RU2802444C2 - Novel hydrazone derivative in which the terminal amino group is replaced by an aryl group or a heteroaryl group and its use - Google Patents

Abstract

FIELD: medicine, therapy.

SUBSTANCE: group of inventions is intended for the prevention or treatment of diseases caused by tau protein aggregation or hyperphosphorylation. New hydrazone derivatives of formula (4) are presented. In another embodiment, a process of their preparation is provided, comprising the reaction of a C_1-6alkyl, aryl, or heteroaryl carboxylic acid, or its anhydride with

to form an amide bond, where Y is either an unprotected or protected amine or nitro group; and the reaction of sodium nitrite, the heterocycle linked to the carboxamido group obtained in the previous step, and malononitrile in the presence of an acid to form an imino bond. Also the pharmaceutical compositions containing these compounds and used to inhibit tau protein aggregation are provided, to inhibit tau protein hyperphosphorylation, to prevent or treat diseases caused by tau protein aggregation or hyperphosphorylation.

EFFECT: group of inventions provides new hydrazone derivatives of formula (4) having inhibitory activity against tau protein aggregation and tau protein hyperphosphorylation.

10 cl, 8 tbl, 176 ex

Description

Technical field

The present invention relates to new hydrazone derivatives in which the terminal amino group is replaced by an aryl or heteroaryl group, and their use.

State of the art

Tau protein (tau(τ) protein), which is a microtubule-associated protein (MAP) mainly expressed in the axons of nerve cells with a molecular weight of 50,000 to 70,000, serves to stabilize microtubules and presents molecular diversity through phosphorylation. In humans, tau protein is produced in six isoforms by the insertion of 29 or 58 amino acid residues at the N-terminus and alternative splicing of mRNA from 3 or 4 repeat 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 pathological hyperphosphorylation occurs, tau protein dissociates from microtubules, resulting in insoluble aggregation. In addition, a structural backbone driving 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 repeated conserved sequences. Among these repetitive sequences, positively charged residues play an important role in binding to highly negatively charged microtubules (20 to 30 electrons per αβ-tubulin dimer). The microtubule binding affinity of tau is also actively regulated by phosphorylation of tau protein, and this phosphorylation causes dynamic rearrangement of microtubule networks. When tau protein is excessively phosphorylated, the balance of this dynamic rearrangement is disrupted and the affinity for microtubules rapidly decreases.

Hyperphosphorylation and/or aggregation of tau proteins causes abnormal accumulation of these tau proteins in nerve cells, which has been cited as a cause of a variety of neurodegenerative diseases and the like. 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. Examination of the microstructures of neurofibrillary tangles (NFTs) shows that their microstructures consist of paired helical filaments (PHFs), in which tau proteins are entangled like thin filaments and are aggregated and hyperphosphorylated, unlike normal tau protein. The phenomenon of abnormal aggregation of tau protein also occurs in tauopathy. In this case, although it is not known exactly what role tau protein aggregation plays in the development of tauopathy, this tau protein aggregation phenomenon is similar to the aggregation phenomenon that is common in common neurodegenerative diseases.

Thus, although hyperphosphorylation and/or aggregation of tau protein is known to cause a variety of neurodegenerative diseases, including Alzheimer's disease and tauopathy, the specific mechanism of how these abnormal tau species cause changes in the signaling pathway and cause neurotoxicity has not yet been confirmed, and so far There are no effective treatments or therapeutic agents to treat these diseases.

Description

Technical problem

The inventors of the present invention have devoted much effort to the discovery of new small molecule compounds capable of inhibiting the aggregation and/or hyperphosphorylation of tau protein. As a result, they found that a series of hydrazone derivatives, in which the terminal amino group is replaced by an aryl or heteroaryl group, effectively inhibited tau protein aggregation and did not exhibit cytotoxicity at effective concentrations. Based on this discovery, the present invention has been completed.

Technical solution

In a first aspect, the present invention provides a compound represented by Formula 1 below, or a pharmaceutically acceptable salt thereof:

in formula 1 above,

R ₁ represents hydrogen or C _1-6 alkyl;

R ₂ represents unsubstituted or substituted C _6-14 and aryl, 5-14 membered heteroaryl or 5-14 membered heterocyclyl;

R ₃ to R ₅ represent i) all hydrogen atoms, ii) form a triple bond together with one N, iii) R ₃ and R ₄ form a double bond together with NH, O or S to form an imine, oxo or thioxo, respectively , and R ₅ is a C _1-6 alkoxy, amino, alkylamino, di(C _1-6 alkyl) amino or 5-14 membered heterocyclyl, or iv) R ₃ to R ₅ are linked to an O, N or S heteroatom or a double bond and contain a carbon and a heteroatom linked thereto to form an unsubstituted or substituted 5-14 membered heteroaryl or heterocyclyl; And

R ₆ to R ₈ represent i) all hydrogen atoms, ii) form a triple bond together with one N, iii) R ₆ and R ₇ form a double bond together with NH, O or S to form an imine, oxo or thioxo, respectively , and R ₈ is C _1-6 alkoxy, amino, C _1-6 alkylamino, di(C _1-6 alkyl) amino or 5-14 membered hegerocyclyl, or iv) R ₆ to R ₈ are linked to an O hegeroatom , N or S with a single or double bond and contain a carbon and a heteroatom linked to it to form an unsubstituted or substituted 5-14 membered heteroaryl or heterocyclyl;

where heteroaryl or heterocyclyl contains at least one of O, N and S,

substituted aryl, heteroaryl or heterocyclyl may contain C _1-6 alkyl; C _1-6 alkoxy; halogen; C _1-6 perfluoroalkyl; C _1-6 perfluoroalkoxy; C _1-6 haloalkyl; carbamoyl; carboxamido; C _6-10 aryloxy; unsubstituted C _6-14 aryl, 5-14 membered heteroaryl or 5-14 membered heterocyclyl; or _C6-14 aryl, 5-14 membered heteroaryl or 5-14 membered heterocyclyl substituted with at least one selected from the group consisting of _C1-6 alkyl, _C1-6 alkoxy, halogen, nitro, C _1-6 alkoxycarbonyl, C _1-6 perfluoroalkyl, C _1-6 perfluoroalkoxy, C _1-6 haloalkyl, amino, C _1-6 alkylamino, di(C _1-6 alkyl)amino and alkoxycarbonyl, as a substituent, and

carbamoyl and carboxamido may be substituted by at least one selected from the group consisting of C _1-6 alkyl, aryl and heteroaryl, unsubstituted or substituted C _1-6 alkoxy, hydroxy, cyano or C _1-6 alkyl.

The second aspect of the present invention provides a method for preparing a compound of the first aspect, comprising the step of reacting sodium nitrite, an amino derivative of R ₂ (R ₂ -NH ₂ ) and in the presence of an acid to form an imino bond.

In a third aspect of the present invention, there is provided a method for preparing the compound of the first aspect, comprising the steps of:

a1) preparation of aniline derivative substituted with aryl or heteroaryl, unsubstituted or substituted with R ₂ ' or R ₂ "; and

a2) reacting with sodium nitrite, an aniline derivative and malononitrile in the presence of an acid to form an imino bond.

A fourth aspect of the present invention provides a method for producing the compound of the first aspect, comprising the step of reacting sodium nitrite, a 5-14 membered heteroaryl or 5-14 membered heterocyclyl derivative containing an amino group, and malononitrile in the presence of an acid to form an imino bond.

In a fifth aspect of the present invention, there is provided a method for producing the compound of the first aspect, comprising the steps of:

introduction into the reaction of carboxylic acid R ₂ ''' or its anhydride (here Y represents an unprotected or protected amine or nitro group) to form an amide bond; And

introducing into the reaction sodium nitrite, a heterocyclic derivative containing R ₂ ''', associated with the carboxamido group obtained in the previous step, and malononitrile in the presence of an acid to form an imino bond.

In a sixth aspect of the present invention, there is provided a method for producing the compound of the first aspect, comprising the steps of:

introduction into the reaction of sodium nitrite, amino derivative R ₂ (R ₂ -NH ₂ ) and formation of imino bonds; And

adjusting the pH of the reaction solution to 5-7 using a base.

A seventh aspect of the present invention provides a composition for inhibiting tau protein aggregation containing a compound of the present invention as an active ingredient.

An eighth aspect of the present invention provides a composition for inhibiting the hyperphosphorylation of tau protein containing a compound of the present invention as an active ingredient.

In a ninth aspect, the present invention provides a pharmaceutical composition for preventing or treating diseases caused by aggregation or hyperphosphorylation of tau protein, containing a compound of the present invention as an active ingredient.

A tenth aspect of the present invention provides a method for preventing or treating diseases caused by aggregation or hyperphosphorylation of tau protein, the method comprising the step of administering a pharmaceutical composition of the present invention to a subject in need thereof.

Beneficial Effects

According to the present invention, since the novel hydrazone derivative in which the terminal amino group is replaced by an aryl or heteroaryl group can effectively inhibit the aggregation and/or hyperphosphorylation of tau protein, the hydrazone derivative can be effectively used for the prevention or treatment of diseases caused by it, such as Alzheimer's and various tauopathies.

The best method according to this invention

In a first aspect, the present invention provides a compound represented by Formula 1 below, or a pharmaceutically acceptable salt thereof:

in formula 1 above,

R ₁ represents hydrogen or C _1-6 alkyl;

R ₁ represents unsubstituted or substituted C _6-14 aryl, 5-14 membered heteroaryl or 5-14 membered heterocyclyl;

R ₃ to R ₅ represent i) all hydrogen atoms, ii) form a triple bond together with one N, iii) R ₃ and R ₄ form a double bond together with NH, O or S to form an imine, oxo or thioxo, respectively , and R ₅ is a C _1-6 alkoxy, amino, alkylamino, di(C _1-6 alkyl) amino or 5-14 membered heterocyclyl, or iv) R ₃ to R ₅ are linked to an O, N or S heteroatom or a double bond and contain a carbon and a heteroatom linked thereto to form an unsubstituted or substituted 5-14 membered heteroaryl or heterocyclyl; And

R ₆ to R ₈ represent i) all hydrogen atoms, ii) form a triple bond together with one N, iii) R ₆ and R ₇ form a double bond together with NH, O or S to form an imine, oxo or thioxo, respectively , and R ₈ is C _1-6 alkoxy, amino, C _1-6 alkylamino, di(C _1-6 alkyl) amino or 5-14 membered heterocyclyl, or iv) R ₆ to R ₈ are linked to an O heteroatom , N or S with a single or double bond and contain a carbon and a heteroatom linked to it to form an unsubstituted or substituted 5-14 membered heteroaryl or heterocyclyl;

where heteroaryl or heterocyclyl contains at least one of O, N and S,

substituted aryl, heteroaryl or heterocyclyl may contain C _1-6 alkyl; C _1-6 alkoxy; halogen; C _1-6 perfluoroalkyl; C _1-6 perfluoroalkoxy; C _1-6 haloalkyl; carbamoyl; carboxamido; C _6-10 aryloxy; unsubstituted C _6-14 aryl, 5-14 membered heteroaryl or 5-14 membered heterocyclyl; or _C6-14 aryl, 5-14 membered heteroaryl or 5-14 membered heterocyclyl substituted with at least one selected from the group consisting of _C1-6 alkyl, _C1-6 alkoxy, halogen, nitro, C _1-6 alkoxycarbonyl, C _1-6 perfluoroalkyl, C _1-6 perfluoroalkoxy, C _1-6 haloalkyl, amino, C _1-6 alkylamino, di(C _1-6 alkyl) amino and C _1-6 alkoxycarbonyl, as a substituent , And

carbamoyl and carboxamido may be substituted by at least one selected from the group consisting of C _1-6 alkyl, aryl and heteroaryl, unsubstituted or substituted C _1-6 alkoxy, hydroxy, cyano or C _1-6 alkyl.

In particular, in the compound of the present invention,

R ₁ represents hydrogen or methyl;

R ₂ is unsubstituted or substituted phenyl, benzothiazolyl, carbazolyl, indazolyl, quinolinyl, indolyl, pyrrolopyridinyl, benzoisoxazolyl, dihydrobenzothiazolyl, oxodihydrobenzothiazolyl, benzoxazolyl, oxodihydrobenzoxazolyl, benzoimidazolyl or oxodihydrobenzoimidazolyl;

from R ₃ to R ₅ form -ON, -CH ₃ , -CO ₂ Me, -CO ₂ Et, -CONH ₂ , -CSNH ₂ ,

(here R ₃ ' represents alkyl) together with C associated with it; and also from R ₆ to R ₈ form -ON, -CH ₃ , -CO ₂ Me, -CO ₂ Et, -CONH ₂ , -CSNH ₂ ,

(here R ₃ ' represents C _1-6 alkyl),

where heteroaryl and heterocyclyl contain at least one O, N or S,

substituted phenyl, benzothiazolyl, carbazolyl, indazolyl, quinolinyl, indolyl, pyrrolopyridinyl, benzoisoxazolyl, dihydrobenzothiazolyl, oxodihydrobenzothiazolyl, benzoxazolyl, oxodihydrobenzolyl, benzoimidazolyl or oxodihydrobenzoimidazolyl may contain methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, fluorine , chlorine, bromine, morpholinyl, carbamoyl, carboxamido, phenoxy or phenyl, piperidinyl, thiazolyl, pyridinyl, pyridazinyl, pyramidinyl, pyrazyl, pyrazolyl, benzothiazolyl, naphthyl, pyrazolopyrimidinyl, imidazopyrimidinyl, quinoxalinyl, imidazopyridinyl, isoquinolinyl, indazolyl, indolyl , furanyl, thiophenyl , oxotetrahydropyridazinyl or oxodihydropyridazinyl, unsubstituted or substituted by at least one selected from the group consisting of methyl, ethyl, ethynyl, methoxy, fluorine, chlorine, bromine, nitro, dimethylamino, methoxycarbonyl, ethoxycarbonyl and trifluoromethyl as a substituent, and

carbamoyl and carboxamide may be replaced by at least one selected from the group consisting of methyl, ethyl and phenyl, pyridinyl, pyrimidinyl and pyrazinyl, unsubstituted or substituted with methyl, methoxy, hydroxy or cyano.

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

in formula 2 above,

R ₁ represents hydrogen or C _1-6 alkyl;

R ₂ ' and R ₂ " are each independently hydrogen, C _1-6 alkyl, alkoxy, halogen, C _1-6 perfluoroalkyl, C _1-6 perfluoroalkoxy, C _1-6 haloalkyl, carbamoyl, unsubstituted or substituted C _{1 -6} alkyl or C _6-14 aryl, 5-14 membered heteroaryl or 5-14 membered heterocyclyl, unsubstituted or substituted by at least one selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy, halogen, nitro, C _1-6 alkoxycarbonyl, C _1-6 perfluoroalkyl, C _1-6 perfluoroalkoxy, C _1-6 haloalkyl, amino, C _1-6 alkylamino, di(C _1-6 alkyl) amino, C _1-6 alkoxycarbonyl and C _6-10 aryloxy.

Specifically, in Formula 2 above,

R ₁ represents hydrogen or methyl;

R ₂ ' is hydrogen, fluorine, methoxy or morpholinyl; And

R ₂ '' represents methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, fluorine, chlorine, bromine, morpholinyl, carbamoyl, carboxamido, phenoxy or thiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazolyl, pyrazolyl, benzothiazolyl, naphthyl, pyrazolopyrimidinyl, imidazopyrimidinyl, quinoxalinyl, imidazopyridinyl, isoquinolinyl, indazolyl, indolyl, oxotetrahydropyridazinyl or oxodihydropyridazinyl, unsubstituted or substituted by at least one selected from the group consisting of methyl, ethyl, ethynyl, methoxy, fluorine, chlorine, bromine , nitro, dimethylamino, ethoxycarbonyl and trifluoromethyl.

For example, the compound of the present invention may be represented by Formula 3 below:

in formula 3 above,

R ₁ represents hydrogen or C _1-6 alkyl;

Cy is an unsubstituted or substituted 5-14 membered heteroaryl or 5-14 membered heterocyclyl: and

substituted 5-14 membered heteroaryl or 5-14 membered heterocyclyl is unsubstituted or substituted with C _1-6 alkyl; C _1-6 alkoxy; halogen; C _1-6 perfluoroalkyl; perfluoroalkoxy; C _1-6 haloalkyl; carbamoyl, unsubstituted or substituted C _1-6 alkyl; C _6-10 aryloxy; or C _6-14 aryl, 5-14 membered heteroaryl or 5-14 membered heterocyclyl, unsubstituted or substituted by at least one selected from the group consisting of C _1-6 alkyl, halogen, and di(C _1-6 alkyl)amino.

Specifically, in Formula 3 above,

R ₁ represents hydrogen;

Cy is unsubstituted or substituted benzothiazolyl, carbazolyl, indazolyl, quinolinyl, indolyl, pyrrolopyridinyl, oxodihydrobenzothiazolyl, oxodihydrobenzoxazolyl or oxodihydrobenzoimidazolyl; And

substituted 5-14 membered heteroaryl or 5-14 membered heterocyclyl is unsubstituted or substituted with methyl, ethyl, propyl, butyl, isopropyl, isobutyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoroethyl, difluoromethyl, trifluoromethoxy, dimethylcarbamoyl, phenoxy or phenyl, pyridinyl, furanyl or thiophenyl, unsubstituted or substituted by at least one selected from the group consisting of methyl, fluorine and dimethylamino.

For example, the compound of the present invention may be represented by Formula 4 below:

in formula 4 above,

X ₁ to X ₃ are different from each other, each selected from C, N, O and S, and each linked to a carboxamido group through a C site;

R ₁ represents hydrogen or C _1-6 alkyl; And

R ₂ ''' is C _1-6 alkyl or aryl or heteroaryl, unsubstituted or substituted by at least one selected from the group consisting of C _1-6 alkoxy, hydroxy, cyano and C _1-6 alkyl.

Specifically, in Formula 4 above,

X ₁ to X ₃ are sequentially N, C and S or O, N and C and are linked to the carboxamido group through the C site;

R ₁ represents hydrogen; And

R ₂ ''' is methyl or phenyl, pyridinyl, pyrazinyl or pyrimidinyl, unsubstituted or substituted by at least one selected from the group consisting of methoxy, hydroxy, cyano and methyl.

For example, the compound of the present invention may be represented by Formula 5 below:

in formula 5 above,

R ₁ represents hydrogen or C _1-6 alkyl;

R ₂ "" represents 5-14 membered heteroaryl or 5-14 membered heterocyclyl, unsubstituted or substituted with C _1-6 alkyl; And

R ₃ to R ₅ are i) all hydrogen atoms, ii) all form a triple bond together with one N, iii) R ₃ and R ₄ form a double bond together with NH, O or S to form an imine, oxo or thioxo, respectively, and R ₅ represents C _1-6 alkoxy, amino, C _1-6 alkylamino, di(C _1-6 alkyl) amino or 5-14 membered heterocyclyl, or iv) R ₃ to R ₅ are linked to a heteroatom O, N or S by a single or double bond and contain a carbon and a heteroatom linked to it to form an unsubstituted or substituted 5-14 membered heteroaryl or heterocyclyl.

Specifically, in Formula 5 above,

R ₁ represents hydrogen;

R ₂ "" is pyrimidinyl or oxotetrahydropyridazinyl, unsubstituted or substituted with at least one substituent selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl and difluoromethyl;

from R ₃ to R ₅ form -ON, -CH ₃ , -CO ₂ Me, -CO ₂ Et, -CONH ₂ , -CSNH ₂ , (here _R3 ' represents methyl) along with its associated C.

More specifically, the connection may be

1. (4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

2. (4-(5-fluoropyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

3. (4-(5-fluoro-4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

4. (4-(5-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

5. (4-(5-ethylpyrimidin-2-yl)phenyl))carbonohydrazonoyl dicyanide,

6. (4-(4-ethylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

7. (4-(5-chloropyrimidin-2-yl)carbonohydrazonoyl dicyanide,

8. (4-(5-methoxypyrimidin-2-yl)-phenyl)carbonohydrazonoyl dicyanide,

9. (4-(2,4-dimethylthiazol-5-yl)phenyl)carbonohydrazonoyl dicyanide,

10. (4-(pyridin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

11. (4-(2-methylthiazol-5-yl)phenyl)carbonohydrazonoyl dicyanide,

12. (4-(4-methylthiazol-5-yl)phenyl)carbonohydrazonoyl dicyanide,

13. biphenyl-4-ylcarbonohydrazonoyl dicyanide,

14. (4'-methylbiphenyl-4-yl)carbonohydrazonoyl dicyanide,

15. (4-(pyridin-3-yl)phenyl)carbonohydrazonoyl dicyanide,

16. (4-(pyridin-4-yl)phenyl)carbonohydrazonoyl dicyanide,

17. (4-(pyridazin-3-yl)phenyl)carbonohydrazonoyl dicyanide,

18. (4-(5-methylthiazol-2-yl)phenyl)carbonohydrazonoyl dicyanide,

19. ethyl 2-(4-(2-(dicyanomethylene)hydrazinyl)phenyl)thiazole-5-carboxylate,

20. (4-(thiazol-5-yl)phenyl)carbonohydrazonoyl dicyanide,

21. (3'-fluoro-4'-nitrobiphenyl-4-yl)carbonohydrazonoyl dicyanide,

22. (4-(6-fluoropyridin-3-yl)phenyl)carbonohydrazonoyl dicyanide,

23. (2',4'-dimethylbiphenyl-4-yl)carbonohydrazonoyl dicyanide,

24. methyl 4'-(2-(dicyanomethylene)hydrazinyl)-2-fluorobiphenyl-4-carboxylate,

25. (2'-methyl-4'-nitrobiphenyl-4-yl)carbonohydrazonoyl dicyanide,

26. (2',4'-dichlorobiphenyl-4-yl)carbonohydrazonoyl dicyanide,

27. (2'-methoxy-4'-methylbiphenyl-4-yl)carbonohydrazonoyl dicyanide,

28. (4-(pyrazin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

29. (4-(5-(trifluoromethyl)pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

30. (4-(4,6-dimethylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

31. (4-(4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

32. (4-(pyrimidin-5-yl)phenyl)carbonohydrazonoyl dicyanide,

33. (4-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)carbonohydrazonoyl dicyanide,

34. (4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)carbonohydrazonoyl dicyanide,

35. (4-(1H-pyrazol-1-yl)phenyl) carbonohydrazonoyl dicyanide,

36. (4-(4-methyl-1H-pyrazol-1-yl)phenyl)carbonohydrazonoyl dicyanide,

37. (2-fluoro-4-(4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

38. (2-fluoro-4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

39. (3-fluoro-4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

40. (3-fluoro-4-(4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

41. (2-methoxy-4-(5-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

42. (2-methoxy-4-(4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

43. (2-methoxy-4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

44. (4-(5-fluoropyrimidin-2-yl)-2-morpholinophenyl)carbonohydrazonoyl dicyanide,

45. methyl-(4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

46. (3-(5-fluoropyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

47. (5-(5-fluoropyrimidin-2-yl)-2-morpholinophenyl)carbonohydrazonoyl dicyanide,

48. (4-(benzo[d]thiazol-6-yl)phenyl)carbonohydrazonoyl dicyanide,

49. (4-(naphthalene-2-yl)phenyl)carbonohydrazonoyl dicyanide,

50. (4-(pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)carbonohydrazonoyl dicyanide,

