New hydrazone derivatives with terminal amine groups substituted by aryl or heteroaryl groups and uses thereof

Abstract

The present invention relates to novel hydrazone derivatives whose terminal amine groups are substituted by aryl groups or heteroaryl groups and uses thereof.

Description

Technical Field

[0001] The present invention relates to novel hydrazone derivatives whose terminal amine groups are substituted by aryl groups or heteroaryl groups and uses thereof. Background Art

[0002] Tau protein (tau (τ) protein) is a microtubule-associated protein (MAP) mainly expressed in the axons of nerve cells, with a molecular weight of 50,000 to 70,000, which plays a role in stabilizing microtubules and exhibits molecular diversity through phosphorylation. In humans, tau protein forms six isoforms by inserting 29 or 58 amino acid residues at the N-terminus and alternatively splicing 3 or 4 repeating structures (called microtubule binding domains) at the C-terminus of mRNA.

[0003] In healthy nerves, tau stabilizes microtubules by promoting axon growth and neuronal polarization. When pathological hyperphosphorylation occurs, tau dissociates from microtubules, resulting in insoluble aggregates. In addition, a structural skeleton that induces tau aggregation has been proposed, and there is evidence that insoluble filaments are formed by 10 soluble monomers, and these filaments are combined into high-dimensional structures called neurofibrillary tangles (NFTs). Human full-length tau contains a microtubule binding domain consisting of four repeated conserved sequences. In these repeated sequences, positively charged residues play an important role in binding to highly negatively charged microtubules (each αβ-tubulin dimer contains 20-30 electrons). The binding affinity of tau to microtubules is also actively regulated by the phosphorylation of tau, and this phosphorylation causes a dynamic rearrangement of the microtubule network. When tau is abnormally hyperphosphorylated, the balance of this dynamic rearrangement is broken, and the affinity for microtubules decreases rapidly.

[0004] Hyperphosphorylation and / or aggregation of tau protein cause these tau proteins to accumulate abnormally in nerve cells, which is pointed out to be the cause of various neurodegenerative diseases, etc. Tau protein aggregates are mainly found in the cell bodies and dendrites of nerve cells, and these tau protein aggregates are called neurofibrillary tangles (NFT) and neuropil filaments. Inspection of the microstructure of neurofibrillary tangles (NFT) shows that this microstructure is composed of paired spiral filaments (pairedhelical filament, PHF), and tau protein therein is tangled together like a fine line, and aggregation and hyperphosphorylation are different from normal tau protein. Abnormal tau protein aggregation phenomenon also occurs in tau protein disease. In this case, although it is still not possible to accurately know what role the aggregation of tau protein plays in the development of tau protein disease, this tau protein aggregation phenomenon seems to be similar to common aggregation phenomenon in general neurodegenerative diseases.

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

[0006] Technical issues

[0007] The present inventors have made many efforts to discover new small molecule compounds that can inhibit the aggregation and / or hyperphosphorylation of tau protein. As a result, they found that a series of hydrazone derivatives whose terminal amine groups are replaced by aryl or heteroaryl groups effectively inhibit the aggregation of tau protein and do not show cytotoxicity at effective concentrations. Based on this discovery, the present invention was completed.

[0008] Technical Solution

[0009] The first aspect of the present invention provides a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof:

[0010] [Formula 1]

[0011]

[0012] In the above formula 1,

[0013] R1 is hydrogen or C 1-6 alkyl;

[0014] R2 is unsubstituted or substituted C 6-14 Aryl, 5- to 14-membered heteroaryl, or 5- to 14-membered heterocyclyl;

[0015] R3-R5 i) are hydrogen, ii) form a triple bond with one N, iii) R3 and R4 form a double bond with NH, O or S to form an imine, oxo or thio respectively, and R5 is C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 iv) R3-R5 are connected to heteroatoms O, N or S by single or double bonds and contain carbon and heteroatoms connected to carbon to form unsubstituted or substituted 5-14 membered heteroaryl or heterocyclyl; and

[0016] R6-R8 i) are all hydrogen, ii) form a triple bond with one N, iii) R3 and R4 form a double bond with NH, O or S to form an imine, oxo or thio respectively, and R5 is C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 iv) R3-R5 are connected to heteroatoms O, N or S by single or double bonds and contain carbon and heteroatoms connected to carbon to form unsubstituted or substituted 5- to 14-membered heteroaryl or heterocyclyl;

[0017] wherein the heteroaryl group or the heterocyclic group contains at least one of O, N and S,

[0018] The substituted aryl, the substituted heteroaryl or the substituted heterocyclic group 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- to 14-membered heteroaryl, or 5- to 14-membered heterocyclyl; or selected from 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 and C 1-6 C substituted with at least one substituent selected from the group consisting of alkoxycarbonyl 6-14 aryl, 5- to 14-membered heteroaryl, or 5- to 14-membered heterocyclyl, and

[0019] The carbamoyl and carboxamide groups may be selected from C 1-6 Alkyl, and unsubstituted or replaced by C 1-6 Alkoxy, hydroxy, cyano or C 1-6 The alkyl group is substituted with at least one selected from the group consisting of an aryl group and a heteroaryl group.

[0020] The second aspect of the present invention provides a method for preparing the compound of the first aspect, comprising reacting sodium nitrite, an amino derivative of R2 (R2-NH2) and A step of reacting in the presence of an acid to form an imine bond.

[0021] The third aspect of the present invention provides a method for preparing the compound of the first aspect, comprising the steps of:

[0022] a1) Preparation of aniline derivatives substituted with unsubstituted or R2' or R2" substituted aryl or heteroaryl groups

[0023] a2) sodium nitrite, the aniline derivative It reacts with malononitrile in the presence of an acid to form an imine bond.

[0024] The fourth aspect of the present invention provides a method for preparing the compound described in the first aspect, comprising the step of reacting sodium nitrite, a 5- to 14-membered heteroaryl or 5- to 14-membered heterocyclic derivative containing an amine group with malononitrile in the presence of an acid to form an imine bond.

[0025] The fifth aspect of the present invention provides a method for preparing the compound of the first aspect, comprising the steps of:

[0026] The carboxylic acid or anhydride of R2″′ is reacted with (wherein Y is an unprotected or protected amine or nitro group) to form an amide bond; and

[0027] Sodium nitrite, the heterocyclic derivative comprising R2'' linked to the carboxamide group obtained in the previous step, and malononitrile are reacted in the presence of an acid to form an imine bond.

[0028] The sixth aspect of the present invention provides a method for preparing the compound of the first aspect, comprising the steps of:

[0029] Sodium nitrite, an amino derivative of R2 (R2-NH2) and reacting to form an imine bond; and

[0030] The pH of the reaction solution was adjusted to 5-7 using a base.

[0031] The seventh aspect of the present invention provides a composition for inhibiting tau protein aggregation, comprising the compound of the present invention as an active ingredient.

[0032] The eighth aspect of the present invention provides a composition for inhibiting the hyperphosphorylation of tau protein, comprising the compound of the present invention as an active ingredient.

[0033] The ninth aspect of the present invention provides a pharmaceutical composition for preventing or treating diseases caused by tau protein aggregation or hyperphosphorylation, comprising the compound of the present invention as an active ingredient.

[0034] The tenth aspect of the present invention provides a method for preventing or treating a disease caused by tau protein aggregation or hyperphosphorylation, the method comprising the step of administering the pharmaceutical composition of the present invention to a subject in need thereof.

[0035] Beneficial Effects

[0036] According to the present invention, since the new hydrazone derivatives whose terminal amine groups are substituted by aryl or heteroaryl groups can effectively inhibit the aggregation and / or hyperphosphorylation of tau protein, the hydrazone derivatives can be effectively used to prevent or treat diseases caused by them, such as Alzheimer's disease and various tauopathies. DETAILED DESCRIPTION

[0037] The first aspect of the present invention provides a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof:

[0038] [Formula 1]

[0039]

[0040] In the above formula 1,

[0041] R1 is hydrogen or C 1-6 alkyl;

[0042] R2 is unsubstituted or substituted C 6-14 Aryl, 5- to 14-membered heteroaryl, or 5- to 14-membered heterocyclyl;

[0043] R3-R5 i) are hydrogen, ii) form a triple bond with one N, iii) R3 and R4 form a double bond with NH, O or S to form an imine, oxo or thio respectively, and R5 is C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 iv) R3-R5 are connected to heteroatoms O, N or S by single or double bonds and contain carbon and heteroatoms connected to carbon to form unsubstituted or substituted 5-14 membered heteroaryl or heterocyclyl; and

[0044] R6-R8 i) are all hydrogen, ii) form a triple bond with one N, iii) R3 and R4 form a double bond with NH, O or S to form an imine, oxo or thio respectively, and R5 is C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 iv) R3-R5 are connected to heteroatoms O, N or S by single or double bonds and contain carbon and heteroatoms connected to carbon to form unsubstituted or substituted 5- to 14-membered heteroaryl or heterocyclyl;

[0045] wherein the heteroaryl group or the heterocyclic group contains at least one of O, N and S,

[0046] The substituted aryl, the substituted heteroaryl or the substituted heterocyclic group may contain: C 1-6 Alkyl; C 1-6 Alkoxy; Halogen; C 1-6 Perfluoroalkyl; C 1-6 Perfluoroalkoxy; C 1-6 Haloalkyl; Carbamoyl; Carboxamide; C 6-10 Aryloxy; Unsubstituted C 6-14 aryl, 5- to 14-membered heteroaryl or 5- to 14-membered heterocyclic group; or a 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 and C 1-6 C substituted with at least one substituent selected from the group consisting of alkoxycarbonyl 6-14 aryl, 5- to 14-membered heteroaryl, or 5- to 14-membered heterocyclyl, and

[0047] The carbamoyl and carboxamide groups may be selected from C 1-6 Alkyl, and unsubstituted or replaced by C 1-6 Alkoxy, hydroxy, cyano or C 1-6 The alkyl group is substituted with at least one selected from the group consisting of an aryl group and a heteroaryl group.

[0048] Specifically, in the compounds described in the present invention,

[0049] R1 is hydrogen or methyl;

[0050] R2 is unsubstituted or substituted phenyl, benzothiazolyl, carbazolyl, indazolyl, quinolyl, indolyl, pyrrolopyridinyl, benzisoxazolyl, dihydrobenzothiazolyl, oxodihydrobenzothiazolyl, benzoxazolyl, oxodihydrobenzoxazolyl, benzimidazolyl, or oxodihydrobenzimidazolyl;

[0051] R3-R5 together with the C to which it is connected form -C≡N, -CH3, -CO2Me, -CO2Et, -CONH2, -CSNH2, (Here, R3' is C 1-6 alkyl); and

[0052] R6-R8 forms -C≡N, -CH3, -CO2Me, -CO2Et, -CONH2, -CSNH2, (Here, R3' is C 1-6 alkyl);

[0053] wherein the heteroaryl group and the heterocyclic group contain at least one O, N or S,

[0054] The substituted phenyl, benzothiazolyl, carbazolyl, indazolyl, quinolyl, indolyl, pyrrolopyridinyl, benzisoxazolyl, dihydrobenzothiazolyl, oxodihydrobenzothiazolyl, benzoxazolyl, oxodihydrobenzoxazolyl, benzimidazolyl, or oxodihydrobenzimidazolyl may contain methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, fluorine, chlorine, bromine, morpholinyl, carbamoyl, carboxamido, phenoxy, or may be unsubstituted or selected from phenyl, piperidinyl, thiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazolyl, pyrazolyl, benzothiazolyl, naphthyl, pyrazolopyrimidinyl, imidazopyrimidinyl, quinoxalinyl, imidazopyridinyl, isoquinolyl, indazolyl, indazolylindolyl, furanyl, thienyl, oxotetrahydropyridazinyl or oxodihydropyridazinyl substituted with at least one substituent selected from the group consisting of methyl, ethyl, ethynyl, methoxy, fluorine, chlorine, bromine, nitro, dimethylamino, methoxycarbonyl, ethoxycarbonyl and trifluoromethyl, and

[0055] The carbamoyl group and the carboxamide group may be substituted with at least one selected from the group consisting of a methyl group, an ethyl group, and a phenyl group, a pyridyl group, a pyrimidyl group, and a pyrazinyl group which are unsubstituted or substituted with a methyl group, a methoxy group, a hydroxyl group, or a cyano group.

[0056] For example, the compound of the present invention can be represented by the following formula 2:

[0057] [Formula 2]

[0058]

[0059] In the above formula 2,

[0060] R1 is hydrogen or C 1-6 alkyl;

[0061] R2' and R2" are each independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Perfluoroalkyl, C 1-6 Perfluoroalkoxy, C 1-6 Haloalkyl, unsubstituted or substituted with C 1-6 Alkyl substituted carbamoyl, or unsubstituted or selected from 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 At least one substituted C 6-14 aryl, 5- to 14-membered heteroaryl or 5- to 14-membered heterocyclyl.

[0062] Specifically, in the above equation 2,

[0063] R1 is hydrogen or methyl;

[0064] R2' is hydrogen, fluorine, methoxy or morpholinyl; and

[0065] R2" is methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, fluorine, chlorine, bromine, morpholinyl, carbamoyl, carboxamido, phenoxy, or unsubstituted or substituted with at least one selected from the group consisting of methyl, ethyl, ethynyl, methoxy, fluorine, chlorine, bromine, nitro, dimethylamino, ethoxycarbonyl and trifluoromethyl, thiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazolyl, pyrazolyl, benzothiazolyl, naphthyl, pyrazolopyrimidinyl, imidazopyrimidinyl, quinoxalinyl, imidazopyridinyl, isoquinolyl, indazolyl, indolyl, oxotetrahydropyridazinyl or oxodihydropyridazinyl.

[0066] For example, the compound of the present invention can be represented by the following formula 3:

[0067] [Formula 3]

[0068]

[0069] In the above formula 3,

[0070] R1 is hydrogen or C 1-6 alkyl;

[0071] Cy is an unsubstituted or substituted 5- to 14-membered heteroaryl or 5- to 14-membered heterocyclyl: and

[0072] The substituted 5- to 14-membered heteroaryl or 5- to 14-membered heterocyclic group is unsubstituted or substituted by the following groups: 1-6 Alkyl; C 1-6 Alkoxy; Halogen; C 1-6 Perfluoroalkyl; C 1-6 Perfluoroalkoxy; C 1-6 Haloalkyl; unsubstituted or replaced by C 1-6 Alkyl substituted carbamoyl; C 6-10 Aryloxy; or unsubstituted or selected from C 1-6 Alkyl, halogen and di(C 1-6 At least one substituted C 6-14 Aryl, 5- to 14-membered heteroaryl or 5- to 14-membered heterocyclic group.

