present invention will be described in more detail with reference to examples and experimental examples. However, these examples and experimental examples are only an illustration of the present invention, and the scope of the present invention is not limited to these examples and experimental examples.

Example 1: Preparation of (1-oxo-1,2-dihydroisoquinolin-7-yl)carbonohydrazonoyl dicyanide (Compound 1)

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

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, and the reaction mixture was stirred at 80 °C for 2 hours in a microwave oven. After completion of the reaction, the reaction product was solidified using distilled water and filtered to obtain 73 mg (yield: 56%) of the title compound.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.76 (s, 1H), 8.90 (d, J=2.5 Hz, 1H), 8.44 (dd, J=8.8 Hz, 2.5 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.46 (d, J=7.1 Hz, 1H), 6.73 (d, J=7.1 Hz, 1H).

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

7-Nitroisoquinolin-1(2H)-one (70 mg, 0.37 mmol) obtained in Step 1-1 was dissolved in 10% Pd/C (78 mg, 0.07 mmol) and 1,4-dioxane, and the reaction mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.82 (s, 1H), 7.40-7.20 (m, 2H), 6.97 (dd, J=8.4 Hz, 2.5 Hz, 1H), 6.80 ( dd, J=7.0 Hz, 5.5 Hz, 1H), 6.34 (d, J=7.0 Hz, 1H), 5.47 (s, 2H).

Step 1-3: Preparation of (1-oxo-1,2-dihydroisoquinolin-7-yl)carbohydrazonoyl dianilide

7-Aminoisoquinolin-1(2H)-one (20 mg, 0.12 mmol) obtained in Step 1-2 and sodium nitrite (13 mg, 0.19 mmol) were dissolved in ethanol under a nitrogen atmosphere, 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 min to form a diazonium salt. Malononitrile (16 mg, 0.25 mmol) was added to the reaction mixture including the diazonium salt, and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was adjusted to pH 6.0 using aqueous sodium hydroxide solution and then further stirred at room temperature for 1 hour. After completion of the reaction, the reaction product was extracted using distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude substance was purified by column chromatography to obtain 20 mg (yield: 67%) of the title compound.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.22 (s, 1H), 11.33 (d, J=5.7 Hz, 1H), 8.24 (d,J=2.4 Hz, 1H), 7.81 ( dd, J=8.7 Hz, 2.4 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.16 (dd, J=7.1 Hz, 5.8 Hz, 1H), 6.56(d, J=7.0 Hz, 1H).

Example 2: Preparation of (2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbonohydrazonoyl dicyanide (Compound 2)

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

2-Methyl-5-nitrobenzoic acid (500 mg, 2.76 mmol) was dissolved in dimethylformamide (DMF, 10 ml), and 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 completion of the reaction, the reaction product was extracted using distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude substance was purified by column chromatography to obtain 65 mg (yield: 12%) of the title compound.

¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

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

1.0 M methylamine (10.5 ml, 20.93 mmol) was added to 7-nitro-1H-isochromen-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 completion of the reaction, the reaction product was extracted using distilled water and dichloromethane to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude substance was purified by column chromatography to obtain 126 mg (yield: 59%) of the title compound.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (d, J=2.5 Hz, 1H), 8.43 (dd, J=8.8 Hz, 2.5 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.75 (d, J=7.3 Hz, 1H), 6.78 (d, J=7.3 Hz, 1H), 3.55 (s, 3H).

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

49 mg (yield: 57%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.36-7.29 (m, 2H), 7.08 (d, J=7.2 Hz, 1H), 6.97 (dd, J=8.4 Hz, 2.5 Hz, 1H), 6.40 (d, J=7.2 Hz, 1H), 5.51 (s, 2H), 3.44 (s, 3H).

Step 2-4: Preparation of (2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbohydrazonoyl dicyanide

49 mg (yield: 85%) of the title compound was obtained in the same manner as in Step 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.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 13.25 (s, 1H), 8.28 (d,J=2.4 Hz, 1H), 7.81 (dd, J=8.7 Hz, 2.4 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.46 (d, J=7.3 Hz, 1H), 6.63 (d, J=7.3 Hz, 1H), 3.52 (s, 3H ).

Example 3: Preparation of (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbonohydrazonoyl dicyanide (Compound 3)

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

Isopropylamine (0.27 ml, 3.14 mmol) and methanol (3 ml) were added to 7-nitro-1H-isochromen-1-one (30 mg, 0.16 mmol) obtained in Step 2-1 of Example 2 above, and the reaction mixture was stirred at 80°C for 12 hours in a microwave oven. After completion of the reaction, the reaction product was extracted using distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and solidified using ether and hexane, and filtered to obtain 20 mg (yield: 54%) of the title compound.

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).

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

54 mg (yield: 89%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

Step 3-3: Preparation of (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbohydrazonoyl dicyanide

30 mg (yield: 72%) of the title compound was obtained in the same manner as in Step 1-3 of Example 1 above, except that 7-amino-2-isopropylisoquinolin-1(2H)-one (30 mg, 0.15 mmol) obtained in Step 3-2 above was used instead of 7-aminoisoquinolin-1(2H)-one.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.25 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 7.81 (dd, J=8.7 Hz, 2.3 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 6.69 (d, J=7.5 Hz, 1H), 5.19 (p, J =6.8 Hz, 1H), 1.33 (d, J=6.8 Hz, 6H).

Example 4: Preparation of (1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide (Compound 4)

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

88 mg (yield: 42%) of the title compound 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.

^1H 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.l Hz, 1H), 7.38 (d, J=6.0 Hz, 1H).

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

45 mg (yield: 45%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.75 (s, 1H), 8.58 (d, J=8.0 Hz, 1H), 8.46 (dd, J=7.9 Hz, 1.4 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 6.97 (d, J=7.6 Hz, 1H).

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

18 mg (yield: 42%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.05 (s, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H), 7.02 ( dd, J=7.4 Hz, 4.8 Hz, 1H), 6.86 (dd, J=7.7 Hz, 1.2 Hz, 1H), 6.67 (d, J=7.4 Hz, 1H), 5.61 (s, 2H).

Step 4-4: Preparation of (1-oxo-1,2-dihydroisoquinolin-5-yl)carbohydrazonoyl dicyanide

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.42 (s, 1H), 8.10 (d, J=7.9 Hz, 1H), 7.69 (dd, J=7.8 Hz, 1.3 Hz, 1H), 7.50 (t, J=7.9 Hz, 1H), 7.27 (dd, J=7.3 Hz, 5.8 Hz, 1H), 6.82 (d, J=7.4 Hz, 1H).

Example 5: Preparation of (2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide (Compound 5)

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

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (d, J=7.9 Hz, 1H), 8.47 (dd, J=7.9 Hz, 1.3 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.03 (dd, J=7.7 Hz, 0.8 Hz, 1H), 3.55 (s, 3H).

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

30 mg (yield: 69%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.42 (d, J=7.9 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 6.84 (dd, J=7.8 Hz, 1.2 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 5.64 (s, 2H), 3.46 (s, 3H ).

Step 5-3: Preparation of (2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbohydrazonoyl dicyanide

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

¹ H NMR (400 MHz, Chloroform-d ₆ ) δ9.87 (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).

Example 6: Preparation of (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide (Compound 6)

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

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

¹ H NMR (400 MHz, Chloroform-d ₆ ) 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).

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

34 mg (yield: 99%) of the title compound was obtained 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.

^1H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J=8.l Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.13 (d, J=7.7 Hz , 1H), 6.94 (dd, J=7.6 Hz, 1.2 Hz, 1H), 6.55-6.42 (m, 1H), 5.40 (p, J=6.9 Hz, 1H), 3.95 (s, 2H), 1.38 (d, J=6.9 Hz, 6H).

Step 6-3: Preparation of (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbohydrazonoyl dicyanide

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.14 (d, J=8.0 Hz, 1H), 7.72-7.58 (m, 2H), 7.51 (t, J=7.9 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 5.18 (p, J=6.8 Hz, 1H), 1.34 (d, J=6.8 Hz, 6H).

Example 7: Preparation of (2,3-dimethyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide (Compound 7)

Step 7-1: Preparation of 3-methyl-5-nitro-1H-isochromen-1-one

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

^1H NMR (400 MHz, Chloroform-d ₆ ) 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).

Step 7-2: Preparation of 2,3-Dimethyl-5-nitroisoquinolin-1(2H)-one

56 mg (yield: 88%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.26 (d, J=7.8 Hz, 1H), 8.18 (d, J=8.2 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 6.23 (d, J=1.0 Hz, 1H), 3.02 (s, 3H), 1.46 (s, 3H).

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

13 mg (yield: 29%) of the title compound was obtained 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(2)-one.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.38 (d, J=7.9 Hz, 1H), 7.08 (t, J=7.8 Hz, 1H), 6.81 (dd, J=7.7 Hz, 1.2 Hz, 1H), 6.64 (s, 1H), 5.51 (s, 2H), 3.48 (s, 3H), 2.39 (d, J=1.0 Hz, 3H).

Step 7-4: Preparation of (2,3-dimethyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbohydrazonoyl dicyanide

13 mg (yield: 92%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.11 (d, J=8.0 Hz, 1H), 7.65 (dd, J=7.8 Hz, 1.3 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 6.78 (s, 1H), 3.54 (s, 3H), 2.47 (s, 3H).

Example 8: Preparation of (2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide (Compound 8)

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

34 mg (yield: 13%) of the title compound 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.36 (s, 1H), 7.66 (d, J=9.5 Hz, 1H), 7.02 (s, 1H), 6.83 (dd, J=8.7 Hz, 2.5 Hz, 1H), 6.71 (d, J=2.5 Hz, 1H), 6.36 (d, J=9.5 Hz, 1H), 4.98 (s, 2H).

Step 8-2: Preparation of (2-oxo-1,2-dihydroisoquinolin-6-yl)carbohydrazonoyl dicyanide

17 mg (yield: 59%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.13 (s, 1H, 11.87 (s, 1H), 7.97 (d, J=9.6 Hz, 1H), 7.74 (s, 1H), 7.66 (dd , J=8.9 Hz, 2.4 Hz, 1H), 7.34 (d, J=8.9 Hz, 1H), 6.55 (d, J=9.6 Hz, 1H).