51. (4-(imidazo[1,2-a]pyrimidin-6-yl)phenyl)carbonohydrazonoyl dicyanide,

52. (4-(quinoxalin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

53. (4-(imidazo[1,2-a]pyridin-6-yl)phenyl)carbonohydrazonoyl dicyanide,

54. (4-(isoquinolin-3-yl)phenyl)carbonohydrazonoyl dicyanide,

55. (4-(2-methyl-2H-indazol-4-yl)phenyl)carbonohydrazonoyl dicyanide,

56. (4-(2-methyl-2H-indazol-5-yl)phenyl)carbonohydrazonoyl dicyanide,

57. (4-(2-methyl-2H-indazol-7-yl)phenyl)carbonohydrazonoyl dicyanide,

58. (4-(1H-indol-5-yl)phenyl)carbonohydrazonoyl dicyanide,

59. (4-methoxybenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide,

60. benzo[d]thiazol-6-ylcarbonohydrazonoyl dicyanide,

61. benzo[d]thiazol-5-ylcarbonohydrazonoyl dicyanide,

62. (9-ethyl-9H-carbazol-3-yl)carbonohydrazonoyl dicyanide,

63. (1-methyl-1H-indazol-6-yl)carbonohydrazonoyl dicyanide,

64. quinolin-3-ylcarbonohydrazonoyl dicyanide,

65. (2-methyl-2H-indazol-6-yl)carbonohydrazonoyl dicyanide,

66. (1-methyl-1H-indazol-5-yl)carbonohydrazonoyl dicyanide,

67. quinolin-6-ylcarbonohydrazonoyl dicyanide,

68. (1-methyl-1H-indol-5-yl)carbonohydrazonoyl dicyanide,

69. (1H-indazol-5-yl)carbonohydrazonoyl dicyanide,

70. (1H-indazol-6-yl)carbonohydrazonoyl dicyanide,

71. (1H-indol-5-yl)carbonohydrazonoyl dicyanide,

72. (1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,

73. (3-methyl-1H-indazol-6-yl)carbonohydrazonoyl dicyanide,

74. (3-methyl-1H-indazol-5-yl)carbonohydrazonoyl dicyanide,

75. (1H-indol-4-yl)carbonohydrazonoyl dicyanide,

76. (1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,

77. (1-propyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,

78. (1-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,

79. (1-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,

80. (1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,

81. (2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,

82. (3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,

83. (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,

84. (4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,

85. (2-(dimethylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide,

86. (2-(4-methoxybenzamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

87. (2-(2-hydroxybenzamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

88. (2-acetamidobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

89. (2-(3-cyanobenzamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

90. (2-(5-methylnicotinamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

91. (2-(3-hydroxypicolinamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

92. (2-(pyrazin-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

93. (2-(5-methylpyrazin-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

94. (2-(pyrimidine-5-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

95. (2-(2-methylpyrimidin-5-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

96. (2-(4-methylpyrimidin-5-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

97. (2-(3-methylpyrazin-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

98. (2-(6-methylpyrazin-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

99. (2-(pyrazin-2-carboxamido)benzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide,

100. (2-(5-methylpyrazin-2-carboxamido)benzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide,

101. (2-phenylbenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

102. (2-(4-fluorophenyl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

103. (2-(4-(dimethylamino)phenyl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

104. (2-(pyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

105. (2-(6-methylpyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

106. (2-(6-fluoropyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

107. (2-(furan-2-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

108. (2-(thiophen-2-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

109. (2-(5-fluoropyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

110. (2-(5-methylpyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

111. (2-(pyridin-3-yl)benzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide,

112. (2-(5-methylpyridin-3-yl)benzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide,

113. benzo[d]thiazol-2-ylcarbonohydrazonoyl dicyanide,

114. (6-fluorobenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide,

115. (6-chlorobenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide,

116. (6-bromobenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide,

117. (6-(trifluoromethyl)benzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide,

118. (4-chlorobenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide,

119. (5-chlorobenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide,

120. (5-bromobenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide,

121. (6-methoxybenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide,

122. (6-ethoxybenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide,

123. (6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide,

124. (6-methylbenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide,

125. (4-methylbenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide,

126. (4,6-dimethylbenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide,

127. (5,6-dimethylbenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide,

128. (6-phenoxybenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide,

129. (6-phenylbenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide,

130. (3-(pyrazin-2-carboxamido)benzo[d]isoxazol-5-yl)carbonohydrazonoyl dicyanide,

131. (3-(5-methylpyrazin-2-carboxamido)benzo[d]isoxazol-5-yl)carbonohydrazonoyl dicyanide,

132. (3-(3-cyanobenzamido)benzo[d]isoxazol-5-yl)carbonohydrazonoyl dicyanide,

133. (3-(4-methoxybenzamido)benzo[d]isoxazol-5-yl)carbonohydrazonoyl dicyanide,

134. (2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

135. (3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

136. (2-methoxybenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

137. (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide,

138. (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide,

139. (2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide,

140. diethyl 2-(2-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)hydrazono)malonate,

141. 2-imino-N'-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)-2-(piperazin-1-yl)acetohydrazonoyl cyanide,

142. 2-imino-N'-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)-2-morpholinoacetohydrazonoyl cyanide,

143. methyl 2-(2-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)hydrazono)propanoate,

144. methyl 2-cyano-2-(2-(4-(pyrimidin-2-yl)phenyl)hydrazono)acetate,

145. 2-amino-2-oxo-N'-(4-(pyrimidin-2-yl)phenyl)acetohydrazonoyl cyanide,

146. ethyl 2-cyano-2-(2-(4-(pyrimidin-2-yl)phenyl)hydrazono)acetate,

147. 2-amino-N'-(4-(pyrimidin-2-yl)phenyl)-2-thioxoacetohydrazonoyl cyanide,

148. 4-methyl-N'-(4-(pyrimidin-2-yl)phenyl)thiazol-2-carbohydrazonoyl cyanide,

149. (4-(5-ethynylpyrimidin-2-yl)phenyl)carbohydrazonoyl dicyanide,

150. (4'-(dimethylamino)-3-fluorobiphenyl-4-yl)carbohydrazonoyl dicyanide,

151. (4'-(dimethylamino)biphenyl-4-yl)carbohydrazonoyl dicyanide,

152. (4-(6-(dimethylamino)pyridin-3-yl)phenyl)carbohydrazonoyl dicyanide,

153. (4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide,

154. (4-(4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide,

155. (4-(5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide,

156. (4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide,

157. (4-(1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide,

158. (4-(1,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide,

159. (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide,

160. (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide,

161. (2-isopropoxybenzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide,

162. (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbohydrazonoyldicyanide,

163. (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbohydrazonoyl dicyanide,

164. (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbohydrazonoyl dicyanide,

165. (1,3-diisopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbohydrazonoyl dicyanide,

166. (1,3-bis(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbohydrazonoyl dicyanide,

167. (2-(methylamino)benzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide,

168. (2-(dimethylamino)benzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide,

169. (4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide,

170. (4-(1-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide, or

171. (4-(1,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide.

In addition, these compounds may be compounds represented by the following formulas.

Meanwhile, the compound of the present invention may exist in the form of a pharmaceutically acceptable salt. As a salt, a salt of an acid formed by a pharmaceutically acceptable free form of the acid can be used. As used herein, the term “pharmaceutically acceptable salt” refers to any organic or inorganic addition salt of the compound represented by Formula 1 that is relatively non-toxic and harmless to patients and the side effects caused by the salt do not interfere with the beneficial effects of the compound.

The acid addition salt is prepared in the usual 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. The same molar amounts of a compound and an acid or alcohol (such as glycol monoethyl ether) in water are heated and the mixture can then be evaporated and dried, or the precipitated salt can be filtered off under vacuum.

In this case, an organic acid or an inorganic acid can be used as the free form of the acid. As the inorganic acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid or the like can be used. The organic acid that can be used is methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid. , glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid or the like. However, the present invention is not limited to this.

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

Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups which may be present in the compounds of Formulas 15 unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of hydroxy 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 n-toluenesulfonate (tosylate). These pharmaceutically acceptable salts can be prepared by salt preparation methods known in the art.

As salts of the compounds of formula 15 of the present invention, any salt in the form of a pharmaceutically acceptable salt can be used without limitation, provided that it exhibits pharmacological activity equivalent to the compound of formula 1, for example, it inhibits aggregation and/or hyperphosphorylation of tau protein.

In addition, the compounds represented by formulas 1-5 according to 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 1-5 can be prepared from the compounds represented by Formulas 1-5 using a method known in the art.

Moreover, the compounds represented by Formulas 15 according to the present invention may be obtained in crystalline or amorphous form, and may optionally be hydrated or solvated if obtained in crystalline form. The present invention may provide compounds containing varying amounts of water, as well as stoichiometric hydrates of the compounds represented by Formulas 1-5. Solvates of the compounds represented by Formulas 1-5 according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.

In a second aspect of the present invention, there is provided a method for preparing a compound of formula 1, comprising the step of reacting sodium nitrite, an amino derivative of R ₂ (R ₂ -NH ₂ ) and in the presence of an acid to form an imino bond. In the production method of the present invention, for the reagents used therein, commercially available compounds can be used as purchased, or can be synthesized by performing one or more reactions known in the art or by changing certain reaction conditions. , known in the field. For example, compounds can be synthesized by sequentially performing one or more reactions taking into account the presence, type and position of reactive functional groups and/or heteroelements existing in the skeleton structure, but the present invention is not limited to this. This process can be similarly applied to the following aspects three through six.

In a third aspect of the present invention there is provided a method for preparing a compound of formula 2, comprising the steps of:

a1) preparation of aniline derivative substituted with aryl or heteroaryl, unsubstituted or substituted with R ₂ ' or R ₂ "; and

a2) reacting with sodium nitrite, an aniline derivative and malononitrile in the presence of an acid to form an imino bond.

For example, when R ₁ in the above formula is C _1-6 alkyl, the method may further include the step of performing alkylation by reaction with a halogenated alkane in the presence of potassium tert-butoxide or sodium hydride in an organic solvent after the imino bond formation step. However, the present invention is not limited to this, and the alkylation reaction known in the art can be suitably modified and carried out taking into account the presence or absence of other reactive substituents or heteroelements.

In particular, an aryl or heteroaryl substituted aniline derivative, unsubstituted or substituted with _R2 ' or _R2 ', can be synthesized by reacting boronic acid pinacol ester, an aniline derivative, unsubstituted or substituted with _R2 ', with a halogenated aryl or heteroaryl derivative, unsubstituted or substituted R ₂ "using a Pd(II) catalyst in the presence of a base. However, the present invention is not limited to this, and commercially available compounds can be used as purchased, or they can be synthesized using a method known in the art.

Moreover, given the potential reactivity of substituents and/or heteroelements present in the skeleton of the compound to be synthesized in the reaction, an aniline derivative substituted with aryl or heteroaryl, unsubstituted or substituted with R ₂ ' or R ₂ ", can be prepared by reduction of the nitrophenyl derivative , containing a nitro group instead of an amino group in the same skeleton, using a palladium catalyst activated with carbon in an atmosphere of hydrogen gas.

In a fourth aspect, the present invention provides a method for preparing a compound of formula 3, comprising the step of reacting sodium nitrite, a 5-14 membered heteroaryl or 5-14 membered heterocyclyl derivative containing an amino group, and malononitrile in the presence of an acid to form an imino bond.

For example, when a 5-14 membered heteroaryl or 5-14 membered heterocyclyl contains a nitrogen other than an amino group attached to it, it contains a protecting group at the nitrogen site. The method may further include the step of removing the protecting group after the imino bond formation step.

Moreover, taking into account the reactivity of functional groups and/or heteroelements present in the skeleton, 5-14 membered heteroaryl or 5-14 membered heterocyclyl can be obtained by reduction of a nitrophenyl derivative containing a nitro group instead of an amino group in the same skeleton, but the present invention by this not limited.

In a fifth aspect of the present invention there is provided a method for preparing a compound of Formula 4, comprising the steps of:

introduction into the reaction of carboxylic acid R ₂ ''' or its anhydride (here Y represents an unprotected or protected amine or nitro group) to form an amide bond; And

introducing into the reaction sodium nitrite, a heterocyclic derivative containing R ₂ ''', associated with the carboxamido group obtained in the previous step, and malononitrile in the presence of an acid to form an imino bond.

Here, when Y represents a protected amino group or a nitro group, the method may further include the step of converting the protected amino group or nitro group into an amino group before the step of forming an imino group.

In a sixth aspect of the present invention there is provided a method for preparing a compound of Formula 5, comprising the steps of:

introduction into the reaction of sodium nitrite, amino derivative R ₂ (R ₂ -NH ₂ ) and with the formation of an imino bond; And

adjusting the pH of the reaction solution to 5-7 using a base.

A seventh aspect of the present invention provides a composition for inhibiting tau protein aggregation containing a compound of the present invention as an active ingredient.

An eighth aspect of the present invention provides a composition for inhibiting the hyperphosphorylation of tau protein containing a compound of the present invention as an active ingredient.

In a ninth aspect, the present invention provides a pharmaceutical composition for preventing or treating diseases caused by aggregation or hyperphosphorylation of tau protein, containing a compound of the present invention as an active ingredient.

In specific embodiments of the present invention, a total of 171 compounds, numbered 1 to 171 and represented by Formula 1, were newly synthesized and the effects of inhibiting aggregation and hyperphosphorylation of tau protein thereof were confirmed. Moreover, to confirm the possibility of use as a pharmaceutical composition, these compounds were confirmed to exhibit no toxicity to cells.

As used herein, the term "prevention" refers to any action that inhibits or delays the onset, propagation and relapse of disease caused by aggregation or hyperphosphorylation of tau protein upon administration of the pharmaceutical composition of the present invention, and the term "treatment" refers to any action that in which the symptoms of a disease are improved or favorably modified by administration of a 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 aggregation or hyperphosphorylation Tau protein. The disease caused by aggregation or hyperphosphorylation of tau protein to which the pharmaceutical composition of the present invention can be applied may be Alzheimer's disease, Parkinson's disease, vascular dementia, acute stroke, trauma, cerebrovascular disease, traumatic brain injury, spinal cord injury, peripheral neuropathy , retinopathy, glaucoma or tauopathy. Non-limiting examples of tauopathy 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), parkinsonism associated with chromosome 17, lytic-body disease (Guam Parkinsonism-dementia complex), ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, pantothenate kinase-associated neurodegeneration, lipofuscinosis and traumatic brain injury .

For example, the composition of the present invention may further contain a pharmaceutically acceptable carrier, diluent or excipient, and may be formulated and administered in a variety of forms, such as oral compositions such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and preparations for injection of sterile injection solutions in accordance with a general method for each purpose of use, and they can be administered orally or can be administered by a variety of routes, including intravenous, intraperitoneal, subcutaneous, rectal and topical administration. Examples of suitable carrier, excipient or diluent included in this composition may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The composition of the present invention may further contain an excipient, an antiplatelet agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, a preservative and the like.

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

As the oral liquid preparation, a suspension, an antidissolution agent, an emulsion, a syrup and the like may be mentioned, and the oral liquid preparation may contain a variety of excipients such as a wetting agent, a sweetening agent, a flavoring agent and a preservative in addition to water and liquid paraffin, which are usually used as a simple thinner.

Preparations for parenteral administration include an aqueous solvent, a non-aqueous solvent, a suspending agent, an emulsifying agent, a lyophilized preparation and a suppository, which are sterilized.

As the non-aqueous solvent or suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. Witepsol, macrogol, Tween 61, cocoa butter, lauric oil, glycerogelatin or the like can be used as a suppository base. Meanwhile, the injection preparations may contain conventional additives such as a solubilizing agent, an isotonic agent, a suspending agent, an emulsifying agent, a stabilizing agent and a preservative.

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

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

For example, since the amount administered may increase or decrease depending on the route of administration, severity of the disease, gender, weight, age, etc., the amount administered does not limit the scope of the present invention in any way.

The preferred administered amount of the compound of the present invention varies depending on the condition and weight of the patient, the extent of the disease, the form of the drug, and the route and duration of administration, but can be appropriately selected by those skilled in the art. However, 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 may be administered once daily or may be divided and administered orally or parenterally.

A tenth aspect of the present invention provides a method for preventing or treating diseases caused by aggregation or hyperphosphorylation of tau protein, the method comprising the step of administering a pharmaceutical composition of the present invention to a subject in need thereof.

As used herein, the term "subject" refers to any animal, including monkeys, cows, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rabbits and guinea pigs, in addition to humans, who have or may develop develop diseases caused by aggregation or hyperphosphorylation of tau protein. Diseases can be effectively prevented or treated by administering to a subject a pharmaceutical composition of the present invention. 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 may occur when this composition is administered in combination with a conventional therapeutic agent.

As used herein, the term “administration” refers to the administration of a predetermined substance to a patient by any suitable route, and the route of administration of the composition of the present invention can be administered by any general route as long as it can reach the target tissues. The composition can be administered by intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration or rectal administration, but the present invention is not limited to this. Meanwhile, the pharmaceutical composition of the present invention can be administered using any device capable of transporting the active substance to the target cell. Preferred administrations and formulations include drugs for intravenous injection, drugs for subcutaneous injection, drugs for intradermal injection, drugs for intramuscular injection and drugs for drip injection. Injectable drugs can 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 (eg, ethyl oleate), or an alcohol (eg, ethanol, benzyl alcohol, propylene glycol). or glycerol) and may contain a pharmaceutical carrier such as a stabilizing agent to prevent denaturation (for example, ascorbic acid, sodium hydrogensulfite, sodium pyrosulfite, BHA, tocopherol or EDTA), an emulsifying agent, a buffering agent to control pH, or a preservative to inhibit the growth of microorganisms (eg, phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, or benzyl alcohol).

Principle 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 illustrative of the present invention, and the scope of the present invention is not limited to these examples and experimental examples.

Example 1: Preparation of (4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 1)

Step 1-1: Preparation of 4-(pyrimidin-2-yl)aniline

2-Bromopyrimidine (175 mg, 1.10 mmol) and 4-aminophenylboronic acid pinacol ester (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline) (200 mg , 0.91 mmol) was dissolved in 15 ml of 1,4-dioxane solution in the presence of nitrogen, and then Pd(PPh ₃ ) ₂ Cl ₂ (63 mg, 0.09 mmol) and 1.0 M aqueous sodium carbonate solution ( 3.64 ml, 3.64 mmol) to obtain the reaction mixture. The reaction mixture was stirred at 80°C for 12 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 115 mg (74% yield) of the title compound.

Step 1-2: Preparation of (4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

4-(Pyrimidin-2-yl)aniline (50 mg, 0.29 mmol) prepared according to step 1-1 and sodium nitrite (24 mg, 0.35 mmol) were dissolved in ethanol (2.5 ml) in the presence of nitrogen, and then added 1.0 M aqueous hydrochloric acid (0.73 ml, 0.73 mmol) to obtain the reaction mixture. The reaction mixture was stirred at 0°C for 1 hour to form the diazonium salt. After formation of the diazonium salt, malononitrile (23 mg, 0.35 mmol) was added, followed by stirring at room temperature for 5 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 57 mg (79% yield) of the title compound.

Example 2: Preparation of (4-(5-fluoropyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 2)

Step 2-1: Preparation of 4-(5-fluoropyrimidin-2-yl)aniline

71 mg (41% yield) of the title compound was obtained by reacting in the same manner as Step 1-1 of Example 1 except that 2-chloro-5-fluoropyrimidine (1.10 mmol) was used instead of 2 -bromopyrimidine.

Step 2-2: Preparation of (4-(5-fluoropyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

30 mg (43% yield) of the title compound was prepared by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-(5-fluoropyrimidin-2-yl)aniline was used instead of 4- (pyrimidin-2-yl)aniline.

Example 3: Preparation of (4-(5-fluoro-4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 3)

Step 3-1: Preparation of 4-(5-fluoro-4-methylpyrimidin-2-yl)aniline

139 mg (75% yield) of the title compound was obtained by reacting in the same manner as Step 1-1 of Example 1 except that 2-chloro-5-fluoro-4-methylpyrimidine (1.10 mmol ) was used instead of 2-bromopyrimidine.

Step 3-2: Preparation of (4-(5-fluoro-4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

40 mg (29% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 4-(5-fluoro-4-methylpyrimidin-2-yl)aniline was used instead of 4-(pyrimidin-2-yl)aniline.

Example 4: Preparation of (4-(5-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 4)

Step 4-1: Preparation of 4-(5-methylpyrimidin-2-yl)aniline

65 mg (39% yield) of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that 2-chloro-5-methylpyrimidine (1.10 mmol) was used instead of 2 -bromopyrimidine.

Step 4-2: Preparation of (4-(5-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

35 mg (50% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 4-(5-methylpyrimidin-2-yl)aniline was used instead of 4- (pyrimidin-2-yl)aniline.

Example 5: Preparation of 4-(5-ethylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 5)

Step 5-1: Preparation of 4-(5-ethylpyrimidin-2-yl)aniline

169 mg (93% yield) of the title compound was obtained by performing the reaction in the same manner as Step 1-1 of Example 1 except that 2-chloro-5-ethylpyrimidine (1.10 mmol) was used instead of 2 -bromopyrimidine.

Step 5-2: Preparation of (4-(5-ethylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

35 mg (25% yield) of the title compound was prepared by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-(5-ethylpyrimidin-2-yl)aniline was used instead of 4- (pyrimidin-2-yl)aniline.

Example 6: Preparation of (4-(4-ethylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 6)

Step 6-1: Preparation of 4-(4-ethylpyrimidin-2-yl)aniline

169 mg (93% yield) of the title compound was obtained by performing the reaction in the same manner as Step 1-1 of Example 1 except that 2-chloro-4-ethylpyrimidine (1.10 mmol) was used instead of 2 -bromopyrimidine.

Step 6-2: Preparation of (4-(4-ethylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

80 mg (66% yield) of the title compound was prepared by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-(4-ethylpyrimidin-2-yl)aniline was used instead of 4- (pyrimidin-2-yl)aniline.

Example 7: Preparation of (4-(5-chloropyrimidin-2-yl)carbonohydrazonoyl dicyanide (Compound 7)

Step 7-1: Preparation of 4-(5-chloropyrimidin-2-yl)aniline

67 mg (36% yield) of the title compound was obtained by reacting in the same manner as Step 1-1 of Example 1 except that 2-chloro-5-chloropyrimidine (1.10 mmol) was used instead of 2 -bromopyrimidine.

Step 7-2: Preparation of 4-(5-chloropyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

30 mg (16% yield) of the title compound was prepared by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-(5-chloropyrimidin-2-yl)aniline was used instead of 4- (pyrimidin-2-yl)aniline.

Example 8: Preparation of (4-(5-methoxypyrimidin-2-yl)-phenyl)carbonohydrazonoyl dicyanide (Compound 8)

Step 8-1: Preparation of 4-(5-methoxypyrimidin-2-yl)aniline

67 mg (36% yield) of the title compound was obtained by reacting in the same manner as Step 1-1 of Example 1 except that 2-chloro-5-methoxypyrimidine (1.10 mmol) was used instead of 2 -bromopyrimidine.

Step 8-2: Preparation of (4-(5-methoxypyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

26 mg (30% yield) of the title compound was obtained by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-(5-methoxypyrimidin-2-yl)aniline was used instead of 4- (pyrimidin-2-yl)aniline.