[0073] Specifically, in the above equation 3,

[0074] R1 is hydrogen;

[0075] Cy is unsubstituted or substituted benzothiazolyl, carbazolyl, indazolyl, quinolyl, indolyl, pyrrolopyridinyl, oxodihydrobenzothiazolyl, oxodihydrobenzoxazolyl or oxodihydrobenzimidazolyl; and

[0076] The substituted 5- to 14-membered heteroaryl or 5- to 14-membered heterocyclic group is unsubstituted or substituted by methyl, ethyl, propyl, butyl, isopropyl, isobutyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoroethyl, difluoromethyl, trifluoromethoxy, dimethylaminoformyl, phenoxy, or phenyl, pyridyl, furyl or thienyl which is unsubstituted or substituted by at least one selected from the group consisting of methyl, fluorine and dimethylamino.

[0077] For example, the compound of the present invention can be represented by the following formula 4:

[0078] [Formula 4]

[0079]

[0080] In the above formula 4,

[0081] X1-X3 are different from each other, each selected from C, N, O and S, and each is connected to the carboxamide group through the C position;

[0082] R1 is hydrogen or C1-6 Alkyl; and

[0083] R2″′ is C 1-6 Alkyl, either unsubstituted or selected from C 1-6 Alkoxy, hydroxy, cyano and C 1-6 The alkyl group is substituted by at least one aryl or heteroaryl group.

[0084] Specifically, in the above equation 4,

[0085] X1-X3 are N, C and S or O, N and C in sequence, and are connected to the carboxamide group via the C site;

[0086] R1 is hydrogen; and

[0087] R2'" is a methyl group, or a phenyl group, a pyridyl group, a pyrazinyl group or a pyrimidinyl group which is unsubstituted or substituted by at least one selected from the group consisting of a methoxy group, a hydroxyl group, a cyano group and a methyl group.

[0088] For example, the compound of the present invention can be represented by the following formula 5:

[0089] [Formula 5]

[0090]

[0091] In the above formula 5,

[0092] R1 is hydrogen or C 1-6 alkyl;

[0093] R2″″ is unsubstituted or replaced by C 1-6 alkyl-substituted 5- to 14-membered heteroaryl or 5- to 14-membered heterocyclyl; and

[0094] R3-R5 i) are hydrogen, ii) form a triple bond with one N, iii) R3 and R4 form a double bond with NH, O or S to form an imine, oxo or thio respectively, and R5 is C 1-6 Alkoxy, amino, C 1-6 Alkylamino, di(C 1-6 iv) R3-R5 are connected to heteroatoms O, N or S via single or double bonds and contain carbon and heteroatoms connected to carbon to form unsubstituted or substituted 5- to 14-membered heteroaryl or heterocyclic groups.

[0095] Specifically, in the above equation 5,

[0096] R1 is hydrogen;

[0097] R2"" is unsubstituted or substituted with at least one substituent selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl and difluoromethyl pyrimidinyl or oxotetrahydropyridazinyl;

[0098] R3-R5 together with the C to which it is connected form -C≡N, -CH3, -CO2Me, -CO2Et, -CONH2, -CSNH2, (Here, R3' is methyl).

[0099] More specifically, the compound may be

[0100] 1. (4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

[0101] 2. (4-(5-fluoropyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

[0102] 3. (4-(5-fluoro-4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

[0103] 4. (4-(5-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

[0104] 5. (4-(5-ethylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

[0105] 6. (4-(4-ethylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

[0106] 7. (4-(5-chloropyrimidin-2-yl)carbonohydrazonoyl dicyanide)

[0107] 8. (4-(5-methoxypyrimidin-2-yl)-phenyl)carbonohydrazonoyl dicyanide,

[0108] 9. (4-(2,4-dimethylthiazol-5-yl)phenyl)carbonohydrazonoyl dicyanide,

[0109] 10. (4-(pyridin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

[0110] 11. (4-(2-methylthiazol-5-yl)phenyl)carbonohydrazonoyl dicyanide,

[0111] 12. (4-(4-methylthiazol-5-yl)phenyl)carbonohydrazonoyl dicyanide,

[0112] 13. Biphenyl-4-ylcarbonohydrazonoyl dicyanide,

[0113] 14. (4'-methylbiphenyl-4-yl)carbonohydrazonoyl dicyanide

[0114] 15. (4-(pyridin-3-yl)phenyl)carbonohydrazonoyl dicyanide

[0115] 16. (4-(pyridin-4-yl)phenyl)carbonohydrazonoyl dicyanide

[0116] 17. (4-(pyridazin-3-yl)phenyl)carbonohydrazonoyl dicyanide

[0117] 18. (4-(5-methylthiazol-2-yl)phenyl)carbonohydrazonoyl dicyanide,

[0118] 19. ethyl 2-(4-(2-(dicyanomethylene)hydrazinyl)phenyl)thiazole-5-carboxylate,

[0119] 20. (4-(thiazol-5-yl)phenyl)carbonohydrazonoyl dicyanide

[0120] 21. (3'-fluoro-4'-nitrobiphenyl-4-yl)carbonohydrazonoyl dicyanide

[0121] 22. (4-(6-fluoropyridin-3-yl)phenyl)carbonohydrazonoyl dicyanide

[0122] 23. (2',4'-dimethylbiphenyl-4-yl)carbonohydrazonoyl dicyanide

[0123] 24. methyl4′-(2-(dicyanomethylene)hydrazinyl)-2-fluorobiphenyl-4-carboxylate,

[0124] 25. (2'-methyl-4'-nitrobiphenyl-4-yl)carbonohydrazonoyl dicyanide

[0125] 26. (2',4'-dichlorobiphenyl-4-yl)carbonohydrazonoyl dicyanide

[0126] 27. (2'-methoxy-4'-methylbiphenyl-4-yl)carbonohydrazonoyl dicyanide

[0127] 28. (4-(pyrazin-2-yl)phenyl)carbonohydrazonoyl dicyanide

[0128] 29. (4-(5-(trifluoromethyl)pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

[0129] 30. (4-(4,6-dimethylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

[0130] 31. (4-(4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

[0131] 32. (4-(pyrimidin-5-yl)phenyl)carbonohydrazonoyl dicyanide

[0132] 33. (4-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)carbonohydrazonoyl dicyanide

[0133] 34. (4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)carbonohydrazonoyl dicyanide

[0134] 35. (4-(1H-pyrazol-1-yl)phenyl)carbonohydrazonoyl dicyanide

[0135] 36. (4-(4-methyl-1H-pyrazol-1-yl)phenyl)carbonohydrazonoyl dicyanide

[0136] 37. (2-fluoro-4-(4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

[0137] 38. (2-fluoro-4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

[0138] 39. (3-fluoro-4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

[0139] 40. (3-fluoro-4-(4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

[0140] 41. (2-methoxy-4-(5-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

[0141] 42. (2-methoxy-4-(4-methylpyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

[0142] 43. (2-methoxy-4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

[0143] 44. (4-(5-fluoropyrimidin-2-yl)-2-morpholinophenyl)carbonohydrazonoyl dicyanide

[0144] 45. Methyl(4-(pyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide,

[0145] 46. ​​(3-(5-fluoropyrimidin-2-yl)phenyl)carbonohydrazonoyl dicyanide

[0146] 47. (5-(5-fluoropyrimidin-2-yl)-2-morpholinophenyl)carbonohydrazonoyl dicyanide

[0147] 48. (4-(benzo[d]thiazol-6-yl)phenyl)carbonohydrazonoyl dicyanide

[0148] 49. (4-(naphthalen-2-yl)phenyl)carbonohydrazonoyl dicyanide

[0149] 50. (4-(pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)carbonohydrazonoyl dicyanide

[0150] 51. (4-(imidazo[1,2-a]pyrimidin-6-yl)phenyl)carbonohydrazonoyl dicyanide

[0151] 52. (4-(quinoxalin-2-yl)phenyl)carbonohydrazonoyl dicyanide

[0152] 53. (4-(imidazo[1,2-a]pyridin-6-yl)phenyl)carbonohydrazonoyl dicyanide

[0153] 54. (4-(isoquinolin-3-yl)phenyl)carbonohydrazonoyl dicyanide

[0154] 55. (4-(2-methyl-2H-indazol-4-yl)phenyl)carbonohydrazonoyl dicyanide

[0155] 56. (4-(2-methyl-2H-indazol-5-yl)phenyl)carbonohydrazonoyl dicyanide

[0156] 57. (4-(2-methyl-2H-indazol-7-yl)phenyl)carbonohydrazonoyl dicyanide

[0157] 58. (4-(1H-indol-5-yl)phenyl)carbonohydrazonoyl dicyanide

[0158] 59. (4-methoxybenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide

[0159] 60. benzo[d]thiazol-6-ylcarbonohydrazonoyldicyanide, 61. benzo[d]thiazol-5-ylcarbonohydrazonoyl dicyanide,

[0160] 62. (9-ethyl-9H-carbazol-3-yl)carbonohydrazonoyl dicyanide

[0161] 63. (1-methyl-1H-indazol-6-yl)carbonohydrazonoyl dicyanide

[0162] 64. Quinolin-3-ylcarbonohydrazonoyl dicyanide,

[0163] 65. (2-methyl-2H-indazol-6-yl)carbonohydrazonoyl dicyanide

[0164] 66. (1-methyl-1H-indazol-5-yl)carbonohydrazonoyl dicyanide

[0165] 67. Quinoline-6-ylcarbonohydrazonoyl dicyanide,

[0166] 68. (1-methyl-1H-indol-5-yl)carbonohydrazonoyl dicyanide

[0167] 69. (1H-indazol-5-yl)carbonohydrazonoyldicyanide

[0168] 70. (1H-indazol-6-yl)carbonohydrazonoyldicyanide

[0169] 71. (1H-indol-5-yl)carbonohydrazonoyldicyanide

[0170] 72. (1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

[0171] 73. (3-methyl-1H-indazol-6-yl)carbonohydrazonoyl dicyanide

[0172] 74. (3-methyl-1H-indazol-5-yl)carbonohydrazonoyl dicyanide

[0173] 75. (1H-indol-4-yl)carbonohydrazonoyldicyanide

[0174] 76. (1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

[0175] 77. (1-propyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

[0176] 78. (1-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

[0177] 79. (1-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

[0178] 80. (1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyldicyanide,

[0179] 81. (2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

[0180] 82. (3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

[0181] 83. (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

[0182] 84. (4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyl dicyanide

[0183] 85. (2-(dimethylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonohydrazonoyldicyanide

[0184] 86. (2-(4-methoxybenzamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

[0185] 87. (2-(2-hydroxybenzamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

[0186] 88. (2-acetamidobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

[0187] 89. (2-(3-cyanobenzamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

[0188] 90. (2-(5-methylnicotinamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

[0189] 91. (2-(3-hydroxypicolinamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

[0190] 92. (2-(pyrazine-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

[0191] 93. (2-(5-methylpyrazine-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyldicyanide

[0192] 94. (2-(pyrimidine-5-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

[0193] 95. (2-(2-methylpyrimidine-5-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyldicyanide

[0194] 96. (2-(4-methylpyrimidine-5-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyldicyanide

[0195] 97. (2-(3-methylpyrazine-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyldicyanide

[0196] 98. (2-(6-methylpyrazine-2-carboxamido)benzo[d]thiazol-6-yl)carbonohydrazonoyldicyanide

[0197] 99. (2-(pyrazine-2-carboxamido)benzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide

[0198] 100. (2-(5-methylpyrazine-2-carboxamido)benzo[d]thiazol-5-yl)carbonohydrazonoyldicyanide,

[0199] 101. (2-phenylbenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

[0200] 102. (2-(4-fluorophenyl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

[0201] 103. (2-(4-(dimethylamino)phenyl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

[0202] 104. (2-(pyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

[0203] 105. (2-(6-methylpyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

[0204] 106. (2-(6-fluoropyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

[0205] 107. (2-(furan-2-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

[0206] 108. (2-(thiophen-2-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

[0207] 109. (2-(5-fluoropyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

[0208] 110. (2-(5-methylpyridin-3-yl)benzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide,

[0209] 111. (2-(pyridin-3-yl)benzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide

[0210] 112. (2-(5-methylpyridin-3-yl)benzo[d]thiazol-5-yl)carbonohydrazonoyl dicyanide,

[0211] 113. benzo[d]thiazol-2-ylcarbonohydrazonoyldicyanide,

[0212] 114. (6-fluorobenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide

[0213] 115. (6-chlorobenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide

[0214] 116. (6-bromobenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide

[0215] 117. (6-(trifluoromethyl)benzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide

[0216] 118. (4-chlorobenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide

[0217] 119. (5-chlorobenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide

[0218] 120. (5-bromobenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide

[0219] 121. (6-methoxybenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide

[0220] 122. (6-ethoxybenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide

[0221] 123. (6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide

[0222] 124. (6-methylbenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide

[0223] 125. (4-methylbenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide

[0224] 126. (4,6-dimethylbenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide

[0225] 127. (5,6-dimethylbenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide

[0226] 128. (6-phenoxybenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide

[0227] 129. (6-phenylbenzo[d]thiazol-2-yl)carbonohydrazonoyl dicyanide

[0228] 130. (3-(pyrazine-2-carboxamido)benzo[d]isoxazol-5-yl)carbonohydrazonoyl dicyanide,

[0229] 131. (3-(5-methylpyrazine-2-carboxamido)benzo[d]isooxazol-5-yl)carbonohydrazonoyldicyanide

[0230] 132. (3-(3-cyanobenzamido)benzo[d]isooxazol-5-yl)carbonohydrazonoyl dicyanide,

[0231] 133. (3-(4-methoxybenzamido)benzo[d]isooxazol-5-yl)carbonohydrazonoyl dicyanide,

[0232] 134. (2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

[0233] 135. (3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

[0234] 136. (2-methoxybenzo[d]thiazol-6-yl)carbonohydrazonoyl dicyanide

[0235] 137. (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide

[0236] 138. (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbonohydrazonoyl dicyanide

[0237] 139. (2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbonohydrazonoyl dicyanide

[0238] 140. diethyl 2-(2-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)hydrazono)malonate,

[0239] 141. 2-Imino-N′-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)-2-(piperazin-1-yl)acetohydrazonoyl cyanide,

[0240] 142. 2-Imino-N′-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)-2-morpholinoacetohydrazonoyl cyanide,

[0241] 143. Methyl 2-(2-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)hydrazono)propanoate,

[0242] 144. Methyl-2-cyano-2-(2-(4-(pyrimidin-2-yl)phenyl)hydrazono)acetate,

[0243] 145. 2-amino-2-oxo-N′-(4-(pyrimidin-2-yl)phenyl)acetohydrazonoyl cyanide,

[0244] 146. Ethyl-2-cyano-2-(2-(4-(pyrimidin-2-yl)phenyl)hydrazono)acetate,

[0245] 147. 2-amino-N′-(4-(pyrimidin-2-yl)phenyl)-2-thioxoacetohydrazonoyl cyanide,

[0246] 148.4-methyl-N′-(4-(pyrimidin-2-yl)phenyl)thiazole-2-carbohydrazonoyl cyanide,

[0247] 149. (4-(5-ethynylpyrimidin-2-yl)phenyl)carbohydrazonoyl dicyanide

[0248] 150. (4'-(dimethylamino)-3-fluorobiphenyl-4-yl)carbohydrazonoyl dicyanide

[0249] 151. (4'-(dimethylamino)biphenyl-4-yl)carbohydrazonoyl dicyanide

[0250] 152. (4-(6-(dimethylamino)pyridin-3-yl)phenyl)carbohydrazonoyl dicyanide

[0251] 153. (4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide

[0252] 154. (4-(4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide

[0253] 155. (4-(5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide

[0254] 156. (4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide

[0255] 157. (4-(1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide

[0256] 158. (4-(1,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide

[0257] 159. (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide

[0258] 160. (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbohydrazonoyldicyanide

[0259] 161. (2-isopropoxybenzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide

[0260] 162. (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbohydrazonoyl dicyanide

[0261] 163. (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbohydrazonoyldicyanide

[0262] 164. (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbohydrazonoyldicyanide

[0263] 165. (1,3-diisopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbohydrazonoyldicyanide

[0264] 166. (1,3-bis(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbohydrazonoyl dicyanide

[0265] 167. (2-(methylamino)benzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide

[0266] 168. (2-(dimethylamino)benzo[d]thiazol-6-yl)carbohydrazonoyl dicyanide

[0267] 169. (4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbohydrazonoyl dicyanide

[0268] 170. (4-(1-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbohydrazonoyldicyanide, or

[0269] 171. (4-(1,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbohydrazonoyldicyanide.