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

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

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 under nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction product was extracted using distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude substance was purified by column chromatography to give 512 mg (yield: 89%) of the title compound.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 10.38 (s, 1H), 10.08 (s, 1H), 7.75 (d, J=6.4 Hz, 1H), 7.09 (d, J=11.2 Hz, 1H).

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

Then, 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 under a nitrogen atmosphere, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.02 mL, 6.84 mmol) and methyl iodide (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 using distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to give 328 mg (yield: 64%) of the title compound.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 7.85 (d, J=6.4 Hz, 1H), 7.26 (d, J=1 1.6 Hz, 1H), 3.49 (s, 3H), 3.46 (s, 3H).

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

5-Fluoro-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(37H)-one (250 mg, 1.11 mmol) obtained in Step 9-2 and iron (496 mg, 8.88 mmol) were dissolved in acetic acid under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction product was extracted using distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude substance was purified by column chromatography to obtain 190 mg (yield: 88%) of the title compound.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 6.84 (d, J=10.8 Hz, 1H), 6.59 (d, J=7.6 Hz, 1H), 4.36 (s, 2H), 3.28 ( s, 3H), 3.26 (s, 3H).

Step 9-4: Preparation of (6-fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide

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 under nitrogen atmosphere, and sodium nitrite (65 mg, 0.77 mmol) was added thereto at 0°C. The reaction mixture was stirred at 0°C for 30 min to form diazonium salt. Malononitrile (51 mg, 0.77 mmol) was added to this reaction mixture including diazonium salt, and the reaction mixture was stirred at room temperature for 11 hours. After completion of the reaction, the reaction product was extracted using distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude substance was purified by column chromatography to obtain 28 mg (yield: 20%) of the title compound.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 7.36 (d, J=6.8 Hz, 1H), 7.15 (d, J=10.8 Hz, 1H), 3.43 (s, 3H), 3.39 ( s, 3H).

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

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

882 mg (yield: 77%) of the title compound was obtained in the same manner as in Step 9-1 of Example 9 above 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.

^1H NMR (400 MHz, Acetone- _d6 ) δ 10.30 (s, 1H), 10.19 (s, 1H), 7.71 (s, 1H), 7.26 (s, 1H).

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

410 mg (yield: 73%) of the title compound was obtained 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.

^1H NMR (400 MHz, Acetone- _d6 ) δ 7.83 (s, 1H), 7.41 (s, 1H), 3.48 (s, 3H), 3.47 (s, 3H).

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

190 mg (yield: 88%) of the title compound was obtained 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.

^1H NMR (400 MHz, Acetone-d ₆ ) δ 6.84 (d, J=10.8 Hz, 1H), 6.59 (d, J=7.6 Hz, 1H), 4.36 (s, 2H), 3.28 ( s, 3H), 3.26 (s, 3H).

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

28 mg (yield: 20%) of the title compound was obtained 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(2H)-one.

^1H NMR (400 MHz, DMSO- _d6 ) δ 7.39 (s, 1H), 7.30 (s, 1H), 3.34 (s, 3H), 3.33 (s, 3H).

Example 11: Preparation of (7-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-17/-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (Compound 11)

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

720 mg (yield: 63%) of the title compound 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.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 10.77 (s, 1H), 10.40 (s, 1H), 8.01 (d, J=2.0 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H).

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

412 mg (yield: 73%) of the title compound was obtained 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.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 7.99 (d, J=2.0 Hz, 1H), 7.95 (d, J=2.4 Hz, 1H), 3.75 (s, 3H), 3.53 ( s, 3H).

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

154 mg (yield: 71%) of the title compound was obtained 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.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 6.39 (d, J=2.0 Hz, 1H), 6.37 (d, J=2.0 Hz, 1H), 4.64 (s, 2H), 3.55 ( s, 3H), 3.26 (s, 3H).

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

42 mg (yield: 41%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.20 (s, 2H), 3.58 (s, 3H).

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

Step 12-1: Preparation of 6-nitro-1H-imidazo[4,5-61pyridin-2(3H)-one

5-Nitropyridine-2,3-diamine (600 mg, 3.89 mmol) and N,N'-disuccinimidyl carbonate (15 g, 5.84 mmol) were dissolved in acetonitrile under a nitrogen atmosphere, and the reaction mixture was stirred at 80°C for 8 hours. After completion of the reaction, the reaction product was filtered using acetonitrile to obtain 570 mg (yield: 81%) of the title compound.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 11.00 (s, 1H), 10.29 (s, 1H), 8.87 (d, J=2.4 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H).

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

351 mg (yield: 76%) of the title compound was obtained 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.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 8.94 (d, J=2.4 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 3.54 (s, 3H), 3.48 ( s, 3H).

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

1,3-Dimethyl-6-nitro-1H-imidazo[4,5-6]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 using methanol, and the filtrate was concentrated to give 241 mg (yield: 94%) of the title compound.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 7.49 (d, J=2.4 Hz, 1H), 6.78 (d, J=2.4 Hz, 1H), 4.49 (s, 2H), 3.30 ( s, 3H), 3.29 (s, 3H).

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

100 mg (yield: 47%) of the title compound was obtained 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.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 8.18 (d, J=2.0 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 3.47 (s, 3H), 3.41 ( s, 3H).

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

Step 13-1: Preparation of 6-aminobenzo[d]thiazol-2(3H)-one

6-Nitrobenzo[d]thiazol-2(3H)-one (200 mg, 1.02 mmol) was dissolved in ethanol/water under a nitrogen atmosphere, and Fe (228 mg, 4.08 mmol) and ammonium chloride (545 mg, 10.19 mmol) were added thereto, and the reaction mixture was stirred at 80°C for 1 hour. After completion of the reaction, the reaction product was extracted using distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude substance was purified by column chromatography to give 83 mg (yield: 49%) of the title compound.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.34 (s, 1H), 6.79 (d, J=8.4 Hz, 1H), 6.69 (d, J=2.2 Hz, 1H), 6.51 ( dd, J=8.5 Hz, 2.3 Hz, 1H), 4.95 (s, 2H).

Step 13-2: Preparation of (2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

34 mg (yield: 47%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.96 (s, 1H), 7.68 (s, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.13 (d, J=8.6 Hz, 1H).

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

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

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

¹ H NMR (400 MHz, Acetone-d ₆ ) 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).

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

79 mg (yield: 91%) of the title compound was obtained 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 as a solvent instead of 1,4-dioxane.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 6.95 (d, J=8.5 Hz, 1H), 6.87 (d, J=2.3 Hz, 1H), 6.72 (dd, J=8.5 Hz, 2.3 Hz, 1H), 4.62 (s, 2H), 3.35 (s, 3H).

Step 14-3: Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 (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).

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

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

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

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 6.83 (d, J=8.3 Hz, 14H), 6.61 (d, J=2.l Hz, 1H), 6.49 (dd, J=8.3 Hz, 2.1 Hz, 1H), 4.60 (s, 2H).

Step 15-2: Preparation of (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.77 (s, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.30 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H).

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

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

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

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 6.87 (d, J=8.3 Hz, 1H), 6.64 (d, J=2.1 Hz, 1H), 6.55 (dd, J=8.3 Hz, 2.1 Hz, 1H), 4.64 (s, 2H), 3.32 (s, 3H).

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

111 mg (yield: 88%) of the title compound was obtained 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.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 6.95 (d, J=8.5 Hz, 1H), 6.87 (d, J =2.3 Hz, 1H), 6.72 (dd, J=8.5 Hz, 2.3 Hz, 1H), 4.62 (s, 2H), 3.35 (s, 3H).

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

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.43 (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).

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

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

1-Chloro-2,4-dinitrobenzene (3 g, 14.81 mmol) was dissolved in THF under nitrogen atmosphere, 2.0 M methylamine (37.03 ml, 74.06 mmol) dissolved in THF was added thereto, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction product was extracted using distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude substance was solidified using ether and filtered to obtain 2.81 g (yield: 96%) of the title compound.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 8.99 (d, J=2.8 Hz, 1H), 8.82 (s, 1H), 8.35-8.32 (m, 1H), 7.23 (d, J=9 .6 Hz, 1H), 3.24 (d, J=5.2 Hz, 3H).

Step 17-2: Preparation of N'-methyl-4-nitrobenzene-1,2-diamine

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

¹ H NMR (400 MHz, Acetone-d ₆ ) 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).

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

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

^1H NMR (400 MHz, Acetone-d ₆ ) 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).

Step 17-4: Preparation of 5-amino-1-methyl-1.3-dihydro-2H-benzo[d]imidazol-2-one

306 mg (yield: 91%) of the title compound was obtained 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 as a solvent instead of 1,4-dioxane.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 9.37 (s, 1H), 6.72 (d, J=8.4 Hz, 1H), 6.44 (d, J=2.0 Hz, 1H), 6.39 ( dd, J=8.4 Hz, 2.0 Hz, 1H), 4.31 (s, 2H), 3.23 (s, 3H).

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

62 mg (yield: 17%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 10.99 (s, 1H), 7.19 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.12-7.10 ( m, 2H), 3.27 (s, 3H).

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

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

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

¹ H NMR (400 MHz, Acetone-d ₆ ) 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, 1H), 1.61 (d, J=6.8 Hz, 6H).

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

112 mg (yield: 85%) of the title compound was obtained 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.

¹ H NMR (400 MHz, Acetone-d ₆ ) 5 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).

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

109 mg (yield: 80%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (d, J=2.4 Hz, 1H), 7.55 (d, J=9.2 Hz, 1H), 7.49 (d, J=2.4 Hz, 1H), 4.81-4.74 (m, 1H), 1.50 (d,J=7.2 Hz, 6H).

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

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

After 6-nitrobenzo[d]thiazol-2(3H)-one (300 mg, 1.53 mmol) was dissolved in DMF under nitrogen atmosphere, sodium 2-chloro-2,2-difluoroacetate (467 mg, 3.06 mmol) and DBU (0.46 ml, 3.06 mmol) were added thereto, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction product was extracted using distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude substance was solidified using methanol and filtered to obtain 176 mg (yield: 47%) of the title compound.