Example 9: Preparation of (4-(2,4-dimethylthiazol-5-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 9)

Step 9-1: Preparation of 4-(2,4-dimethylthiazol-5-yl)aniline

48 mg (26% yield) of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that 5-bromo-2,4-dimethylthiazole (1.10 mmol) was used instead of 2-bromopyrimidine.

Step 9-2: Preparation of (4-(2,4-dimethylthiazol-5-yl)phenyl)carbonohydrazonoyl dicyanide

55 mg (93% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 4-(2,4-dimethylthiazol-5-yl)aniline was used instead 4-(pyrimidin-2-yl)aniline.

Example 10: Preparation of (4-(pyridin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 10)

Step 10-1: Preparation of 4-(pyridin-2-yl)aniline

101 mg (65% yield) of the title compound was obtained by reacting in the same manner as Step 1-1 of Example 1 except that 2-bromopyridine (1.10 mmol) was used instead of 2-bromopyrimidine.

Step 10-2: Preparation of (4-(pyridin-2-yl)phenyl)carbonohydrazonoyl dicyanide

18 mg (25% yield) of the title compound was prepared by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-(pyridin-2-yl)aniline was used instead of 4-(pyrimidine -2-yl)aniline.

Example 11: Preparation of (4-(2-methylthiazol-5-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 11)

Step 11-1: Preparation of 4-(2-methylthiazol-5-yl)aniline

112 mg (57% yield) of the title compound were obtained by performing the reaction in the same manner as Step 1-1 of Example 1 except that 5-bromo-2-methylthiazole (1.10 mmol) was used instead of 2 -bromopyrimidine.

Step 11-2: Preparation of (4-(2-methylthiazol-5-yl)phenyl)carbonohydrazonoyl dicyanide

11 mg (16% yield) of the title compound was obtained by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-(2-methylthiazol-5-yl)aniline was used instead of 4- (pyrimidin-2-yl)aniline.

Example 12: Preparation of (4-(4-methylthiazol-5-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 12)

Step 12-1: Preparation of 4-(4-methylthiazol-5-yl)aniline

133 mg (76% yield) of the title compound was obtained by performing the reaction in the same manner as Step 1-1 of Example 1 except that 5-bromo-4-methylthiazole (1.10 mmol) was used instead of 2 -bromopyrimidine.

Step 12-2: Preparation of (4-(4-methylthiazol-5-yl)phenyl)carbonohydrazonoyl dicyanide

62 mg (89% yield) of the title compound was obtained by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-(4-methylthiazol-5-yl)aniline was used instead of 4- (pyrimidin-2-yl)aniline.

Example 13: Preparation of biphenyl-4-ylcarbonohydrazonoyl dicyanide (Compound 13)

Step 13-1: Preparation of biphenyl-4-amine

109 mg (70% yield) of the title compound was obtained by reacting in the same manner as Step 1-1 of Example 1 except that bromobenzene (1.10 mmol) was used instead of 2-bromopyrimidine.

Step 13-2: Preparation of biphenyl-4-ylcarbonohydrazonoyl dicyanide

29 mg (38% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that biphenyl-4-amine was used instead of 4-(pyrimidin-2-yl) aniline.

Example 14: Preparation of (4'-methylbiphenyl-4-yl)carbonohydrazonoyl dicyanide (Compound 14)

Step 14-1: Preparation of 4'-methylbiphenyl-4-amine

The title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that 1-bromo-4-methylbenzene (1.10 mmol) was used instead of 2-bromopyrimidine.

Step 14-2: Preparation of (4'-methylbiphenyl-4-yl)carbonohydrazonoyl dicyanide

48 mg (23% yield) of the title compound was obtained by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4'-methylbiphenyl-4-amine was used instead of 4-(pyrimidine-2 -yl)aniline.

Example 15: Preparation of (4-(pyridin-3-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 15) Step 15-1: Preparation of 4-(pyridin-3-yl)aniline

367 mg (23% yield) of the title compound was obtained by reacting in the same manner as Step 1-1 of Example 1 except that 3-bromopyridine (10.95 mmol) was used instead of 2-bromopyrimidine.

Step 15-2: Preparation of (4-(pyridin-3-yl)phenyl)carbonohydrazonoyl dicyanide

533 mg (100% yield) of the title compound was obtained by carrying out the reaction in the same manner as Step 1-2 of Example 1 except that 4-(pyridin-3-yl)aniline was used instead of 4-(pyrimidine -2-yl)aniline.

Example 16: Preparation of (4-(pyridin-4-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 16)

Step 16-1: Preparation of 4-(pyridin-4-yl)aniline

70 mg (32% yield) of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that 4-bromopyridine hydrochloride (1.53 mmol) was used instead of 2-bromopyrimidine.

Step 16-2: Preparation of (4-(pyridin-4-yl)phenyl)carbonohydrazonoyl dicyanide

9 mg (9% yield) of the title compound was prepared by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-(pyridin-4-yl)aniline was used instead of 4-(pyrimidine -2-yl)aniline.

Example 17: Preparation of (4-(pyridazin-3-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 17)

Step 17-1: Preparation of 4-(pyridazin-3-yl)aniline

76 mg (84% yield) of the title compound was obtained by reacting in the same manner as Step 1-1 of Example 1 except that 3-bromopyridazine (0.64 mmol) was used instead of 2-bromopyrimidine.

Step 17-2: Preparation of (4-(pyridazin-3-yl)phenyl)carbonohydrazonoyl dicyanide

42 mg (38% yield) of the title compound was obtained by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-(pyridazin-3-yl)aniline was used instead of 4-(pyrimidine -2-yl)aniline.

Example 18: Preparation of (4-(5-methylthiazol-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 18)

Step 18-1: Preparation of 4-(5-methylthiazol-2-yl)aniline

88 mg (68% yield) of the title compound was obtained by reacting in the same manner as Step 1-1 of Example 1 except that 2-bromo-5-methylthiazole (0.69 mmol) was used instead of 2 -bromopyrimidine.

Step 18-2: Preparation of (4-(5-methylthiazol-2-yl)phenyl)carbonohydrazonoyl dicyanide

30 mg (42% yield) of the title compound was prepared by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-(5-methylthiazol-2-yl)aniline was used instead of 4- (pyrimidin-2-yl)aniline.

Example 19: Preparation of ethyl 2-(4-(2-(dicyanomethylene)hydrazinyl)phenyl)thiazole-5-carboxylate (Compound 19)

Step 19-1: Preparation of ethyl 2-(4-aminophenyl)thiazole-5-carboxylate

12 mg (3% yield) of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that ethyl 2-bromothiazole-5-carboxylate (1.61 mmol) was used instead of 2-bromopyrimidine.

Step 19-2: Preparation of ethyl 2-(4-(2-(dicyanomethylene)hydrazinyl)phenyl)thiazole-5-carboxylate

12 mg (75% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that ethyl 2-(4-aminophenyl)thiazole-5-carboxylate was used instead 4-(pyrimidin-2-yl)aniline.

Example 20: Preparation of (4-(thiazol-5-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 20)

Step 20-1: Preparation of 4-(thiazol-5-yl)aniline

137 mg (85% yield) of the title compound was obtained by reacting in the same manner as Step 1-1 of Example 1 except that 5-bromothiazole (0.91 mmol) was used instead of 2-bromopyrimidine.

Step 20-2: Preparation of (4-(thiazol-5-yl)phenyl)carbonohydrazonoyl dicyanide

60 mg (83% yield) of the title compound was prepared by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-(thiazol-5-yl)aniline was used instead of 4-(pyrimidine -2-yl)aniline.

Example 21: Preparation of (3'-fluoro-4'-nitrobiphenyl-4-yl)carbonohydrazonoyl dicyanide (Compound 21)

6 mg (7% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 3'-fluoro-4'-nitrobiphenyl-4-amine was used instead of 4 -(pyrimidin-2-yl)aniline.

Example 22: Preparation of (4-(6-fluoropyridin-3-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 22)

Step 22-1: Preparation of 4-(6-fluoropyridin-3-yl)aniline

38 mg (45% yield) of the title compound was obtained by reacting in the same manner as Step 1-1 of Example 1 except that 3-bromo-6-fluoropyridine (0.55 mmol) was used instead of 2 -bromopyrimidine.

Step 22-2: Preparation of (4-(6-fluoropyridin-3-yl)phenyl)carbonohydrazonoyl dicyanide

23 mg (53% yield) of the title compound was obtained by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-(6-fluoropyridin-3-yl)aniline was used instead of 4- (pyrimidin-2-yl)aniline.

Example 23: Preparation of (2',4'-dimethylbiphenyl-4-yl)carbonohydrazonoyl dicyanide (Compound 23)

8 mg (6% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 2',4'-dimethylbiphenyl-4-amine was used instead of 4-( pyrimidin-2-yl)aniline.

Example 24: Preparation of methyl 4'-(2-(dicyanomethylene)hydrazinyl)-2-fluorobiphenyl-4-carboxylate (Compound 24)

Step 24-1: Preparation of methyl 4'-amino-2-fluorobiphenyl-4-carboxylate

93 mg (60% yield) of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that methyl 4-bromo-3-fluorobenzoate (0.69 mmol) was used instead of 2-bromopyrimidine.

Step 24-2: Preparation of methyl 4'-(2-(dicyanomethylene)hydrazinyl)-2-fluorobiphenyl]-4-carboxylate

16 mg (16% yield) of the title compound was obtained by performing the reaction in the same manner as Steps 1-2 of Example 1 except that 4'-amino-2-fluorobiphenyl-4-carboxylate was used instead of 4- (pyrimidin-2-yl)aniline.

Example 25: Preparation of (2'-methyl-4'-nitrobiphenyl-4-yl)carbonohydrazonoyl dicyanide (Compound 25)

Step 25-1: Preparation of 2'-methyl-4'-nitrobiphenyl-4-amine

98 mg (63% yield) of the title compound were prepared by reacting in the same manner as Step 1-1 of Example 1 except that 1-bromo-2-methyl-4-nitrobenzene (0.69 mmol ) was used instead of 2-bromopyrimidine.

Step 25-2: Preparation of (2'-methyl-4'-nitrobiphenyl-4-yl)carbonohydrazonoyl dicyanide

38 mg (27% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 2'-methyl-4'-nitrobiphenyl-4-amine was used instead of 4 -(pyrimidin-2-yl)aniline.

Example 26: Preparation of (2',4'-dichlorobiphenyl-4-yl)carbonohydrazonoyl dicyanide (Compound 26)

Step 26-1: Preparation of 2',4'-dichlorobiphenyl-4-amine

182 mg (84% yield) of the title compound were obtained by performing the reaction in the same manner as Step 1-1 of Example 1 except that 1-bromo-2,4-dichlorobenzene (0.91 mmol) was used instead of 2-bromopyrimidine.

Step 26-2: Preparation of (2',4'-(dichlorobiphenyl-4-yl)carbonohydrazonoyl dicyanide

47 mg (20% yield) of the title compound was obtained by reacting in the same manner as Step 1-2 of Example 1 except that 2',4'-dichlorobiphenyl-4-amine was used instead of 4-( pyrimidin-2-yl)aniline.

Example 27: Preparation of (2'-methoxy-4'-methylbiphenyl-4-yl)carbonohydrazonoyl dicyanide (Compound 27)

Step 27-1: Preparation of 2'-methoxy-4'-methylbiphenyl-4-amine

36 mg (24% yield) of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that 1-bromo-2-methoxy-4-methylbenzene (0.69 mmol ) was used instead of 2-bromopyrimidine.

Step 27-2: Preparation of (2'-methoxy-4'-methylbiphenyl-4-yl)carbonohydrazonoyl dicyanide

3 mg (6% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 2'-methoxy-4'-methylbiphenyl-4-amine was used instead of 4 -(pyrimidin-2-yl)aniline.

Example 28: Preparation of (4-(pyrazin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 28) Step 28-1: Preparation of 4-(pyrazin-2-yl)aniline

72 mg (33% yield) of the title compound was obtained by reacting in the same manner as Step 1-1 of Example 1 except that 2-bromopyrazine (1.26 mmol) was used instead of 2-bromopyrimidine.

Step 28-2: Preparation of (4-(pyrazin-2-yl)phenyl)carbonohydrazonoyl dicyanide

12 mg (12% yield) of the title compound was prepared by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-(pyrazin-2-yl)aniline was used instead of 4-(pyrimidine -2-yl)aniline.

Example 29: Preparation of (4-(5-(trifluoromethyl)pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 29)

Step 29-1: Preparation of 4-(5-(trifluoromethyl)pyrimidin-2-yl)aniline

127 mg (78% yield) of the title compound were prepared by reacting in the same manner as Step 1-1 of Example 1 except that 2-chloro-5-(trifluoromethyl)pyrimidine (0.83 mmol) was used instead of 2-bromopyrimidine.

Step 29-2: Preparation of (4-(5-(trifluoromethyl)pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

47 mg (31% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 4-(5-(trifluoromethyl)pyrimidin-2-yl)aniline was used instead of 4-(pyrimidin-2-yl)aniline.

Example 30: Preparation of (4-(4,6-dimethylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 30)

Step 30-1: Preparation of 4-(4,6-dimethylpyrimidin-2-yl)aniline

118 mg (67% yield) of the title compound was obtained by performing the reaction in the same manner as Step 1-1 of Example 1 except that 2-chloro-4,6-dimethylpyrimidine (1.05 mmol) was used instead of 2-bromopyrimidine.

Step 30-2: Preparation of (4-(4,6-dimethylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

110 mg (77% yield) of the title compound were prepared by reacting in the same manner as Step 1-2 of Example 1 except that 4-(4,6-dimethylpyrimidin-2-yl)aniline was used instead 4-(pyrimidin-2-yl)aniline.

Example 31: Preparation of (4-(4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 31)

Step 31-1: Preparation of 4-(4-methylpyrimidin-2-yl)aniline

77 mg (57% yield) of the title compound was obtained by reacting in the same manner as Step 1-1 of Example 1 except that 2-bromo-4-methylpyrimidine (0.87 mmol) was used instead of 2 -bromopyrimidine.

Step 31-2: Preparation of (4-(4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

66 mg (61% yield) of the title compound was obtained by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-(4-methylpyrimidin-2-yl)aniline was used instead of 4- (pyrimidin-2-yl)aniline.

Example 32: Preparation of (4-(pyrimidin-5-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 32)

Step 32-1: Preparation of 4 (pyrimidin 5-yl)aniline

502 mg (64% yield) of the title compound was obtained by reacting in the same manner as Step 1-1 of Example 1 except that 5-bromopyrimidine (0.87 mmol) was used instead of 2-bromopyrimidine.

Step 32-2: Preparation of (4-(pyrimidin-5-yl)phenyl)carbonohydrazonoyl dicyanide

100 mg (69% yield) of the title compound was prepared by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-(pyrimidin-5-yl)aniline was used instead of 4-(pyrimidine -2-yl)aniline.

Example 33: Preparation of (4-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 33)

Step 33-1: Preparation of 4-(1-methyl-1H-1,2,4-triazol-5-yl)aniline

40 mg (20% yield) of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that 5-bromo-1-methyl-1H-1,2,4- triazole (0.96 mmol) was used instead of 2-bromopyrimidine.

Step 33-2: Preparation of (4-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)carbonohydrazonoyl dicyanide

18 mg (25% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 4-(1-methyl-1H-1,2,4-triazole -5-yl)aniline was used instead of 4-(pyrimidin-2-yl)aniline.

Example 34: Preparation of (4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 34)

Step 34-1: Preparation of 4-(1-methyl-1H-1,2,4-triazol-3-yl)aniline

100 mg (50% yield) of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that 3-bromo-1-methyl-1H-1,2,4- triazole (0.96 mmol) was used instead of 2-bromopyrimidine.

Step 34-2: Preparation of (4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)carbonohydrazonoyl dicyanide

29 mg (40% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 4-(1-methyl-1H-1,2,4-triazole -3-yl)aniline was used instead of 4-(pyrimidin-2-yl)aniline.

Example 35: Preparation of (4-(1H-pyrazol-1-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 35)

163 mg (55% yield) of the title compound was obtained by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-(1H-pyrazol-1-yl)aniline was used instead of 4- (pyrimidin-2-yl)aniline.

Example 36: Preparation of (4-(4-methyl-1H-pyrazol-1-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 36)

Step 36-1: Preparation of 4-methyl-1-(4-nitrophenyl)-1H-pyrazole

4-Methyl-1H-pyrazole (100 mg, 1.22 mmol) was dissolved in 1.5 ml DMSO in the presence of nitrogen, and then solid potassium tert-butoxide (164 mg, 1.46 mmol) and 1-fluoro-4 were added -nitrobenzene (189 mg, 1.46 mmol) to obtain the reaction mixture. The reaction mixture was stirred at 72°C for 20 hours. When the reaction was completed, the reaction product was cooled and then extracted using distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by recrystallization using an ethanol solvent to obtain 96 mg (39% yield) of the title compound.

Step 36-2: Preparation of 4-(4-methyl-1H-pyrazol-1-yl)aniline

4-Methyl-1-(4-nitrophenyl)-1H-pyrazole obtained in accordance with step 1-1 was dissolved in 2.5 ml of ethanol, and then 10% (32 mg, 0.06 mmol) palladium catalyst was added, activated carbon, followed by stirring at room temperature for 1 hour in the presence of hydrogen gas. After completion of the reaction, the catalyst in the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 50 mg (98% yield) of the title compound.

Step 36-3: Preparation of (4-(4-methyl-1H-pyrazol-1-yl)phenyl)carbonohydrazonoyl dicyanide

50 mg (69% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 4-(4-methyl-1H-pyrazol-1-yl)aniline was used instead of 4-(pyrimidin-2-yl)aniline.

Example 37: Preparation of (2-fluoro-4-(4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 37)

Step 37-1: Preparation of 2-fluoro-4-(4-methylpyrimidin-2-yl)aniline

100 mg (50% yield) of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that 4-amino-3-fluorophenylboronic acid pinacol ester (2-fluoro-4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline) (0.84 mmol) was used instead of 4-aminophenylboronic acid pinacol ester, and 2-bromo-4-methylpyrimidine ( 1.01 mmol) was used instead of 2-bromopyrimidine.

Step 37-2: Preparation of (2-fluoro-4-(4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

46 mg (67% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 2-fluoro-4-(4-methylpyrimidin-2-yl)aniline was used instead of 4-(pyrimidin-2-yl)aniline.

Example 38: Preparation of (2-fluoro-4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 38)

Step 38-1: Preparation of 2-fluoro-4-(pyrimidin-2-yl)aniline

41 mg (17% yield) of the title compound was prepared by reacting in the same manner as Step 37-1 of Example 37 except that 2-bromopyrimidine (1.26 mmol) was used instead of 2-bromo-4 -methylpyrimidine.

Step 38-2: Preparation of (2-fluoro-4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

11 mg (19% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 2-fluoro-4-(pyrimidin-2-yl)aniline was used instead 4-(pyrimidin-2-yl)aniline.

Example 39: Preparation of (3-fluoro-4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 39)

Step 39-1: Preparation of 3-fluoro-4-(pyrimidin-2-yl)aniline

156 mg (66% yield) of the title compound were prepared by reacting in the same manner as Step 1-1 of Example 1 except that 4-amino-2-fluorophenylboronic acid pinacol ester (1.38 mmol) was used instead of pinacol ester of 4-aminophenylboronic acid.

Step 39-2: Preparation of (3-fluoro-4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

80 mg (81% yield) of the title compound was prepared by reacting in the same manner as Steps 1-2 of Example 1 except that 3-fluoro-4-(pyrimidin-2-yl)aniline was used instead 4-(pyrimidin-2-yl)aniline.

Example 40: Preparation of (3-fluoro-4-(4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 40)

Step 40-1: Preparation of 3-fluoro-4-(4-methylpyrimidin-2-yl)aniline

82 mg (35% yield) of the title compound was obtained by reacting in the same manner as Step 39-1 of Example 39 except that 2-bromo-4-methylpyrimidine (1.16 mmol) was used instead of 2 -bromopyrimidine.

Step 40-2: Preparation of (3-fluoro-4-(4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

56 mg (92% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 3-fluoro-4-(4-methylpyrimidin-2-yl)aniline was used instead of 4-(pyrimidin-2-yl)aniline.

Example 41: Preparation of (2-methoxy-4-(5-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 41)

Step 41-1: Preparation of 2-methoxy-4-(5-methylpyrimidin-2-yl)aniline

99 mg (47% yield) of the title compound were prepared by reacting in the same manner as Step 1-1 of Example 1 except that 4-amino-3-methoxyboronic acid pinacol ester (0.99 mmol) was used instead of 4-aminophenylboronic acid pinacol ester, and 2-chloro-5-methylpyrimidine (1.19 mmol) was used instead of 2-bromopyrimidine.

Step 41-2: Preparation of (2-methoxy-4-(5-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

25 mg (61% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 2-methoxy-4-(5-methylpyrimidin-2-yl)aniline was used instead of 4-(pyrimidin-2-yl)aniline.

Example 42: Preparation of (2-methoxy-4-(4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 42)

Step 42-1: Preparation of 2-methoxy-4-(4-methylpyrimidin-2-yl)aniline

80 mg (42% yield) of the title compound was prepared by reacting in the same manner as Step 41-1 of Example 41 except that 2-bromo-4-methylpyrimidine (1.12 mmol) was used instead of 2 -chloro-5-methylpyrimidine.

Step 42-2: Preparation of (2-methoxy-4-(4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

10 mg (58% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 2-methoxy-4-(4-methylpyrimidin-2-yl)aniline was used instead of 4-(pyrimidin-2-yl)aniline.

Example 43: Preparation of (2-methoxy-4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 43)

Step 43-1: Preparation of 2-methoxy-4-(pyrimidin-2-yl)aniline

29 mg (18% yield) of the title compound was prepared by reacting in the same manner as Step 41-1 of Example 41 except that 2-bromopyrimidine (0.96 mmol) was used instead of 2-chloro-5 -methylpyrimidine.

Step 43-2: Preparation of (2-methoxy-4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

26 mg (65% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 2-methoxy-4-(pyrimidin-2-yl)aniline was used instead 4-(pyrimidin-2-yl)aniline.

Example 44: Preparation of (4-(5-fluoropyrimidin-2-yl)-2-morpholinophenyl)carbonohydrazonoyl dicyanide (Compound 44)

Step 44-1: Preparation of 2-(3-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4-Bromo-2-fluoro-1-nitrobenzene (2 g, 7.88 mmol) and bis(pinacolato)diboron (4,4,4',4',5,5,5',5'-octamethyl-2 ,2'-bi(1,3,2-dioxaborolane); 2.1 g, 9.45 mmol) was dissolved in 60 ml of 1,4-dioxane solution in the presence of nitrogen, and then Pd(dppf) ₂ Cl ₂ ( 1.3 g, 1.58 mmol) and potassium acetate (3.1 g, 31.5 mmol) to obtain the reaction mixture. The reaction mixture was stirred at 80°C for 12 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 1.6 g of the title compound.

Step 44-2: Preparation of 4-(2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine

2-(3-Fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, prepared according to step 44-1, and morpholine (0.68 ml, 7.79 mmol) was dissolved in acetonitrile (20 ml) in the presence of nitrogen to obtain a reaction mixture, and then the reaction mixture was stirred at 80°C for 12 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 700 g of the title compound.