[0270] Furthermore, these compounds may be compounds represented by the following formulae.

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282] At the same time, the compounds of the present invention may exist in the form of pharmaceutically acceptable salts. As salts, acid salts formed from pharmaceutically acceptable free acids are effective. As used herein, the term "pharmaceutically acceptable salt" refers to any organic or inorganic addition salt of a compound represented by Formula 1, which is relatively nontoxic and harmless to patients, and the side effects caused by such salts do not impair the beneficial effects of such compounds.

[0283] Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an excess of aqueous acid solution and precipitating the solution with a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The compound and acid or alcohol (e.g. ethylene glycol monoethyl ether) of equal molar amount are heated in water, followed by evaporation of the mixture and drying, or the salt of the precipitation can be filtered by suction.

[0284] In this case, an organic acid or an inorganic acid can be used as a free acid. Hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as an inorganic acid. Methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used as an organic acid. However, the present invention is not limited thereto.

[0285] In addition, a base can be used to prepare a pharmaceutically acceptable metal salt. Alkali metal salts or alkaline earth metal salts are obtained by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble composite salt, and then evaporating and drying the filtrate. In this case, sodium salts, potassium salts or calcium salts are prepared as metal salts suitable for pharmaceutical use, but the present invention is not limited thereto. In addition, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0286] Unless otherwise indicated, the pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compounds of formula 1-5. For example, pharmaceutically acceptable salts may include sodium salts, calcium salts and potassium salts of hydroxyl groups, and other pharmaceutically acceptable salts of amino groups may include hydrobromate, sulfate, bisulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, mesylate (mesylate) and p-toluenesulfonate (toluenesulfonate). These pharmaceutically acceptable salts may be prepared by methods for preparing salts known in the art.

[0287] As the salt of the compound of Formula 1-5 of the present invention, any salt may be used as a pharmaceutically acceptable salt without limitation as long as it exhibits pharmacological activity comparable to that of the compound of Formula 1, for example, it inhibits aggregation and / or hyperphosphorylation of tau protein.

[0288] In addition, the compounds represented by formula 1-5 according to the present invention include, but are not limited to, pharmaceutically acceptable salts thereof, and solvates such as possible hydrates that can be prepared therefrom, and all possible stereoisomers. Solvates and stereoisomers of compounds represented by formula 1-5 can be prepared by using methods known in the art from compounds represented by formula 1-5.

[0289] In addition, the compounds represented by formula 1-5 according to the present invention can be prepared in crystalline form or amorphous form, and if prepared in crystalline form, can be optionally hydrated or solvated. In the present invention, compounds containing different amounts of water and stoichiometric hydrates of compounds represented by formula 1-5 can be provided. Solvates of compounds represented by formula 1-5 according to the present invention include stoichiometric solvates and non-stoichiometric solvates.

[0290] The second aspect of the present invention provides a method for preparing a compound of formula 1, comprising reacting sodium nitrite, an amino derivative of R2 (R2-NH2) and A step of reacting in the presence of an acid to form an imine bond.

[0291] In the preparation method of the present invention, for the reactants used therein, purchased commercial compounds can be used, or they can be synthesized by accurately implementing one or more reactions known in the art or by changing some reaction conditions of reactions known in the art. For example, considering the presence, type and position of reactive functional groups and / or heterogeneous elements present in the skeleton structure, compounds can be synthesized by performing one or more reactions in sequence, but the present invention is not limited thereto. This process can be similarly applied to the following third to sixth aspects.

[0292] The third aspect of the present invention provides a method for preparing a compound of formula 2, comprising the steps of:

[0293] a1) Preparation of aniline derivatives substituted by aryl or heteroaryl groups (which are unsubstituted or substituted by R2' or R2" and

[0294] a2) sodium nitrite, the aniline derivative It reacts with malononitrile in the presence of an acid to form an imine bond.

[0295] For example, when R1 in the above formula is C 1-6 When the alkyl group is an alkyl, after the step of forming the imine bond, the method may further include a step of alkylating the alkyl group by reacting with an alkyl halide in an organic solvent in the presence of potassium tert-butoxide or sodium hydride. However, the present invention is not limited thereto, and the alkylation reaction known in the art may be appropriately modified and implemented in consideration of the presence or absence of other reactive substituents or heterogeneous elements.

[0296] Specifically, the aniline derivative substituted with an aryl or heteroaryl group (which is unsubstituted or substituted with R2' or R2") can be synthesized by reacting a boric acid pinacol ester derivative of an aniline that is unsubstituted or substituted with R2' with a halogenated aryl or heteroaryl derivative that is unsubstituted or substituted with R2" in the presence of a base using a Pd(II) catalyst. However, the present invention is not limited thereto, and purchased commercially available compounds can be used, or can be synthesized by methods known in the art.

[0297] Furthermore, taking into account the potential reactivity of substituents and / or heterogeneous elements present in the skeleton of the compound to be synthesized under the reaction conditions, the aniline derivatives substituted with aryl or heteroaryl groups (which are unsubstituted or substituted with R2' or R2") can be prepared by reducing nitrophenyl derivatives containing a nitro group instead of an amine group in the same skeleton using a palladium catalyst activated with carbon under hydrogen.

[0298] The fourth aspect of the present invention provides a method for preparing a compound of formula 3, comprising the step of reacting sodium nitrite, a 5- to 14-membered heteroaryl or 5- to 14-membered heterocyclic derivative containing an amine group with malononitrile in the presence of an acid to form an imine bond.

[0299] For example, when the 5- to 14-membered heteroaryl or 5- to 14-membered heterocyclic group contains a nitrogen other than an amine group to which it can be bonded, it contains a protecting group at the nitrogen position. After the step of forming the imine bond, the method may further include the step of removing the protecting group.

[0300] Furthermore, the 5- to 14-membered heteroaryl group or 5- to 14-membered heterocyclic group may be prepared by reducing a nitrophenyl derivative containing a nitro group instead of an amine group in the same skeleton, taking into account the reactivity of functional groups and / or heterogeneous elements present in the skeleton, but the present invention is not limited thereto.

[0301] A fifth aspect of the present invention provides a method for preparing a compound of formula 4, comprising the steps of:

[0302] The carboxylic acid or anhydride of R2″′ is reacted with (wherein Y is an unprotected or protected amine or nitro group) to form an amide bond; and

[0303] Sodium nitrite, the heterocyclic derivative comprising R2'' linked to the carboxamide group obtained in the previous step, and malononitrile are reacted in the presence of an acid to form an imine bond.

[0304] In this case, when Y is a protected amine group or a nitro group, the method may further include a step of converting the protected amine group or the nitro group into an amine group before the step of forming the imine group.

[0305] The sixth aspect of the present invention provides a method for preparing a compound of formula 5, comprising the steps of:

[0306] Sodium nitrite, an amino derivative of R2 (R2-NH2) and reacting to form an imine bond; and

[0307] The pH of the reaction solution was adjusted to 5-7 using a base.

[0308] The seventh aspect of the present invention provides a composition for inhibiting tau protein aggregation, comprising the compound of the present invention as an active ingredient.

[0309] The eighth aspect of the present invention provides a composition for inhibiting the hyperphosphorylation of tau protein, comprising the compound of the present invention as an active ingredient.

[0310] The ninth aspect of the present invention provides a pharmaceutical composition for preventing or treating diseases caused by tau protein aggregation or hyperphosphorylation, comprising the compound of the present invention as an active ingredient.

[0311] In a specific embodiment of the present invention, a total of 171 compounds numbered 1-171 and represented by Formula 1 were newly synthesized, and their effects of inhibiting tau protein aggregation and hyperphosphorylation were confirmed. In addition, in order to confirm the possibility of being used as a pharmaceutical composition, it was confirmed that these compounds did not show toxicity to cells.

[0312] As used herein, the term "prevention" refers to any effect of inhibiting or delaying the occurrence, spread and recurrence of diseases induced by tau protein aggregation or hyperphosphorylation by administering the pharmaceutical composition of the present invention, and the term "treatment" refers to any effect of improving or favorably changing the symptoms of the disease by administering the pharmaceutical composition of the present invention.

[0313] As described above, since the compound of the present invention not only inhibits the aggregation or hyperphosphorylation of tau protein, but also does not show toxicity to cells, the pharmaceutical composition containing such compound as an active ingredient can be used to prevent or treat diseases caused by tau protein aggregation or hyperphosphorylation. The diseases caused by tau protein aggregation or hyperphosphorylation to which the pharmaceutical composition of the present invention is applicable can be Alzheimer's disease, Parkinson's disease, vascular dementia, acute stroke, trauma, cerebrovascular disease, brain and spinal cord trauma, spinal cord trauma, peripheral neuropathy, retinopathy, glaucoma or tauopathy. Non-limiting examples of the tauopathies may include: chronic traumatic encephalopathy (CTE), primary age-related tauopathy, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, argyrophilic grain disease (AGD), frontotemporal dementia (FTD), Parkinson's disease associated with chromosome 17, Lytico-bodig disease (Guam Parkinson-dementia syndrome), ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic Parkinson's disease, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, pantothenate kinase-related neurodegeneration, lipofuscinosis and traumatic brain injury.

[0314] For example, the composition of the present invention can also include a pharmaceutically acceptable carrier, diluent or excipient, and can be prepared and used in various forms according to the general method of each use purpose, such as oral preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, and injections of sterile injections; and can be administered orally, or can be administered by various routes, including intravenous administration, intraperitoneal administration, subcutaneous administration, rectal administration and topical administration. Examples of suitable carriers, excipients or diluents included in the composition can include: lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil. The composition of the present invention may further include fillers, anti-aggregating agents, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, and the like.

[0315] Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations are prepared by mixing one or more excipients (such as starch, calcium carbonate, sucrose, lactose and gelatin) with the composition. In addition to simple excipients, lubricants such as magnesium stearate or talc can also be used.

[0316] As oral liquid preparations, suspensions, anti-solutions, emulsions, syrups and the like can be cited, and oral liquid preparations may contain various excipients such as wetting agents, sweeteners, flavors and preservatives in addition to water and liquid paraffin generally used as simple diluents.

[0317] Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations and suppositories.

[0318] Propylene glycol, polyethylene glycol, vegetable oil (such as olive oil), ester for injection (such as ethyl oleate), etc. can be used as non-aqueous solvent or suspension. Synthetic fatty acid ester (witepsol), polyethylene glycol, Tween 61 (twin 61), cocoa butter, laurel oil, glycerin gelatin, etc. can be used as the base of suppository. At the same time, the injection can contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.

[0319] The preparation can be prepared by conventional mixing, granulation or coating methods, and can contain about 0.1wt% to 75wt%, preferably about 0.1wt% to 50wt% of the active ingredient. The unit preparation for a mammal weighing about 50kg to 70kg contains about 10mg to 200mg of the active ingredient.

[0320] In this case, the composition of the present invention is used with a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" refers to the amount of the disease that is sufficient to be applicable to medical treatment and does not cause a reasonable benefit / risk ratio for treating a side effect, and the level of the effective amount can be determined according to the patient's health, disease type, severity, drug activity, sensitivity to the drug, administration method, administration time, route of administration, excretion rate, treatment cycle, including the factors of the combined or simultaneously used medicine, and other well-known factors in the medical field. The composition of the present invention can be administered as a single therapeutic agent or co-administered with other therapeutic agents, and the composition of the present invention can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered in a single dose or multiple doses. Taking all of the above factors into account, it is important to be able to obtain the maximum effect with a minimum amount and not have the amount of side effects, which can be easily determined by those skilled in the art.

[0321] For example, since the dosage can be increased or decreased depending on the administration route, severity of the disease, gender, body weight, age, etc., the dosage does not limit the scope of the present invention in any way.

[0322] The preferred dosage of the compound of the present invention varies according to the patient's condition and body weight, disease extent, drug form, and route of administration and duration, but can be appropriately selected by those skilled in the art. However, in order to obtain the desired effect, the compound of the present invention can be administered in an amount of 0.0001mg / kg to 100mg / kg (body weight) per day, preferably 0.001mg / kg to 100mg / kg (body weight) per day. The compound can be administered once a day or can be administered in divided doses, and administered by oral or parenteral routes.

[0323] The tenth aspect of the present invention provides a method for preventing or treating a disease caused by tau protein aggregation or hyperphosphorylation, the method comprising the step of administering the pharmaceutical composition of the present invention to a subject in need thereof.

[0324] As used herein, the term "subject" refers to any animal, including, in addition to humans, monkeys, cattle, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rabbits and guinea pigs, which have developed or may develop a disease caused by tau protein aggregation or hyperphosphorylation. The disease can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to the subject. In addition, since the pharmaceutical composition of the present invention exhibits a therapeutic effect by inhibiting the aggregation or hyperphosphorylation of tau protein, a synergistic effect can be exhibited by administering the composition in combination with a conventional therapeutic agent.