^1H NMR (400 MHz, Acetone-d ₆ ) 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).

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

125 mg (yield: 95%) of the title compound was obtained 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 as a solvent instead of 1,4-dioxane.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 7.55 (t, J=58.0 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 6.93 (d, J=2.4 Hz, 1H), 6.76 (dd, J=8.6 Hz, 2.2 Hz, 1H), 4.89 (s, 2H).

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

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.90 (s, 1H), 7.82 (t, J=56.8 Hz, 1H), 7.53 (s, 2H).

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

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

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

¹ H NMR (400 MHz, Acetone-d ₆ ) 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), 4.72-1.65 (m, 1H), 1.61 (d, J=6.8 Hz, 6H).

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

124 mg (yield: 85%) of the title compound was obtained 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 as a solvent instead of 1,4-dioxane.

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

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

99 mg (yield: 59%) of the title compound was obtained 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.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 7.47-7.43 (m, 2H), 7.33 (dd, J=8.8 Hz, 2.0 Hz, 1H), 4.51-4.44 (m, 1H), 1.46 (d, J=6.8 Hz, 6H).

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

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

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

^1H NMR (400 MHz, Acetone-d ₆ ) δ 8.34-8.30 (m, 2H), 7.68 (d, J=8.8 Hz, 1H), 7.65 (t, J=57.6 Hz, 1H).

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

110 mg (yield: 98%) of the title compound was obtained 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 as a solvent instead of 1,4-dioxane.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 7.68 (t, J=58.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.61 (dd, J=8.4 Hz, 2.0 Hz, 1H) 4.91 (s, 2H).

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

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.73 (t, J=57.2 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.45-7.40 (m, 2H).

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

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

207 mg (yield: 64%) of the title compound was obtained 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.

¹ H NMR (400 MHz, Acetone-d ₆ ) 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).

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

105 mg (yield: 82%) of the title compound was obtained 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 as a solvent instead of 1,4-dioxane.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 6.76 (d, J=8.0 Hz, 1H), 6.43-6.40 (m, 2H), 4.38 (s, 2H), 3.27 (s, 3H), 3.26 (s, 3H).

Step 22-3: Preparation of (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide

11 mg (yield: 8%) of the title compound was obtained 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.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 7.18-7.14 (m, 2H), 6.97 (d, J=8.0 Hz, 1H), 3.37 (s, 3H), 3.35 (s, 3H).

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

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

204 mg (yield: 46%) of the title compound was obtained 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 methyl iodide.

^1H NMR (400 MHz, Acetone-d ₆ ) δ 8.05-8.02 (m, 2H), 7.46 (d, J=8.8 Hz, 1H), 4.80-4.72 (m, 2H), 1.58-1.54(m , 12H).

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

118 mg (yield: 89%) of the title compound was obtained 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 as a solvent instead of 1,4-dioxane.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 6.92 (d, J=8.0 Hz, 1H), 6.64 (d, J=2.0 Hz, 1H), 6.37 (dd, J=8.4 Hz, 2.4 Hz, 1H), 4.62-4.54 (m, 2H), 4.33 (s, 2H), 1.46-1.43 (m, 12H).

Step 23-3: Preparation of (1,3-Diisopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide

12 mg (yield: 10%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.22-7.20 (m, 2H), 7.04 (dd, J=8.8 Hz, 1.6 Hz, 1H), 4.61-4.55 (m, 2H), 1.44- 1.42 (m, 12H).

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

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

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

¹ H NMR (400 MHz, Acetone-d ₆ ) 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).

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

69 mg (yield: 96%) of the title compound was obtained 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 as a solvent instead of 1,4-dioxane.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 7.62-7.32 (m, 2H), 7.13 (d, J=8.8 Hz, 1H), 6.82 (s, 1H), 6.63 (dd, J=8 .6 Hz, 2.2 Hz, 1H), 4.90 (s, 2H).

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

45 mg (yield: 58%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.93-7.61 (m, 2H), 7.56 (s, 1H), 7.49-7.42 (m, 2H).

Example 25: Preparation of (1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide (Compound 25)

Step 25-1: Preparation of 1-methyl-6-nitroquinolin-2(17/)-one

123 mg (yield: 38%) of the title compound 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.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (d, J=2.7 Hz, 1H), 8.40 (dd, J=9.4 Hz, 2.7 Hz, 1H), 8.15 (d, J=9.5 Hz, 1H), 7.73 (d, J=9.3 Hz, 1H), 6.80 (d, J=9.5 Hz, 1H), 3.67 (s, 3H).

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

56 mg (yield: 59%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.66 (d, J=9.4 Hz, 1H), 7.25 (d, J=8.9 Hz, 1H), 6.94 (dd, J=8.9 Hz, 2.7 Hz, 1H), 6.78 (d, J=2.6 Hz, 1H), 6.48 (d, J=9.4 Hz, 1H), 5.09 (s, 2H), 3.53 (s, 3H).

Step 25-3: Preparation of (1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.16 (s, 1H), 7.98 (d, J=9.5 Hz, 1H), 7.79 (d, J=2.5 Hz, 1H), 7.74 ( dd, J=9.l Hz, 2.6 Hz, 1H), 7.59 (d, J=9.l Hz, 1H), 6.66 (d, J=9.5 Hz, 1H), 3.61 (s, 3H ).

Example 26: Preparation of (4-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide (Compound 26)

Step 26-1: Preparation of 4-methyl-6-nitroquinolin-2(1H)-one

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.18 (s, 1H), 8.51 (d, J=2.6 Hz, 1H), 8.35 (dd, J=9.0 Hz, 2.5 Hz, 1H), 7.44 (d, J=9.0 Hz, 1H), 6.58 (s, 1H).

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

47 mg (yield: 37%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.22 (s, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.87-6.78 (m, 2H), 6.28 (s, 1H), 5.00 (s, 2H), 2.31 (s, 3H).

Step 26-3: Preparation of (4-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.13 (s, 1H), 11.73 (s, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.66 (dd, J=8.9 Hz, 2.4 Hz, 1H), 7.34 (d, J=8.9 Hz, 1H), 6.47 (s, 1H), 2.41 (s, 3H).

Example 27: Preparation of (1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide (Compound 27)

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

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (d, J=2.6 Hz, 1H), 8.42 (ddd, J=9.3 Hz, 2.6 Hz, 1.1 Hz, 1H) , 7.73 (dd, J=9.4 Hz, 1.1 Hz, 1H), 6.72 (s, 1H), 3.65 (s, 3H), 2.53 (s, 3H).

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

33 mg (yield: 19%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.25 (d, J=8.9 Hz, 1H), 6.94 (dd, J=8.9 Hz, 2.5 Hz, 1H), 6.89 (d, J=2.5 Hz, 1H), 6.42 (s, 1H), 5.10 (s, 2H), 3.52 (s, 3H), 2.32 (s, 3H).

Step 27-3: Preparation of (1,4-Dimethyl-2-oxo-1,2-Dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.14 (s, 1H), 7.82 (d, J=2.5 Hz, 1H), 7.73 (dd, J=9.2 Hz, 2.5 Hz, 1H), 7.58 (d, J=9.2 Hz, 1H), 6.59 (s, 1H), 3.59 (s, 3H), 2.42 (s, 3H).

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

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

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.21 (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).

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

150 mg (yield: 88%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.95 (d, J=8.5 Hz, 1H), 6.37 (d, J=2.2 Hz, 1H), 6.28 (dd, J=8.5 Hz, 2.2 Hz, 1H), 5.07 (s, 2H), 3.23 (s, 3H).

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

73 mg (yield: 38%) of the title compound was obtained in the same manner as in Step 1-3 of Example 1 above except that 5-amino-3-methylbenzo[d]oxazol-2(3H)-one obtained in Step 28-2 was used instead of 7-aminoisoquinolin-1(2H)-one.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.11 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.32 (d, J=2.1 Hz, 1H), 7.24 ( dd, J=8.6 Hz, 2.2 Hz, 1H).

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

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

94 mg (yield: 25%) of the title compound was obtained in the same manner as in Step 28-1 of Example 28 above except that 2-iodopropane was used instead of methyl iodide.

¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

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

48 mg (yield: 61%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.96 (d, J=8.4 Hz, 1H), 6.57 (d, J=2.2 Hz, 1H), 6.28 (dd, J=8.4 Hz, 2.2 Hz, 1H), 5.01 (s, 2H), 4.37 (hept, J=6.9 Hz, 1H), 1.42 (d, J=7.l Hz, 6H).

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

9 mg (yield: 15%) of the title compound was obtained in the same manner as in Step 1-3 of Example 1 above except that 5-amino-3-isopropylbenzo[d]oxazol-2(3H)-one obtained in Step 29-2 was used instead of 7-aminoisoquinolin-1(2H)-one.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 7.46 (d, J=2.1 Hz, 1H, 7.38 (d, J=8.7 Hz, 1H), 7.24 (dd , J=8.7 Hz, 2.2 Hz, 1H), 4.51 (hept, J=6.9 Hz, 1H), 1.46 (d, J=6.9 Hz, 6H).

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

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

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (s, 1H), 8.71 (s, 1H), 8.38 (dd, J=9.0 Hz, 2.3 Hz, 1H), 8.06 (d, J=9.0 Hz, 1H).

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

The title compound was prepared 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 further purification.

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

30 mg (yield: 22%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.13 (s, 1H), 8.80 (s, 1H), 7.85-7.81 (m, 2H), 7.59 (dd, J=9.0 Hz, 2.1 Hz, 1H).

Example 31: Preparation of (1,31b-trimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (Compound 31)

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

67 mg (yield: 29%) of the title compound was obtained in the same manner as in Step 9-1 of Example 9 above except that 4-methyl-5-nitrobenzene-1,2-diamine was used instead of 4-fluoro-5-nitrobenzene-1,2-diamine.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.25 (s, 1H), 11.00 (s, 1H), 7.59 (s, 1H), 6.96 (s, 1H), 2.55 (s, 3H).

Step 31-2: Preparation of 13,5-trimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)one

268 mg (yield: 78%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.91 (s, 1H), 7.26 (s, 1H), 3.37 (d, J=5.5 Hz, 6H), 2.60 (s, 3H).