Step 44-3: Preparation of 4-(5-(5-fluoropyrimidin-2-yl)-2-nitrophenyl)morpholine

164 mg (26% yield) of the title compound was obtained by reacting in the same manner as Step 1-1 of Example 1 except that 4-(2-nitro-5-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine, prepared according to step 44-2, was used instead of 4-aminophenylboronic acid pinacol ester, and 2-chloro-5-fluoropyrimidine (2.51 mmol) was used instead of 2-bromopyrimidine.

Step 44-4: Preparation of 4-(5-fluoropyrimidin-2-yl)-2-morpholinoaniline

4-(5-(5-Fluoropyrimidin-2-yl)-2-nitrophenyl)morpholine obtained in accordance with step 44-3 was dissolved in ethyl acetate, and reduced in a manner similar to step 36-2 of Example 36 to obtain 84 mg (57% yield) of the title compound.

Step 44-5: Preparation of (4-(5-fluoropyrimidin-2-yl)-2-morpholinophenyl)carbonohydrazonoyl dicyanide

70 mg (65% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 4-(5-fluoropyrimidin-2-yl)-2-morpholinoaniline was prepared according to step 44-4 was used instead of 4-(pyrimidin-2-yl)aniline.

Example 45: Preparation of methyl (4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 45)

(4-(Pyrimidin-2-yl)phenyl)carbonohydrazonoyldide (50 mg, 0.20 mmol), obtained according to example 1, was dissolved in 1.5 ml of tetrahydrofuran, and then potassium tert-butoxide (29 mg, 0.26 mmol) at room temperature, and further iodomethane (25 μL, 0.40 mmol) was added to obtain a reaction mixture. The reaction mixture was stirred at 60°C for 4 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by recrystallization using an ethanol solvent to obtain 3 mg (6% yield) of the title compound.

Example 46: Preparation of (3-(5-fluoropyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 46)

Step 46-1: Preparation of 3-(5-fluoropyrimidin-2-yl)aniline

180 mg of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 41 except that 3-aminophenylboronic acid pinacol ester (1.37 mmol) was used instead of 4-aminophenylboronic acid pinacol ester, and 2 α-chloro-5-fluoropyrimidine (1.64 mmol) was used instead of 2-bromopyrimidine.

Step 46-2: Preparation of (3-(5-fluoropyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

70.5 mg of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 3-(5-fluoropyrimidin-2-yl)aniline was used instead of 4-(pyrimidin-2- yl)aniline.

Example 47: Preparation of (5-(5-fluoropyrimidin-2-yl)-2-morpholinophenyl)carbonohydrazonoyl dicyanide (Compound 47)

Step 47-1: Preparation of 4-(2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine

480 mg (41% yield) of the title compound were prepared by reacting in the same manner as Step 44-2 of Example 44 except that 2-(4-chloro-3-nitrophenyl)-4,4. 5,5-Tetramethyl-1,3,2-dioxaborolane was used instead of 2-(3-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

Step 47-2: Preparation of 4-(4-(5-fluoropyrimidin-2-yl)-2-nitrophenyl)morpholine

300 mg (70% yield) of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that 4-(2-nitro-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine prepared according to step 47-1 was used instead of 4-aminopinacol phenylboronic acid ester, and 2-chloro-5-fluoropyrimidine was used instead of 2- Bromopyrimidine.

Step 47-3: Preparation of 5-(5-fluoropyrimidin-2-yl)-2-morpholinoaniline

4-(5-(5-Fluoropyrimidin-2-yl)-2-nitrophenyl)morpholine obtained in accordance with step 44-3 was dissolved in dichloromethane (DCM), and reduced in a manner similar to step 36-2 of Example 36 , obtaining 86 mg (48% yield) of the title compound.

Step 47-4: Preparation of (5-(5-fluoropyrimidin-2-yl)-2-morpholinophenyl)carbonohydrazonoyl dicyanide

84 mg (77% yield) of the title compound were prepared by reacting in the same manner as Step 1-2 of Example 1 except that 5-(5-fluoropyrimidin-2-yl)-2-morpholinoaniline, obtained in accordance with step 47-3 was used instead of 4-(pyrimidin-2-yl)aniline.

Example 48: Preparation of (4-(benzo[d]thiazol-6-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 48)

Step 48-1: Preparation of 4-(benzo[d]thiazol-6-yl)aniline

58 mg (68% yield) of the title compound was obtained by performing the reaction in the same manner as Step 1-1 of Example 1 except that 6-bromobenzo[d]thiazole (0.55 mmol) was used instead of 2 -bromopyrimidine.

Step 48-2: Preparation of (4-(benzo[d]thiazol-6-yl)phenyl)carbonohydrazonoyl dicyanide

10 mg (13% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 4-(benzo[d]thiazol-6-yl)aniline was used instead 4-(pyrimidin-2-yl)aniline.

Example 49: Preparation of (4-(naphthalene-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 49)

Step 49-1: Preparation of 4-(naphthalene-2-yl)aniline

40 mg (21% yield) of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that 2-bromonaphthalene (0.46 mmol) was used instead of 2-bromopyrimidine.

Step 49-2: Preparation of (4-(naphthalene-2-yl)phenyl)carbonohydrazonoyl dicyanide

5 mg (9% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 4-(naphthalene-2-yl)aniline was used instead of 4-(pyrimidine -2-yl)aniline.

Example 50: Preparation of (4-(pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 50)

Step 50-1: Preparation of 4-(pyrazolo[1,5-a]pyrimidin-6-yl)aniline

180 mg (62% yield) of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that 6-bromopyrazolo[1,5-a]pyrimidine (1.65 mmol ) was used instead of 2-bromopyrimidine.

Step 50-2: Preparation of (4-(pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)carbonohydrazonoyl dicyanide

79 mg (32% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 4-(pyrazolo[1,5-a]pyrimidin-6-yl )aniline was used instead of 4-(pyrimidin-2-yl)aniline.

Example 51: Preparation of (4-(imidazo[1,2-a]pyrimidin-6-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 51)

Step 51-1: Preparation of 4-(imidazo[1,2-a]pyrimidin-6-yl)aniline

76 mg (17% yield) of the title compound were prepared by reacting in the same manner as Step 1-1 of Example 1 except that 6-bromimidazo[1,2-a]pyrimidine (2.53 mmol ) was used instead of 2-bromopyrimidine.

Step 51-2: Preparation of (4-(imidazo[1,2-a]pyrimidin-6-yl)phenyl)carbonohydrazonoyl dicyanide

40 mg (38% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 4-(imidazo[1,2-a]pyrimidin-6-yl )aniline was used instead of 4-(pyrimidin-2-yl)aniline.

Example 52: Preparation of (4-(quinoxalin-2-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 52)

Step 52-1: Preparation of 4-(quinoxalin-2-yl)aniline

100 mg (33% yield) of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that 2-chloroquinoxaline (1.64 mmol) was used instead of 2-bromopyrimidine.

Step 52-2: Preparation of (4-(quinoxalin-2-yl)phenyl)carbonohydrazonoyl dicyanide

30 mg (44% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 4-(quinoxalin-2-yl)aniline was used instead of 4-(pyrimidine -2-yl)aniline.

Example 53: Preparation of (4-(imidazo[1,2-a]pyridin-6-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 53)

Step 53-1: Preparation of 4-(imidazo[1,2-a]pyridin-6-yl)aniline

100 mg (33% yield) of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that 6-bromimidazo[1,2-a]pyridine (1.64 mmol ) was used instead of 2-bromopyrimidine.

Step 53-2: Preparation of 4-(imidazo[1,2-a]pyridin-6-yl)phenyl)carbonohydrazonoyl dicyanide

22 mg (32% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 4-(imidazo[1,2-a]pyridin-6-yl )aniline was used instead of 4-(pyrimidin-2-yl)aniline.

Example 54: Preparation of (4-(isoquinolin-3-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 54)

Step 54-1: Preparation of 4-(isoquinolin-3-yl)aniline

80 mg (16% yield) of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that 3-chloroisoquinoline (2.80 mmol) was used instead of 2-bromopyrimidine.

Step 54-2: Preparation of (4-(isoquinolin-3-yl)phenyl)carbonohydrazonoyl dicyanide

23 mg (42% yield) of the title compound was obtained by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-(isoquinolin-3-yl)aniline was used instead of 4-(pyrimidine -2-yl)aniline.

Example 55: Preparation of (4-(2-methyl-2H-indazol-4-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 55)

Step 55-1: Preparation of 4-(2-methyl-2H-indazol-4-yl)aniline

331 mg (80% yield) of the title compound was obtained by reacting in the same manner as Step 1-1 of Example 1 except that 4-bromo-2-methyl-2H-indazole (2.20 mmol ) was used instead of 2-bromopyrimidine.

Step 55-2: Preparation of (4-(2-methyl-2H-indazol-4-yl)phenyl)carbonohydrazonoyl dicyanide

100 mg (24% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 4-(2-methyl-2H-indazol-4-yl)aniline was used instead of 4-(pyrimidin-2-yl)aniline.

Example 56: Preparation of (4-(2-methyl-2H-indazol-5-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 56)

Step 56-1: Preparation of 4-(2-methyl-2H-indazol-5-yl)aniline

100 mg (38% yield) of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that 5-bromo-2-methyl-2H-indazole (2.20 mmol ) was used instead of 2-bromopyrimidine.

Step 56-2: Preparation of (4-(2-methyl-2H-indazol-5-yl)phenyl)carbonohydrazonoyl dicyanide

26 mg (65% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 4-(2-methyl-2H-indazol-5-yl)aniline was used instead of 4-(pyrimidin-2-yl)aniline.

Example 57: Preparation of (4-(2-methyl-2H-indazol-7-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 57)

Step 57-1: Preparation of 4-(2-methyl-2H-indazol-7-yl)aniline

550 mg (86% yield) of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that 7-bromo-2-methyl-2H-indazole (2.20 mmol ) was used instead of 2-bromopyrimidine.

Step 57-2: Preparation of (4-(2-methyl-2H-indazol-7-yl)phenyl)carbonohydrazonoyl dicyanide

345 mg (47% yield) of the title compound were prepared by reacting in the same manner as Step 1-2 of Example 1 except that 4-(2-methyl-2H-indazol-7-yl)aniline was used instead of 4-(pyrimidin-2-yl)aniline.

Example 58: Preparation of (4-(1H-indol-5-yl)phenyl)carbonohydrazonoyl dicyanide (Compound 58)

Step 58-1: Preparation of tert-butyl 5-(4-aminophenyl)-1H-indole-1-carboxylate

596 mg (6% yield) of the title compound was obtained by reacting in the same manner as Step 1-1 of Example 1 except that tert-butyl 5-bromo-1H-indole-1-carboxylate ( 3.38 mmol) was used instead of 2-bromopyrimidine.

Step 58-2: Preparation of tert-butyl 5-(4-(2-(dicyanomethylene)hydrazinyl)phenyl)-1H-indol-1-ylcarboxylate

107 mg (14% yield) of the title compound were prepared by reacting in the same manner as Step 1-2 of Example 1 except that tert-butyl-5-(4-aminophenyl)-1H-indole- 1-Carboxylate was used instead of 4-(pyrimidin-2-yl)aniline.

Step 58-3: Preparation of (4-(1H-indol-5-yl)phenyl)carbonohydrazonoyl dicyanide

tert-Butyl-5-(4-(2-(dicyanomethylene)hydrazinyl)phenyl)-1H-indol-1-ylcarboxylate was dissolved in 8.0 ml of dichloromethane in the presence of nitrogen, and then trifluoroacetic acid was added to obtain a reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. When the reaction was complete, the reaction product was concentrated under reduced pressure to obtain 40 mg (44% yield) of the title compound.

Example 59: Preparation of (4-methoxybenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide (Compound 59)

141 mg (51% yield) of the title compound was obtained by performing the reaction in the same manner as Step 1-2 of Example 1 except that 4-methoxybenzo[d]thiazol-2-amine was used instead of 4-( pyrimidin-2-yl)aniline.

Example 60: Preparation of benzo[d]thiazol-6-ylcarbonohydrazonoyl dicyanide (Compound 60)

290 mg (48% yield) of the title compound was obtained by carrying out the reaction in the same manner as Step 1-2 of Example 1 except that benzo[d]thiazol-6-amine was used instead of 4-(pyrimidin- 2-yl)aniline.

Example 61: Preparation of benzo[d]thiazol-5-ylcarbonohydrazonoyl dicyanide (Compound 61)

180 mg (40% yield) of the title compound was obtained by carrying out the reaction in the same manner as Step 1-2 of Example 1 except that benzo[d]thiazol-5-amine was used instead of 4-(pyrimidin- 2-yl)aniline.

Example 62: Preparation of (9-ethyl-9H-carbazol-3-yl)carbonohydrazonoyl dicyanide (Compound 62)

77 mg (11% yield) of the title compound was obtained by reacting in the same manner as Step 1-2 of Example 1 except that 9-ethyl-9H-carbazole-3-amine was used instead of 4-( pyrimidin-2-yl)aniline.

Example 63: Preparation of (1-methyl-1H-indazol-6-yl)carbonohydrazonoyl dicyanide (Compound 63)

246 mg (54% yield) of the title compound was obtained by performing the reaction in the same manner as Step 1-2 of Example 1 except that 1-methyl-1H-indazol-6-amine was used instead of 4-( pyrimidin-2-yl)aniline.

Example 64: Preparation of quinolin-3-ylcarbonohydrazonoyl dicyanide (Compound 64)

163 mg (27% yield) of the title compound were prepared by reacting in the same manner as Step 1-2 of Example 1 except that quinolin-3-amine was used instead of 4-(pyrimidin-2-yl) aniline.

Example 65: Preparation of (2-methyl-2H-indazol-6-yl)carbonohydrazonoyl dicyanide (Compound 65)

23 mg (3% yield) of the title compound was obtained by reacting in the same manner as Step 1-2 of Example 1 except that 2-methyl-2H-indazol-6-amine was used instead of 4-( pyrimidin-2-yl)aniline.

Example 66: Preparation of (1-methyl-1H-indazol-5-yl)carbonohydrazonoyl dicyanide (Compound 66)

128 mg (17% yield) of the title compound was obtained by reacting in the same manner as Step 1-2 of Example 1 except that 1-methyl-1H-indazol-5-amine was used instead of 4-( pyrimidin-2-yl)aniline.

Example 67: Preparation of quinolin-6-ylcarbonohydrazonoyl dicyanide (Compound 67)

56 mg (9% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that quinolin-6-amine was used instead of 4-(pyrimidin-2-yl) aniline.

Example 68: Preparation of (1-methyl-1H-indol-5-yl)carbonohydrazonoyl dicyanide (Compound 68)

69 mg (11% yield) of the title compound was obtained by reacting in the same manner as Step 1-2 of Example 1 except that 1-methyl-1H-indol-5-amine was used instead of 4-( pyrimidin-2-yl)aniline.

Example 69: Preparation of (1H-indazol-5-yl)carbonohydrazonoyl dicyanide (Compound 69)

70 mg (19% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that tert-butyl-5-amino-1H-indazole-1-carboxylate was used instead of 4-(pyrimidin-2-yl)aniline.

Example 70: Preparation of (1H-indazol-6-yl)carbonohydrazonoyl dicyanide (Compound 70)

62 mg (12% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that tert-butyl-6-amino-1H-indazole-1-carboxylate was used instead of 4-(pyrimidin-2-yl)aniline.

Example 71: Preparation of (1H-indol-5-yl)carbonohydrazonoyl dicyanide (Compound 71)

Step 71-1: Preparation of tert-butyl 5-(2-(dicyanomethylene)hydrazinyl)-1H-indole-1-carboxylate

25 mg (6% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that tert-butyl-5-amino-1H-indole-1-carboxylate was used instead of 4-(pyrimidin-2-yl)aniline.

Step 71-2: Preparation of (1H-indol-5-yl)carbonohydrazonoyl dicyanide

15 mg (88% yield) of the title compound was prepared by reacting in the same manner as Step 58-3 of Example 58 except that tert-butyl-5-(2-(dicyanomethylene)hydrazinyl)-1H α-indol-1-ylcarboxylate was used instead of tert-butyl-5-(4-(2-(dicyanomethylene)hydrazinyl)phenyl)-1H-indol-1-ylcarboxylate.

Example 72: Preparation of (1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide (Compound 72)

Step 72-1: Preparation of tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

5-Nitro-1H-pyrrolo[2,3-b]pyridine (2 g, 12.27 mmol), di-tert-butyl dicarbonate (3.2 g, 14.71 mmol) and 4-dimethylaminopyridine (150 mg, 1 .23 mmol) was dissolved in 40 ml of acetonitrile solution in the presence of nitrogen, and then stirred at room temperature for 3 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 1.23 g (38% yield) of the title compound.

Step 72-2: Preparation of tert-butyl-5-amino-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

tert-Butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (600 mg, 2.28 mmol) obtained in accordance with step 72-1 was dissolved in 5 ml of acetic acid solution in presence of nitrogen, and then iron (1.2 g, 22.80 mmol) was added to obtain the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. When the reaction was completed, 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 then filtered.

The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 261 mg (48% yield) of the title compound.

Step 72-3: Preparation of (1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

128 mg (54% yield) of the title compound was obtained by carrying out the reaction in the same manner as Step 1-2 of Example 1 except that tert-butyl-5-amino-1H-pyrrolo[2,3- b]pyridin-1-carboxylate was used instead of 4-(pyrimidin-2-yl)aniline.

Example 73: Preparation of (3-methyl-1H-indazol-6-yl)carbonohydrazonoyl dicyanide (Compound 73)

Step 73-1: Preparation of tert-butyl-3-methyl-6-nitro-1H-indazole-1-carboxylate

1.43 g (92% yield) of the title compound was prepared by reacting in the same manner as Step 72-1 of Example 72 except that 3-methyl-6-nitro-1H-indazole was used instead of 5 -nitro-1H-pyrrolo[2,3-b]pyridine.

Step 73-2: Preparation of tert-butyl-6-amino-3-methyl-1H-indazole-1-carboxylate

tert-Butyl-3-methyl-6-nitro-1H-indazole-1-carboxylate obtained in accordance with step 73-1 was dissolved in ethyl acetate, and reduced in a manner similar to step 36-2 of Example 36 to obtain 500 mg (80% yield) of the title compound.

Step 73-3: Preparation of (3-methyl-1H-indazol-6-yl)carbonohydrazonoyl dicyanide

40 mg (10% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that tert-butyl-6-amino-3-methyl-1H-indazol- 1-Carboxylate was used instead of 4-(pyrimidin-2-yl)aniline.

Example 74: Preparation of (3-methyl-1H-indazol-5-yl)carbonohydrazonoyl dicyanide (Compound 74)

Step 74-1: Preparation of tert-butyl-3-methyl-5-nitro-1H-indazole-1-carboxylate

2.83 g (90% yield) of the title compound were prepared by reacting in the same manner as Step 72-1 of Example 72 except that 3-methyl-5-nitro-1H-indazole (1. 29 mmol) was used instead of 5-nitro-1H-pyrrolo[2,3-b]pyridine.

Step 74-2: Preparation of tert-butyl-5-amino-3-methyl-1H-indazole-1-carboxylate

tert-Butyl-3-methyl-5-nitro-1H-indazole-1-carboxylate obtained in accordance with step 74-1 was dissolved in ethyl acetate, and reduced in a manner similar to step 36-2 of Example 36 to obtain 761 mg (85% yield) of the title compound.

Step 74-3: Preparation of (3-methyl-1H-indazol-5-yl)carbonohydrazonoyl dicyanide

100 mg (15% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that tert-butyl-5-amino-3-methyl-1H-indazol- 1-Carboxylate was used instead of 4-(pyrimidin-2-yl)aniline.

Example 75: Preparation of (1H-indol-4-yl)carbonohydrazonoyl dicyanide (Compound 75)

Step 75-1: Preparation of trary-butyl-4-amino-1H-indole-1-carboxylate

tert-Butyl-4-nitro-1H-indole-1-carboxylate was dissolved in acetonitrile (MeCN), and reduced in a manner similar to step 36-2 of Example 36 to give 198 mg (75% yield) of the title connections.

Step 75-2: Preparation of (1H-indol-4-yl)carbonohydrazonoyl dicyanide

40 mg (10% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that tert-butyl-4-amino-1H-indole-1-carboxylate was used instead of 4-(pyrimidin-2-yl)aniline.

Example 76: Preparation of (1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide (Compound 76)

Step 76-1: Preparation of 1-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine

5-Nitro-1H-pyrrolo[2,3-b]pyridine (600 mg, 3.72 mmol) was dissolved in DMF (6 ml) in the presence of nitrogen, and then sodium hydride (60%, 300 mg, 7.44) was added mmol) followed by the addition of sweep (0.93 mL, 14.88 mmol) to obtain the reaction mixture. The reaction mixture was stirred at room temperature for 4 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 380 mg (57% yield) of the title compound.

Step 76-2: Preparation of 1-methyl-1H-pyrrolo[2,3-b]pyridin-5-amine

69 mg (55% yield) of the title compound was prepared by reacting in the same manner as Step 72-2 of Example 72 except that 1-methyl-5-nitro-1H-pyrrolo[2,3- The b]pyridine obtained in step 76-1 was used instead of tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate.

Step 76-3: Preparation of (1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

8 mg (9% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 1-methyl-1H-pyrrolo[2,3-b]pyridinium- 5-amine was used instead of 4-(pyrimidin-2-yl)aniline.

Example 77: Preparation of (1-propyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide (Compound 77)

Step 77-1: Preparation of 5-nitro-1-propyl-1H-pyrrolo[2,3-b]pyridine

5-Nitro-1H-pyrrolo[2,3-b]pyridine (600 mg, 3.72 mmol), cesium carbonate (CsCO ₃ , 2.4 g, 7.44 mmol) and 1-iodopropane (1.10 ml , 11.01 mmol) was dissolved in DMF to obtain the reaction mixture, and then the reaction mixture was stirred at 60°C for 17 hours to obtain 523 mg (70% yield) of the title compound.

Step 77-2: Preparation of 1-propyl-1H-pyrrolo[2,3-b]pyridin-5-amine

297 mg (67% yield) of the title compound were obtained by reacting in the same manner as Step 72-2 of Example 72 except that 5-nitro-1-propyl-1H-pyrrolo[2,3- The b]pyridine obtained in step 77-1 was used instead of tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate.

Step 77-3: Preparation of (1-propyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

98 mg (23% yield) of the title compound were prepared by reacting in the same manner as Step 1-2 of Example 1 except that 1-propyl-1H-pyrrolo[2,3-b]pyridinium- 5-amine was used instead of 4-(pyrimidin-2-yl)aniline.

Example 78: Preparation of (1-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide (Compound 78)

Step 78-1: Preparation of 5-nitro-1-isopropyl-1H-pyrrolo[2,3-b]pyridine

591 mg (78% yield) of the title compound was obtained by reacting in the same manner as Step 77-1 of Example 77 except that 2-iodopropane (1.10 mL, 11.01 mmol) was used instead 1-iodopropane.

Step 78-2: Preparation of 1-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-amine

270 mg (54% yield) of the title compound were prepared by reacting in the same manner as Step 72-2 of Example 72 except that 5-nitro-1-isopropyl-1H-pyrrolo[2,3- The b]pyridine obtained in step 78-1 was used instead of tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate.