[0325] As used herein, the term "administration" refers to providing a predetermined substance to a patient by any suitable method, and the route of administration of the composition of the present invention can be administered by any general route as long as it can reach the target tissue. The composition can be administered by intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration or rectal administration, but the present invention is not limited thereto. At the same time, the pharmaceutical composition of the present invention can be administered by any device that can move the active substance to the target cell. Preferred modes of administration and dosage forms include intravenous injection of drugs, subcutaneous injection of drugs, intradermal injection of drugs, intramuscular injection of drugs and infusion of drugs. Injectable medicines can be prepared by using an aqueous solvent (such as physiological saline, or Ringer's solution) or a non-aqueous solvent (such as vegetable oil, higher fatty acid esters (such as ethyl oleate), or alcohols (such as ethanol, benzyl alcohol, propylene glycol or glycerol)), and may contain a pharmaceutical carrier such as a stabilizer for preventing denaturation (such as ascorbic acid, sodium bisulfite, sodium pyrosulfite, BHA, tocopherol or EDTA), an emulsifier, a buffer for pH control, or a preservative for inhibiting the growth of microorganisms (such as phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol or benzyl alcohol).

[0326] Implementation

[0327] 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 for illustrating the present invention, and the scope of the present invention is not limited to these Examples and Experimental Examples.

[0328] Example 1: Preparation of (4-(pyrimidin-2-yl)phenyl)carbonyl dinitrile (Compound 1)

[0329] Step 1-1: Preparation of 4-(pyrimidin-2-yl)aniline

[0330] In the presence of nitrogen, 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) were dissolved in 15 mL of 1,4-dioxane solution, and then Pd(PPh3)2Cl2 (63 mg, 0.09 mmol) and 1.0 M aqueous sodium carbonate solution (3.64 mL, 3.64 mmol) were added to obtain a reaction mixture. The reaction mixture was stirred at 80°C for 12 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 (yield 74%) of the title compound.

[0331] Step 1-2: Preparation of (4-(pyrimidin-2-yl)phenyl)carbonyl dinitrile

[0332] In the presence of nitrogen, 4-(pyrimidine-2-yl)aniline (50mg, 0.29mmol) and sodium nitrite (24mg, 0.35mmol) prepared according to step 1-1 were dissolved in ethanol (2.5mL), and then 1.0M aqueous hydrochloric acid solution (0.73mL, 0.73mmol) was added to obtain a reaction mixture. The reaction mixture was stirred at 0°C for 1 hour to form a diazonium salt. After the diazonium salt was formed, malononitrile (23mg, 0.35mmol) was added, followed by stirring at room temperature for 5 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to obtain 57mg (yield 79%) of the title compound.

[0333] Example 2: Preparation of (4-(5-fluoropyrimidin-2-yl)phenyl)carbonyl dinitrile (Compound 2)

[0334] Step 2-1: Preparation of 4-(5-fluoropyrimidin-2-yl)aniline

[0335] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 2-chloro-5-fluoropyrimidine (1.10 mmol) was used instead of 2-bromopyrimidine, 71 mg (41% yield) of the title compound was obtained.

[0336] Step 2-2: Preparation of (4-(5-fluoropyrimidin-2-yl)phenyl)carbonyl dinitrile

[0337] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(5-fluoropyrimidin-2-yl)aniline (1.10 mmol) instead of 4-(pyrimidin-2-yl)aniline, 30 mg (43% yield) of the title compound was obtained.

[0338] Example 3: Preparation of (4-(5-fluoro-4-methylpyrimidin-2-yl)phenyl)carbonyl dinitrile (Compound 3)

[0339] Step 3-1: Preparation of 4-(5-fluoro-4-methylpyrimidin-2-yl)aniline

[0340] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 2-chloro-5-fluoro-4-methylpyrimidine (1.10 mmol) was used instead of 2-bromopyrimidine, 139 mg (75% yield) of the title compound was obtained.

[0341] Step 3-2: Preparation of (4-(5-fluoro-4-methylpyrimidin-2-yl)phenyl)carbonyl dinitrile

[0342] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(5-fluoro-4-methylpyrimidin-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 40 mg (29% yield) of the title compound was obtained.

[0343] Example 4: Preparation of (4-(5-methylpyrimidin-2-yl)phenyl)carbonyl dinitrile (Compound 4)

[0344] Step 4-1: Preparation of 4-(5-methylpyrimidin-2-yl)aniline

[0345] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 2-chloro-5-methylpyrimidine (1.10 mmol) was used instead of 2-bromopyrimidine, 65 mg (39% yield) of the title compound was obtained.

[0346] Step 4-2: Preparation of (4-(5-methylpyrimidin-2-yl)phenyl)carbonyl dinitrile

[0347] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(5-methylpyrimidin-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 35 mg (50% yield) of the title compound was obtained.

[0348] Example 5: Preparation of 4-(5-ethylpyrimidin-2-yl)phenyl)carbonyl dinitrile (Compound 5)

[0349] Step 5-1: Preparation of 4-(5-ethylpyrimidin-2-yl)aniline

[0350] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 2-chloro-5-ethylpyrimidine (1.10 mmol) was used instead of 2-bromopyrimidine, 169 mg (93% yield) of the title compound was obtained.

[0351] Step 5-2: Preparation of 4-(5-ethylpyrimidin-2-yl)phenyl)carbonyl dinitrile

[0352] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(5-ethylpyrimidin-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 35 mg (25% yield) of the title compound was obtained.

[0353] Example 6: Preparation of (4-(4-ethylpyrimidin-2-yl)phenyl)carbonyl dinitrile (Compound 6)

[0354] Step 6-1: Preparation of 4-(4-ethylpyrimidin-2-yl)aniline

[0355] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 2-chloro-4-ethylpyrimidine (1.10 mmol) was used instead of 2-bromopyrimidine, 169 mg (93% yield) of the title compound was obtained.

[0356] Step 6-2: Preparation of (4-(4-ethylpyrimidin-2-yl)phenyl)carbonyl dinitrile

[0357] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(4-ethylpyrimidin-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 80 mg (66% yield) of the title compound was obtained.

[0358] Example 7: Preparation of (4-(5-chloropyrimidin-2-yl)carbonyl dinitrile (Compound 7)

[0359] Step 7-1: Preparation of 4-(5-chloropyrimidin-2-yl)aniline

[0360] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 2-chloro-5-chloropyrimidine (1.10 mmol) was used instead of 2-bromopyrimidine, 67 mg (36% yield) of the title compound was obtained.

[0361] Step 7-2: Preparation of (4-(5-chloropyrimidin-2-yl)phenyl)carbonyl dinitrile

[0362] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(5-chloropyrimidin-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 30 mg (16% yield) of the title compound was obtained.

[0363] Example 8: Preparation of (4-(5-methoxypyrimidin-2-yl)-phenyl)carbonyl dinitrile (Compound 8)

[0364] Step 8-1: Preparation of 4-(5-methoxypyrimidin-2-yl)aniline

[0365] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 2-chloro-5-methoxypyrimidine (1.10 mmol) was used instead of 2-bromopyrimidine, 67 mg (36% yield) of the title compound was obtained.

[0366] Step 8-2: Preparation of (4-(5-methoxypyrimidin-2-yl)phenyl)carbonyl dinitrile

[0367] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except that 4-(5-methoxypyrimidin-2-yl)aniline was used instead of 4-(pyrimidin-2-yl)aniline, 26 mg (30% yield) of the title compound was obtained.

[0368] Example 9: Preparation of (4-(2,4-dimethylthiazol-5-yl)phenyl)carbonyl dinitrile (Compound 9)

[0369] Step 9-1: Preparation of 4-(2,4-dimethylthiazol-5-yl)aniline

[0370] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 5-bromo-2,4-dimethylthiazole (1.10 mmol) was used instead of 2-bromopyrimidine, 48 mg (26% yield) of the title compound was obtained.

[0371] Step 9-2: Preparation of (4-(2,4-dimethylthiazol-5-yl)phenyl)carbazone dinitrile

[0372] The title compound was obtained by reacting in the same manner as in Step 1-2 of Example 1, except that 4-(2,4-dimethylthiazol-5-yl)aniline was used instead of 4-(pyrimidin-2-yl)aniline.

[0373] Example 10: Preparation of (4-(pyridin-2-yl)phenyl)carbonyl dinitrile (Compound 10)

[0374] Step 10-1: Preparation of 4-(pyridin-2-yl)aniline

[0375] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 2-bromopyridine (1.10 mmol) was used instead of 2-bromopyrimidine, 101 mg (65% yield) of the title compound was obtained.

[0376] Step 10-2: Preparation of (4-(pyridin-2-yl)phenyl)carbonyl dinitrile

[0377] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except that 4-(pyridin-2-yl)aniline was used instead of 4-(pyrimidin-2-yl)aniline, 18 mg (25% yield) of the title compound was obtained.

[0378] Example 11: Preparation of (4-(2-methylthiazol-5-yl)phenyl)carbonyl dinitrile (Compound 11)

[0379] Step 11-1: Preparation of 4-(2-methylthiazol-5-yl)aniline

[0380] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 5-bromo-2-methylthiazole (1.10 mmol) was used instead of 2-bromopyrimidine, 112 mg (57% yield) of the title compound was obtained.

[0381] Step 11-2: Preparation of (4-(2-methylthiazol-5-yl)phenyl)carbazone dinitrile

[0382] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(2-methylthiazol-5-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 11 mg (16% yield) of the title compound was obtained.

[0383] Example 12: Preparation of (4-(4-methylthiazol-5-yl)phenyl)carbazone dinitrile (Compound 12)

[0384] Step 12-1: Preparation of 4-(4-methylthiazol-5-yl)aniline

[0385] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 5-bromo-4-methylthiazole (1.10 mmol) was used instead of 2-bromopyrimidine, 133 mg (76% yield) of the title compound was obtained.

[0386] Step 12-2: Preparation of (4-(4-methylthiazol-5-yl)phenyl)carbazone dinitrile

[0387] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(4-methylthiazol-5-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 62 mg (89% yield) of the title compound was obtained.

[0388] Example 13: Preparation of biphenyl-4-ylcarbazonyl dinitrile (Compound 13)

[0389] Step 13-1: Preparation of biphenyl-4-amine

[0390] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that bromobenzene (1.10 mmol) was used instead of 2-bromopyrimidine, 109 mg (70% yield) of the title compound was obtained.

[0391] Step 13-2: Preparation of biphenyl-4-ylcarbazonyl dinitrile

[0392] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except that biphenyl-4-amine was used instead of 4-(pyrimidin-2-yl)aniline, 29 mg (38% yield) of the title compound was obtained.

[0393] Example 14: Preparation of (4'-methylbiphenyl-4-yl)carbohydrazine dinitrile (Compound 14)

[0394] Step 14-1: Preparation of 4'-methylbiphenyl-4-amine

[0395] The title compound was obtained by conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 1-bromo-4-methylbenzene (1.10 mmol) was used instead of 2-bromopyrimidine.

[0396] Step 14-2: Preparation of (4'-methylbiphenyl-4-yl)carbohydrazine dinitrile

[0397] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except that 4'-methylbiphenyl-4-amine was used instead of 4-(pyrimidin-2-yl)aniline, 48 mg (23% yield) of the title compound was obtained.

[0398] Example 15: Preparation of (4-(pyridin-3-yl)phenyl)carbazone dinitrile (Compound 15)

[0399] Step 15-1: Preparation of 4-(pyridin-3-yl)aniline

[0400] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 3-bromopyridine (10.95 mmol) was used instead of 2-bromopyrimidine, 367 mg (23% yield) of the title compound was obtained.

[0401] Step 15-2: Preparation of (4-(pyridin-3-yl)phenyl)carbazone dinitrile

[0402] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(pyridin-3-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 533 mg (100% yield) of the title compound was obtained.

[0403] Example 16: Preparation of (4-(pyridin-4-yl)phenyl)carbonyl dinitrile (Compound 16)

[0404] Step 16-1: Preparation of 4-(pyridin-4-yl)aniline

[0405] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 4-bromopyridine hydrochloride (1.53 mmol) was used instead of 2-bromopyrimidine, 70 mg (32% yield) of the title compound was obtained.

[0406] Step 16-2: Preparation of (4-(pyridin-4-yl)phenyl)carbazone dinitrile

[0407] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(pyridin-4-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 9 mg (9% yield) of the title compound was obtained.

[0408] Example 17: Preparation of (4-(pyridazin-3-yl)phenyl)carbonyl dinitrile (Compound 17)

[0409] Step 17-1: Preparation of 4-(pyridazin-3-yl)aniline

[0410] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 3-bromopyridazine (0.64 mmol) was used instead of 2-bromopyrimidine, 76 mg (84% yield) of the title compound was obtained.

[0411] Step 17-2: Preparation of (4-(pyridazin-3-yl)phenyl)carbazone dinitrile

[0412] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except that 4-(pyridazin-3-yl)aniline was used instead of 4-(pyrimidin-2-yl)aniline, 42 mg (38% yield) of the title compound was obtained.

[0413] Example 18: Preparation of (4-(5-methylthiazol-2-yl)phenyl)carbazone dinitrile (Compound 18)

[0414] Step 18-1: Preparation of 4-(5-methylthiazol-2-yl)aniline

[0415] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 2-bromo-5-methylthiazole (0.69 mmol) was used instead of 2-bromopyrimidine, 88 mg (68% yield) of the title compound was obtained.

[0416] Step 18-2: Preparation of (4-(5-methylthiazol-2-yl)phenyl)carbazone dinitrile

[0417] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(5-methylthiazol-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 30 mg (42% yield) of the title compound was obtained.

[0418] Example 19: Preparation of ethyl 2-(4-(2-(dicyanomethylene)hydrazino)phenyl)thiazole-5-carboxylate (Compound 19)

[0419] Step 19-1: Preparation of ethyl 2-(4-aminophenyl)thiazole-5-carboxylate

[0420] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that ethyl 2-bromothiazole-5-carboxylate (1.61 mmol) was used instead of 2-bromopyrimidine, 12 mg (3% yield) of the title compound was obtained.

[0421] Step 19-2: Preparation of ethyl 2-(4-(2-(dicyanomethylene)hydrazino)phenyl)thiazole-5-carboxylate

[0422] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using ethyl 2-(4-aminophenyl)thiazole-5-carboxylate instead of 4-(pyrimidin-2-yl)aniline, 12 mg (75% yield) of the title compound was obtained.

[0423] Example 20: Preparation of (4-(thiazol-5-yl)phenyl)carbazone dinitrile (Compound 20)

[0424] Step 20-1: Preparation of 4-(thiazol-5-yl)aniline

[0425] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 5-bromothiazole (0.91 mmol) was used instead of 2-bromopyrimidine, 137 mg (85% yield) of the title compound was obtained.

[0426] Step 20-2: Preparation of (4-(thiazol-5-yl)phenyl)carbazone dinitrile

[0427] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(thiazol-5-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 60 mg (83% yield) of the title compound was obtained.