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

169 mg (yield: 78%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.73 (s, 1H), 6.41 (s, 1H), 4.55 (s, 2H), 3.20 (d, J=5.0 Hz, 6H), 2.09 (s, 3H).

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

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

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

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

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

336 mg (yield: 98%) of the title compound 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.

^1H NMR (400 MHz, DMSO- _d6 ) δ 11.26 (s, 1H), 10.86 (s, 1H), 7.48 (s, 1H), 6.81 (s, 1H), 3.90 (s, 3H).

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

224 mg (yield: 66%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 (s, 1H), 7.19 (s, 1H), 3.95 (s, 3H), 3.39 (s, 3H), 3.34 (s, 3H).

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

78 mg (yield: 44%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.78 (s, 1H), 6.47 (s, 1H), 4.45 (s, 2H), 3.78 (s, 3H), 3.25 (s, 3H), 3.20 ( s, 3H).

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

37 mg (yield: 54%) of the title compound was obtained in the same manner as in Step 1-3 of Example 1 above except that 5-amino-6-methoxy-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-one obtained in Step 32-3 was used instead of 7-aminoisoquinolin-1(2H)-one.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.75 (s, 1H), 7.21 (s, 1H), 7.12 (s, 1H), 3.94 (s, 3H), 3.34 (s, 3H), 3.31 ( s, 3H).

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

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

509 mg (yield: 89%) of the title compound was obtained in the same manner as in Step 9-1 of Example 9 above except that 3-methoxy-5-nitrobenzene-1,2-diamine was used instead of 4-fluoro-5-nitrobenzene-1,2-diamine.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.57 (s, 1H), 11.15 (s, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 3.96 (s, 3H).

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

119 mg (yield: 70%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.83 (d, J=2.0 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 3.98 (s, 3H), 3.55 (s, 3H), 3.40 (s, 3H).

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

15 mg (yield: 16%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.04 (d, J=1.7 Hz, 1H), 5.97 (d, J=1.7 Hz, 1H), 4.85 (s, 2H), 3.76 (s, 3H), 3.38 (s, 3H), 3.17 (s, 2H).

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

20 mg (yield: 30%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 6.96 (d, J=1.8 Hz, 1H), 6.91 (d, J=1.8 Hz, 1H), 3.87 (s, 3H), 3.48 (s, 3H), 3.30 (s, 3H).

Example 34: Preparation of (1,3-Diisopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide (Compound 34)

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

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.94 (d, J=2.3 Hz, 1H), 8.32 (d, J=2.3 Hz, 1H), 4.72 (dhept, J=16.6 Hz, 6.9 Hz, 2H), 1.50 (dd, J=16.1 Hz, 6.9 Hz, 12H).

Step 34-2: Preparation of 6-amino-13-Diisopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

162 mg (yield: 42%) of the title compound was obtained in the same manner as in Step 28-2 of Example 28 above except that 1,3-diisopropyl-6-nitro-1H-imidazo[4,5-6]pyridin-2(3H)-one obtained in Step 34-1 was used instead of 1-methyl-6-nitroquinolin-2(1H)-one.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.37 (d, J=2.2 Hz, 1H), 6.92 (d, J=2.2 Hz, 1H), 4.84 (s, 2H), 4.61- 4.48 (m, J=7.0 Hz, 2H), 1.41 (dd, J=19.6 Hz, 6.9 Hz, 12H).

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

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13 (d, J=2.2 Hz, 1H), 7.64 (d, J=2.2 Hz, 1H), 4.64 (dp, J=l 1, 5 Hz, 6.9 Hz, 2H), 1.46 (dd, J=19.8 Hz, 6.9 Hz, 12H).

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

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

1-Methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one (150 mg, 0.78 mmol) was dissolved in DMF (3 ml), and potassium carbonate (214.7 mg, 1.55 mmol) was added thereto, and then the reaction mixture was cooled to 0°C. Ethyl iodide (0.156 ml, 1.94 mmol) was slowly added thereto, and the reaction mixture was slowly warmed to room temperature and stirred at room temperature for 17 hours. After completion of the reaction, the reaction product was extracted using distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude substance was solidified using ether and filtered to obtain 133.5 mg (yield: 77%) of the title compound.

¹ H NMR (400 MHz, Chloroform-d ₆ ) 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).

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

74.7 mg (yield: 68%) of the title compound was obtained 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(37/)-one obtained in Step 35-1 was used instead of 7-nitroisoquinolin-1(2H)-one.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.79 (d, J=8.3 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 6.31 (dd, J=8.2 Hz, 2.1 Hz, 1H), 4.76 (s, 2H), 3.74 (q, J=7.2 Hz, 2H), 3.21 (s, 3H), 1.16 (t, J=7.2 Hz, 3H).

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

60.9 mg (yield: 58%) of the title compound was obtained in the same manner as in Step 1-3 of Example 1 above except that 5-amino-3-ethyl-1-methyl-1H-benzo[diimidazol-2(3H)-one obtained in Step 35-2 was used instead of 7-aminoisoquinolin-1(2H)-one.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.04 (s, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.23 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 3.88 (q, J=7.2 Hz, 2H), 3.32 (s, 3H), 1.20 (t, J=7.2 Hz, 3H).

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

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

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 methyl iodide.

¹ H NMR (400 MHz, Chloroform-d ₆ ) 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).

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

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.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 6.78 (d, J=8.2 Hz, 1H), 6.56 (d,J=2.0 Hz, 1H), 6.30 (dd, J=8.3 Hz, 2.0 Hz, 1H), 4.73 (s, 2H), 4.49 (hept, J=7.0 Hz, 1H), 3.19 (s, 3H), 1.39 (d, J=7.0 Hz, 6H ).

Step 36-3: Preparation of (3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide

15.2 mg (yield: 9%) of the title compound was obtained in the same manner as in Step 1-3 of Example 1 above except that 5-amino-3-isopropyl-1-methyl-1H-benzo[d]imidazol-2(3H)-one obtained in Step 36-2 was used instead of 7-aminoisoquinolin-1(2d)-one.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.96 (s, 1H), 7.42 (d, J=1.9 Hz, 1H), 7.22 (dd, J=8.5 Hz, 1.9 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 4.61 (hept, J=7.0 Hz, 1H), 3.30 (s, 3H), 1.44 (d, J=6.9 Hz, 6H ).

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

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

After 1-methyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one (100 mg, 0.52 mmol) was dissolved in DMF under nitrogen atmosphere, sodium 2-chloro-2,2-difluoroacetate (157.9 mg, 1.04 mmol) and potassium carbonate (143.1 mg, 1.04 mmol) were added thereto, and the reaction mixture was heated to 80°C and stirred for 5 hours. After completion of the reaction, water was added thereto, and the resulting precipitate was filtered and purified by column chromatography to give 58.5 mg (yield: 46%) of the title compound.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.23 (dd, J=8.8 Hz, 2.2 Hz, 1H), 8.05 (d, J=2.2 Hz, 1H), 7.81 (t, J=57.5 Hz, 1H), 7.52 (d, J=8.8 Hz, W), 3.41 (s, 3H).

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

56.1 mg (yield: 72%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.56 (t, J=58.3 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 6.45 (dd, J=8.4 Hz, 2.1 Hz, 1H), 5.03 (s, 2H), 3.24 (s, 3H).

Step 37-3: Preparation of (3-difluoromethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide

53.2 mg (yield: 71%) of the title compound was obtained 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.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 11.86 (s, 1H), 7.56 (d, J=2.l 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).

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

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

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.

¹ H NMR (400 MHz, Chloroform-d ₆ ) 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).

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

1.46 g (yield: 88%) of the title compound was obtained in the same manner as in Step 17-2 of Example 17 above except that N-ethyl-2,4-dinitroaniline obtained in Step 38-1 was used instead of N-methyl-2,4-dinitroaniline.

¹ H NMR (400 MHz, Chloroform-d ₆ ) 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).

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

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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.42 (s, 1H), 8.01 (dd, J=8.7 Hz, 2.3 Hz, 1H), 7.75 (d, J=2.3 Hz, 1H), 7.36 (d, J=8.7 Hz, 1H), 3.90 (q, J=7.2 Hz, 2H), 1.21 (t, J=7.2 Hz, 3H).

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

172.0 mg (yield: 80%) of the title compound was obtained 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 methyl iodide was used instead of ethyl iodide.

¹ H NMR (400 MHz, Chloroform-d ₆ ) 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).

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

117.6 mg (yield: 80%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.82 (d, J=8.2 Hz, 1H), 6.35 (d, J=2.1 Hz, 1H), 6.30 (dd, J=8.2 Hz, 2.1 Hz, 1H), 4.78 (s, 2H), 3.75 (q, J=7.1 Hz, 2H), 3.20 (s, 3H), 1.15 (t, J=7.1 Hz, 3H).

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

10.8 mg (yield: 6%) of the title compound was obtained in the same manner as in Step 1-3 of Example 1 above 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.07 (s, 1H), 7.26-7.22 (m, 3H), 3.86 (q, J=7.2 Hz, 2H), 1.20 (t, J=7.1 Hz, 3H).

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

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

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

¹ H NMR (400 MHz, DMSO-d ₆ ) 5 8.22 (dd, J=8.8 Hz, 2.2 Hz, 1H), 8.06 (d, J=2.2 Hz, 1H), 7.81 (t, J=57.5 Hz, 1H), 7.60 (d, J=8.9 Hz, 1H), 3.97 (q, J=7.2 Hz, 2H), 1.26 (t, J=7.2 Hz, 3H ).

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

88.2 mg (yield: 75%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.56 (t, J=58.3 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 6.44 (dd, J=8.4 Hz, 2.1 Hz, 1H), 5.03 (s, 2H), 3.77 (q, J=7.2 Hz, 2H), 1.19 (t, J =7.2 Hz, 3H).

Step 39-3: Preparation of (3-difluoromethyl-1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide

64.7 mg (yield: 56%) of the title compound was obtained in the same manner as in Step 1-3 of Example 1 above except that 5-amino-3-difluoromethyl-1-ethyl-1H-benzo[d]imidazol-2(3H)-one obtained in Step 39-2 was used instead of 7-aminoisoquinolin-1(2H)-one.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 11.85 (s, 1H), 7.57 (d, J=2.l Hz, W), 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).