Step 78-3: Preparation of (1-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

81 mg (21% yield) of the title compound were prepared by reacting in the same manner as Step 1-2 of Example 1 except that 1-isopropyl-1H-pyrrolo[2,3-b]pyridinium- 5-amine was used instead of 4-(pyrimidin-2-yl)aniline.

Example 79: Preparation of (1-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide (Compound 79)

Step 79-1: Preparation of 1-ethyl-5-nitro-1H-pyrrolo[2,3-b]pyridine

363 mg (52% yield) of the title compound was obtained by reacting in the same manner as Step 77-1 of Example 77 except that iodoethane (0.83 mL, 10.14 mmol) was used instead of 1- iodopropane.

Step 79-2: Preparation of 1-ethyl-1H-pyrrolo[2,3-b]pyridin-5-amine

184 mg (61% yield) of the title compound were prepared by reacting in the same manner as Step 72-2 of Example 72 except that 1-ethyl-5-nitro-1H-pyrrolo[2,3- The b]pyridine obtained in step 79-1 was used instead of tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate.

Step 79-3: Preparation of (1-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

187 mg (69% yield) of the title compound was obtained by carrying out the reaction in the same manner as Step 1-2 of Example 1 except that 1-ethyl-1H-pyrrolo[2,3-b]pyridinium- 5-amine was used instead of 4-(pyrimidin-2-yl)aniline.

Example 80: Preparation of (1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide (Compound 80)

Step 80-1: Preparation of 5-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine

784 mg (52% yield) of the title compound were obtained by reacting in the same manner as Step 77-1 of Example 77 except that 1,1,1-trifluoro-2-iodoethane (1.80 ml , 18.39 mmol) was used instead of 1-iodopropane.

Step 80-2: Preparation of 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-amine

235 mg (53% yield) of the title compound were prepared by reacting in the same manner as Step 72-2 of Example 72 except that 5-nitro-1-(2,2,2-trifluoroethyl)- 1H-pyrrolo[2,3-b]pyridine obtained in step 80-1 was used instead of tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate.

Step 80-3: Preparation of (1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

150 mg (55% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[ 2,3-b]pyridin-5-amine was used instead of 4-(pyrimidin-2-yl)aniline.

Example 81: Preparation of (2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide (Compound 81)

Step 81-1: Preparation of tert-butyl-2-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

1.83 g (98% yield) of the title compound were prepared by reacting in the same manner as Step 72-1 of Example 72 except that 2-methyl-1H-pyrrolo[2,3-b] pyridine was used instead of 5-nitro-1H-pyrrolo[2,3-b]pyridine.

Step 81-2: Preparation of tert-butyl-2-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

tert-Butyl-2-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate and tetrabutyl ammonium nitrate were dissolved in dichloromethane in the presence of nitrogen and then stirred at 0°C for 10 minutes. Thereafter, trifluoroacetic anhydride (TFAA, 1.43 ml, 0.125 mmol) was added, stirring was carried out at 0° C. for 5 minutes, and then stirring was further carried out at room temperature for 3 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 1.34 g (61% yield) of the title compound.

Step 81-3: Preparation of tert-butyl-5-amino-2-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

311 mg (58% yield) of the title compound were prepared by reacting in the same manner as Step 72-2 of Example 72 except that tert-butyl-2-methyl-5-nitro-1H-pyrrolo[ The 2,3-b]pyridine-1-carboxylate obtained in step 81-2 was used instead of tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate.

Step 81-4: Preparation of tert-butal-5-(2-(dicyanomethylene)hydrazinyl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

160 mg (68% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that tert-butyl-5-amino-2-methyl-1H-pyrrolo[ 2,3-b]pyridin-1-carboxylate was used instead of 4-(pyrimidin-2-yl)aniline.

Step 81-5: Preparation of (2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

29 mg (71% yield) of the title compound was prepared by reacting in the same manner as Step 58-3 of Example 58 except that tert-butyl-5-(2-(dicyanomethylene)hydrazinyl)-2 -Methyl-1H-pyrrolo[2,3-b]pyridin-1-ylcarboxylate was used instead of tert-butyl-5-(4-(2-(dicyanomethylene)hydrazinyl)phenyl)-1H-indol-1-ylcarboxylate.

Example 82: Preparation of (3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide (Compound 82)

Step 82-1: Preparation of tert-butyl-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

3.4 g (97% yield) of the title compound were prepared by reacting in the same manner as Step 72-1 of Example 72 except that 3-methyl-1H-pyrrolo[2,3-b] pyridine was used instead of 5-nitro-1H-pyrrolo[2,3-b]pyridine.

Step 82-2: Preparation of tert-butyl-3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

800 mg (42% yield) of the title compound were prepared by reacting in the same manner as Step 81-2 of Example 81 except that tert-butyl-3-methyl-1H-pyrrolo[2,3- b]pyridine-1-carboxylate was used instead of tert-butyl-2-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate.

Step 82-3: Preparation of tert-butyl-5-amino-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

tert-Butyl-3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was dissolved in ethyl acetate and reduced in a manner similar to step 36-2 of Example 36 to give 367 mg (82% -output) specified in the connection header.

Step 82-4: Preparation of tert-butal-5-(2-(dicyanomethylene)hydrazinyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

106 mg (40% yield) of the title compound were prepared by reacting in the same manner as Step 1-2 of Example 1 except that tert-butyl-5-amino-3-methyl-1H-pyrrolo[ 2,3-b]pyridin-1-carboxylate was used instead of 4-(pyrimidin-2-yl)aniline.

Step 82-5: Preparation of (3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

30 mg (88% yield) of the title compound was prepared by reacting in the same manner as Step 58-3 of Example 58 except that tert-butyl-5-(2-(dicyanomethylene)hydrazinyl)-3 -Methyl-1H-pyrrolo[2,3-b]pyridin-1-ylcarboxylate was used instead of tert-butyl-5-(4-(2-(dicyanomethylene)hydrazinyl)phenyl)-1H-indol-1-ylcarboxylate.

Example 83: Preparation of (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide (Compound 83)

Step 83-1: Preparation of 3-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine

5-Nitro-1H-pyrrolo[2,3-b]pyridine and N-chlorosuccinimide were dissolved in DMF (7 ml) in the presence of nitrogen and then stirred at room temperature for 12 minutes. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 664 mg (55% yield) of the title compound.

Step 83-2: Preparation of tert-butyl-3-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

419 g (70% yield) of the title compound were obtained by reacting in the same manner as Step 72-1 of Example 72 except that 3-chloro-5-nitro-1H-pyrrolo[2,3- b]pyridine was used instead of 5-nitro-1H-pyrrolo[2,3-b]pyridine.

Step 83-3: Preparation of tert-butyl-5-amino-3-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

tert-Butyl-3-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was dissolved in ethyl acetate and reduced in a similar manner to step 36-2 of Example 36 to give 118 mg (60% -output) specified in the connection header.

Step 83-4: Preparation of tert-butyl 5-(2-(dicyanomethylene)hydrazinyl)-3-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

35 mg (23% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that tert-butyl-5-amino-3-chloro-1H-pyrrolo[ 2,3-b]pyridin-1-carboxylate was used instead of 4-(pyrimidin-2-yl)aniline.

Step 83-5: Preparation of (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

20 mg (91% yield) of the title compound was prepared by reacting in the same manner as Step 58-3 of Example 58 except that tert-butyl-5-(2-(dicyanomethylene)hydrazinyl)-3 -chloro-1H-pyrrolo[2,3-b]pyridin-1-ylcarboxylate was used instead of tert-butyl-5-(4-(2-(dicyanomethylene)hydrazinyl)phenyl)-1H-indol-1-ylcarboxylate.

Example 84: Preparation of (4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide (Compound 84)

Step 84-1: Preparation of 4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine

2.0 mg (60% yield) of the title compound was prepared by reacting in the same manner as Step 81-2 of Example 81 except that 4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[ 2,3-b]pyridine was used instead of tert-butyl-2-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate.

Step 84-2: Preparation of 4-methoxy-5-nitro-1H-pyrrolo[2,3-b]pyridine

4-Chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine and solid potassium carbonate were dissolved in a mixed solution of methanol:water = 3:1 in the presence of nitrogen and refluxed for 7 o'clock. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 235 mg (68% yield) of the title compound.

Step 84-3: Preparation of tert-butyl-4-methoxy-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

234 mg (77% yield) of the title compound were obtained by reacting in the same manner as Step 72-1 of Example 72 except that 4-methoxy-5-nitro-1H-pyrrolo[2,3- b]pyridine was used instead of 5-nitro-1H-pyrrolo[2,3-b]pyridine.

Step 84-4: Preparation of tert-butyl-5-amino-4-methoxy-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

tert-Butyl-4-methoxy-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was dissolved in ethyl acetate and reduced in a manner similar to step 36-2 of Example 36 to give 107 mg (99% -output) specified in the connection header.

Step 84-5: Preparation of (4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

22 mg (17% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that tert-butyl-5-amino-4-methoxy-1H-pyrrolo[ 2,3-b]pyridin-1-carboxylate was used instead of 4-(pyrimidin-2-yl)aniline.

Example 85: Preparation of (2-(dimethylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide (Compound 85)

Step 85-1: Preparation of N,N-dimethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

N,N-Diisopropylamine (DIPEA, 1.20 ml, 6.62 mmol) and azabenzotriazoletetramethyluronium hexafluorophosphate (HATU, 2 g, 4.30 mmol) were added to 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b] pyridine-2-carboxylic acid (1 g, 3.31 mmol) in the presence of nitrogen, and then stirred at room temperature for 10 minutes. A solution of dimethylamine (2.0 M in THF, 3.32 mL, 6.62 mmol) was then added, followed by stirring at room temperature for 10 minutes. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 800 mg (79% yield) of the title compound.

Step 85-2: Preparation of N,N-dimethyl-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

373 mg (41% yield) of the title compound were prepared by reacting in the same manner as Step 81-2 of Example 81 except that N,N-dimethyl-1-(phenylsulfonyl)-1H-pyrrolo[ 2,3-b]pyridine-2-carboxamide was used instead of tert-butyl-2-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate.

Step 85-3: Preparation of N,N-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

N,N-Dimethyl-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (0.95 mmol) and solid potassium tert-butoxide (0.95 mmol) were dissolved in dioxane (15 ml) in the presence of nitrogen and stirred at 80°C for 12 hours.

When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 71 mg (48% yield) of the title compound.

Step 85-4: Preparation of tert-butyl-2-(dimethylcarbamoyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

100 mg (99% yield) of the title compound was prepared by reacting in the same manner as Step 72-1 of Example 72 except that N,N-dimethyl-5-nitro-1H-pyrrolo[2, 3-b]pyridine-2-carboxamide was used instead of 5-nitro-1H-pyrrolo[2,3-b]pyridine.

Step 85-5: Preparation of tert-butyl-5-amino-2-(dimethylcarbamoyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

tert-Butyl-2-(dimethylcarbamoyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was dissolved in ethyl acetate and reduced in a similar manner to step 36-2 of Example 36 to give 90 mg (97% yield) of the title compound.

Step 85-6: Preparation of tert-butal-5-(2-(dicyanomethylene)hydrazinyl)-2-(dimethylcarbamoyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

78 mg (69% yield) of the title compound was prepared by reacting in the same manner as Step 1-2 of Example 1 except that tert-butyl-5-amino-2-(dimethylcarbamoyl)-1H- pyrrolo[2,3-b]pyridin-1-carboxylate was used instead of 4-(pyrimidin-2-yl)aniline.

Step 85-7: Preparation of (2-(dimethylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

41 mg (72% yield) of the title compound was prepared by reacting in the same manner as Step 58-3 of Example 58 except that tert-butyl-5-(2-(dicyanomethylene)hydrazinyl)-2 -(dimethylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-1-carboxylate was used instead of tert-butyl 5-(4-(2-(dicyanomethylene)hydrazinyl)phenyl)-1H-indol-1-ylcarboxylate.

Example 86: Preparation of (2-(4-methoxybenzamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 86)

Step 86-1: Preparation of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide

4-Methoxybenzoic acid (1 g, 6.57 mmol) was dissolved in MeCN in the presence of nitrogen, and then HATU (2.75 g, 7.23 mmol) and triethylamine (TEA, 1.39 mL, 9.86 mmol) were added to obtain a reaction mixture, and the reaction mixture was stirred at room temperature for 4 hours. Thereafter, 6-nitrobenzo[d]thiazol-2-amine (1.28 g, 6.57 mmol) was added and the reaction mixture was refluxed for 24 hours. When the reaction was complete, the reaction product was filtered using MeCN to obtain 1.6 g (74% yield) of the compound as a solid filtrate.

Step 86-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide

4-Methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide (100 mg, 0.30 mmol) and 10% Pd/C (64 mg, 0.06 mmol) were dissolved in DMF to obtain the reaction mixtures. The reaction mixture was stirred at 60°C for 2 hours in the presence of hydrogen. When the reaction was complete, the reaction product was filtered using DMF. The filtrate was concentrated under reduced pressure and the concentrate was solidified with ethyl acetate to give 39 mg (43% yield) of the title compound.

Step 86-3: Preparation of (2-(4-methoxybenzamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

78 mg (69% yield) of the title compound were prepared by reacting in the same manner as Steps 1-2 of Example 1 except that N-(6-aminobenzo[d]thiazol-2-yl)- 4-methoxybenzamide was used instead of 4-(pyrimidin-2-yl)aniline, a 10:3 mixed solution of ethanol and water was used as the solvent, and 35% HCl aqueous solution was used as the acidic solution.

Example 87: Preparation of (2-(2-hydroxybenzamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 87)

Step 87-1: Preparation of N-(6-nitrobenzo[d]thiazol-2-yl)-2-hydroxybenzamide

611 mg (65% yield) of the title compound was prepared by reacting in the same manner as Step 86-1 of Example 86 except that 2-hydroxybenzoic acid (3.62 mmol) was used instead of 4-methoxybenzoic acid .

Step 87-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-2-hydroxybenzamide

48 mg (53% yield) of the title compound was prepared by reacting in the same manner as Step 86-2 of Example 86 except that 2-hydroxy-N-(6-nitrobenzo[d]thiazole-2 -yl)benzamide obtained in accordance with step 87-1 was used instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide.

Step 87-3: Preparation of (2-(2-hydroxybenzamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

36 mg (59% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that N-(6-aminobenzo[d]thiazol-2-yl)- The 2-hydroxybenzamide prepared according to step 87-2 was used in place of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 88: Preparation of (2-acetamidobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 88)

Step 88-1: Preparation of N-(6-nitrobenzo[d]thiazol-2-yl)acetamide

6-Nitrobenzo[d]thiazol-2-amine was dissolved in MeCN in the presence of nitrogen, then DIPEA and acetic anhydride were added to obtain a reaction mixture, and the reaction mixture was stirred at 60°C for 14 hours. When the reaction was complete, the reaction product was filtered using MeCN to obtain 200 mg (75% yield) of the compound as a solid filtrate.

Step 88-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)acetamide

66 mg (83% yield) of the title compound was prepared by reacting in the same manner as Step 86-2 of Example 86 except that N-(6-nitrobenzo[d]thiazol-2-yl)acetamide was used instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide.

Step 88-3: Preparation of (2-acetamidobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

28 mg (42% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that N-(6-aminobenzo[d]thiazol-2-yl)acetamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 89: Preparation of (2-(3-cyanobenzamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 89)

Step 89-1: Preparation of 3-cyano-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide

718 mg (65% yield) of the title compound was prepared by reacting in the same manner as Step 86-1 of Example 86 except that 3-cyanobenzoic acid (3.62 mmol) was used instead of 4-methoxybenzoic acid .

Step 89-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-3-cyanobenzamide

82 mg (90% yield) of the title compound was prepared by reacting in the same manner as Step 86-2 of Example 86 except that 3-cyano-N-(6-nitrobenzo[d]thiazole-2 -yl)benzamide was used instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide.

Step 89-3: Preparation of (2-(3-cyanobenzamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

33 mg (52% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that N-(6-aminobenzo[d]thiazol-2-yl)- 3-cyanobenzamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 90: Preparation of (2-(5-methylnicotinamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 90)

Step 90-1: Preparation of 5-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)nicotinamide

1.02 g (88% yield) of the title compound was obtained by reacting in the same manner as Step 86-1 of Example 86 except that 5-methylnicotinic acid (3.65 mmol) was used instead of 4- methoxybenzoic acid.

Step 90-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-5-methylnicotinamide

75 mg (83% yield) of the title compound was prepared by reacting in the same manner as Step 86-2 of Example 86 except that 5-methyl-N-(6-nitrobenzo[d]thiazole-2 -yl)nicotinamide was used instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide.

Step 90-3: Preparation of (2-(5-methylnicotinamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

32 mg (49% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that N-(6-aminobenzo[d]thiazol-2-yl)- 5-Methylnicotinamide was prepared according to step 90-2 and was used in place of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 91: Preparation of (2-(3-hydroxypicolinamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 91)

Step 91-1: Preparation of 3-hydroxy-N-(6-nitrobenzo[d]thiazol-2-yl)picolinamide

327 mg (72% yield) of the title compound was prepared by reacting in the same manner as Step 86-1 of Example 86 except that 3-hydroxypicolinic acid (1.44 mmol) was used instead of 4-methoxybenzoic acid .

Step 91-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-3-hydroxypicolinamide

46 mg (51% yield) of the title compound was prepared by reacting in the same manner as Step 86-2 of Example 86 except that 3-hydroxy-N-(6-nitrobenzo[d]thiazole-2 -yl)picolinamide was used instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide.

Step 91-3: Preparation of (2-(3-hydroxypicolinamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

22 mg (35% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that N-(6-aminobenzo[d]thiazol-2-yl)- The 3-hydroxypicolinamide prepared according to step 91-2 was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 92: Preparation of (2-(pyrazin-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 92)

Step 92-1: Preparation of N-(6-nitrobenzo[d]thiazol-2-yl)pyrazin-2-carboxamide

870 mg (71% yield) of the title compound was obtained by reacting in the same manner as Step 86-1 of Example 86 except that pyrazine-2-carboxylic acid (3.65 mmol) was used instead of 4- methoxybenzoic acid.

Step 92-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)pyrazin-2-carboxamides

155 mg (87% yield) of the title compound were prepared by reacting in the same manner as Step 86-2 of Example 86 except that N-(6-nitrobenzo[d]thiazol-2-yl)pyrazine -2-carboxamide was used instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide.

Step 92-3: Preparation of (2-(pyrazin-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

55 mg (43% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that N-(6-aminobenzo[d]thiazol-2-yl)pyrazine -2-carboxamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 93: Preparation of (2-(5-methylpyrazin-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 93)

Step 93-1: Preparation of 5-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)pyrazin-2-carboxamide

766 mg (67% yield) of the title compound was obtained by reacting in the same manner as Step 86-1 of Example 86 except that 5-methylpyrazine-2-carboxylic acid (3.65 mmol) was used instead 4-methoxybenzoic acid.

Step 93-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-5-methylpyrazin-2-carboxamide

165 mg (92% yield) of the title compound were prepared by reacting in the same manner as Step 86-2 of Example 86 except that 5-methyl-N-(6-nitrobenzo[d]thiazole-2 -yl)pyrazin-2-carboxamide was used instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide.

Step 93-3: Preparation of (2-(5-methylpyrazin-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

20 mg (16% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that N-(6-aminobenzo[d]thiazol-2-yl)- 5-methylpyrazin-2-carboxamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 94: Preparation of (2-(pyrimidine-5-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 94)

Step 94-1: Preparation of N-(6-nitrobenzo[d]thiazol-2-yl)pyrimidin-5-carboxamide

510 mg (70% yield) of the title compound was obtained by reacting in the same manner as Step 86-1 of Example 86 except that pyrimidine-5-carboxylic acid (3.65 mmol) was used instead of 4- methoxybenzoic acid.

Step 94-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)pyrimidin-5-carboxamide

113 mg (83% yield) of the title compound were prepared by reacting in the same manner as Step 86-2 of Example 86 except that N-(6-nitrobenzo[d]thiazol-2-yl)pyrimidine -5-carboxamide was used instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide.

Step 94-3: Preparation of (2-(pyrimidine-5-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

15 mg (24% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that N-(6-aminobenzo[d]thiazol-2-yl)pyrimidine -5-carboxamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 95: Preparation of (2-(2-methylpyrimidine-5-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 95)

Step 95-1: Preparation of 2-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)pyrimidin-5-carboxamide

414 mg (61% yield) of the title compound were obtained by reacting in the same manner as Step 86-1 of Example 86 except that 2-methylpyrimidine-5-carboxylic acid (3.65 mmol) was used instead 4-methoxybenzoic acid.

Step 95-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-2-methylpyrimidin-5-carboxamide

119 mg (88% yield) of the title compound were prepared by reacting in the same manner as Step 86-2 of Example 86 except that 2-methyl-N-(6-nitrobenzo[d]thiazole-2 -yl)pyrimidin-5-carboxamide was used instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide.

Step 95-3: Preparation of (2-(2-methylpyrimidin-5-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

21 mg (21% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that N-(6-aminobenzo[d]thiazol-2-yl)- 2-methylpyrimidin-5-carboxamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 96: Preparation of (2-(4-methylpyrimidine-5-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 96)

Step 96-1: Preparation of 4-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)pyrimidin-5-carboxamide

327 mg (72% yield) of the title compound was obtained by reacting in the same manner as Step 86-1 of Example 86 except that 4-methylpyrimidine-5-carboxylic acid (3.65 mmol) was used instead 4-methoxybenzoic acid.

Step 96-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-4-methylpyrimidin-5-carboxamide

131 mg (96% yield) of the title compound were prepared by reacting in the same manner as Step 86-2 of Example 86 except that 4-methyl-N-(6-nitrobenzo[d]thiazole-2 -yl)pyrimidin-5-carboxamide was used instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide.

Step 96-3: Preparation of (2-(4-methylpyrimidin-5-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

28 mg (28% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that N-(6-aminobenzo[d]thiazol-2-yl)- 4-methylpyrimidin-5-carboxamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 97: Preparation of (2-(3-methylpyrazin-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 97)

Step 97-1: Preparation of 3-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)pyrazin-2-carboxamide

542 mg (79% yield) of the title compound were obtained by reacting in the same manner as Step 86-1 of Example 86 except that 3-methylpyrazine-2-carboxylic acid (3.65 mmol) was used instead 4-methoxybenzoic acid.

Step 97-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-3-methylpyrazin-2-carboxamide

158 mg (88% yield) of the title compound were prepared by reacting in the same manner as Step 86-2 of Example 86 except that 3-methyl-N-(6-nitrobenzo[d]thiazole-2 -yl)pyrazin-2-carboxamide was used instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide.

Step 97-3: Preparation of (2-(3-methylpyrazin-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

86 mg (68% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that N-(6-aminobenzo[d]thiazol-2-yl)- 3-Methylpyrazin-2-carboxamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 98: Preparation of (2-(6-methylpyrazin-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 98)

Step 98-1: Preparation of 6-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)pyrazin-2-carboxamide

542 mg (79% yield) of the title compound were obtained by reacting in the same manner as Step 86-1 of Example 86 except that 6-methylpyrazine-2-carboxylic acid (3.65 mmol) was used instead 4-methoxybenzoic acid.