[0428] Example 21: Preparation of (3'-fluoro-4'-nitrobiphenyl-4-yl)carbohydrazine dinitrile (Compound 21)

[0429] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 3'-fluoro-4'-nitrobiphenyl-4-amine instead of 4-(pyrimidin-2-yl)aniline, 6 mg (7% yield) of the title compound was obtained.

[0430] Example 22: Preparation of (4-(6-fluoropyridin-3-yl)phenyl)carbonyl dinitrile (Compound 22)

[0431] Step 22-1: Preparation of 4-(6-fluoropyridin-3-yl)aniline

[0432] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 3-bromo-6-fluoropyridine (0.55 mmol) was used instead of 2-bromopyrimidine, 38 mg (45% yield) of the title compound was obtained.

[0433] Step 22-2: Preparation of (4-(6-fluoropyridin-3-yl)phenyl)carbonyl dinitrile

[0434] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(6-fluoropyridin-3-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 23 mg (53% yield) of the title compound was obtained.

[0435] Example 23: Preparation of (2',4'-dimethylbiphenyl-4-yl)carbohydrazine dinitrile (Compound 23)

[0436] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 2′,4′-dimethylbiphenyl-4-amine instead of 4-(pyrimidin-2-yl)aniline, 8 mg (6% yield) of the title compound was obtained.

[0437] Example 24: Preparation of methyl 4'-(2-(dicyanomethylene)hydrazino)-2-fluorobiphenyl-4-carboxylate (Compound 24)

[0438] Step 24-1: Preparation of methyl 4'-amino-2-fluorobiphenyl-4-carboxylate

[0439] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that methyl 4-bromo-3-fluorobenzoate (0.69 mmol) was used instead of 2-bromopyrimidine, 93 mg (60% yield) of the title compound was obtained.

[0440] Step 24-2: Preparation of methyl 4'-(2-(dicyanomethylene)hydrazino)-2-fluorobiphenyl-4-carboxylate

[0441] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4'-amino-2-fluorobiphenyl-4-carboxylate instead of 4-(pyrimidin-2-yl)aniline, 16 mg (16% yield) of the title compound was obtained.

[0442] Example 25: Preparation of (2'-methyl-4'-nitrobiphenyl-4-yl)carbohydrazine dinitrile (Compound 25)

[0443] Step 25-1: Preparation of 2'-methyl-4'-nitrobiphenyl-4-amine

[0444] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 1-bromo-2-methyl-4-nitrobenzene (0.69 mmol) was used instead of 2-bromopyrimidine, 98 mg (63% yield) of the title compound was obtained.

[0445] Step 25-2: Preparation of (2'-methyl-4'-nitrobiphenyl-4-yl)carbohydrazine dinitrile

[0446] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 2'-methyl-4'-nitrobiphenyl-4-amine instead of 4-(pyrimidin-2-yl)aniline, 38 mg (27% yield) of the title compound was obtained.

[0447] Example 26: Preparation of (2',4'-dichlorobiphenyl-4-yl)carbohydrazine dinitrile (Compound 26)

[0448] Step 26-1: Preparation of 2',4'-dichlorobiphenyl-4-amine

[0449] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 1-bromo-2,4-dichlorobenzene (0.91 mmol) was used instead of 2-bromopyrimidine, 182 mg (84% yield) of the title compound was obtained.

[0450] Step 26-2: Preparation of (2',4'-dichlorobiphenyl-4-yl)carbohydrazine dinitrile

[0451] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 2′,4′-dichlorobiphenyl-4-amine instead of 4-(pyrimidin-2-yl)aniline, 47 mg (20% yield) of the title compound was obtained.

[0452] Example 27: Preparation of (2'-methoxy-4'-methylbiphenyl-4-yl)carbohydrazine dinitrile (Compound 27)

[0453] Step 27-1: Preparation of 2'-methoxy-4'-methylbiphenyl-4-amine

[0454] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 1-bromo-2-methoxy-4-methylbenzene (0.69 mmol) was used instead of 2-bromopyrimidine, 36 mg (24% yield) of the title compound was obtained.

[0455] Step 27-2: Preparation of (2'-methoxy-4'-methylbiphenyl-4-yl)carbazone dinitrile

[0456] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 2'-methoxy-4'-methylbiphenyl-4-amine instead of 4-(pyrimidin-2-yl)aniline, 3 mg (6% yield) of the title compound was obtained.

[0457] Example 28: Preparation of (4-(pyrazin-2-yl)phenyl)carbazone dinitrile (Compound 28)

[0458] Step 28-1: Preparation of 4-(pyrazin-2-yl)aniline

[0459] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 2-bromopyrazine (1.26 mmol) was used instead of 2-bromopyrimidine, 72 mg (33% yield) of the title compound was obtained.

[0460] Step 28-2: Preparation of (4-(pyrazin-2-yl)phenyl)carbazone dinitrile

[0461] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except that 4-(pyrazin-2-yl)aniline was used instead of 4-(pyrimidin-2-yl)aniline, 12 mg (12% yield) of the title compound was obtained.

[0462] Example 29: Preparation of (4-(5-(trifluoromethyl)pyrimidin-2-yl)phenyl)carbonyl dinitrile (Compound 29)

[0463] Step 29-1: Preparation of 4-(5-(trifluoromethyl)pyrimidin-2-yl)aniline

[0464] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 2-chloro-5-(trifluoromethyl)pyrimidine (0.83 mmol) was used instead of 2-bromopyrimidine, 127 mg (78% yield) of the title compound was obtained.

[0465] Step 29-2: Preparation of (4-(5-(trifluoromethyl)pyrimidin-2-yl)phenyl)carbonyl dinitrile

[0466] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(5-(trifluoromethyl)pyrimidin-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 47 mg (31% yield) of the title compound was obtained.

[0467] Example 30: Preparation of (4-(4,6-dimethylpyrimidin-2-yl)phenyl)carbonyl dinitrile (Compound 30)

[0468] Step 30-1: Preparation of 4-(4,6-dimethylpyrimidin-2-yl)aniline

[0469] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 2-chloro-4,6-dimethylpyrimidine (1.05 mmol) was used instead of 2-bromopyrimidine, 118 mg (67% yield) of the title compound was obtained.

[0470] Step 30-2: Preparation of (4-(4,6-dimethylpyrimidin-2-yl)phenyl)carbonyl dinitrile

[0471] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(4,6-dimethylpyrimidin-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 110 mg (77% yield) of the title compound was obtained.

[0472] Example 31: Preparation of (4-(4-methylpyrimidin-2-yl)phenyl)carbonyl dinitrile (Compound 31)

[0473] Step 31-1: Preparation of 4-(4-methylpyrimidin-2-yl)aniline

[0474] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 2-bromo-4-methylpyrimidine (0.87 mmol) was used instead of 2-bromopyrimidine, 77 mg (57% yield) of the title compound was obtained.

[0475] Step 31-2: Preparation of (4-(4-methylpyrimidin-2-yl)phenyl)carbonyl dinitrile

[0476] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(4-methylpyrimidin-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 66 mg (61% yield) of the title compound was obtained.

[0477] Example 32: Preparation of (4-(pyrimidin-5-yl)phenyl)carbonyl dinitrile (Compound 32)

[0478] Step 32-1: Preparation of 4-(pyrimidin-5-yl)aniline

[0479] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 5-bromopyrimidine (0.87 mmol) was used instead of 2-bromopyrimidine, 502 mg (64% yield) of the title compound was obtained.

[0480] Step 32-2: Preparation of (4-(pyrimidin-5-yl)phenyl)carbonyl dinitrile

[0481] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(pyrimidin-5-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 100 mg (69% yield) of the title compound was obtained.

[0482] Example 33: Preparation of (4-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)carbazone dinitrile (Compound 33)

[0483] Step 33-1: Preparation of 4-(1-methyl-1H-1,2,4-triazol-5-yl)aniline

[0484] By conducting a reaction in the same manner as in 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, 40 mg (20% yield) of the title compound was obtained.

[0485] Step 33-2: Preparation of (4-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)carbazone dinitrile

[0486] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(1-methyl-1H-1,2,4-triazol-5-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 18 mg (25% yield) of the title compound was obtained.

[0487] Example 34: Preparation of (4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)carbazone dinitrile (Compound 34)

[0488] Step 34-1: Preparation of 4-(1-methyl-1H-1,2,4-triazol-3-yl)aniline

[0489] By conducting a reaction in the same manner as in 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, 100 mg (50% yield) of the title compound was obtained.

[0490] Step 34-2: Preparation of (4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)carbazone dinitrile

[0491] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(1-methyl-1H-1,2,4-triazol-3-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 29 mg (40% yield) of the title compound was obtained.

[0492] Example 35: Preparation of (4-(1H-pyrazol-1-yl)phenyl)carbazone dinitrile (Compound 35)

[0493] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(1H-pyrazol-1-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 163 mg (55% yield) of the title compound was obtained.

[0494] Example 36: Preparation of (4-(4-methyl-1H-pyrazol-1-yl)phenyl)carbazone dinitrile (Compound 36)

[0495] Step 36-1: Preparation of 4-methyl-1-(4-nitrophenyl)-1H-pyrazole

[0496] In the presence of nitrogen, 4-methyl-1H-pyrazole (100 mg, 1.22 mmol) was dissolved in 1.5 mL of DMSO, and then solid potassium tert-butoxide (164 mg, 1.46 mmol) and 1-fluoro-4-nitrobenzene (189 mg, 1.46 mmol) were added to obtain a reaction mixture. The reaction mixture was stirred at 72 ° C for 20 hours. After the reaction was complete, the reaction product was cooled, then extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by recrystallization with an ethanol solvent to obtain 96 mg (yield 39%) of the title compound.

[0497] Step 36-2: Preparation of 4-(4-methyl-1H-pyrazol-1-yl)aniline

[0498] The 4-methyl-1-(4-nitrophenyl)-1H-pyrazole prepared according to step 1-1 was dissolved in 2.5 mL of ethanol, and then 10% (32 mg, 0.06 mmol) of carbon-activated palladium catalyst was added, followed by stirring at room temperature for 1 hour in the presence of hydrogen. After the reaction was complete, the catalyst in the reaction mixture was filtered using diatomaceous earth. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to obtain 50 mg (yield 98%) of the title compound.

[0499] Step 36-3: Preparation of (4-(4-methyl-1H-pyrazol-1-yl)phenyl)carbazone dinitrile

[0500] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(4-methyl-1H-pyrazol-1-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 50 mg (69% yield) of the title compound was obtained.

[0501] Example 37: Preparation of (2-fluoro-4-(4-methylpyrimidin-2-yl)phenyl)carbonyl dinitrile (Compound 37)

[0502] Step 37-1: Preparation of 2-fluoro-4-(4-methylpyrimidin-2-yl)aniline

[0503] The reaction was carried out in the same manner as in 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. 100 mg (50% yield) of the title compound was obtained.

[0504] Step 37-2: Preparation of (2-fluoro-4-(4-methylpyrimidin-2-yl)phenyl)carbonyl dinitrile

[0505] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 2-fluoro-4-(4-methylpyrimidin-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 46 mg (67% yield) of the title compound was obtained.

[0506] Example 38: Preparation of (2-fluoro-4-(pyrimidin-2-yl)phenyl)carbonyl dinitrile (Compound 38)

[0507] Step 38-1: Preparation of 2-fluoro-4-(pyrimidin-2-yl)aniline

[0508] By conducting a reaction in the same manner as in Step 37-1 of Example 37, except that 2-bromopyrimidine (1.26 mmol) was used instead of 2-bromo-4-methylpyrimidine, 41 mg (17% yield) of the title compound was obtained.

[0509] Step 38-2: Preparation of (2-fluoro-4-(pyrimidin-2-yl)phenyl)carbonyl dinitrile

[0510] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 2-fluoro-4-(pyrimidin-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 11 mg (19% yield) of the title compound was obtained.

[0511] Example 39: Preparation of (3-fluoro-4-(pyrimidin-2-yl)phenyl)carbonyl dinitrile (Compound 39)

[0512] Step 39-1: Preparation of 3-fluoro-4-(pyrimidin-2-yl)aniline

[0513] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 4-amino-2-fluorophenylboronic acid pinacol ester (1.38 mmol) was used instead of 4-aminophenylboronic acid pinacol ester, 156 mg (66% yield) of the title compound was obtained.

[0514] Step 39-2: Preparation of (3-fluoro-4-(pyrimidin-2-yl)phenyl)carbonyl dinitrile

[0515] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 3-fluoro-4-(pyrimidin-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 80 mg (81% yield) of the title compound was obtained.

[0516] Example 40: Preparation of (3-fluoro-4-(4-methylpyrimidin-2-yl)phenyl)carbonyl dinitrile (Compound 40)

[0517] Step 40-1: Preparation of 3-fluoro-4-(4-methylpyrimidin-2-yl)aniline

[0518] By conducting a reaction in the same manner as in Step 39-1 of Example 39, except that 2-bromo-4-methylpyrimidine (1.16 mmol) was used instead of 2-bromopyrimidine, 82 mg (35% yield) of the title compound was obtained.

[0519] Step 40-2: Preparation of (3-fluoro-4-(4-methylpyrimidin-2-yl)phenyl)carbonyl dinitrile

[0520] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 3-fluoro-4-(4-methylpyrimidin-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 56 mg (92% yield) of the title compound was obtained.

[0521] Example 41: Preparation of (2-methoxy-4-(5-methylpyrimidin-2-yl)phenyl)carbonyl dinitrile (Compound 41)

[0522] Step 41-1: Preparation of 2-methoxy-4-(5-methylpyrimidin-2-yl)aniline

[0523] By conducting a reaction in the same manner as in 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, 99 mg (47% yield) of the title compound was obtained.

[0524] Step 41-2: Preparation of (2-methoxy-4-(5-methylpyrimidin-2-yl)phenyl)carbazone dinitrile

[0525] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 2-methoxy-4-(5-methylpyrimidin-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 25 mg (61% yield) of the title compound was obtained.

[0526] Example 42: Preparation of (2-methoxy-4-(4-methylpyrimidin-2-yl)phenyl)carbonyl dinitrile (Compound 42)

[0527] Step 42-1: Preparation of 2-methoxy-4-(4-methylpyrimidin-2-yl)aniline

[0528] By conducting a reaction in the same manner as in Step 41-1 of Example 41, except that 2-bromo-4-methylpyrimidine (1.12 mmol) was used instead of 2-chloro-5-methylpyrimidine, 80 mg (42% yield) of the title compound was obtained.

[0529] Step 42-2: Preparation of (2-methoxy-4-(4-methylpyrimidin-2-yl)phenyl)carbonyl dinitrile

[0530] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 2-methoxy-4-(4-methylpyrimidin-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 10 mg (58% yield) of the title compound was obtained.