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

Step 40-1: Preparation of N-cyclopropyl-2,4-dinitroaniline 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.

¹ H NMR (400 MHz, Chloroform-d ₆ ) δ 9.13 (d, J=2.6 Hz, 1H), 8.56 (s, 1H), 8.31 (ddd, J=9.5 Hz, 2.6 Hz, 0.7 Hz, 1H), 7.40 (d, J=9.5 Hz, SH), 2.70 (tdt, J=6.8 Hz, 3.8 Hz, 1.8 Hz, 1H), 1.12-0.98 (m, 2H), 0.82-0.67 (m, 2H).

Step 40-2: Preparation of N'-cyclopropyl-4-nitrobenzene-1,2-diamine

1.69 g (yield: 89%) of the title compound was obtained in the same manner as in Step 17-2 of Example 17 above except that N-cyclopropyl-2,4-dinitroaniline obtained in Step 40-1 above was used instead of N-methyl-2,4-dinitroaniline.

^1H NMR (400 MHz, Chloroform-d ₆ ) δ 7.85 (ddd, J=8.9 Hz, 2.5 Hz, 0.6 Hz, 1H), 7.61 (d, J=2.5 Hz, 1H), 6.98 (d, J=8.9 Hz, 1H), 4.66 (s, 1H), 3.29 (s, 2H), 2.53 (ttd, J=6.7 Hz, 3.6 Hz, 1.3 Hz, 1H) , 0.93-0.82 (m, 2H), 0.63-0.55 (t, 2H).

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

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.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.30 (s, 1H), 8.01 (dd, J=8.7 Hz, 2.3 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 2.93 (tt, J=7.0 Hz, 3.7 Hz), 1.09-1.01 (m, 2H), 0.93-0.85 (m, 2H ).

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

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

^1H NMR (400 MHz, Chloroform-d ₆ ) 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).

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

41.6 mg (yield: 75%) of the title compound was obtained 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 as a solvent instead of dioxane.

¹ H NMR (400 MHz, Chloroform-d ₆ ) 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) .

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

29.9 mg (yield: 52%) of the title compound was obtained in the same manner as in Step 1-3 of Example 1 above 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.

¹ H NMR (400 MHz, Chloroform-d ₆ ) 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).

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

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

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.09 (d, J=2.2 Hz, 1H), 8.07 (dd, J=8.6 Hz, 2.3 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H), 3.94 (q, J=7.1 Hz, 2H), 2.98 (tt, J=7.l Hz, 3.7 Hz, 1H), 1.21 (t, J=7 ,2 Hz, 3H), 1.12-1.03 (m, 2H), 0.95-0.86 (m, 2H).

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

83.2 mg (yield: 61%) of the title compound was obtained 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 as a solvent instead of dioxane.

¹ H NMR (400 MHz, Chloroform-d ₆ ) 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 (brs, 2H), 2.90-2.72 (m, 1H), 1.28 (t, J=7.2 Hz , 3H), 1.08-0.94 (m, 4H).

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

53.6 mg (yield: 49%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.04 (s, 1P), 7.52-7.06 (m, 3H), 3.83 (q, J=7.2 Hz, 2H), 2.89 (tt, J=7.0 Hz, 3.7 Hz, 1H), 1.18 (t, J=7.2 Hz, 3H), 1.02 (td, J=7.3 Hz, 5.0 Hz, 2H), 0.92-0.82 (m, 2H).

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

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

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.17 (d, J=2.3 Hz, 1H), 8.03 (dd, J=8.8 Hz, 2.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 5.27 (hept, J=6.2 Hz, 1H), 3.18 (tt, J=7.1 Hz, 3.7 Hz, 1H), 1.43 (d, J=6 ,2 Hz, 6H), 1.13 (td, J=7.4 Hz, 5.2 Hz, 2H), 0.98-0.90 (m, 2H).

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

114.5 mg (yield: 62%) of the title compound was obtained 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 as a solvent instead of dioxane.

¹ H NMR (400 MHz, Chloroform-d ₆ ) δ 6.97 (d, J=8.2 Hz, 1H), 6.52 (d, J=2.1 Hz, 1H), 6.43 (dd, J=8.2 Hz, 2.1 Hz, 1H), 4.65 (hept, J=7.0 Hz, 1H), 3.56 (s, 2H), 2.84-2.71 (m, 1H), 1.48 (d, J=7.0 Hz , 6H), 1.07-0.94 (m, 4H).

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

39.8 mg (yield: 26%) of the title compound was obtained in the same manner as in Step 1-3 of Example 1 above except that 5-amino-1-cyclopropyl-3-isopropyl-1H-benzo[d]imidazol-2(3H)-one obtained in Step 42-2 was used instead of 7-aminoisoquinolin-1(2H)-one.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.96 (s, 1H), 7.39 (d, J=1.3 Hz, 1H), 7.22 (d, J=l.2 Hz, 2H), 4.58 ( hept, J=6.9 Hz, 1H), 2.87 (tt,J=7.0 Hz, 3.6 Hz, 1H), 1.42 (d, J=6.9 Hz, 6H), 1.01 (td, J=7 .2 Hz, 5.0 Hz, 2H), 0.90-0.82 (m, 2H).

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

Step 43-1: Preparation of N-isopropyl-2,4-Dinitroaniline

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.

¹ H NMR (400 MHz, Chloroform-d ₆ ) 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).

Step 43-2: Preparation of N ¹ -isopropyl-4-nitrobenzene-1,2-diamine

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 a solvent.

¹ H NMR (400 MHz, Chloroform-d ₆ ) δ 7.84 (dd, J=8.9 Hz, 2.6 Hz, 1H), 7.63 (d, J=2.6 Hz, 1H), 6.55 (d, J=9.0 Hz, 1H), 4.20 (s, 1H), 3.82-3.63 (m, J=6.3 Hz, 1H), 3.29 (s, 2H), 1.29 (d, J=6.3 Hz , 6H).

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

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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.42 (s, 1H), 7.96 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.74 (d, j=2.3 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 4.63 (hept, J=6.9 Hz, 1H), 1.46 (d, J=7.0 Hz, 6H).

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

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.17 (dd, J=8.9 Hz, 2.3 Hz, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.79 (t, J=57.6 Hz, 1H), 7.69 (d, J=8.9 Hz, 1H), 4.68 (hept, J=6.9 Hz, 1H), 1.49 (d, J=6.9 Hz, 6H ).

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

67.2 mg (yield: 84%) of the title compound was obtained 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 as a solvent instead of dioxane.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.53 (t, J=58.4 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 6.65 (d, J=2.1 Hz, 1H), 6.42 (dd, J=8.5 Hz, 2.1 Hz, 1H), 5.03 (s, 2H), 4.49 (hept, J=6.9 Hz, 1H), 1.41 (d, J =6.9 Hz, 6H).

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

53.6 mg (yield: 60%) of the title compound was obtained in the same manner as in Step 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 a solvent.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 13.10 (s, 1H), 7.69 (t, J=57.8 Hz, 1H), 7.53-7.44 (m, 2H), 7.35 (dd, J=8 .8 Hz, 2.1 Hz, 1H), 4.59 (p, J=6.9 Hz, 1H), 1.46 (d, J=7.0 Hz, 6H).

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

Step 44-1: Preparation of N-methyl-3.5-dinitropyridine 2 amine

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.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 9.27 (d, J=2.6 Hz, 1H), 9.13 (s, 1H), 9.10 (d, J=2.6 Hz, 1H), 3.30 ( d,J=1.2 Hz, 3H).

Step 44-2: Preparation of N'-methyl-5-nitropyridine-2,3-diamine

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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.40 (d, J=2.5 Hz, 1H), 7.34 (d, J=2.6 Hz, 1H), 7.12 (s, 1H), 5.32 (s, 2H), 2.97 (d, J=4.6 Hz, 3H).

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

669.7 mg (yield: 53%) of the title compound 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.69 (s, 1H), 8.92 (d, J=2.3 Hz, 1H), 7.92 (d, J=2.3 Hz, 1H), 3.36 (s, 3H).

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

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-1/7-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.

¹ H NMR (400 MHz, Chloroform-d ₆ ) δ 9.03 (d, J=2.2 Hz, 1H), 7.96 (d, J=2.2 Hz, 1H), 4.01 (q, J=7.3 Hz, 2H), 3.56 (s, 3H), 1.40 (t, J=7.3 Hz, 3H).

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

92.8 mg (yield: 74%) of the title compound was obtained in the same manner as in Step 1-2 of Example 1 above except that 1-ethyl-3-methyl-6-nitro-1/7-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 a solvent instead of dioxane, and the reaction was carried out at 40°C.

¹ H NMR (400 MHz, Chloroform-d ₆ ) δ 7.56 (d, J=2.2 Hz, 1H), 6.65 (d, J=2.3 Hz, 1H), 3.88 (q, J=7.3 Hz, 2H), 3.52 (s, 2H), 3.43 (s, 3H), 1.31 (t, J=7.2 Hz, 3H).

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

45.8 mg (yield: 31%) of the title compound was obtained in the same manner as in Step 1-3 of Example 1 above 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.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 13.10 (s, 1H), 8.16(d, J=2.l Hz, 1H), 7.62 (d, J=2.1 Hz, 1H), 3.92 ( q, J=7.1 Hz, 2H), 3.33 (s, 4H), 1.20 (t, J=7.1 Hz, 3H).

Example 45: Preparation of (1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-A]pyridin-6-yl)carbonohydrazonoyl dicyanide (Compound 45)

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

98.5 mg (yield: 40%) 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[4,5-6]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.

^1H NMR (400 MHz, Chloroform-d ₆ ) δ 9.01 (d, J=2.2 Hz, 1H), 8.05 (d, J=2.3 Hz, 1H), 4.76 (hept, J=7.0 Hz, 1H), 3.54 (s, 3H), 1.57 (d, J=7.0 Hz, 6H).

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

64.1 mg (yield: 81%) of the title compound was obtained 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 as a solvent instead of dioxane.

¹ H NMR (400 MHz, Chloroform-d ₆ ) δ 7.55 (d, J=2.3 Hz, 1H), 6.78 (d, J=2.2 Hz, 1H), 4.71 (hept, J=7.0 Hz, 1H), 3.51 (s, 2H), 3.41 (s, 3H), 1.48 (d, J=7.0 Hz, 6H).