Step 98-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-6-methylpyrazin-2-carboxamide

105 mg (58% yield) of the title compound were prepared by reacting in the same manner as Step 86-2 of Example 86 except that 6-methyl-N-(6-nitrobenzo[d]thiazole-2 -yl)pyrazin-2-carboxamide was used instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide.

Step 98-3: Preparation of (2-(6-methylpyrazin-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

54 mg (53% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that N-(6-aminobenzo[d]thiazol-2-yl)- 6-Methylpyrazin-2-carboxamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 99: Preparation of (2-(pyrazin-2-carboxamido)benzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide (Compound 99)

Step 99-1: Preparation of N-(5-nitrobenzo[d]thiazol-2-yl)pyrazin-2-carboxamide

486 mg (67% yield) of the title compound was obtained by performing the reaction in the same manner as Step 86-1 of Example 86 except that pyrazine-2-carboxylic acid (3.65 mmol) was used instead of 4- methoxybenzoic acid, and 5-nitrobenzo[d]thiazol-2-amine were used instead of 6-nitrobenzo[d]thiazol-2-amine.

Step 99-2: Preparation of N-(5-aminobenzo[d]thiazol-2-yl)pyrazin-2-carboxamides

110 mg (81% yield) of the title compound were prepared by reacting in the same manner as Step 86-2 of Example 86 except that N-(5-nitrobenzo[d]thiazol-2-yl)pyrazine -2-carboxamide was used instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide.

Step 99-3: Preparation of (2-(pyrazin-2-carboxamido)benzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide

22 mg (21% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that N-(5-aminobenzo[d]thiazol-2-yl)pyrazine -2-carboxamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 100: Preparation of (2-(5-methylpyrazin-2-carboxamido)benzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide (Compound 100)

Step 100-1: Preparation of 5-methyl-N-(5-nitrobenzo[d]thiazol-2-yl)pyrazin-2-carboxamide

512 mg (75% yield) of the title compound were prepared by reacting in the same manner as Step 86-1 of Example 86 except that 5-methylpyrazine-2-carboxylic acid (3.65 mmol) was used instead 4-methoxybenzoic acid, and 5-nitrobenzo[d]thiazol-2-amine were used instead of 6-nitrobenzo[d]thiazol-2-amine.

Step 100-2: Preparation of N-(5-aminobenzo[d]thiazol-2-yl)-5-methylpyrazin-2-carboxamide

83 mg (65% yield) of the title compound was prepared by reacting in the same manner as Step 86-2 of Example 86 except that 5-methyl-N-(5-nitrobenzo[d]thiazole-2 -yl)pyrazin-2-carboxamide was used instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide.

Step 100-3: Preparation of (2-(5-methylpyrazin-2-carboxamido)benzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide

102 mg (80% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that N-(5-aminobenzo[d]thiazol-2-yl)- 5-methylpyrazin-2-carboxamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 101: Preparation of (2-phenylbenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 101)

Step 101-1: Preparation of 2-bromo-6-nitrobenzo[d]thiazole

6-Nitrobenzo[d]thiazol-2-amine (500 mg, 2.56 mmol) was dissolved in water, and then CuBr (55 mg, 0.38 mmol) and 48% HBr (5 ml) were added to obtain the reaction mixture. Thereafter, sodium nitrite (1.41 g, 20.48 mmol) was added to the reaction mixture at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. When the reaction was completed, the reaction product was extracted using saturated aqueous NaCl and ethyl acetate twice, and the moisture was dried with anhydrous magnesium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure and the concentrate solidified and was filtered with methanol to obtain 564 mg (85% yield) of the title compound in solid state.

Step 101-2: Preparation of 2-bromo-benzo[d]thiazol-6-amine

2-Bromo-6-nitrobenzo[d]thiazole obtained in step 101-1 and Fe (539 mg, 9.65 mmol) were dissolved in acetic acid to obtain a reaction mixture, and then the reaction mixture was stirred at room temperature for 16 hours. When the reaction was completed, the reaction product was extracted using saturated aqueous NaCl and ethyl acetate twice, and the moisture was dried with anhydrous magnesium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 342 mg (69% yield) of the title compound.

Step 101-3: Preparation of 2-phenylbenzo[d]thiazol-6-amine

56 mg (48% yield) of the title compound was prepared by reacting in the same manner as Step 1-1 of Example 1 except that 2-bromobenzo[d]thiazol-6-amine was used instead of 2-bromopyrimidine , phenylboronic acid pinacol ester was used instead of 4-aminophenylboronic acid pinacol ester, and aqueous potassium carbonate was used instead of aqueous sodium carbonate.

Step 101-4: Preparation of (2-phenylbenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

46 mg (76% yield) of the title compound was obtained by reacting in the same manner as Step 86-3 of Example 86 except that 2-phenylbenzo[d]thiazol-6-amine was used instead of N-( 6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 102: Preparation of (2-(4-fluorophenyl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 102)

Step 102-1: Preparation of 2-(4-fluorophenyl)benzo[d]thiazol-6-amine

30 mg (28% yield) of the title compound was prepared by reacting in the same manner as Step 101-3 of Example 101 except that 4-fluorophenylboronic acid pinacol ester was used instead of phenylboronic acid pinacol ester.

Step 102-2: Preparation of (2-(4-fluorophenyl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

31 mg (79% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that 2-(4-fluorophenyl)benzo[d]thiazol-6-amine was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 103: Preparation of 2-(4-(dimethylamino)phenyl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 103)

Step 103-1: Preparation of 2-(4-(dimethylamino)phenyl)benzo[d]thiazol-6-amine

43 mg (37% yield) of the title compound was prepared by reacting in the same manner as Step 101-3 of Example 101 except that 4-(dimethylamino)phenylboronic acid pinacol ester was used instead of phenylboronic acid pinacol ester.

Step 103-2: Preparation of (2-(4-(dimethylamino)phenyl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

31 mg (79% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that 2-(4-(dimethylamino)phenyl)benzo[d]thiazol- 6-amine was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 104: Preparation of (2-(pyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 104)

Step 104-1: Preparation of 2-(pyridin-3-yl)benzo[d]thiazol-6-amine hydrochloride

The reaction was carried out in the same manner as in step 101-3 of Example 101, except that pyridin-3-ylboronic acid pinacol ester was used instead of phenylboronic acid pinacol ester. 48 mg (41% yield) of the title compound in hydrochloride form was prepared using a solution of 4 M HCl dissolved in dioxane.

Step 104-2: Preparation of (2-(pyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

15 mg (26% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that 2-(pyridin-3-yl)benzo[d]thiazol-6 -amine hydrochloride was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 105: Preparation of (2-(6-methylpyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 105)

Step 105-1: Preparation of 2-(6-methylpyridin-3-yl)benzo[d]thiazol-6-amine

68 mg (52% yield) of the title compound was prepared by reacting in the same manner as Step 101-3 of Example 101 except that 6-methylpyridin-3-ylboronic acid pinacol ester was used instead of phenylboronic acid pinacol ester .

Step 105-2: Preparation of (2-(6-methylpyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

6 mg (9% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that 2-(6-methylpyridin-3-yl)benzo[d]thiazole -6-amine was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 106: Preparation of (2-(6-fluoropyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 106)

Step 106-1: Preparation of 2-(6-fluoropyridin-3-yl)benzo[d]thiazol-6-amine

25 mg (23% yield) of the title compound was prepared by reacting in the same manner as Step 101-3 of Example 101 except that 6-fluoropyridin-3-ylboronic acid pinacol ester was used instead of phenylboronic acid pinacol ester .

Step 106-2: Preparation of (2-(6-fluoropyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

22 mg (63% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that 2-(6-fluoropyridin-3-yl)benzo[d]thiazole -6-amine was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 107: Preparation of (2-(furan-2-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 107)

Step 107-1: Preparation of 2-(furan-2-yl)benzo[d]thiazol-6-amine hydrochloride

The reaction was carried out in the same manner as in step 101-3 of Example 101, except that pinacol ester of furan-2-ylboronic acid was used instead of pinacol ester of phenylboronic acid. 68 mg (61% yield) of the title compound in hydrochloride form was prepared using a solution of 4 M HCl dissolved in dioxane.

Step 107-2: Preparation of (2-(furan-2-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

53 mg (48% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that 2-(furan-2-yl)benzo[d]thiazol-6 -amine hydrochloride was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 108: Preparation of (2-(thiophen-2-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 108)

Step 108-1: Preparation of 2-(thiophen-2-yl)benzo[d]thiazol-6-amine hydrochloride

The reaction was carried out in the same manner as in step 101-3 of Example 101, except that pinacol ester of thiophen-2-ylboronic acid was used instead of pinacol ester of phenylboronic acid. 32 mg (27% yield) of the title compound in hydrochloride form was prepared using a solution of 4 M HCl dissolved in dioxane.

Step 108-2: Preparation of (2-(thiophen-2-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

13 mg (27% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that 2-(thiophen-2-yl)benzo[d]thiazol-6 -amine hydrochloride was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 109: Preparation of (2-(5-fluoropyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 109)

Step 109-1: Preparation of 2-(5-fluoropyridin-3-yl)benzo[d]thiazol-6-amine hydrochloride

The reaction was carried out in the same manner as in step 101-3 of Example 101, except that 5-fluoropyridin-3-ylboronic acid pinacol ester was used instead of phenylboronic acid pinacol ester. 56 mg (45% yield) of the title compound in hydrochloride form was prepared using a solution of 4 M HCl dissolved in dioxane.

Step 109-2: Preparation of (2-(5-fluoropyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

42 mg (57% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that 2-(5-fluoropyridin-3-yl)benzo[d]thiazole -6-amine hydrochloride was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 110: Preparation of (2-(5-methylpyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 110)

Step 110-1: Preparation of 2-(5-methylpyridin-3-yl)benzo[d]thiazol-6-amine hydrochloride

The reaction was carried out in the same manner as in step 101-3 of Example 101, except that 5-methylpyridin-3-ylboronic acid pinacol ester was used instead of phenylboronic acid pinacol ester. 56 mg (45% yield) of the title compound in hydrochloride form was prepared using a solution of 4 M HCl dissolved in dioxane.

Step 110-2: Preparation of (2-(5-methylpyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

9 mg (36% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that 2-(5-methylpyridin-3-yl)benzo[d]thiazole -6-amine hydrochloride was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 111: Preparation of (2-(pyridin-3-yl)benzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide (Compound 111)

Step 111-1: Preparation of 2-bromo-5-nitrobenzo[d]thiazole

780 mg (59% yield) of the title compound was prepared by reacting in the same manner as Step 101-1 of Example 101 except that 5-nitrobenzo[d]thiazol-2-amine was used instead of 6-nitrobenzo [d]thiazol-2-amine.

Step 111-2: Preparation of 2-bromobenzo[d]thiazol-5-amine

153 mg (58% yield) of the title compound were prepared by reacting in the same manner as Step 101-2 of Example 101 except that 2-bromo-5-nitrobenzo[d]thiazole was used instead of 2-bromo -6-nitrobenzo[d]thiazole.

Step 111-3: Preparation of 2-(pyridin-3-yl)benzo[d]thiazol-5-amine

48 mg (48% yield) of the title compound was prepared by reacting in the same manner as Step 101-3 of Example 101 except that 2-bromobenzo[d]thiazol-5-amine was used instead of 2-bromobenzo [d]thiazol-6-amine, and pyridin-3-ylboronic acid pinacol ester was used instead of phenylboronic acid pinacol ester.

Step 111-4: Preparation of 2-(hydrazonoyl)benzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide

18 mg (23% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that 2-(pyridin-3-yl)benzo[d]thiazol-5 -amine was used instead of 2 N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 112: Preparation of (2-(5-methylpyridin-3-yl)benzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide (Compound 112)

26 mg (39% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that 2-(5-methylpyridin-3-yl)benzo[d]thiazole -5-amine was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 113: Preparation of benzo[d]thiazol-2-ylcarbonohydrazonoyl dicyanide (Compound 113)

29 mg (19% yield) of the title compound was obtained by reacting in the same manner as Step 86-3 of Example 86 except that benzo[d]thiazol-2-amine was used instead of N-(6- aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, and water was used as a solvent.

Example 114: Preparation of (6-fluorobenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide (Compound 114)

29 mg (19% yield) of the title compound was prepared by reacting in the same manner as Example 113 except that 6-fluorobenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2 -amine.

Example 115: Preparation of (6-chlorobenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide (Compound 115)

29 mg (21% yield) of the title compound was prepared by reacting in the same manner as Example 113 except that 6-chlorobenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2 -amine.

Example 116: Preparation of (6-bromobenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide (Compound 116)

23 mg (17% yield) of the title compound was prepared by reacting in the same manner as Example 113 except that 6-bromobenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2 -amine.

Example 117: Preparation of (6-(trifluoromethyl)benzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide (Compound 117)

27 mg (20% yield) of the title compound was prepared by reacting in the same manner as Example 113 except that 6-(trifluoromethyl)benzo[d]thiazol-2-amine was used instead of benzo[d] thiazol-2-amine.

Example 118: Preparation of (4-chlorobenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide (Compound 118)

20 mg (15% yield) of the title compound was prepared by reacting in the same manner as Example 113 except that 4-chlorobenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2 -amine.

Example 119: Preparation of (5-chlorobenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide (Compound 119)

11 mg (8% yield) of the title compound was prepared by reacting in the same manner as Example 113 except that 5-chlorobenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2 -amine.

Example 120: Preparation of (5-bromobenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide (Compound 120)

18 mg (7% yield) of the title compound was prepared by reacting in the same manner as Example 113 except that 5-bromobenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2 -amine.

Example 121: Preparation of (6-methoxybenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide (Compound 121)

26 mg (18% yield) of the title compound was prepared by reacting in the same manner as Example 113 except that 6-methoxybenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2 -amine.

Example 122: Preparation of (6-ethoxybenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide (Compound 122)

40 mg (29% yield) of the title compound was prepared by reacting in the same manner as Example 113 except that 6-ethoxybenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2 -amine.

Example 123: Preparation of (6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide (Compound 123)

15 mg (10% yield) of the title compound was prepared by reacting in the same manner as Example 113 except that 6-(trifluoromethoxy)benzo[d]thiazol-2-amine was used instead of benzo[d] thiazol-2-amine.

Example 124: Preparation of (6-methylbenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide (Compound 124)

36 mg (24% yield) of the title compound was prepared by reacting in the same manner as Example 113 except that 6-methylbenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2 -amine.

Example 125: Preparation of (4-methylbenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide (Compound 125)

68 mg (46% yield) of the title compound was prepared by reacting in the same manner as Example 113 except that 4-methylbenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2 -amine.

Example 126: Preparation of (4,6-dimethylbenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide (Compound 126)

41 mg (29% yield) of the title compound was prepared by reacting in the same manner as Example 113 except that 4,6-dimethylbenzo[d]thiazol-2-amine was used instead of benzo[d]thiazole -2-amine.

Example 127: Preparation of (5,6-dimethylbenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide (Compound 127)

32 mg (22% yield) of the title compound was prepared by reacting in the same manner as Example 113 except that 5,6-dimethylbenzo[d]thiazol-2-amine was used instead of benzo[d]thiazole -2-amine.

Example 128: Preparation of (6-phenoxybenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide (Compound 128)

6 mg (4% yield) of the title compound was prepared by reacting in the same manner as Example 113 except that 6-phenoxybenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2 -amine.

Example 129: Preparation of (6-phenylbenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide (Compound 129)

Step 129-1: Preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine

6-Bromobenzo[d]thiazol-2-amine (50 mg, 0.22 mmol) was dissolved in dioxane in the presence of nitrogen, and then Pd(dppf)Cl ₂ -DCM (36 mg, 0.04 mmol), bis( pinacolato)diboron (84 mg, 0.33 mmol) and potassium acetate (65 mg, 0.66 mmol) to obtain the reaction mixture. The reaction mixture was stirred at 90°C for 3 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 38 mg (62% yield) of the title compound.

Step 129-2: Preparation of 6-phenylbenzo[d]thiazol-2-amine

81 mg (50% yield) of the title compound was prepared by reacting in the same manner as Step 101-3 of Example 101 except that bromobenzene was used instead of 2-bromobenzo[d]thiazol-6-amine, and 2-aminobenzo[d]thiazol-6-ylboronic acid pinacol ester was used instead of phenylboronic acid pinacol ester.

Step 129-3: Preparation of (6-phenylbenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide

6 mg (5% yield) of the title compound was prepared by reacting in the same manner as Example 113 except that 6-phenylbenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2 -amine.

Example 130: Preparation of (3-(pyrazin-2-carboxamido)benzo[d]isoxazol-5-yl)carbonohydrazonoyl dicyanide (Compound 130)

Step 130-1: Preparation of 5-(tert-butoxycarbonyl)amino-2-fluorobenzonitrile and 5-di(tert-butoxycarbonyl)amino-2-fluorobenzonitrile

5-Amino-2-fluorobenzonitrile (1 g, 7.35 mmol) and DMAP (4-dimethylaminopyridine, 90 mg, 0.74 mmol) were dissolved in DCM in the presence of nitrogen, followed by di-tert-butyl dicarbonate ((Boc) ₂ O, 2.4 g, 11.02 mmol) was added to obtain a reaction mixture. The reaction mixture was refluxed for 12 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 1.8 g of the title compounds (5-(tert-butoxycarbonyl)amino-2-fluorobenzonitrile and 5-di(tert-butoxycarbonyl)amino-2-fluorobenzonitrile).

Step 130-2: Preparation of tert-butyl-3-aminobenzo[d]isoxazol-5-ylcarbamate

Potassium carbonate (8.34 g, 60.36 mmol) and acetohydroxamic acid (2.27 g, 30.18 mmol) were dissolved in DCM/H ₂ O in the presence of nitrogen, followed by a mixture (1.44 g) of 5-( tert-butoxycarbonyl)amino-2-fluorobenzonitrile and 5-di(tert-butoxycarbonyl)amino-2-fluorobenzonitrile obtained in accordance with step 130-1 were added to obtain a reaction mixture. The reaction mixture was stirred for 12 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with ether and then filtered to obtain 743 mg of the title compound.

Step 130-3: Preparation of trary-butyl-3-(pyrazin-2-carboxamido)benzo[d]isoxazol-5-ylcarbamate

Pyrazine-2-carboxylic acid (200 mg, 1.61 mmol) was dissolved in DCM in the presence of nitrogen, then oxalyl chloride (0.25 ml, 2.93 mmol) and a drop of DMF were added to obtain the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. Thereafter, tert-butyl-3-aminobenzo[d]isoxazol-5-ylcarbamate (365 mg, 1.47 mmol) obtained in accordance with step 130-2 and pyridine were added and the reaction mixture was stirred for 12 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was solidified with methanol and then filtered to obtain 225 mg (43% yield) of the title compound.

Step 130-4: Preparation of 3-(pyrazine-2-carboxamido)benzo[d]isoxazole-5-ammonium 2,2,2-trifluoroacetate

tert-Butyl-3-(pyrazin-2-carboxamido)benzo[d]isoxazol-5-ylcarbamate prepared according to step 130-3 (100 mg, 0.28 mmol) was dissolved in DCM in the presence of nitrogen and then trifluoroacetic acid (0.43 mL, 5.63 mmol) was added to form a reaction mixture. The reaction mixture was stirred at room temperature for 6 hours. When the reaction was complete, the reaction product was concentrated under reduced pressure and then dried for 4 hours. The filtrate was concentrated under reduced pressure and the concentrate was solidified with methanol and then filtered to obtain 225 mg (43% yield) of the title compound. The concentrate was then solidified with ethyl acetate and then filtered to obtain 97 mg (93% yield) of the title compound.

Step 130-5: Preparation of (3-(pyrazin-2-carboxamido)benzo[d]isoxazol-5-yl)carbonohydrazonoyl dicyanide

29 mg (63% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that 3-(pyrazine-2-carboxamido)benzo[d]isoxazole-5 -Ammonium 2,2,2-trifluoroacetate was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 131: Preparation of (3-(5-methylpyrazin-2-carboxamido)benzo[d]isoxazol-5-yl)carbonohydrazonoyl dicyanide (Compound 131)

Step 131-1: Preparation of tert-butyl-3-(5-methylpyrazin-2-carboxamido)benzo[d]isoxazol-5-ylcarbamate

209 mg (43% yield) of the title compound were prepared by reacting in the same manner as Step 130-3 of Example 130 except that 5-methylpyrazine-2-carboxylic acid was used instead of pyrazine-2-carboxylic acid .

Step 131-2: Preparation of 3-(5-methylpyrazine-2-carboxamido)benzo[d]isoxazole-5-ammonium 2,2,2-trifluoroacetate

84 mg (81% yield) of the title compound were prepared by reacting in the same manner as Step 130-4 of Example 130 except that tert-butyl-3-(5-methylpyrazine-2-carboxamido)benzo [d]isoxazol-5-ylcarbamate was used instead of tert-butyl-3-(pyrazin-2-carboxamido)benzo[d]isoxazol-5-ylcarbamate.

Step 131-3: Preparation of (3-(5-methylpyrazin-2-carboxamido)benzo[d]isoxazol-5-yl)carbonohydrazonoyl dicyanide

34 mg (75% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that 3-(5-methylpyrazine-2-carboxamido)benzo[d]isoxazole -5-ammonium 2,2,2-trifluoroacetate was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 132: Preparation of (3-(3-cyanobenzamido)benzo[d]isoxazol-5-yl)carbonohydrazonoyl dicyanide (Compound 132)

Step 132-1: Preparation of tert-butyl-3-(3-cyanobenzamido)benzo[d]isoxazol-5-ylcarbamate

203 mg (43% yield) of the title compound was obtained by reacting in the same manner as Step 130-3 of Example 130 except that 3-cyanobenzoic acid was used instead of pyrazine-2-carboxylic acid.

Step 132-2: Preparation of N-(5-aminobenzo[d]isoxazol-3-yl)-3-cyanobenzamide

tert-Butyl-3-(3-cyanobenzamido)benzo[d]isoxazol-5-ylcarbamate obtained according to Step 132-1 was dissolved in DCM in the presence of nitrogen, and then trifluoroacetic acid was added to obtain a reaction mixture. The reaction mixture was stirred at room temperature for 6 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and dried for 4 hours. The concentrate was then solidified with ethyl acetate and then filtered to obtain 71 mg (96% yield) of the title compound.

Step 132-3: Preparation of (3-(3-cyanobenzamipyrado)benzo[d]isooxazol-5-yl)carbonohydrazonoyl dicyanide

42 mg (65% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that N-(5-aminobenzo[d]isoxazol-3-yl)- 3-cyanobenzamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 133: Preparation of (3-(4-methoxybenzamido)benzo[d]isoxazol-5-yl)carbonohydrazonoyl dicyanide (Compound 133)

Step 133-1: Preparation of tert-butyl-3-(4-methoxybenzamido)benzo[d]isoxazol-5-ylcarbamate

312 mg (68% yield) of the title compound was obtained by reacting in the same manner as Step 130-3 of Example 130 except that 4-methoxybenzoic acid was used instead of pyrazine-2-carboxylic acid.

Step 133-2: Preparation of N-(5-aminobenzo[d]isoxazol-3-yl)-4-methoxybenzamide

116 mg (78% yield) of the title compound were prepared by reacting in the same manner as Step 132-2 of Example 132 except that tert-butyl-3-(4-methoxybenzamido)benzo[d]isoxazole -5-ylcarbamate was used instead of tert-butyl-3-(3-cyanobenzamido)benzo[d]isoxazol-5-ylcarbamate.