[0531] Example 43: Preparation of (2-methoxy-4-(pyrimidin-2-yl)phenyl)carbonyl dinitrile (Compound 43)

[0532] Step 43-1: Preparation of 2-methoxy-4-(pyrimidin-2-yl)aniline

[0533] By conducting a reaction in the same manner as in Step 41-1 of Example 41, except that 2-bromopyrimidine (0.96 mmol) was used instead of 2-chloro-5-methylpyrimidine, 29 mg (18% yield) of the title compound was obtained.

[0534] Step 43-2: Preparation of (2-methoxy-4-(pyrimidin-2-yl)phenyl)carbonyl dinitrile

[0535] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 2-methoxy-4-(pyrimidin-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 26 mg (65% yield) of the title compound was obtained.

[0536] Example 44: Preparation of (4-(5-fluoropyrimidin-2-yl)-2-morpholinophenyl)carbonyl dinitrile (Compound 44)

[0537] Step 44-1: Preparation of 2-(3-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0538] In the presence of nitrogen, 4-bromo-2-fluoro-1-nitrobenzene (2 g, 7.88 mmol) and bis(pinacol)diboron (4,4,4',4',5,5,5',5'-octamethyl-2,2'-di(1,3,2-dioxaborolane); 2.1 g, 9.45 mmol) were dissolved in 60 mL of 1,4-dioxane solution, and then Pd(dppf)2Cl2 (1.3 g, 1.58 mmol) and potassium acetate (3.1 g, 31.5 mmol) were added to obtain a reaction mixture. The reaction mixture was stirred at 80° C. for 12 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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.

[0539] Step 44-2: Preparation of 4-(2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine

[0540] In the presence of nitrogen, 2-(3-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and morpholine (0.68 mL, 7.79 mmol) prepared according to step 44-1 were dissolved in acetonitrile (20 mL) to obtain a reaction mixture, and the reaction mixture was then stirred at 80 ° C for 12 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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.

[0541] Step 44-3: Preparation of 4-(5-(5-fluoropyrimidin-2-yl)-2-nitrophenyl)morpholine

[0542] By conducting a reaction in the same manner as in 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, 164 mg (26% yield) of the title compound was obtained.

[0543] Step 44-4: Preparation of 4-(5-fluoropyrimidin-2-yl)-2-morpholinoaniline

[0544] 4-(5-(5-fluoropyrimidin-2-yl)-2-nitrophenyl)morpholine prepared according to Step 44-3 was dissolved in ethyl acetate and reduced in the same manner as in Step 36-2 of Example 36 to give 84 mg (57% yield) of the title compound.

[0545] Step 44-5: Preparation of (4-(5-fluoropyrimidin-2-yl)-2-morpholinophenyl)carbonyl dinitrile

[0546] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except that 4-(5-fluoropyrimidin-2-yl)-2-morpholinoaniline prepared according to Step 44-4 was used instead of 4-(pyrimidin-2-yl)aniline, 70 mg (65% yield) of the title compound was obtained.

[0547] Example 45: Preparation of methyl (4-(pyrimidin-2-yl)phenyl) carbohydrazine dinitrile (Compound 45)

[0548] The (4-(pyrimidin-2-yl)phenyl)carbonyl dinitrile (50 mg, 0.20 mmol) prepared according to Example 1 was dissolved in 1.5 mL of tetrahydrofuran, and then potassium tert-butoxide (29 mg, 0.26 mmol) was added at room temperature, and methyl iodide (25 μL, 0.40 mmol) was added to obtain a reaction mixture. The reaction mixture was stirred at 60° C. for 4 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by recrystallization with an ethanol solvent to obtain 3 mg (yield 6%) of the title compound.

[0549] Example 46: Preparation of (3-(5-fluoropyrimidin-2-yl)phenyl)carbazone dinitrile (Compound 46)

[0550] Step 46-1: Preparation of 3-(5-fluoropyrimidin-2-yl)aniline

[0551] By conducting a reaction in the same manner as in Step 1-1 of Example 41, except using 3-aminophenylboronic acid pinacol ester (1.37 mmol) instead of 4-aminophenylboronic acid pinacol ester and using 2-chloro-5-fluoropyrimidine (1.64 mmol) instead of 2-bromopyrimidine, 180 mg of the title compound was obtained.

[0552] Step 46-2: Preparation of (3-(5-fluoropyrimidin-2-yl)phenyl)carbazone dinitrile

[0553] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 3-(5-fluoropyrimidin-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 70.5 mg of the title compound was obtained.

[0554] Example 47: Preparation of (5-(5-fluoropyrimidin-2-yl)-2-morpholinophenyl)carbonyl dinitrile (Compound 47)

[0555] Step 47-1: Preparation of 4-(2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine

[0556] By conducting a reaction in the same manner as in Step 44-2 of Example 44, except using 2-(4-chloro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 2-(3-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 480 mg (41% yield) of the title compound was obtained.

[0557] Step 47-2: Preparation of 4-(4-(5-fluoropyrimidin-2-yl)-2-nitrophenyl)morpholine

[0558] By conducting a reaction in the same manner as in 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-aminophenylboronic acid pinacol ester, and 2-chloro-5-fluoropyrimidine was used instead of 2-bromopyrimidine, 300 mg (70% yield) of the title compound was obtained.

[0559] Step 47-3: Preparation of 5-(5-fluoropyrimidin-2-yl)-2-morpholinoaniline

[0560] 4-(5-(5-fluoropyrimidin-2-yl)-2-nitrophenyl)morpholine prepared according to Step 44-3 was dissolved in dichloromethane and reduced in the same manner as in Step 36-2 of Example 36 to give 86 mg (48% yield) of the title compound.

[0561] Step 47-4: Preparation of (5-(5-fluoropyrimidin-2-yl)-2-morpholinophenyl)carbonyl dinitrile

[0562] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except that 5-(5-fluoropyrimidin-2-yl)-2-morpholinoaniline prepared according to Step 47-3 was used instead of 4-(pyrimidin-2-yl)aniline, 84 mg (77% yield) of the title compound was obtained.

[0563] Example 48: Preparation of (4-(Benzo[d]thiazol-6-yl)phenyl)carbazone dinitrile (Compound 48)

[0564] Step 48-1: Preparation of 4-(Benzo[d]thiazol-6-yl)aniline

[0565] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 6-bromobenzo[d]thiazole (0.55 mmol) was used instead of 2-bromopyrimidine, 58 mg (68% yield) of the title compound was obtained.

[0566] Step 48-2: Preparation of (4-(Benzo[d]thiazol-6-yl)phenyl)carbazone dinitrile

[0567] The title compound (10 mg, 13% yield) was obtained by conducting a reaction in the same manner as in Step 1-2 of Example 1, except that 4-(benzo[d]thiazol-6-yl)aniline was used instead of 4-(pyrimidin-2-yl)aniline.

[0568] Example 49: Preparation of (4-(naphthalen-2-yl)phenyl)carbazone dinitrile (Compound 49)

[0569] Step 49-1: Preparation of 4-(naphthalen-2-yl)aniline

[0570] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 2-bromonaphthalene (0.46 mmol) was used instead of 2-bromopyrimidine, 40 mg (21% yield) of the title compound was obtained.

[0571] Step 49-2: Preparation of (4-(naphthalen-2-yl)phenyl)carbonyl dinitrile

[0572] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(naphthalen-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 5 mg (9% yield) of the title compound was obtained.

[0573] Example 50: Preparation of (4-(pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)carbonyl dinitrile (Compound 50)

[0574] Step 50-1: Preparation of 4-(pyrazolo[1,5-a]pyrimidin-6-yl)aniline

[0575] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 6-bromopyrazolo[1,5-a]pyrimidine (1.65 mmol) was used instead of 2-bromopyrimidine, 180 mg (62% yield) of the title compound was obtained.

[0576] Step 50-2: Preparation of (4-(pyrazolo[1,5-a]pyrimidin-6-yl)phenyl)carbonyl dinitrile

[0577] The title compound (79 mg, 32% yield) was obtained by reacting in the same manner as in 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.

[0578] Example 51: Preparation of (4-(imidazo[1,2-a]pyrimidin-6-yl)phenyl)carbazone dinitrile (Compound 51)

[0579] Step 51-1: Preparation of 4-(imidazo[1,2-a]pyrimidin-6-yl)aniline

[0580] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 6-bromoimidazo[1,2-a]pyrimidine (2.53 mmol) was used instead of 2-bromopyrimidine, 76 mg (17% yield) of the title compound was obtained.

[0581] Step 51-2: Preparation of (4-(imidazo[1,2-a]pyrimidin-6-yl)phenyl)carbonyl dinitrile

[0582] The title compound was obtained by reacting in the same manner as in 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.

[0583] Example 52: Preparation of (4-(quinoxalin-2-yl)phenyl)carbonyl dinitrile (Compound 52)

[0584] Step 52-1: Preparation of 4-(quinoxalin-2-yl)aniline

[0585] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 2-chloroquinoxaline (1.64 mmol) was used instead of 2-bromopyrimidine, 100 mg (33% yield) of the title compound was obtained.

[0586] Step 52-2: Preparation of (4-(quinoxalin-2-yl)phenyl)carbonyl dinitrile

[0587] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(quinoxalin-2-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 30 mg (44% yield) of the title compound was obtained.

[0588] Example 53: Preparation of (4-(imidazo[1,2-a]pyridin-6-yl)phenyl)carbonyl dinitrile (Compound 53)

[0589] Step 53-1: Preparation of 4-(imidazo[1,2-a]pyridin-6-yl)aniline

[0590] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 6-bromoimidazo[1,2-a]pyridine (1.64 mmol) was used instead of 2-bromopyrimidine, 100 mg (33% yield) of the title compound was obtained.

[0591] Step 53-2: Preparation of (4-(imidazo[1,2-a]pyridin-6-yl)phenyl)carbazone dinitrile

[0592] The title compound (22 mg, 32% yield) was obtained by reacting in the same manner as in 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.

[0593] Example 54: Preparation of (4-(isoquinolin-3-yl)phenyl)carbazone dinitrile (Compound 54)

[0594] Step 54-1: Preparation of 4-(isoquinolin-3-yl)aniline

[0595] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 3-chloroisoquinoline (2.80 mmol) was used instead of 2-bromopyrimidine, 80 mg (16% yield) of the title compound was obtained.

[0596] Step 54-2: Preparation of (4-(isoquinolin-3-yl)phenyl)carbazone dinitrile

[0597] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(isoquinolin-3-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 23 mg (42% yield) of the title compound was obtained.

[0598] Example 55: Preparation of (4-(2-methyl-2H-indazol-4-yl)phenyl)carbazone dinitrile (Compound 55)

[0599] Step 55-1: Preparation of 4-(2-methyl-2H-indazol-4-yl)aniline

[0600] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except using 4-bromo-2-methyl-2H-indazole (2.20 mmol) instead of 2-bromopyrimidine, 331 mg (80% yield) of the title compound was obtained.

[0601] Step 55-2: Preparation of (4-(2-methyl-2H-indazol-4-yl)phenyl)carbazone dinitrile

[0602] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(2-methyl-2H-indazol-4-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 100 mg (24% yield) of the title compound was obtained.

[0603] Example 56: Preparation of (4-(2-methyl-2H-indazol-5-yl)phenyl)carbazone dinitrile (Compound 56)

[0604] Step 56-1: Preparation of 4-(2-methyl-2H-indazol-5-yl)aniline

[0605] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 5-bromo-2-methyl-2H-indazole (2.20 mmol) was used instead of 2-bromopyrimidine, 100 mg (38% yield) of the title compound was obtained.

[0606] Step 56-2: Preparation of (4-(2-methyl-2H-indazol-5-yl)phenyl)carbazone dinitrile

[0607] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(2-methyl-2H-indazol-5-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 26 mg (65% yield) of the title compound was obtained.

[0608] Example 57: Preparation of (4-(2-methyl-2H-indazol-7-yl)phenyl)carbazone dinitrile (Compound 57)

[0609] Step 57-1: Preparation of 4-(2-methyl-2H-indazol-7-yl)aniline

[0610] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except that 7-bromo-2-methyl-2H-indazole (2.20 mmol) was used instead of 2-bromopyrimidine, 550 mg (86% yield) of the title compound was obtained.

[0611] Step 57-2: Preparation of (4-(2-methyl-2H-indazol-7-yl)phenyl)carbazone dinitrile

[0612] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-(2-methyl-2H-indazol-7-yl)aniline instead of 4-(pyrimidin-2-yl)aniline, 345 mg (47% yield) of the title compound was obtained.

[0613] Example 58: Preparation of (4-(1H-indol-5-yl)phenyl)carbazone dinitrile (Compound 58)

[0614] Step 58-1: Preparation of tert-butyl 5-(4-aminophenyl)-1H-indole-1-carboxylate

[0615] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except using tert-butyl 5-bromo-1H-indole-1-carboxylate (3.38 mmol) instead of 2-bromopyrimidine, 596 mg (6% yield) of the title compound was obtained.

[0616] Step 58-2: Preparation of tert-butyl 5-(4-(2-(dicyanomethylene)hydrazino)phenyl)-1H-indol-1-ylcarboxylate

[0617] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using tert-butyl 5-(4-aminophenyl)-1H-indole-1-carboxylate instead of 4-(pyrimidin-2-yl)aniline, 107 mg (14% yield) of the title compound was obtained.

[0618] Step 58-3: Preparation of (4-(1H-indol-5-yl)phenyl)carbazone dinitrile

[0619] In the presence of nitrogen, tert-butyl 5-(4-(2-(dicyanomethylene)hydrazine)phenyl)-1H-indol-1-ylcarboxylate was dissolved in 8.0 mL of dichloromethane, and trifluoroacetic acid was added to obtain a reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction product was concentrated under reduced pressure to obtain 40 mg of the title compound (yield 44%).

[0620] Example 59: Preparation of (4-methoxybenzo[d]thiazol-2-yl)carbazone dinitrile (Compound 59)

[0621] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 4-methoxybenzo[d]thiazol-2-amine instead of 4-(pyrimidin-2-yl)aniline, 141 mg (51% yield) of the title compound was obtained.

[0622] Example 60: Preparation of benzo[d]thiazol-6-ylcarbazolidine dinitrile (Compound 60)

[0623] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using benzo[d]thiazol-6-amine instead of 4-(pyrimidin-2-yl)aniline, 290 mg (48% yield) of the title compound was obtained.

[0624] Example 61: Preparation of benzo[d]thiazol-5-ylcarbazone dinitrile (Compound 61)

[0625] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using benzo[d]thiazol-5-amine instead of 4-(pyrimidin-2-yl)aniline, 180 mg (40% yield) of the title compound was obtained.