Step 45-3: Preparation of (1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide

8.6 mg (yield: 9%) of the title compound was obtained 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 45-2 was used instead of 7-aminoisoquinolin-1(2H)-one.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.10 (s, 1H), 8.15 (d, J=2.1 Hz, 1H), 7.66 (d, J=2.1 Hz, 1H), 4.64 ( hept, J=6.9 Hz, 1H), 3.32 (s, 3H), 1.44 (d, J=6.9 Hz, 6H).

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

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

58.5 mg (yield: 46%) of the title compound was obtained in the same manner as in Step 37-1 of Example 37 above 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.11 (d, J=2.3 Hz, 1H), 8.25 (d, J=2.3 Hz, 1H), 7.87 (t, J=57.4 Hz, 1H), 3.40 (s, 3H).

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

121.1 mg (yield: 88%) of the title compound was obtained 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 as a solvent instead of dioxane.

¹ H NMR (400 MHz, Chloroform-d ₆ ) δ 7.66 (d, J=2.4 Hz, 1H), 7.31 (t, J=58.9 Hz, 1H), 7.02 (d, J=2.3 Hz, 1H), 3.62 (s, 2H), 3.42 (s, 3H).

Step 46-3: Preparation of (1-difluoromethyl-3-methyl-2-oxo-2.3-Dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide

57.3 mg (yield: 81%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.29 (d, J=2.1 Hz, 1H), 7.79 (t, J=57.6 Hz, 1H), 7.68 (d, J=2.1 Hz, 1H), 3.33 (s, 3H).

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

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

3-Methyl-6-nitro-1H-imidazo[4,5-6]pyridin-2(3H)-one (50 mg, 0.26 mmol) obtained in Step 44-3 of Example 44, potassium carbonate (71.2 mg, 0.52 mmol), copper iodide (9.8 mg, 0.052 mmol) and trans-4-hydroxy-L-proline (13.5 mg, 0.10 mmol) were dissolved in DMSO, and benzene iodide (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 h. After completion of the reaction, the reaction product was extracted using a saturated aqueous solution of ammonium chloride and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude substance was purified by column chromatography to obtain 36.6 mg (yield: 52%) of the title compound.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (d, J=2.3 Hz, 1H), 7.88 (d, J=2.3 Hz, 1H), 7.63 (d, J=5.7 Hz, 4H), 7.58-7.47 (m, 1H), 3.50 (s, 3H).

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

18.2 mg (yield: 34%) of the title compound was obtained 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 a solvent instead of dioxane, and the reaction was carried out at 60°C.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.61-7.49 (m, 4H), 7.46 (d, J=2.3 Hz, 1H), 7.45-7.41 (m, 1H), 6.73 (d, J=2.2 Hz, 1H), 4.96 (s, 2H), 3.32 (s, 3H).

Step 47-3: Preparation of (1-difluoromethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide

14.0 mg (yield: 58%) of the title compound was obtained 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.

^1H NMR (400 MHz, Acetone-d ₆ ) δ 11.91 (s, 1H), 8.26 (d, J=2.2 Hz, 1H), 7.67-7.56 (m, 4H), 7.53 (d, J=2 ,2 Hz, 1H), 7.48 (tt, J=6,l Hz, 2.2 Hz, 1H), 3.48 (s, 3H).

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

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

1.66 g (yield: 79%) 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, and ethylamine was used instead of methylamine.

¹ H NMR (400 MHz, Chloroform-d ₆ ) 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).

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

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 a solvent.

¹ H NMR (400 MHz, Chloroform-d ₆ ) 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).

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

891.8 mg (yield: 68%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.69 (s, 1H), 8.93 (d, J=2.4 Hz, 1H), 7.93 (d, J=2.3 Hz, 1H), 3.92 ( q, J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H).

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

127.8 mg (yield: 80%) of the title compound was obtained 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 methyl iodide was used instead of ethyl iodide.

¹ H NMR (400 MHz, Chloroform-d ₆ ) δ 9.03 (d, J=2.2 Hz, 1H), 7.94 (d, J=2.2 Hz, 1H), 4.11 (q, J=7.2 Hz, 2H), 3.50 (s, 3H), 1.41 (t, J=7.2 Hz, 3H).

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

94.8 mg (yield: 87%) of the title compound was obtained in the same manner as in Step 1-2 of Example 1 above except that 3-ethyl-1-methyl-6-nitro-1/7-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 as a solvent instead of dioxane.

¹ H NMR (400 MHz, Chloroform-d) 5 7.55 (d, J=2.3 Hz, 1H), 6.61 (d, J=2.3 Hz, 1H), 3.98 (q, J=7.2 Hz, 2H), 3.53 (s, 2H), 3.35 (s, 3H), 1.34 (t, J=7.2 Hz, 3H).

Step 48-6: Preparation of (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-i l)carbonohydrazonoyl dicyanide

61.6 mg (yield: 46%) of the title compound was obtained in the same manner as in Step 1-3 of Example 1 above 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.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 8.15 (d, J=2.2 Hz, 1H), δ.61 (d, J=2.2 Hz, 1H), 3.96 (q, J=7 ,2 Hz, 2H), 3.45 (s, 3H), 1.31 (t, J=7.2 Hz, 3H).

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

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

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

¹ H NMR (400 MHz, Chloroform-d ₆ ) δ 9.01 (d, J=2.2 Hz, 1H), 8.05 (d, J=2.2 Hz, 1H), 4.77 (hept, J=7.0 Hz, 1H), 4.10 (q, J=7.2 Hz, 2H), 1.57 (d, J=7.1 Hz, 6H), 1.41 (t, J=7.2 Hz, 3H).

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

75.2 mg (yield: 82%) of the title compound was obtained 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 as a solvent instead of dioxane.

¹ H NMR (400 MHz, Chloroform-d ₆ ) δ 7.54 (d, J=2.3 Hz, 1H), 6.78 (d, J=2.2 Hz, 1H), 4.71 (hept, J=7.0 Hz, 1H), 3.97 (q, J=7.2 Hz, 2H), 3.51 (s, 2H), 1.48 (d, J=7.0 Hz, 6H), 1.34 (t, J=7.2 Hz, 3H).

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

43.5 mg (yield: 42%) of the title compound was obtained 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 a solvent.

¹ H NMR (400 MHz, Acetone-d ₆ ) δ 11.89 (s, 1H), 8.16 (d, J=2.2 Hz, 1H), 7.72 (d, J=2.2 Hz, 1H), 4.72 ( hept, J=6.9 Hz, 1H), 3.95 (q, J=7.2 Hz, 2H), 1.52 (d, J=7.0 Hz, 6H), 1.30 (t, J=7.2 Hz , 3H).

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

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

129.6 mg (yield: 70%) of the title compound was obtained in the same manner as in Step 37-1 of Example 37 above 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.12 (d, J = 2.3 Hz, 1H), 8.26 (d, J = 2.3 Hz, 1H), 7.87 (t, J = 57.4 Hz, 1H), 3.97 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H).

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

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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.67 (t, J=58.2 Hz, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.02 (d, J=2.2 Hz, 1H), 5.18 (s, 2H), 3.81 (q, J=7.2 Hz, 2H), 1.23 (t, J=7.2 Hz, 3H).

Step 50-3: Preparation of (3-difluoromethyl-1-ethyl-2-oxo-2,3-dihydro-1-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide

69.3 mg (yield: 80%) of the title compound was obtained in the same manner as in Step 1-3 of Example 1 above 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (d, J=2.l Hz, 1H), 7.79 (t, J=57.6 Hz, 1H), 7.70 (d, J=2.2 Hz, 1H), 3.90 (q, J=7.2 Hz, 2H), 1.28 (t, J=7.2 Hz, 3H).

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

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

1.99 g (yield: 90%) 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, and cyclopropylamine was used instead of methylamine.

¹ H NMR (400 MHz, Chloroform-d ₆ ) 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).

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

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-dinitropyridin-2-amine obtained in Step 51-1 was used instead of N-methyl-2,4-dinitroaniline, and a 1:1 mixed solution of methanol and water was used as the solvent.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (d, J=2.5 Hz, 1H), 7.34 (d, J=2.5 Hz, 1H), 7.12 (d, J=3.6 Hz, 1H), 5.35 (s, 2H), 2.93 (tq, J=7.3 Hz, 3.8 Hz, 1H), 0.84-0.71 (m, 2H), 0.57-0.45 (m, 2H).

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

1.16 g (yield: 77%) of the title compound was obtained in the same manner as in Step 9-1 of Example 9 above except that ^N2 -cyclopropyl-5-nitropyridine-2,3-diamine obtained in Step 51-2 was used instead of 4-fluoro-5-nitrobenzene-1,2-diamine.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.56 (s, 1H), 8.91 (d, J=2.4 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 3.07-2.92 (m, 1H), 1.17-0.78 (m, 4H).

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

172.0 mg (yield: 80%) 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, and methyl iodide was used instead of ethyl iodide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (d, J=2.3 Hz, 1H), 8.31 (d, J=2.3 Hz, 1H), 3.40 (s, 3H), 3.08-2.97 (m, 1H), 1.11-0.99 (m, 4H).

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

89.3 mg (yield: 78%) of the title compound was obtained 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 as a solvent instead of dioxane.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.37 (d, J=2.3 Hz, 1H), 6.69 (d, J=2.3 Hz, 1H), 4.92 (s, 2H), 3.20 ( s, 3H), 2.86 (tt, J=7.2 Hz, 3.5 Hz, 1H), 1.04-0.85 (m, 4H).

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

25.6 mg (yield: 20%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.15 (d, J=2.2 Hz, 1H), 7.52 (d, J=2.2 Hz, 1H), 3.32 (s, 3H), 2.94 (td, J=6.8 Hz, 3.6 Hz, 1H), 0.99 (d, J=7.5 Hz, 4H).

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

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

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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ Chloroform-d ₆ ) 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) .

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

112.0 mg (yield: 71%) of the title compound was obtained 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 as a solvent instead of dioxane.