Step 133-3: Preparation of (3-(4-methoxybenzamido)benzo[d]isoxazol-5-yl)carbonohydrazonoyl dicyanide

38 mg (58% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that N-(5-aminobenzo[d]isoxazol-3-yl)- 4-methoxybenzamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide

Example 134: Preparation of (2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 134)

Step 134-1: 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 in the presence of nitrogen, and then Fe (228 mg, 4.08 mmol) and ammonium chloride (545 mg, 10.19 mmol) to obtain the reaction mixture. The reaction mixture was stirred at 80°C for 1 hour. When the reaction was completed, 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 then filtered.

The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 83 mg (49% yield) of the title compound.

Step 134-2: Preparation of (2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

34 mg (47% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that 6-aminobenzo[d]thiazol-2(3H)-one was used instead N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 135: Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 135)

Step 135-1: Preparation of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one

6-Nitrobenzo[d]thiazol-2(3H)-one (100 mg, 0.48 mmol) and 10% Pd/C (101 mg, 0.10 mmol) were dissolved in methanol in the presence of nitrogen, followed by methyl iodide (0 .05 mL, 0.76 mmol) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 0.11 mL, 0.76 mmol) were added to form a reaction mixture. The reaction mixture was stirred at room temperature for 16 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was solidified with methanol to give 68 mg (64% yield) of the title compound.

Step 135-2: Preparation of 6-amino-3-methylbenzo[d]thiazol-2(3H)-one

3-Methyl-6-nitrobenzo[d]thiazol-2(3H)-one (100 mg, 0.48 mmol) and 10% Pd/C (101 mg, 0.10 mmol) were dissolved in methanol in the presence of nitrogen to give reaction mixture. The reaction mixture was stirred at room temperature for 1 hour in the presence of hydrogen. When the reaction was complete, the reaction product was filtered, and then the filtrate was concentrated under reduced pressure to obtain 79 mg (91% yield) of the title compound.

Step 135-3: Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

94 mg (83% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that 6-amino-3-methylbenzo[d]thiazole-2(3H) -one was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 136: Preparation of (2-methoxybenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide (Compound 136)

Step 136-1: Preparation of 2-methoxy-6-nitrobenzo[d]thiazole

60% sodium hydride (45 mg, 1.12 mmol) and methanol (0.05 ml, 1.12 mmol) were dissolved in tetrahydrofuran at 0°C in the presence of nitrogen, and then 2-chloro-6-nitrobenzo[d] was added thiazole (200 mg, 0.93 mmol) to obtain the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 95 mg (49% yield) of the title compound.

Step 136-2: Preparation of 2-methoxybenzo[d]thiazol-6-amine 69 mg (90% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86, except that 2-methoxy-6-nitrobenzo[d]thiazole was used instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one.

Step 136-3: Preparation of (2-methoxybenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

60 mg (61% yield) of the title compound was prepared by reacting in the same manner as Step 135-2 of Example 135 except that 2-methoxybenzo[d]thiazol-6-amine was used instead of N-( 6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 137: Preparation of (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide (Compound 137)

Step 137-1: Preparation of 6-aminobenzo[d]oxazol-2(3H)-one

131 mg (78% yield) of the title compound were prepared by reacting in the same manner as Step 135-2 of Example 135 except that 6-nitrobenzo[d]oxazol-2(3H)-one was used instead 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one.

Step 137-2: Preparation of (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide

115 mg (76% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that 6-aminobenzo[d]oxazol-2(3H)-one was used instead N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 138: Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide (Compound 138)

Step 138-1: Preparation of 3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one

111 mg (88% yield) of the title compound were prepared by reacting in the same manner as Step 135-1 of Example 135 except that 6-nitrobenzo[d]oxazol-2(3H)-one was used instead 6-nitrobenzo[d]thiazol-2(3H)-one.

Step 138-2: Preparation of 6-amino-3-methylbenzo[d]oxazol-2(3H)-one

282 mg (87% yield) of the title compound were prepared by reacting in the same manner as Step 135-2 of Example 135 except that 3-methyl-6-nitrobenzo[d]oxazole-2(3H) -one was used instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one.

Step 138-3: Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide

107 mg (73% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that 6-amino-3-methylbenzo[d]oxazole-2(3H) -one was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 139: Preparation of (2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide (Compound 139)

Step 139-1: Preparation of 5-amino-1H-benzo[d]imidazol-2(3H)-one

122 mg (73% yield) of the title compound were prepared by reacting in the same manner as Step 135-2 of Example 135 except that 5-nitro-1H-benzo[d]imidazole-2(3H) -one was used instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one.

Step 139-2: Preparation of (2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide

15 mg (10% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that 5-amino-1H-benzo[d]imidazole-2(3H) -one was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 140: Preparation of diethyl 2-(2-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)hydrazono)malonate (Compound 140)

6-(4-Aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (50 mg, 0.25 mmol) and sodium nitrite (40 mg, 0.29 mmol) were dissolved in ethanol in the presence nitrogen, and then 1.0 M aqueous hydrochloric acid (0.74 mL, 0.74 mmol) was added to obtain a reaction mixture. The reaction mixture was stirred at 0°C for 10 minutes to form the diazonium salt. After the formation of the diazonium salt, diethyl malonate (80 μL, 0.50 mmol) was added, followed by stirring at room temperature for 10 minutes. Thereafter, the pH of the reaction mixture was adjusted using an aqueous solution of sodium acetate, and then the reaction mixture was further stirred at room temperature for 1 hour. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 17 mg (18% yield) of the title compound.

Example 141: Preparation of 2-imino-N'-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)-2-(piperazin-1-yl)acetohydrazonoyl cyanide (Connection 141)

(4-(4-Methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbonohydrazonoyl dicyanide (50 mg, 0.18 mmol) and piperazine (23 mg, 0.27 mmol) were dissolved in ethanol and then stirred at 80°C for 17.5 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was solidified with ethanol to give 50 mg (76% yield) of the title compound.

Example 142: Preparation of 2-amino-N'-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)-2-morpholinoacetohydrazonoyl cyanide (Compound 142)

61 mg (93% yield) of the title compound was prepared by reacting in the same manner as Example 141 except that morpholine was used instead of piperazine.

Example 143: Preparation of methyl 2-(2-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)hydrazono)propanoate (Compound 143)

6-(4-Aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (200 mg, 0.98 mmol), sodium nitrite (81.4 mg, 1.18 mmol) and 1, 0 M aqueous hydrochloric acid (2.9 ml, 2.95 mmol) was mixed to obtain a reaction mixture, and the reaction mixture was stirred at 0° C. for 10 minutes. Tin(II) chloride hydrate (666 mg, 2.95 mmol) and 1.0 M aqueous hydrochloric acid (0.68 ml) were then added, followed by stirring at 0°C for 10 minutes, and then methyl pyruvate ( 0.18 ml, 1.97 mmol) followed by stirring at room temperature for 30 minutes. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was solidified with ethanol to give 177 mg (60% yield) of the title compound.

Example 144: Preparation of methyl 2-cyano-2-(2-(4-(pyrimidin-2-yl)phenyl)hydrazono)acetate (Compound 144)

4-(Pyrimidin-2-yl)aniline (50 mg, 0.29 mmol) and sodium nitrite (24 mg, 0.35 mmol) were dissolved in ethanol in the presence of nitrogen and then in 1.0 M aqueous hydrochloric acid ( 0.88 ml, 0.88 mmol) was added to obtain a reaction mixture, and the reaction mixture was stirred at 0°C for 10 minutes. After the formation of the diazonium salt, diethyl malonate (80 μL, 0.50 mmol) was added, followed by stirring at room temperature for 10 minutes. Methyl 2-cyanoacetate (31 μL, 0.35 mmol) was added, followed by stirring at room temperature for 10 minutes. The pH of the reaction mixture was adjusted to 6.0 with an aqueous sodium hydroxide solution, and then the reaction mixture was further stirred at room temperature for 1 hour. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 25 mg (64% yield) of the title compound.

Example 145: Preparation of 2-amino-2-oxo-N'-(4-(pyrimidin-2-yl)phenyl)acetohydrazonoyl cyanide (Compound 145)

14 mg (18% yield) of the title compound was prepared by reacting in the same manner as Example 144 except that 2-cyanoacetamide was used instead of methyl 2-cyanoacetate.

Example 146: Preparation of ethyl 2-cyano-2-(2-(4-(pyrimidin-2-yl)phenyl)hydrazono)acetate (Compound 146)

24 mg (30% yield) of the title compound was prepared by reacting in the same manner as Example 144 except that 2-cyanoacetamide was used instead of methyl 2-cyanoacetate.

Example 147: Preparation of 2-amino-N'-(4-(pyrimidin-2-yl)phenyl)-2-thioxoacetohydrazonoyl cyanide (Compound 147)

35 mg (43% yield) of the title compound was prepared by reacting in the same manner as Example 144 except that 2-cyanoethanethanioamide was used instead of methyl 2-cyanoacetate.

Example 148: Preparation of 4-methyl-N'-(4-(pyrimidin-2-yl)phenyl)thiazol-2-carbohydrazonoyl cyanide (Compound 148)

Step 148-1: Preparation of 2-(4-methylthiazol-2-yl)acetonitrile

2-Cyanoethanethanioamide (500 mg, 4.99 mmol), chloroacetone (0.45 mL, 5.49 mmol) and triethylamine (0.70 mL, 4.99 mmol) were dissolved in dimethylformamide to obtain a reaction mixture, and the reaction mixture was stirred at 40°C for 1.5 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 163 mg (24% yield) of the title compound.

Step 148-2: Preparation of 4-methyl-N'-(4-(pyrimidin-2-yl)phenyl)thiazol-2-carbohydrazonoyl cyanide

18 mg (19% yield) of the title compound were prepared by reacting in the same manner as Example 144 except that the 2-(4-methylthiazol-2-yl)acetonitrile obtained in accordance with step 148- 1 was used instead of 2-cyanoethanethanioamide.

Example 149: Preparation of (4-(5-ethynylpyrimidin-2-yl)phenyl)carbohydrazonoyl dicyanide (Compound 149)

Step 149-1: Preparation of 4-(5-bromopyrimidin-2-yl)aniline

2,5-Dibromopyrimidine (2 g, 8.41 mmol) and 4-aminophenylboronic acid pinacol ester (2.3 g, 10.51 mmol) were dissolved in a solution of 1,4-dioxane, followed by Pd(PPh ₃ ) ₄ ( 484 mg, 0.42 mmol) and 2.0 M potassium phosphate aqueous solution (12.6 mL, 25.2 mmol) were added to obtain a reaction mixture. The reaction mixture was stirred at 90°C for 2.5 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 1.8 g (68% yield) of the title compound.

Step 149-2: Preparation of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline

4-(5-Bromopyrimidin-2-yl)aniline (220 mg, 0.88 mmol) was prepared according to step 149-1 and ethynyltrimethylsilane (1.32 mmol) was dissolved in dimethylformamide followed by Pd(PPh ₃ ) ₂ Cl ₂ (31 mg, 0.04 mmol), copper iodide (CuI, 13 mg, 0.07 mmol) and triethylamine (0.3 ml, 2.2 mmol) were added to obtain a reaction mixture. The reaction mixture was stirred at 100°C for 2 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 148 mg (63% yield) of the title compound.

Step 149-3: Preparation of (4-(5-ethynylpyrimidin-2-yl)phenyl)carbohydrazonoyl dicyanide

92 mg (22% yield) of the title compound was prepared by reacting in the same manner as Example 144 except that malononitrile was used instead of methyl 2-cyanoacetate, and 4-(5-((trimethylsilyl)ethynyl )pyrimidin-2-yl)aniline obtained in accordance with step 149-2 was used instead of 4-(pyrimidin-2-yl)aniline.

Example 150: Preparation of (4'-(dimethylamino)-3-fluorobiphenyl-4-yl)carbohydrazonoyl dicyanide (Compound 150)

Step 150-1: Preparation of 3'-fluoro-N,N-dimethyl-4'-nitrobiphenyl-4-amine

134 mg (54% yield) of the title compound were prepared by reacting in the same manner as Step 149-1 of Example 149 except that 4-bromo-2-fluoro-1-nitrobenzene was used instead of 2,5 -dibromopyrimidine, and 4-dimethylaminophenylboronic acid pinacol ester was used instead of 4-aminophenylboronic acid pinacol ester.

Step 150-2: Preparation of 3-fluoro-N ^4' ,N ^4' -dimethylbiphenyl-4,4'-diamine

51 mg (48% yield) of the title compound was obtained by reacting in the same manner as Step 135-2 of Example 135 except that 3'-fluoro-N,N-dimethyl-4'-nitrobiphenyl- 4-amine was used instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one.

Step 150-3: Preparation of (4'-(dimethylamino)-3-fluorobiphenyl-4-yl)carbohydrazonoyl dicyanide

11 mg (14% yield) of the title compound were prepared by reacting in the same manner as Step 149-3 of Example 149 except that 3-fluoro-N ^4' ,N ^4' -dimethylbiphenyl-4, 4'-diamine was used instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline.

Example 151: Preparation of (4'-(dimethylamino)biphenyl-4-yl)carbohydrazonoyl dicyanide (Compound 151)

Step 151-1: Preparation of N,N-dimethyl-4'-nitrobiphenyl-4-amine

182 mg (93% yield) of the title compound were prepared by reacting in the same manner as Step 149-1 of Example 149 except that 4-bromo-1-nitrobenzene was used instead of 2,5-dibromopyrimidine, and 4-dimethylaminophenylboronic acid pinacol ester was used instead of 4-aminophenylboronic acid pinacol ester.

Step 151-2: Preparation of N ^4' ,N ^4' -dimethylbiphenyl-4,4'-diamine

51 mg (48% yield) of the title compound was obtained by reacting in the same manner as Step 135-2 of Example 135 except that N,N-dimethyl-4'-nitrobiphenyl-4-amine was used instead 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one.

Step 151-3: Preparation of (4'-(dimethylamino)biphenyl-4-yl)carbohydrazonoyl dicyanide

10 mg (6% yield) of the title compound was prepared by reacting in the same manner as Step 149-3 of Example 149 except that N ^4' ,N ^4' -dimethylbiphenyl-4,4'-diamine was used instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline.

Example 152: Preparation of (4-(6-(dimethylamino)pyridin-3-yl)phenyl)carbohydrazonoyl dicyanide (Compound 152)

Step 152-1: Preparation of 5-(4-aminophenyl)-N,N-dimethylpyridin-2-amine

127 mg (60% yield) of the title compound were prepared by reacting in the same manner as Step 149-1 of Example 149 except that 5-bromo-N,N-dimethylpyridin-2-amine was used instead of 2 ,5-dibromopyrimidine.

Step 152-2: Preparation of (4-(6-(dimethylamino)pyridin-3-yl)phenyl)carbohydrazonoyl dicyanide

16 mg (38% yield) of the title compound were prepared by reacting in the same manner as Step 149-3 of Example 149 except that 5-(4-aminophenyl)-N,N-dimethylpyridinium-2- the amine was used instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline.

Example 153: Preparation of (4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide (Compound 153)

Step 153-1: Preparation of 6-chloropyridazin-3(2H)-one

3,6-Dichloropyridazine (1 g, 6.71 mmol) was dissolved in acetic acid (26 ml) to obtain a reaction mixture, and then the reaction mixture was stirred at 110°C for 12 hours. When the reaction was completed, the reaction product was concentrated and an aqueous sodium hydrogen carbonate solution was added, and then the reaction product was stirred at room temperature until solidified and concentrated under reduced pressure to obtain 420 mg (48% yield) of the title compound.

Step 153-2: Preparation of 6-(4-aminophenyl)pyridazin-3(2H)-one

6-Chloropyridazin-3(2H)-one (100 mg, 0.77 mmol) and 4-aminophenylboronic acid pinacol ester (168 mg, 0.77 mmol) were dissolved in a solution of 1,4-dioxane, followed by Pd(PPh ₃ ) ₄ (89 mg, 0.08 mmol) and aqueous potassium carbonate (423 mg, 3.06 mmol) were added to obtain a reaction mixture. The reaction mixture was stirred in a microwave oven at 160°C for 1.5 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 36 mg (25% yield) of the title compound.

Step 153-3: Preparation of (4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide

96 mg (68% yield) of the title compound was obtained by reacting in the same manner as Step 149-3 of Example 149 except that 6-(4-aminophenyl)pyridazin-3(2H)-one was used instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline.

Example 154: Preparation of (4-(4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide (Compound 154)

Step 154-1: Preparation of 6-chloro-5-methylpyridazin-3(2H)-one and 6-chloro-4-methylpyridazin-3(2H)-one

3,6-Dichloro-4-methylpyridazine (500 mg, 3.07 mmol) was dissolved in acetic acid (13 ml) to obtain a reaction mixture, and then the reaction mixture was stirred at 110°C for 12 hours. When the reaction was completed, the reaction product was concentrated, then an aqueous sodium hydrogen carbonate solution was added, and the reaction product was stirred at room temperature. Thereafter, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to give the title compounds, 184 mg (41% yield) of 6-chloro-5-methylpyridazin-3(2H)-one and 31 mg (7% yield ) 6-chloro-4-methylpyridazin-3(2H)-one.

Step 154-2: Preparation of 6-(4-aminophenyl)-5-methylpyridazin-3(2H)-one

122 mg (44% yield) of the title compound were prepared by reacting in the same manner as Step 153-2 of Example 153 except that a mixture of 6-chloro-5-methylpyridazin-3(2H)-one and 6-chloro-4-methylpyridazin-3(2H)-one was used instead of 6-chloropyridazin-3(2H)-one.

Step 154-3: Preparation of (4-(4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide

96 mg (70% yield) of the title compound were prepared by reacting in the same manner as Step 149-3 of Example 149 except that 6-(4-aminophenyl)-5-methylpyridazin-3(2H) -one was used instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline.

Example 155: Preparation of (4-(5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide (Compound 155)

Step 155-1: Preparation of 6-(4-aminophenyl)-4-methylpyridazin-3(2H)-one

87 mg (62% yield) of the title compound was prepared by reacting in the same manner as Step 153-2 of Example 153 except that a mixture of 6-chloro-5-methylpyridazin-3(2H)-one and 6-chloro-4-methylpyridazin-3(2H)-one was used instead of 6-chloropyridazin-3(2H)-one.

Step 155-2: Preparation of (4-(5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide

60 mg (87% yield) of the title compound was prepared by reacting in the same manner as Step 149-3 of Example 149 except that 6-(4-aminophenyl)-4-methylpyridazin-3(2H) -one was used instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline.

Example 156: Preparation of (4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide (Compound 156)

Step 156-1: Preparation of 6-chloro-2-methylpyridazin-3(2H)-one

6-Chloropyridazin-3(2H)-one (100 mg, 0.77 mmol), methyl iodide (95 μL, 1.53 mmol) and potassium carbonate (212 mg, 1.53 mmol) were dissolved in dimethylformamide to obtain the reaction mixture, and then the reaction mixture was stirred at room temperature for 4 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 82 mg (74% yield) of the title compound.

Step 156-2: Preparation of 6-(4-aminophenyl)-2-methylpyridazin-3(2H)-one

86 mg (95% yield) of the title compound was prepared by reacting in the same manner as Step 153-2 of Example 153 except that 6-chloro-2-methylpyridazin-3(2H)-one was used instead 6-chloropyridazin-3(2H)-one.

Step 156-3: Preparation of (4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide

41 mg (59% yield) of the title compound was prepared by reacting in the same manner as Step 149-3 of Example 149 except that 6-(4-aminophenyl)-2-methylpyridazin-3(2H) -one was used instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline.

Example 157: Preparation of (4-(1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide (Compound 157)

Step 157-1: Preparation of 6-chloro-2,5-dimethylpyridazin-3(2H)-one

53 mg (49% yield) of the title compound was prepared by reacting in the same manner as Step 156-1 of Example 156 except that 6-chloro-5-methylpyridazin-3(2H)-one was used instead 6-chloropyridazin-3(2H)-one.

Step 157-2: Preparation of 6-(4-aminophenyl)-2,5-dimethylpyridazin-3(2H)-one

51 mg (76% yield) of the title compound was prepared by reacting in the same manner as Step 153-2 of Example 153 except that 6-chloro-2,5-dimethylpyridazin-3(2H)-one was used instead of 6-chloropyridazin-3(2H)-one.

Step 157-3: Preparation of (4-(1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide

37 mg (77% yield) of the title compound was prepared by reacting in the same manner as Step 149-3 of Example 149 except that 6-(4-aminophenyl)-2,5-dimethylpyridazine-3( 2H)-one was used instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline.

Example 158: Preparation of (4-(1,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide (Compound 158)

Step 158-1: Preparation of 6-chloro-2,4-dimethylpyridazin-3(2H)-one

50 mg (65% yield) of the title compound was prepared by reacting in the same manner as Step 156-1 of Example 156 except that 6-chloro-4-methylpyridazin-3(2H)-one was used instead 6-chloropyridazin-3(2H)-one.

Step 158-2: Preparation of 6-(4-aminophenyl)-2,4-dimethylpyridazin-3(2H)-one

47 mg (70% yield) of the title compound were prepared by reacting in the same manner as Step 153-2 of Example 153 except that 6-chloro-2,4-dimethylpyridazin-3(2H)-one was used instead of 6-chloropyridazin-3(2H)-one.

Step 158-3: Preparation of (4-(1,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide

11 mg (22% yield) of the title compound were prepared by reacting in the same manner as Step 149-3 of Example 149 except that 6-(4-aminophenyl)-2,4-dimethylpyridazine-3( 2H)-one was used instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline.

Example 159: Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide (Compound 159)

Step 159-1: Preparation of 3-isopropyl-6-nitrobenzo[d]thiazol-2(3H)-one

162 mg (44% yield) of the title compound were obtained by reacting in the same manner as Step 135-1 of Example 135 except that 2-iodopropane was used instead of methyl iodide.

Step 159-2: Preparation of 6-amino-3-isopropylbenzo[d]thiazol-2(3H)-one

112 mg (85% yield) of the title compound were prepared by reacting in the same manner as Step 135-2 of Example 135 except that 3-isopropyl-6-nitrobenzo[d]thiazole-2(3H) -one was used instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one.

Step 159-3: Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

109 mg (80% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that 6-amino-3-isopropylbenzo[d]thiazole-2(3H) -one was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 160: Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide (Compound 160)

Step 160-1: Preparation of 3-(difluoromethyl)-6-nitrobenzo[d]thiazol-2(3H)-one

6-Nitrobenzo[d]thiazol-2(3H)-one (300 mg, 1.53 mmol) was dissolved in DMF in the presence of nitrogen, and then sodium 2-chloro-2,2-difluoroacetate (467 mg, 3.06 mmol) and DBU (0.46 mL, 3.06 mmol) to obtain a reaction mixture, and the reaction mixture was stirred at room temperature for 16 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was solidified with methanol to give 176 mg (47% yield) of the title compound.

Step 160-2: Preparation of 6-amino-3-(difluoromethyl)benzo[d]thiazol-2(3H)-one

125 mg (95% yield) of the title compound were prepared by reacting in the same manner as Step 135-2 of Example 135 except that 3-(difluoromethyl)-6-nitrobenzo[d]thiazole-2( 3H)-one was used instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one.