[0626] Example 62: Preparation of (9-ethyl-9H-carbazole-3-yl)carbohydrazone dinitrile (Compound 62)

[0627] The reaction was carried out in the same manner as in Step 1-2 of Example 1, except that 9-ethyl-9H-carbazole-3-amine was used instead of 4-(pyrimidin-2-yl)aniline, to give 77 mg (11% yield) of the title compound.

[0628] Example 63: Preparation of (1-methyl-1H-indazol-6-yl)carbazone dinitrile (Compound 63)

[0629] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 1-methyl-1H-indazol-6-amine instead of 4-(pyrimidin-2-yl)aniline, 246 mg (54% yield) of the title compound was obtained.

[0630] Example 64: Preparation of quinolin-3-ylcarbazone dinitrile (Compound 64)

[0631] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except that quinolin-3-amine was used instead of 4-(pyrimidin-2-yl)aniline, 163 mg (27% yield) of the title compound was obtained.

[0632] Example 65: Preparation of (2-methyl-2H-indazol-6-yl)carbazone dinitrile (Compound 65)

[0633] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 2-methyl-2H-indazol-6-amine instead of 4-(pyrimidin-2-yl)aniline, 23 mg (3% yield) of the title compound was obtained.

[0634] Example 66: Preparation of (1-methyl-1H-indazol-5-yl)carbazone dinitrile (Compound 66)

[0635] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 1-methyl-1H-indazol-5-amine instead of 4-(pyrimidin-2-yl)aniline, 128 mg (17% yield) of the title compound was obtained.

[0636] Example 67: Preparation of quinolin-6-ylcarbazone dinitrile (Compound 67)

[0637] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except that quinolin-6-amine was used instead of 4-(pyrimidin-2-yl)aniline, 56 mg (9% yield) of the title compound was obtained.

[0638] Example 68: Preparation of (1-methyl-1H-indol-5-yl)carbazone dinitrile (Compound 68)

[0639] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 1-methyl-1H-indol-5-amine instead of 4-(pyrimidin-2-yl)aniline, 69 mg (11% yield) of the title compound was obtained.

[0640] Example 69: Preparation of (1H-indazol-5-yl)carbazone dinitrile (Compound 69)

[0641] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using tert-butyl 5-amino-1H-indazole-1-carboxylate instead of 4-(pyrimidin-2-yl)aniline, 70 mg (19% yield) of the title compound was obtained.

[0642] Example 70: Preparation of (1H-indazol-6-yl)carbazone dinitrile (Compound 70)

[0643] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using tert-butyl 6-amino-1H-indazole-1-carboxylate instead of 4-(pyrimidin-2-yl)aniline, 62 mg (12% yield) of the title compound was obtained.

[0644] Example 71: Preparation of (1H-indol-5-yl)carbazone dinitrile (Compound 71)

[0645] Step 71-1: Preparation of tert-butyl 5-(2-(dicyanomethylene)hydrazino)-1H-indole-1-carboxylate

[0646] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using tert-butyl 5-amino-1H-indole-1-carboxylate instead of 4-(pyrimidin-2-yl)aniline, 25 mg (6% yield) of the title compound was obtained.

[0647] Step 71-2: Preparation of (1H-indol-5-yl)carbazone dinitrile

[0648] The reaction was carried out in the same manner as in Step 58-3 of Example 58, except that tert-butyl 5-(2-(dicyanomethylene)hydrazino)-1H-indole-1-carboxylate was used instead of tert-butyl 5-(4-(2-(dicyanomethylene)hydrazino)phenyl)-1H-indol-1-ylcarboxylate, to give 15 mg (88% yield) of the title compound.

[0649] Example 72: Preparation of (1H-pyrrolo[2,3-b]pyridin-5-yl)carbonyl dinitrile (Compound 72)

[0650] Step 72-1: Preparation of tert-butyl 5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0651] In the presence of nitrogen, 5-nitro-1H-pyrrolo[2,3-b]pyridine (2g, 12.27mmol), di-tert-butyl dicarbonate (3.2g, 14.71mmol) and 4-dimethylaminopyridine (150mg, 1.23mmol) were dissolved in 40mL of acetonitrile solution and then stirred at room temperature for 3 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 1.23g (yield 38%) of the title compound.

[0652] Step 72-2: Preparation of tert-butyl 5-amino-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0653] In the presence of nitrogen, 5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (600mg, 2.28mmol) prepared according to step 72-1 was dissolved in 5mL of acetic acid solution, and iron (1.2g, 22.80mmol) was then added to obtain a reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 261mg (yield 48%) of the title compound.

[0654] Step 72-3: Preparation of (1H-pyrrolo[2,3-b]pyridin-5-yl)carbonyl dinitrile

[0655] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using tert-butyl 5-amino-1H-pyrrolo[2,3-b]pyridine-1-carboxylate instead of 4-(pyrimidin-2-yl)aniline, 128 mg (54% yield) of the title compound was obtained.

[0656] Example 73: Preparation of (3-methyl-1H-indazol-6-yl)carbazone dinitrile (Compound 73)

[0657] Step 73-1: Preparation of tert-butyl 3-methyl-6-nitro-1H-indazole-1-carboxylate

[0658] By conducting a reaction in the same manner as in Step 72-1 of Example 72, except using 3-methyl-6-nitro-1H-indazole instead of 5-nitro-1H-pyrrolo[2,3-b]pyridine, 1.43 g (92% yield) of the title compound was obtained.

[0659] Step 73-2: Preparation of tert-butyl 6-amino-3-methyl-1H-indazole-1-carboxylate

[0660] tert-Butyl 3-methyl-6-nitro-1H-indazole-1-carboxylate prepared according to Step 73-1 was dissolved in ethyl acetate and reduced in the same manner as in Step 36-2 of Example 36 to give 500 mg (80% yield) of the title compound.

[0661] Step 73-3: Preparation of (3-methyl-1H-indazol-6-yl)carbazone dinitrile

[0662] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using tert-butyl 6-amino-3-methyl-1H-indazole-1-carboxylate instead of 4-(pyrimidin-2-yl)aniline, 40 mg (10% yield) of the title compound was obtained.

[0663] Example 74: Preparation of (3-methyl-1H-indazol-5-yl)carbohydrazine dinitrile (Compound 74)

[0664] Step 74-1: Preparation of tert-butyl 3-methyl-5-nitro-1H-indazole-1-carboxylate

[0665] By conducting a reaction in the same manner as in Step 72-1 of Example 72, except using 3-methyl-5-nitro-1H-indazole (1.29 mmol) instead of 5-nitro-1H-pyrrolo[2,3-b]pyridine, 2.83 g (90% yield) of the title compound was obtained.

[0666] Step 74-2: Preparation of tert-butyl 5-amino-3-methyl-1H-indazole-1-carboxylate

[0667] tert-Butyl 3-methyl-5-nitro-1H-indazole-1-carboxylate prepared according to Step 74-1 was dissolved in ethyl acetate and reduced in the same manner as in Step 36-2 of Example 36 to give 761 mg (85% yield) of the title compound.

[0668] Step 74-3: Preparation of (3-methyl-1H-indazol-5-yl)carbazone dinitrile

[0669] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using tert-butyl 5-amino-3-methyl-1H-indazole-1-carboxylate instead of 4-(pyrimidin-2-yl)aniline, 100 mg (15% yield) of the title compound was obtained.

[0670] Example 75: Preparation of (1H-indol-4-yl)carbazone dinitrile (Compound 75)

[0671] Step 75-1: Preparation of tert-butyl 4-amino-1H-indole-1-carboxylate

[0672] tert-Butyl 4-nitro-1H-indole-1-carboxylate was dissolved in acetonitrile (MeCN) and reduced in the same manner as in Step 36-2 of Example 36 to give 198 mg (75% yield) of the title compound.

[0673] Step 75-2: Preparation of (1H-indol-4-yl)carbazone dinitrile

[0674] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using tert-butyl 4-amino-1H-indole-1-carboxylate instead of 4-(pyrimidin-2-yl)aniline, 40 mg (10% yield) of the title compound was obtained.

[0675] Example 76: Preparation of (1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbohydrazine dinitrile (Compound 76)

[0676] Step 76-1: Preparation of 1-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine

[0677] In the presence of nitrogen, 5-nitro-1H-pyrrolo[2,3-b]pyridine (600mg, 3.72mmol) was dissolved in DMF (6mL), and then sodium hydride (60%, 300mg, 7.44mmol) was added, followed by iodomethane (0.93mL, 14.88mmol) to obtain a reaction mixture. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 380mg (yield 57%) of the title compound.

[0678] Step 76-2: Preparation of 1-methyl-1H-pyrrolo[2,3-b]pyridin-5-amine

[0679] The reaction was carried out in the same manner as in Step 72-2 of Example 72, except that 1-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine obtained in Step 76-1 was used instead of tert-butyl 5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate, to give 69 mg (55% yield) of the title compound.

[0680] Step 76-3: Preparation of (1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile

[0681] The reaction was carried out in the same manner as in Step 1-2 of Example 1, except that 1-methyl-1H-pyrrolo[2,3-b]pyridin-5-amine was used instead of 4-(pyrimidin-2-yl)aniline, to give 8 mg (9% yield) of the title compound.

[0682] Example 77: Preparation of (1-propyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbohydrazine dinitrile (Compound 77)

[0683] Step 77-1: Preparation of 5-nitro-1-propyl-1H-pyrrolo[2,3-b]pyridine

[0684] 5-Nitro-1H-pyrrolo[2,3-b]pyridine (600 mg, 3.72 mmol), cesium carbonate (CsCO3, 2.4 g, 7.44 mmol) and 1-iodopropane (1.10 mL, 11.01 mmol) were dissolved in DMF to obtain a reaction mixture, and the reaction mixture was then stirred at 60°C for 17 hours to obtain 523 mg of the title compound (yield 70%).

[0685] Step 77-2: Preparation of 1-propyl-1H-pyrrolo[2,3-b]pyridin-5-amine

[0686] The reaction was carried out in the same manner as in Step 72-2 of Example 72, except that 5-nitro-1-propyl-1H-pyrrolo[2,3-b]pyridine obtained in Step 77-1 was used instead of tert-butyl 5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate, to give 297 mg (67% yield) of the title compound.

[0687] Step 77-3: Preparation of (1-propyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile

[0688] The title compound (98 mg, 23% yield) was obtained by conducting a reaction in the same manner as in Step 1-2 of Example 1, except that 1-propyl-1H-pyrrolo[2,3-b]pyridin-5-amine was used instead of 4-(pyrimidin-2-yl)aniline.

[0689] Example 78: Preparation of (1-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbohydrazine dinitrile (Compound 78)

[0690] Step 78-1: Preparation of 5-nitro-1-isopropyl-1H-pyrrolo[2,3-b]pyridine

[0691] By conducting a reaction in the same manner as in Step 77-1 of Example 77, except that 2-iodopropane (1.10 mL, 11.01 mmol) was used instead of 1-iodopropane, 591 mg (78% yield) of the title compound was obtained.

[0692] Step 78-2: Preparation of 1-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-amine

[0693] The reaction was carried out in the same manner as in Step 72-2 of Example 72, except that 5-nitro-1-isopropyl-1H-pyrrolo[2,3-b]pyridine obtained in Step 78-1 was used instead of tert-butyl 5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate, to give 270 mg (54% yield) of the title compound.

[0694] Step 78-3: Preparation of (1-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile

[0695] The title compound (81 mg, 21% yield) was obtained by conducting a reaction in the same manner as in Step 1-2 of Example 1, except that 1-isopropyl-1H-pyrrolo[2,3-b]pyridin-5-amine was used instead of 4-(pyrimidin-2-yl)aniline.

[0696] Example 79: Preparation of (1-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbohydrazine dinitrile (Compound 79)

[0697] Step 79-1: Preparation of 1-ethyl-5-nitro-1H-pyrrolo[2,3-b]pyridine

[0698] By conducting a reaction in the same manner as in Step 77-1 of Example 77, except that iodoethane (0.83 mL, 10.14 mmol) was used instead of 1-iodopropane, 363 mg (52% yield) of the title compound was obtained.

[0699] Step 79-2: Preparation of 1-ethyl-1H-pyrrolo[2,3-b]pyridin-5-amine

[0700] By conducting a reaction in the same manner as in Step 72-2 of Example 72, except that 1-ethyl-5-nitro-1H-pyrrolo[2,3-b]pyridine obtained in Step 79-1 was used instead of tert-butyl 5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate, 184 mg (61% yield) of the title compound was obtained.

[0701] Step 79-3: Preparation of (1-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile

[0702] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using 1-ethyl-1H-pyrrolo[2,3-b]pyridin-5-amine instead of 4-(pyrimidin-2-yl)aniline, 187 mg (69% yield) of the title compound was obtained.

[0703] Example 80: Preparation of (1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonyl dinitrile (Compound 80)

[0704] Step 80-1: Preparation of 5-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine

[0705] By conducting a reaction in the same manner as in Step 77-1 of Example 77, except using 1,1,1-trifluoro-2-iodoethane (1.80 mL, 18.39 mmol) instead of 1-iodopropane, 784 mg (52% yield) of the title compound was obtained.

[0706] Step 80-2: Preparation of 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-amine

[0707] The reaction was carried out in the same manner as in 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, to give 235 mg (53% yield) of the title compound.

[0708] Step 80-3: Preparation of (1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbonyl dinitrile

[0709] The title compound (150 mg, 55% yield) was obtained by conducting a reaction in the same manner as in 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.

[0710] Example 81: Preparation of (2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbohydrazine dinitrile (Compound 81)

[0711] Step 81-1: Preparation of tert-butyl 2-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0712] By conducting a reaction in the same manner as in Step 72-1 of Example 72, except using 2-methyl-1H-pyrrolo[2,3-b]pyridine instead of 5-nitro-1H-pyrrolo[2,3-b]pyridine, 1.83 g (98% yield) of the title compound was obtained.

[0713] Step 81-2: Preparation of tert-butyl 2-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0714] In the presence of nitrogen, tert-butyl 2-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate and tetrabutylammonium nitrate were dissolved in dichloromethane and stirred at 0 ° C for 10 minutes. Thereafter, trifluoroacetic anhydride (TFAA, 1.43mL, 0.125mmol) was added, stirred at 0 ° C for 5 minutes, and then further stirred at room temperature for 3 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 the title compound 1.34g (yield 61%).

[0715] Step 81-3: Preparation of tert-butyl 5-amino-2-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0716] The reaction was carried out in the same manner as in Step 72-2 of Example 72, except that tert-butyl 5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was replaced with tert-butyl 2-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate obtained in Step 81-2, to give 311 mg (58% yield) of the title compound.

[0717] Step 81-4: Preparation of tert-butyl 5-(2-(dicyanomethylene)hydrazino)-2-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0718] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using tert-butyl 5-amino-2-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate instead of 4-(pyrimidin-2-yl)aniline, 160 mg (68% yield) of the title compound was obtained.