¹ H NMR (400 MHz, Chloroform-d) δ 7.58 (d, J=2.3 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 3.84 (q, J=7.3 Hz, 2H), 3.52 (s, 2H), 2.93 (tt, J=6.4 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).

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

66.2 mg (yield: 44%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.11 (s, 1H), 8.16 (d, J=2.2 Hz, 1H), 7.58 (d, J=2.2 Hz, 1H), 3.88 ( q, J=7.1 Hz, 2H), 2.95 (td, J=7.0 Hz, 3.6 Hz, 1H), 1.19 (t, J=7.l Hz, 3H), 1.00 (ddt, J =9.9 Hz, 5.2 Hz, 2.7 Hz, 4H).

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

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

187.7 mg (yield: 76%) 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, and isopropyl iodide was used instead of ethyl iodide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ Chloroform-d ₆ ) 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.l Hz, 6H), 1.24-1.12 (m, 4H) .

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

130.9 mg (yield: 79%) of the title compound was obtained 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 as a solvent instead of dioxane.

¹ H NMR (400 MHz, Chloroform-d ₆ ) δ 7.58 (d, J=2.3 Hz, 1H), 6.75 (d, J=2.3 Hz, 1H), 4.69 (hept, J=7.0 Hz, 1H), 3.50 (s, 2H), 2.92 (tt, J=6.5 Hz, 4.1 Hz, 1H), 1.47 (d, J=7.0 Hz, 6H), 1.10 (dddd, J=9.7 Hz, 4.2 Hz, 2.6 Hz, 1.2 Hz, 4H).

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

22.9 mg (yield: 34%) of the title compound was obtained 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 a solvent.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.13 (s, 1H), 8.14 (d, J=2.l Hz, 1H), 7.62 (d,J=2.2 Hz, 1H), 4.61 ( hept, J=6.9 Hz, 1H), 3.03-2.79 (m, 1H), 1.42 (d,J=6.9 Hz, 6H), 1.08-0.91 (m, 4H).

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

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

2.07 g (yield: 93%) 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, and isopropylamine was used instead of methylamine.

¹ H NMR (400 MHz, Chloroform-d ₆ ) 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).

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

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-dinitropyridin-2-amine obtained in Step 54-1 was used instead of N-methyl-2,4-dinitroaniline, and a 1:1 mixed solution of methanol and water was used as the solvent.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.37 (d, J=2.5 Hz, 1H), 7.32 (d, J=2.6 Hz, 1H), 6.74 (d, J=7.2 Hz, 1H), 5.41 (s, 2H), 4.39-4.26 (m, J=6.6 Hz, 1H), 1.21 (d, J=6.5 Hz, 6H).

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

1.08 g (yield: 91%) of the title compound was obtained in the same manner as in Step 9-1 of Example 9 above except that ^N2 -isopropyl-5-nitropyridine-2,3-diamine obtained in Step 54-2 was used instead of 4-fluoro-5-nitrobenzene-1,2-diamine.

¹ H NMR (400 MHz, DMSO-d ₆ ) 8.91 (d, J=2.4 Hz, 1H), 7.91 (d, J=2.4 Hz, 1H), 4.69 (hept, J=6, 9 Hz, 1H), 1.51 (d, J=6.9 Hz, 6H).

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

143.5 mg (yield: 67%) of the title compound was obtained 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 methyl iodide was used instead of ethyl iodide.

¹ H NMR (400 MHz, Chloroform-d ₆ ) δ 9.01 (d, J=2.3 Hz, 1H), 7.92 (d, J=2.3 Hz, 1H), 4.88 (hept, J=6.9 Hz, 1H), 3.48 (s, 3H), 1.61 (d, J=6.9 Hz, 6H).

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

97.2 mg (yield: 78%) 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-6-nitro-1P-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 as a solvent instead of dioxane.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.37 (d, J=2.3 Hz, 1H), 6.71 (d, J=2.2 Hz, 1H), 4.90 (s, 2H), 4.55 ( hept, J=6.9 Hz, 1H), 3.22 (s, 3H), 1.44 (d, J=6.9 Hz, 6H).

Step 54-6: Preparation of (3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide

103.5 mg (yield: 77%) of the title compound was obtained 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.

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

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

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

194.1 mg (yield: 86%) of the title compound was obtained 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.

¹ H NMR (400 MHz, Chloroform-d ₆ ) δ 9.00 (d, J=2.3 Hz, 1H), 7.92 (d, J=2.3 Hz, 1H), 4.87 (hept, J=6.9 Hz, 1H), 3.98 (q, J=7.2 Hz, 2H), 1.61 (d, J=6.9 Hz, 6H), 1.39 (t, J=7.3 Hz, 3H).

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

27.4 mg (yield: 16%) of the title compound was obtained 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 as a solvent instead of dioxane.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.37 (d, J=2.2 Hz, 1H), 6.77 (d, J=2.3 Hz, 1H), 4.88 (s, 2H), 4.55 (hept, J=6.9 Hz, 1H), 3.75 (q, J=7.2 Hz, 2H), 1.44 (d, J=6.9 Hz, 6H), 1.17 (t, J=7.2 Hz, 3H).

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

5.7 mg (yield: 15%) of the title compound was obtained 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.17 (s, 1H), 8.16 (d, J=2.2 Hz, 1H), 7.61 (d, J=2.2 Hz, 1H), 4.65 (h, J=7.0 Hz, 1H), 3.90 (q, J=7.2 Hz, 2H), 1.49 (d, J=6.9 Hz, 6H), 1.21 (t, J=7.0 Hz, 3H).

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

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.48-7.15 (m, 3H), 4.10-3.84 (m, 3H), 3.35 (s, 6H).

Example 57: Preparation of acetyl(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (Compound 57)

(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (150 mg, 0.59 mmol) obtained in Example 22 and KOH (36 mg, 0.65 mmol) were dissolved in methanol, and this solution was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was solidified using ether. Then, 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 completion of the reaction, the reaction product was extracted using distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and solidified using ether and then filtered. The filtrate was concentrated again under reduced pressure and solidified using hexane to obtain 43 mg (yield: 25%) of the title compound.

¹ H NMR (400 MHz, Chloroform-d ₆ ) 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).

[Examples of drugs]

In this case, the novel compound represented by formula 1 of the present invention can be prepared as a preparation in various forms. The following examples illustratively describe several methods for preparing preparations including the compound represented by formula 1 of the present invention as an active ingredient, and the present invention is not limited thereto.

Example of Preparation 1: Preparation of a tablet by direct compression

5.0 mg of each of the active ingredients obtained in Examples 1-57 were sieved, mixed with 14.1 mg lactose, 0.8 mg crospovidone USNF and 0.1 mg magnesium stearate, and then compressed into tablets.

Example of Preparation 2: Tablet preparation by wet granulation

5.0 mg of each of the active ingredients obtained in Examples 1 to 57 were sieved and mixed with 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg of polysorbate 80 was dissolved in pure water, and this solution was added to the mixture in an appropriate amount, followed by spraying 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 pressed into tablets.

Preparation Example 3: Preparation of Powder and Capsule 5.0 mg of each of the active ingredients obtained in Examples 1 to 57 were sieved and then mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone, and 0.2 mg of magnesium stearate. The mixture was filled into No. 5 hard gelatin capsules using a suitable capsule preparation machine.

Example of Preparation 4: Preparation of an injectable medicinal product

100 mg of each of the active ingredients obtained in Examples 1-57 were mixed with 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ ⋅12H ₂ O and 2974 mg of distilled water to obtain injection preparations.

Experimental Example 1: Selection of a Tau Aggregation Inhibiting Substance Using a Cell Model

To select new compounds that inhibit tau protein aggregation, a tau-BiFC cell model in which tau oligomer formation is readily observed in living cells was used. Aliquots of Tau-BiFC cells were placed in a 384-well plate. The next day, the cells were treated with each of the compounds prepared according to Examples 1-57 at concentrations of 1 μM, 3 μM, and 10 μM, together with forskolin (at a treatment concentration of 30 μM), which is a compound that induces tau protein aggregation by activating the tau phosphorylase PKA. After 48 hours, the nuclei in the cells were stained with Hoechst (at a treatment concentration of 2 μg/mL), and the fluorescence intensity of BiFC was automatically measured using Operetta (PerkinElmer) to count the stained nuclei in each well of the entire well plate. The group receiving only forskolin, which induces tau protein aggregation, was set as the reference point of 100% of the aggregated state of tau protein, and the effects of the compounds were confirmed using the equation of "BiFC fluorescence intensity induced by the compound synthesized according to an embodiment of the present invention / (fluorescence intensity of the control group receiving only forskolin, which induces tau protein aggregation - fluorescence intensity of the untreated control group) x 100". In addition, the degree of cytotoxicity induced by the newly synthesized compound was also measured by taking 100% of the cell viability in the forskolin alone group as the reference, and the cytotoxicity value of each compound was calculated by the equation of "(number of stained nuclei in the compound-treated group / number of stained nuclei in the forskolin-treated group) x 100". Based on these treatment results, intracellular tau aggregation inhibiting compounds were selected from a number of candidate groups that demonstrated tau aggregation inhibition rates of 70% or greater and cell viability of 100% at treatment compound concentrations of 10 μM or greater.

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

In order to evaluate the dose-dependent inhibition of tau protein aggregation by 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, respectively, together with forskolin (at a treatment concentration of 30 μM), which is a substance that induces tau protein aggregation. After 48 hours, the tau protein aggregation response and the cytotoxicity rate were analyzed by monitoring the cell images. The IC50 and toxicity of the compounds were analyzed by nonlinear regression analysis of prism software (Graph Pad). The calculation results of representative compounds are shown in Table 2 below.

Experimental Example 3: Inhibitory effect of a new compound on CYP coenzyme activity

The inhibitory effect of the compounds obtained according to Examples 1-57 on the activity of the CYP coenzyme was revealed. Specifically, human liver microsomes (0.25 mg/ml), 0.1 M phosphate buffer solution (pH 7.4), a cocktail of drug-substrates of five types of drug metabolism enzymes (50 μM phenacetin, 10 μM diclofenac, 100 μM S-mephenytoin, 5 μM dextromethorphan and 2.5 μM midazolam) and a compound at a concentration of 0 μM or 10 μM were mixed and pre-cultured at 37°C for 5 minutes, and then further cultured at 37°C for 15 minutes together with the NADPH generation system solution added thereto. After this, the reaction was stopped by adding an internal standard solution (terfenadine) in acetonitrile and centrifuged for 5 min (14000 rpm, 4°C), and then the supernatant was injected into the LC-MS/MS system for simultaneous analysis of the metabolites of the drug substrates, thus evaluating the inhibitory effect on drug metabolism.