Step 160-3: Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

85 mg (63% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that 6-amino-3-(difluoromethyl)benzo[d]thiazole-2 (3H)-one was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 161: Preparation of (2-isopropoxybenzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide (Compound 161)

Step 161-1: Preparation of 2-isopropoxy-6-nitrobenzo[d]thiazole -

60% sodium hydride (84 mg, 2.10 mmol) and isopropanol (0.16 ml, 2.10 mmol) were dissolved in THF at 0°C in the presence of nitrogen, followed by 2-chloro-6-nitrobenzo[d]thiazole ( 300 mg, 1.40 mmol) was added to obtain a reaction mixture, and the reaction mixture was stirred at room temperature for 1 hour. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 184 mg (55% yield) of the title compound.

Step 161-2: Preparation of 2-isopropoxybenzo[d]thiazol-6-amine

126 mg (96% yield) of the title compound were prepared by reacting in the same manner as Step 135-2 of Example 135 except that 2-isopropoxy-6-nitrobenzo[d]thiazole was used instead of 3-methyl -6-nitrobenzo[d]thiazol-2(3H)-one.

Step 161-3: Preparation of (2-isopropoxybenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

30 mg (22% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that 2-isopropoxybenzo[d]thiazol-6-amine was used instead of N-( 6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 162: Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbohydrazonoyl dicyanide (Compound 162)

Step 162-1: Preparation of 3-isopropyl-6-nitrobenzo[d]oxazol-2(3H)-one

201 mg (54% yield) of the title compound were prepared by reacting in the same manner as Step 135-1 of Example 135 except that 6-nitrobenzo[d]oxazol-2(3H)-one was used instead 6-nitrobenzo[d]thiazol-2(3H)-one, and 2-iodopropane were used instead of methyl iodide.

Step 162-2: Preparation of 6-amino-3-isopropylbenzo[d]oxazol-2(3H)-one

124 mg (85% yield) of the title compound were prepared by reacting in the same manner as Step 135-2 of Example 135 except that 3-isopropyl-6-nitrobenzo[d]thiazole-2(3H) -one was used instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one.

Step 162-3: Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide

99 mg (59% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that 6-amino-3-isopropylbenzo[d]oxazole-2(3H) -one was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 163: Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbohydrazonoyl dicyanide (Compound 163)

Step 163-1: Preparation of 3-(difluoromethyl)-6-nitrobenzo[d]oxazol-2(3H)-one

144 mg (38% yield) of the title compound were prepared by reacting in the same manner as Step 160-1 of Example 160 except that 6-nitrobenzo[d]oxazol-2(3H)-one was used instead 6-nitrobenzo[d]thiazol-2(3H)-one.

Step 163-2: Preparation of 6-amino-3-(difluoromethyl)benzo[d]oxazol-2(3H)-one

110 mg (98% yield) of the title compound were prepared by reacting in the same manner as Step 135-2 of Example 135 except that 3-(difluoromethyl)-6-nitrobenzo[d]oxazole-2( 3H)-one was used instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one.

Step 163-3: Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide

85 mg (63% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that 6-amino-3-(difluoromethyl)benzo[d]oxazole-2 (3H)-one was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 164: Preparation of (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbohydrazonoyl dicyanide (Compound 164)

Step 164-1: Preparation of 1,3-dimethyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

207 mg (64% yield) of the title compound were prepared by reacting in the same manner as Step 135-1 of Example 135 except that 5-nitro-1H-benzo[d]imidazole-2(3H) -one was used instead of 6-nitrobenzo[d]thiazol-2(3H)-one.

Step 164-2: Preparation of 5-amino-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

105 mg (82% yield) of the title compound were prepared by reacting in the same manner as Step 135-2 of Example 135 except that 1,3-dimethyl-5-nitro-1H-benzo[d] Imidazol-2(3H)-one was used instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one.

Step 164-3: Preparation of (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide

11 mg (8% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that 5-amino-1,3-dimethyl-1H-benzo[d] Imidazol-2(3H)-one was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 165: Preparation of (1,3-diisopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbohydrazonoyl dicyanide (Compound 165)

Step 165-1: Preparation of 1,3-diisopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

204 mg (46% yield) of the title compound were prepared by reacting in the same manner as Step 135-1 of Example 135 except that 5-nitro-1H-benzo[d]imidazole-2(3H) -one was used instead of 6-nitrobenzo[d]thiazol-2(3H)-one, and 2-iodopropane was used instead of methyl iodide.

Step 165-2: Preparation of 5-amino-1,3-diisopropyl-1H-benzo[d]imidazol-2(3H)-one

118 mg (89% yield) of the title compound were prepared by reacting in the same manner as Step 135-2 of Example 135 except that 1,3-diisopropyl-5-nitro-1H-benzo[d] Imidazol-2(3H)-one was used instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one.

Step 165-3: Preparation of (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide

12 mg (10% yield) of the title compound were prepared by reacting in the same manner as Step 86-3 of Example 86 except that 5-amino-1,3-diisopropyl-1H-benzo[d] Imidazol-2(3H)-one was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 166: Preparation of (1,3-bis(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbohydrazonoyl dicyanide (Compound 166)

Step 166-1: Preparation of 1,3-bis(difluoromethyl)-5-nitro-1H-benzo[d]imidazol-2(3H)-one

179 mg (38% yield) of the title compound were prepared by reacting in the same manner as Step 160-1 of Example 160 except that 5-nitro-1H-benzo[d]imidazole-2(3H) -one was used instead of 6-nitrobenzo[d]thiazol-2(3H)-one.

Step 166-2: Preparation of 5-amino-1,3-bis(difluoromethyl)-1H-benzo[d]imidazol-2(3H)-one

69 mg (96% yield) of the title compound was prepared by reacting in the same manner as Step 135-2 of Example 135 except that 1,3-bis(difluoromethyl)-6-nitro-1H-benzo [d]imidazol-2(3H)-one was used instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one.

Step 166-3: Preparation of (1,3-bis(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide

45 mg (58% yield) of the title compound was prepared by reacting in the same manner as Step 86-3 of Example 86 except that 5-amino-1,3-bis(difluoromethyl)-1H-benzo [d]imidazol-2(3H)-one was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide.

Example 167: Preparation of (2-(methylamino)benzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide (Compound 167)

Step 167-1: Preparation of N-methyl-6-nitrobenzo[d]thiazol-2-amine

2-Chloro-6-nitrobenzo[d]thiazole (500 mg, 2.33 mmol) was dissolved in THF at room temperature in the presence of nitrogen, and then 2.0 M methylamine (2.56 ml, 5.13 mmol) was dissolved in THF was added to obtain the reaction mixture, and the reaction mixture was stirred at room temperature for 15 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was solidified with ethyl acetate to give 442 mg (91% yield) of the title compound.

Step 167-2: Preparation of N ² -methylbenzo[d]thiazole-2,6-diamine

101 mg (78% yield) of the title compound was prepared by reacting in the same manner as Step 135-2 of Example 135 except that N-methyl-6-nitrobenzo[d]thiazol-2-amine was used instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one.

Step 167-3: Preparation of (2-(methylamino)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

5 mg (4% yield) of the title compound was prepared by reacting in the same manner as Example 113 except that N ² -methylbenzo[d]thiazole-2,6-diamine was used instead of benzo[d] thiazol-2-amine.

Example 168: Preparation of (2-(dimethylamino)benzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide (Compound 168)

Step 168-1: Preparation of N,N-dimethyl-6-nitrobenzo[d]thiazol-2-amine

392 mg (75% yield) of the title compound was obtained by reacting in the same manner as Step 167-1 of Example 167 except that dimethylamine was used instead of methylamine.

Step 168-2: Preparation of N ² ,N ² -dimethylbenzo[d]thiazol-2,6-diamine

103 mg (80% yield) of the title compound were prepared by reacting in the same manner as Step 135-2 of Example 135 except that N,N-dimethyl-6-nitrobenzo[d]thiazol-2- the amine was used instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one.

Step 168-3: Preparation of (2-(dimethylamino)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

11 mg (10% yield) of the title compound were prepared by reacting in the same manner as Example 113 except that N ² ,N ² -dimethylbenzo[d]thiazole-2,6-diamine was used instead of benzo [d]thiazol-2-amine.

Example 169: Preparation of (4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide (Compound 169)

Step 169-1: Preparation of N-(4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide

4-(4-Acetamidophenyl)-4-oxobutanoic acid (100 mg, 0.42 mmol) was dissolved in ethanol, and then hydrazine hydrate (25 μL, 0.51 mmol) was added to obtain the reaction mixture, and the reaction mixture was stirred at 90°C for 3.5 hours. When the reaction was complete, the reaction product was filtered to obtain 47 mg (48% yield) of the title compound.

Step 169-2: Preparation of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)-one

1.0 M aqueous hydrochloric acid (21.6 mL, 21.6 mmol) was added to N-(4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide obtained according to step 169-1, and then reacted at 110°C for 1.5 hours. Thereafter, the reaction product was neutralized with aqueous ammonium hydroxide and filtered to obtain 118 mg (28% yield) of the title compound.

Step 169-3: Preparation of (4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide

66 mg (93% yield) of the title compound was prepared by reacting in the same manner as Step 149-3 of Example 149 except that 6-(4-aminophenyl)-4,5-dihydropyridazine-3( 2H)-one was used instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline.

Example 170: Preparation of (4-(1-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide (Compound 170)

Step 170-1: Preparation of 6-(4-aminophenyl)-2-methyl-4,5-dihydropyridazin-3(2H)-one

6-(4-Aminophenyl)-4,5-dihydropyridazin-3(2H)-one (105 mg, 0.55 mmol) and 60% sodium hydride (24 mg, 0.61 mmol) were dissolved in a mixed solvent of DMF and THF , and then methyl iodide (34 μL, 0.55 mmol) was added to obtain a reaction mixture, and the reaction mixture was stirred at 0°C for 12 hours. When the reaction was completed, 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 then filtered. The filtrate was concentrated under reduced pressure and the concentrate was purified by column chromatography to obtain 33 mg (29% yield) of the title compound.

Step 170-2: Preparation of (4-(1-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide

90 mg (95% yield) of the title compound were prepared by reacting in the same manner as Step 149-3 of Example 149 except that 6-(4-aminophenyl)-2-methyl-4,5- Dihydropyridazin-3(2H)-one was used instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline.

Example 171: Preparation of (4-(1,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide (Compound 171)

Step 171-1: Preparation of 6-(4-aminophenyl)-2,5-dimethyl-4,5-dihydropyridazin-3(2H)-one

131 mg (61% yield) of the title compound were prepared by reacting in the same manner as Step 170-1 of Example 170 except that 6-(4-aminophenyl)-5-methyl-4,5- Dihydropyridazin-3(2H)-one was used instead of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)-one.

Step 171-2: Preparation of (4-(1,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide

82 mg (76% yield) of the title compound were prepared by reacting in the same manner as Step 149-3 of Example 149 except that 6-(4-aminophenyl)-2,5-dimethyl-4, 5-dihydropyridazin-3(2H)-one was used instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline.

Preparation of Example 1: Preparation of tablets by direct compression

5.0 mg of each of the active ingredients obtained in Examples 1 to 171 was sieved, mixed with 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate, and then compressed to obtain tablets.

Preparation of Example 2: Preparation of tablets by wet granulation method

5.0 mg of each of the active ingredients obtained in Examples 1 to 171 was sifted and then mixed with 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg of polysorbate 80 was dissolved in pure water, and this solution was added to the mixture in a suitable amount, followed by spraying to obtain fine particles. After drying, the fine particles were sieved, mixed with 2.7 mg of colloidal silica and 2.0 mg of magnesium stearate and compressed to form tablets.

Preparation of Example 3: Preparation of Powder and Capsules

5.0 mg of each of the active ingredients obtained in Examples 1 to 171 was sieved and then mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. The mixture was filled into No. 5 hard gelatin capsules using a suitable capsule forming apparatus.

Preparation of Example 4: Preparation of Injectable Drugs

100 mg of each of the active ingredients obtained in Examples 1 to 171 was mixed with 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ ⋅ 12 H ₂ O, and 2974 mg of distilled water to prepare injection preparations.

Experimental Example 1: Selection of Tau Aggregation Inhibiting Materials Using Cell Models

To select new materials that inhibit tau aggregation, tau-BiFC cell models were used, in which the formation of tau oligomers can be easily observed in living cells. Tau-BiFC cells were poured into 384-well plates, and the next day, the compounds prepared according to Examples 1 to 171 were treated at a concentration of 1 μM, 3 μM, and 10 μM, respectively, along with forskolin (treatment concentration 30 μM), which stimulates tau phosphorylation through activation of PKA and induces tau protein aggregation. After 48 h, intracellular nuclei were stained with Hoechst (2 μg/mL treatment concentration), and BiFC fluorescence intensity was automatically quantified using Operetta (PerkinElmer) to count the stained nuclei in each well from all wells of the plates. The group receiving only forskolin, which induces tau protein agglutination, was set as a control point in the aggregation state of 100% tau protein, and its effect was confirmed by the equation “Fluorescence intensity of BiFC compound synthesized in accordance with an embodiment of the present invention / ( fluorescence intensity of the control group treated only with forskolin, which causes tau protein aggregation - fluorescence intensity of the untreated control group) x 100.” In addition, the degree of cytotoxicity caused by the newly synthesized compound is also based on the 100% survival rate of the forskolin-only group, and the cytotoxicity value of the compound was calculated by the equation “number of stained nuclei in the compound-treated group/number of stained nuclei in the forskolin-treated group x 100 " Based on the treatment results, materials that inhibit intracellular tau aggregation were selected from a number of candidate groups based on 70% or more inhibition of tau aggregation and 100% cell survival at a compound treatment concentration of 10 μM or more.

Experimental Example 2: Confirmation of Concentration-Dependent Tau Aggregation Inhibitory Effects of Novel Compounds

To evaluate the dose-dependent effects of tau aggregation inhibition of compounds selected according to Experimental Example 1, selected compounds were treated in tau-BiFC cells 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 (treatment concentration 30 μM) as tau aggregation-inducing material. After 48 hours, the tau aggregation reaction and the degree of cytotoxicity were analyzed by observing the images of the cells. IC ₅₀ and toxicity of compounds were analyzed using non-linear regression analysis of Prism software (Graph Pad). The results calculated for representative compounds are illustrated in Table 1 below.

Experimental Example 3: Effects of Inhibition of CYP Coenzyme Activity by Novel Compounds

The effects of inhibition of CYP coenzyme activity by compounds obtained in accordance with examples 1-171 were confirmed. In particular, human liver microsomes (0.25 mg/ml), 0.1 M phosphate buffer solution (pH 7.4), cocktails of substrate drugs (phenacetin 50 μM, diclofenac 10 μM, S-mephenytoin (100 μM, dextromethorphan 5 µM and midazolam 2.5 µM) of five kinds of drug metabolism enzymes, and compounds with a concentration of 0 µM or 10 µM, respectively, were added.The mixture was then pre-cultured at 37°C for 5 minutes, and then further cultured at 37°C in for 15 minutes along with the addition of NADPH generation system solution.The reaction was then stopped by adding acetonitrile solution containing internal standard material (terfenadine), separation by centrifugation (14000 rpm, 4°C) was performed for 5 minutes, and then the supernatant was injected into the LC-MS/MS system. Metabolites of drug substrates were simultaneously analyzed to evaluate the ability to inhibit drug metabolism.

The metabolites of each CYP coenzyme indicator drug produced during the reaction were analyzed using a Shimadzu Nexera XR and TSQ vantage system (Thermo). Kinetex C18 (2.1 mm × 100 mm, 2.6 μm particle size; Phenomenex, USA) was used in the HPLC column, and (A) distilled water containing 0.1% formic acid, and (B) acetonitrile, containing 0 1% formic acid were used as mobile phases and the gradient program illustrated in Table 2 was applied.

The generated metabolites were quantified using MRM (Multiple Reaction Monitoring) quantification mode and Xcalibur (version 1.6.1) was used for data analysis. Table 3 illustrates the CYP coenzyme activity inhibition effects of novel compounds prepared in accordance with embodiments of the present invention.

Experimental Example 4: Confirmation of Liver Microsomal Stability of New Compounds

The microsomal stability in the liver of the compounds prepared in accordance with Examples 1-171 was confirmed. Specifically, four kinds of liver microsomes (human, dog, rat and mouse, each 0.25 mg/ml), 0.1 M phosphate buffer solution (pH 7.4) and compounds with a concentration of 1 μM were added, respectively. The mixture was then pre-cultured at 37°C for 5 minutes, and then further cultured at 37°C for 30 minutes along with the addition of NADPH generation system solution. The reaction was then stopped by adding an acetonitrile solution containing internal standard material (chlorpropamide), centrifugation separation (14,000 rpm, 4°C) was performed for 5 minutes, and then the supernatant was injected into the LC-MS/MS system. Drug substrates were analyzed to evaluate the metabolic stability of 8 types of compounds.

The amount of substrate remaining after the reaction was analyzed using a Shimadzu Nexera XR and TSQ vantage system (Thermo). Kinetex XB-C18 (2.1 mm × 100 mm, 2.6 μm particle size; Phenomenex, USA) was used in the HPLC column, and (A) distilled water containing 0.1% formic acid, and (B) Acetonitrile containing 0 1% formic acid was used as mobile phases. Analytical software (version 1.6.3) and Xcalibur (version 1.6.1) were used for data analysis. The calculated results are illustrated in Table 4 below.

Experimental Example 5: Pharmacokinetic Study of New Compounds

The pharmacokinetics of the compounds prepared in accordance with examples 1-171 were studied using experimental animal models. Specifically, a 7 to 8 week old SD rat (Core Tech, Hana Trading Co., Ltd.) having a body weight of about 250 to 300 g was purchased and kept in a simple small animal breeding room at 22°C. ±2°C, relative humidity 50%±5%, lighting time 12 hours (lights on at 8:00 am, off at 8:00 pm) and illumination from 150 lux to 300 lux. During the entire test period, free access to food and OS water was provided, and fasting was carried out for 16 hours before oral administration of the drug. After preparing the drug under the conditions illustrated in Table 5 below, the drug was administered intravenously (IV) or orally (PO). 500 μl of transfused blood was collected in a tube containing sodium heparin and centrifuged at 2-8°C at 8000 rpm for 6 minutes to obtain plasma from the blood.

The resulting plasma was added to 180 μl of acetonitrile containing internal standard materials, vortexed, and then centrifuged at 15,000 rpm at 4°C for 5 minutes to obtain the supernatant. The resulting supernatant was analyzed by LC-MS/MS. The HPLC and MS conditions used for analysis are illustrated in Tables 6 and 7 below.

Specific PK parameters were obtained using Phoenix WinNonlin version 6.4 (Pharsight, USA) and calculated using a non-compartmental analysis model. The results are presented in Table 8 below:

Those skilled in the art will appreciate that the present invention, as described above, may be embodied in other specific forms without departing from the technical spirit or essential characteristics thereof. Thus, it should be appreciated that the embodiments of the present invention described above are intended to be illustrative in all aspects and not limiting. The scope of the present invention is represented by the appended claims, which will be described below, rather than by detailed description, and it is to be interpreted that the spirit and scope of the appended claims and all variations or modified forms derived from their equivalents are within the scope of the present invention.

Claims (40)

1. The compound represented by Formula 4 below, or a pharmaceutically acceptable salt thereof, in the above formula 4 X ₁ to X ₃ are different from each other, each selected from C, N, O and S, and each linked to a carboxamido group through a C site; R ₁ represents hydrogen or C _1-6 alkyl; And R ₂ ''' is C _1-6 alkyl or aryl or heteroaryl, unsubstituted or substituted by at least one selected from the group consisting of C _1-6 alkoxy, hydroxy, cyano and C _1-6 alkyl. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, where X ₁ to X ₃ are sequentially N, C and S or O, N and C and are linked to the carboxamido group through the C site; R ₁ represents hydrogen; And R ₂ ''' is methyl or phenyl, pyridinyl, pyrazinyl or pyrimidinyl, unsubstituted or substituted by at least one selected from the group consisting of methoxy, hydroxy, cyano and methyl. 3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 86. (2-(4-methoxybenzamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 87. (2-(2-hydroxybenzamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 88. (2-acetamidobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 89. (2-(3-cyanobenzamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 90. (2-(5-methylnicotinamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 91. (2-(3-hydroxypicolinamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 92. (2-(pyrazin-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 93. (2-(5-methylpyrazin-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 94. (2-(pyrimidine-5-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 95. (2-(2-methylpyrimidin-5-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 96. (2-(4-methylpyrimidin-5-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 97. (2-(3-methylpyrazin-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 98. (2-(6-methylpyrazin-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide, 99. (2-(pyrazin-2-carboxamido)benzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide, 100. (2-(5-methylpyrazin-2-carboxamido)benzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide, 130. (3-(pyrazin-2-carboxamido)benzo[d]isoxazol-5-yl)carbonohydrazonoyl dicyanide, 131. (3-(5-methylpyrazin-2-carboxamido)benzo[d]isoxazol-5-yl)carbonohydrazonoyl dicyanide, 132. (3-(3-cyanobenzamido)benzo[d]isoxazol-5-yl)carbonohydrazonoyl dicyanide, 133. (3-(4-methoxybenzamido)benzo[d]isoxazol-5-yl)carbonohydrazonoyl dicyanide. 4. A method for producing a compound according to claim 1, including the steps: introducing carboxylic acid R2''' or its anhydride into the reaction with (here Y represents an unprotected or protected amine or nitro group) to form an amide bond; And introducing into the reaction sodium nitrite, a heterocycle containing R2''' bound to the carboxamido group obtained in the previous step, and malononitrile in the presence of an acid to form an imino bond. 5. Method according to claim 4, wherein when Y represents a protected amino group or a nitro group, the method further includes the step of converting the protected amino group or nitro group into an amino group before the step of forming an imino group. 6. Pharmaceutical composition for inhibiting tau protein aggregation, containing an effective amount of a compound according to any one of paragraphs. 1-3 as an active ingredient and a pharmaceutically acceptable carrier. 7. Pharmaceutical composition for inhibiting hyperphosphorylation of tau protein, containing an effective amount of a compound according to any one of paragraphs. 1-3 as an active ingredient and a pharmaceutically acceptable carrier. 8. Pharmaceutical composition for the prevention or treatment of diseases caused by aggregation or hyperphosphorylation of tau protein, containing an effective amount of a compound according to any one of paragraphs. 1-3 as an active ingredient and a pharmaceutically acceptable carrier. 9. The pharmaceutical composition according to claim 8, characterized in that the disease caused by aggregation or hyperphosphorylation of tau protein is selected from the group consisting of Alzheimer's disease, Parkinson's disease, vascular dementia, acute stroke, trauma, cerebrovascular disease, traumatic brain injury, spinal cord injury, peripheral neuropathy, retinopathy, glaucoma and tauopathy. 10. The pharmaceutical composition of claim 9, wherein the tauopathy is selected from the group consisting of non-limiting examples of tauopathy, which 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), parkinsonism associated with chromosome 17, lytic-body disease (Parkinsonism-dementia complex of Guam), ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, pantothenate kinase-related neurodegeneration, lipofuscinosis and traumatic brain injury.