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

The metabolites produced were quantified using the multiple reaction monitoring (MRM) quantification mode, and Xcalibur (version 1.6.1) was used to analyze the data. To display the inhibitory effect of the novel compound prepared according to the examples of the present invention on the CYP coenzyme activity, the CYP coenzyme activity (%) relative to the control group not receiving the compound is shown in Table 4 below.

Experimental Example 4: Identification of liver microsome stability mediated by a novel compound

The stability of liver microsomes provided by the compounds prepared in Examples 1 to 57 was confirmed. Specifically, four types of liver microsomes (human, dog, rat and mouse, each at 0.25 mg/mL), 0.1 M phosphate buffer solution (pH 7.4) and each of the compounds at a concentration of 1 μM were mixed and pre-cultured at 37°C for 5 minutes and then cultured at 37°C for 30 minutes together with the addition of the NADPH generation system solution. After that, the reaction was stopped by adding an internal standard solution (chlorpropamide) in acetonitrile and centrifuged for 5 minutes (14,000 rpm, 4°C), and then the supernatant was injected into an LC-MS/MS system for substrate drug analysis, to thereby evaluate the metabolic stability of the 8 types of compounds.

The amount of substrate remaining after the reaction was analyzed using a Shimadzu Nexera XR system and TSQ Vantage (Thermo). A Kinetex XB-C18 column (2.1 mm × 100 mm, particle size 2.6 μm; Phenomenex, USA) was used for HPLC, and the mobile phases were (A) distilled water containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid. Analyst (version 1.6.3) and Xcalibur (version 1.6.1) software were used for data analysis. The calculation results are presented in Table 5 below.

The above description of the present invention is provided for illustrative purposes, and it will be understood by those skilled in the art that various changes and modifications can be made without changing the technical concept and essential features of the present invention. Thus, it is understood that the above-described embodiments are illustrative in all respects and do not limit the present invention. The various embodiments disclosed herein are not intended to be limiting, and the true scope and spirit are indicated in the following claims. The present invention should be limited only by the terms of the appended claims, as well as the full scope of equivalents to which such claims extend.

Claims (120)

1. A compound represented by formula 1 below, or a pharmaceutically acceptable salt thereof: where in formula 1: X ₁ - X ₃ each independently represents N or C(H); Y ₁ and Y ₂ each independently represent N(R ₄ ), C(H), O or S, and at least one of Y ₁ and Y ₂ represents N(R ₄ ); n is 0 or 1; represents or with the formation of an aromatic or non-aromatic condensed heterocyclic ring; R ₁ is hydrogen, C _1-6 alkyl or C _1-6 alkylcarbonyl; R ₂ and R ₃ each independently represent hydrogen, C _1-6 alkyl, halogen or C _1-6 alkoxy; and R ₄ is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl-C _0-6 alkyl or C _6-10 aryl. 2. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₁ is hydrogen, C _1-6 alkyl or C _1-6 alkylcarbonyl; R ₂ is hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy; R ₃ is hydrogen or C _1-6 alkyl; and R4 is hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl-C _0-6 alkyl or C _6-10 aryl. 3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ₁ is hydrogen, methyl or acetyl; R ₂ represents hydrogen, chlorine, fluorine, methyl or methoxy; R ₃ is hydrogen or methyl; and R ₄ is hydrogen, methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl or phenyl. 4. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is represented by formula 2 below: where in formula 2 above: one of Y ₁ and Y ₂ is CH and the other is NR ₄ ; when connected with SN it represents , A when associated with NR ₄ it represents ; R ₃ is hydrogen or methyl; and R ₄ is hydrogen, methyl or isopropyl. 5. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is represented by formula 3 below: where in formula 3 above: X ₃ represents C(H) or N; R ₁ is hydrogen, methyl or acetyl; R ₂ is hydrogen, chlorine, fluorine, methyl or methoxy; and R _4' and R _4ʺ each independently represent hydrogen, methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl or phenyl. 6. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is represented by formula 4 below: where in formula 4 above: Y ₁ represents S or O; and R ₄ is hydrogen, methyl, isopropyl or difluoromethyl. 7. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is 1) (1-oxo-1,2-dihydroisoquinolin-7-yl)carbonohydrazonoyl dicyanide, 2) (2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbonohydrazonoyl dicyanide, 3) (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-7-yl)carbonohydrazonoyl dicyanide, 4) (1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide, 5) (2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide, 6) (2-isopropyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide, 7) (2,3-dimethyl-1-oxo-1,2-dihydroisoquinolin-5-yl)carbonohydrazonoyl dicyanide, 8) (2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide, 9) (6-fluoro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 10) (6-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 11) (7-chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 12) (1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide, 13) (2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 14) (3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 15) (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 16) (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 17) (1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 18) (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 19) (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 20) (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide, 21) (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d|oxazol-6-yl)carbonohydrazonoyl dicyanide, 22) (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 23) (1,3-diisopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 24) (1,3-bis(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 25) (1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide, 26) (4-methyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide, 27) (1,4-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl)carbonohydrazonoyl dicyanide, 28) (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide, 29) (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide, 30) (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)carbonohydrazonoyl dicyanide, 31) (1,3,6-trimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 32) (6-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 33) (7-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 34) (1,3-diisopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide, 35) (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 36) (3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 37) (3-(difluoromethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 38) (1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 39) (3-(difluoromethyl)-1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 40) (1-cyclopropyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 41) (1-cyclopropyl-3-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 42) (1-cyclopropyl-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 43) (3-(difluoromethyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide, 44) (1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide, 45) (1-isopropyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide, 46) (1-(difluoromethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide, 47) (3-methyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide, 48) (3-ethyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide, 49) (3-ethyl-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide, 50) (1-(difluoromethyl)-3-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide, 51) (3-cyutopropyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide, 52) (3-cyclopropyl-1-ethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide, 53) (3-cyclopropyl-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide, 54) (3-isopropyl-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide, 55) (1-ethyl-3-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)carbonohydrazonoyl dicyanide, 56) (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)(methyl)carbonohydrazonoyl dicyanide or 57) acetyl (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl) carbonohydrazonoyl dicyanide. 8. A method for producing a compound according to any of paragraphs 1-7, comprising: a first step of reacting a compound represented by formula 5 below, comprising a reactive amino group at one end, with sodium nitrite and malononitrile in the presence of an acid to form an imine bond; and optionally, a second step of introducing a substituent R ₁ into the product obtained in the previous step, when R ₁ is a substituent other than hydrogen: where in formula 5 above: X ₁ - X ₃ , Y ₁ , Y ₂ , n, , R ₂ and R ₃ are as defined in paragraph 1, and when Y ₁ and Y ₂ are N(H), then N(H) is protected by tert-butoxycarbonyl. 9. The method of claim 8, wherein when N(H) in Y ₁ and Y ₂ is protected with tert-butoxycarbonyl, the method further comprises a deprotection step after said reaction. 10. The method according to claim 8, wherein the first stage is carried out in the form of a series of processes including the stages: 1-1) dissolving the compound of formula 5 and sodium nitrite in a solvent C _1-4 lower alcohol and adding to it an aqueous solution of acid at a temperature from -5°C to 5°C to form a diazonium salt, 1-2) adding malononitrile to the reaction solution comprising the diazonium salt obtained in step 1-1), and carrying out the reaction at a temperature of 15°C to 40°C, and 1-3) neutralization of the reaction solution from step 1-2) by adding an aqueous solution of a base to it. 11. The method according to claim 8, wherein the compound of formula 5 is obtained from a compound represented by any of formulas 5-a to 5-c: 12. The method according to claim 11, further comprising, before the first stage, a stage of reducing the nitro group of the compound represented by one of the formulas from 5-a to 5-c to an amino group. 13. The method according to claim 12, wherein the compound represented by formula 5-a above is obtained by reacting a precursor of a compound in which one of Y ₁ and Y ₂ is CH and the other is O with an amine-based compound NH ₂ R ₄ in a state of dissolution in an organic solvent so that the O-site is replaced by NR ₄ . 14. The method according to claim 13, wherein the precursor of the compound represented by formula 5-a above, in which one of Y ₁ and Y ₂ is CH and the other is O, is optionally obtained by cyclization between a nitrobenzoic acid derivative and N,N-dimethylformamide dimethyl acetal or acetone acetal. 15. The method according to claim 11, wherein the compound represented by formula 5-b or 5-c above is optionally obtained by further carrying out the step of introducing the substituent R ₄ by reaction with a precursor of the compound comprising R ₄ and a reactive halide. 16. The method of claim 11, wherein the compound represented by formula 5-b above is optionally obtained by cyclization between unsubstituted or R ₂ -substituted 1,2-diaminnitrophenyl and carbonyldiimidazole (CDI). 17. A pharmaceutical composition for inhibiting tau protein aggregation, comprising an effective amount of the compound according to claim 1 as an active ingredient and a pharmaceutically acceptable carrier. 18. A pharmaceutical composition for preventing or treating a disease caused by tau protein aggregation, comprising an effective amount of the compound according to claim 1 as an active ingredient and a pharmaceutically acceptable carrier. 19. The pharmaceutical composition of claim 18, wherein the disease caused by tau protein aggregation is selected from the group consisting of Alzheimer's disease, Parkinson's disease, vascular dementia, acute stroke, trauma, cerebrovascular disease, brain injury, spinal cord injury, peripheral neuropathy, retinopathy, glaucoma and tauopathy. 20. The pharmaceutical composition of claim 19, wherein the tauopathy is 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), chromosome 17-associated parkinsonism, lytico-bodig's disease (Guam complex parkinsonism-dementia), ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, pantothenate kinase-associated neurodegeneration, lipofuscinosis, posttraumatic stress disorder and traumatic injury brain.