[0719] Step 81-5: Preparation of (2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile

[0720] The reaction was carried out in the same manner as in Step 58-3 of Example 58, except that tert-butyl 5-(2-(dicyanomethylene)hydrazino)-2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylcarboxylate was replaced with tert-butyl 5-(4-(2-(dicyanomethylene)hydrazino)phenyl)-1H-indol-1-ylcarboxylate, to give 29 mg (71% yield) of the title compound.

[0721] Example 82: Preparation of (3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbohydrazine dinitrile (Compound 82)

[0722] Step 82-1: Preparation of tert-butyl 3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0723] 3.4 g (97% yield) of the title compound was obtained by conducting a reaction in the same manner as in 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.

[0724] Step 82-2: Preparation of tert-butyl 3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0725] By conducting a reaction in the same manner as in 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, 800 mg (42% yield) of the title compound was obtained.

[0726] Step 82-3: Preparation of tert-butyl 5-amino-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0727] tert-Butyl 3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was dissolved in ethyl acetate and reduced in the same manner as in Step 36-2 of Example 36 to give 367 mg (82% yield) of the title compound.

[0728] Step 82-4: Preparation of tert-butyl 5-(2-(dicyanomethylene)hydrazino)-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0729] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except that 5-amino-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester was used instead of 4-(pyrimidin-2-yl)aniline, 106 mg (40% yield) of the title compound was obtained.

[0730] Step 82-5: Preparation of (3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile

[0731] The reaction was carried out in the same manner as in Step 58-3 of Example 58, except that tert-butyl 5-(2-(dicyanomethylene)hydrazino)-3-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylcarboxylate was used instead of tert-butyl 5-(4-(2-(dicyanomethylene)hydrazino)phenyl)-1H-indol-1-ylcarboxylate, to give 30 mg (88% yield) of the title compound.

[0732] Example 83: Preparation of (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)carbohydrazine dinitrile (Compound 83)

[0733] Step 83-1: Preparation of 3-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine

[0734] In the presence of nitrogen, 5-nitro-1H-pyrrolo[2,3-b]pyridine and N-chlorosuccinimide were dissolved in DMF (7 mL) and then stirred at room temperature for 12 minutes. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 of the title compound (yield 55%).

[0735] Step 83-2: Preparation of tert-butyl 3-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0736] By conducting a reaction in the same manner as in Step 72-1 of Example 72, except using 3-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine instead of 5-nitro-1H-pyrrolo[2,3-b]pyridine, 419 g (70% yield) of the title compound was obtained.

[0737] Step 83-3: Preparation of tert-butyl 5-amino-3-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0738] tert-Butyl 3-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was dissolved in ethyl acetate and reduced in the same manner as in Step 36-2 of Example 36 to give 118 mg (60% yield) of the title compound.

[0739] Step 83-4: Preparation of tert-butyl 5-(2-(dicyanomethylene)hydrazino)-3-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0740] By conducting a reaction in the same manner as in Step 1-2 of Example 1, except using tert-butyl 5-amino-3-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate instead of 4-(pyrimidin-2-yl)aniline, 35 mg (23% yield) of the title compound was obtained.

[0741] Step 83-5: Preparation of (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile

[0742] The reaction was carried out in the same manner as in Step 58-3 of Example 58, except that tert-butyl 5-(2-(dicyanomethylene)hydrazino)-3-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was used instead of tert-butyl 5-(4-(2-(dicyanomethylene)hydrazino)phenyl)-1H-indol-1-ylcarboxylate, to give 20 mg (91% yield) of the title compound.

[0743] Example 84: Preparation of (4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)carbohydrazine dinitrile (Compound 84)

[0744] Step 84-1: Preparation of 4-chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine

[0745] The reaction was carried out in the same manner as in Step 81-2 of Example 81, except that 4-chloro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine was used instead of tert-butyl 2-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate, to give 2.0 mg (60% yield) of the title compound.

[0746] Step 84-2: Preparation of 4-methoxy-5-nitro-1H-pyrrolo[2,3-b]pyridine

[0747] In the presence of nitrogen, 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 and refluxed for 7 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 of the title compound (yield 68%).

[0748] Step 84-3: Preparation of tert-butyl 4-methoxy-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0749] By conducting a reaction in the same manner as in Step 72-1 of Example 72, except using 4-methoxy-5-nitro-1H-pyrrolo[2,3-b]pyridine instead of 5-nitro-1H-pyrrolo[2,3-b]pyridine, 234 mg (77% yield) of the title compound was obtained.

[0750] Step 84-4: Preparation of tert-butyl 5-amino-4-methoxy-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0751] tert-Butyl 4-methoxy-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was dissolved in ethyl acetate and reduced in the same manner as in Step 36-2 of Example 36 to give 107 mg (99% yield) of the title compound.

[0752] Step 84-5: Preparation of (4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile

[0753] The reaction was carried out in the same manner as in Step 1-2 of Example 1, except that 5-amino-4-methoxy-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester was used instead of 4-(pyrimidin-2-yl)aniline, to give 22 mg (17% yield) of the title compound.

[0754] Example 85: Preparation of (2-(dimethylaminoformyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile (Compound 85)

[0755] Step 85-1: Preparation of N,N-dimethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0756] In the presence of nitrogen, N, N-diisopropylamine (DIPEA, 1.20mL, 6.62mmol) and azabenzotriazole tetramethyluronium hexafluorophosphate (HATU, 2g, 4.30mmol) were added to 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (1g, 3.31mmol), and then stirred at room temperature for 10 minutes. Then, dimethylamine solution (2.0M in THF, 3.32mL, 6.62mmol) was added, and then stirred at room temperature for 10 minutes. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 800mg (yield 79%) of the title compound.

[0757] Step 85-2: Preparation of N,N-dimethyl-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0758] The reaction was carried out in the same manner as in Step 81-2 of Example 81, except that N,N-dimethyl-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide was used instead of tert-butyl 2-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate, to give 373 mg (41% yield) of the title compound.

[0759] Step 85-3: Preparation of N,N-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

[0760] In the presence of nitrogen, 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) and stirred at 80 ° C for 12 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 (yield 48%) of the title compound.

[0761] Step 85-4: Preparation of tert-butyl 2-(dimethylcarbamoyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0762] By conducting a reaction in the same manner as in Step 72-1 of Example 72, except using N,N-dimethyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide instead of 5-nitro-1H-pyrrolo[2,3-b]pyridine, 100 mg (99% yield) of the title compound was obtained.

[0763] Step 85-5: Preparation of tert-butyl 5-amino-2-(dimethylcarbamoyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0764] Tert-butyl 2-(dimethylcarbamoyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was dissolved in ethyl acetate and reduced in the same manner as in Step 36-2 of Example 36 to give 90 mg (97% yield) of the title compound.

[0765] Step 85-6: Preparation of tert-butyl 5-(2-(dicyanomethylene)hydrazino)-2-(dimethylcarbamoyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

[0766] The reaction was carried out in the same manner as in Step 1-2 of Example 1, except that tert-butyl 5-amino-2-(dimethylcarbamoyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was used instead of 4-(pyrimidin-2-yl)aniline, to give 78 mg (69% yield) of the title compound.

[0767] Step 85-7: Preparation of (2-(dimethylaminoformyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile

[0768] The reaction was carried out in the same manner as in Step 58-3 of Example 58, except that tert-butyl 5-(2-(dicyanomethylene)hydrazino)-2-(dimethylcarbamoyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was used instead of tert-butyl 5-(4-(2-(dicyanomethylene)hydrazino)phenyl)-1H-indol-1-ylcarboxylate, to give 41 mg (72% yield) of the title compound.

[0769] Example 86: Preparation of (2-(4-methoxybenzamido)benzo[d]thiazol-6-yl)carbazone dinitrile (Compound 86) Step 86-1: Preparation of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide

[0770] 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. Then, 6-nitrobenzo[d]thiazole-2-amine (1.28 g, 6.57 mmol) was added, and the reaction mixture was refluxed for 24 hours. After the reaction was complete, the reaction product was filtered using MeCN to obtain 1.6 g (74% yield) of the title compound as a solid filtrate.

[0771] Step 86-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide

[0772] 4-Methoxy-N-(6-nitrobenz[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 a reaction mixture. The reaction mixture was stirred at 60° C. for 2 hours in the presence of hydrogen. After 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 obtain 39 mg (43% yield) of the title compound.

[0773] Step 86-3: Preparation of (2-(4-methoxybenzamido)benzo[d]thiazol-6-yl)carbazone dinitrile

[0774] The reaction was carried out in the same manner as in Step 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 a 35% aqueous HCl solution was used as the acidic solution to give 78 mg (69% yield) of the title compound.

[0775] Example 87: Preparation of (2-(2-hydroxybenzamido)benzo[d]thiazol-6-yl)carbazone dinitrile (Compound 87)

[0776] Step 87-1: Preparation of N-(6-nitrobenzo[d]thiazol-2-yl)-2-hydroxybenzamide

[0777] By conducting a reaction in the same manner as in Step 86-1 of Example 86, except that 2-hydroxybenzoic acid (3.62 mmol) was used instead of 4-methoxybenzoic acid, 611 mg (65% yield) of the title compound was obtained.

[0778] Step 87-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-2-hydroxybenzamide

[0779] The reaction was carried out in the same manner as in Step 86-2 of Example 86, except that 4-methoxy-N-(6-nitrobenz[d]thiazol-2-yl)benzamide was replaced with 2-hydroxy-N-(6-nitrobenz[d]thiazol-2-yl)benzamide prepared according to Step 87-1, to give 48 mg (53% yield) of the title compound.

[0780] Step 87-3: Preparation of (2-(2-hydroxybenzamido)benzo[d]thiazol-6-yl)carbazone dinitrile

[0781] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that N-(6-aminobenzo[d]thiazol-2-yl)-2-hydroxybenzamide prepared according to Step 87-2 was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 36 mg (59% yield) of the title compound.

[0782] Example 88: Preparation of (2-acetamidobenzo[d]thiazol-6-yl)carbazone dinitrile (Compound 88)

[0783] Step 88-1: Preparation of N-(6-nitrobenzo[d]thiazol-2-yl)acetamide

[0784] In the presence of nitrogen, 6-nitrobenz[d]thiazol-2-amine was dissolved in MeCN, and then DIPEA and acetic anhydride were added to obtain a reaction mixture, and the reaction mixture was stirred for 14 hours at 60° C. After the reaction was completed, the reaction product was filtered using MeCN to obtain 200 mg (75% yield) of the title compound as a solid filtrate.

[0785] Step 88-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)acetamide

[0786] By conducting a reaction in the same manner as in Step 86-2 of Example 86, except using N-(6-nitrobenzo[d]thiazol-2-yl)acetamide instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide, 66 mg (83% yield) of the title compound was obtained.

[0787] Step 88-3: Preparation of (2-acetamidobenzo[d]thiazol-6-yl)carbazone dinitrile

[0788] The reaction was carried out in the same manner as in 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, to give 28 mg (42% yield) of the title compound.

[0789] Example 89: Preparation of (2-(3-cyanobenzamido)benzo[d]thiazol-6-yl)carbazone dinitrile (Compound 89)

[0790] Step 89-1: Preparation of 3-cyano-N-(6-nitrobenz[d]thiazol-2-yl)benzamide

[0791] By conducting a reaction in the same manner as in Step 86-1 of Example 86, except that 3-cyanobenzoic acid (3.62 mmol) was used instead of 4-methoxybenzoic acid, 718 mg (65% yield) of the title compound was obtained.

[0792] Step 89-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-3-cyanobenzamide

[0793] The reaction was carried out in the same manner as in Step 86-2 of Example 86, except that 3-cyano-N-(6-nitrobenz[d]thiazol-2-yl)benzamide was used instead of 4-methoxy-N-(6-nitrobenz[d]thiazol-2-yl)benzamide, to give 82 mg (90% yield) of the title compound.

[0794] Step 89-3: Preparation of (2-(3-cyanobenzamido)benzo[d]thiazol-6-yl)carbazone dinitrile

[0795] The reaction was carried out in the same manner as in 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, to give 33 mg (52% yield) of the title compound.

[0796] Example 90: Preparation of (2-(5-methylnicotinamido)benzo[d]thiazol-6-yl)carbazone dinitrile (Compound 90)

[0797] Step 90-1: Preparation of 5-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)nicotinamide

[0798] By conducting a reaction in the same manner as in Step 86-1 of Example 86, except that 5-methylnicotinic acid (3.65 mmol) was used instead of 4-methoxybenzoic acid, 1.02 g (88% yield) of the title compound was obtained.

[0799] Step 90-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-5-methylnicotinamide

[0800] The reaction was carried out in the same manner as in Step 86-2 of Example 86, except that 5-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)nicotinamide was used instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide, to give 75 mg (83% yield) of the title compound.

[0801] Step 90-3: Preparation of (2-(5-methylnicotinamido)benzo[d]thiazol-6-yl)carbazone dinitrile

[0802] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that N-(6-aminobenzo[d]thiazol-2-yl)-5-methylnicotinamide prepared according to Step 90-2 was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 32 mg (49% yield) of the title compound.

[0803] Example 91: Preparation of (2-(3-hydroxypyridinecarboxamido)benzo[d]thiazol-6-yl)carbohydrazine dinitrile (Compound 91) Step 91-1: Preparation of 3-hydroxy-N-(6-nitrobenzo[d]thiazol-2-yl)picolinamide

[0804] By conducting a reaction in the same manner as in Step 86-1 of Example 86, except that 3-hydroxypicolinic acid (1.44 mmol) was used instead of 4-methoxybenzoic acid, 327 mg (72% yield) of the title compound was obtained.

[0805] Step 91-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-3-hydroxypicolinamide

[0806] The reaction was carried out in the same manner as in Step 86-2 of Example 86, except that 3-hydroxy-N-(6-nitrobenz[d]thiazol-2-yl)picolinamide was used instead of 4-methoxy-N-(6-nitrobenz[d]thiazol-2-yl)benzamide, to give 46 mg (51% yield) of the title compound.

[0807] Step 91-3: Preparation of (2-(3-hydroxypicolinamido)benzo[d]thiazol-6-yl)carbazone dinitrile

[0808] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that N-(6-aminobenzo[d]thiazol-2-yl)-3-hydroxypicolinamide prepared according to Step 91-2 was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 22 mg (35% yield) of the title compound.

[0809] Example 92: Preparation of (2-(pyrazine-2-carboxamido)benzo[d]thiazol-6-yl)carbazone dinitrile (Compound 92)

[0810] Step 92-1: Preparation of N-(6-nitrobenzo[d]thiazol-2-yl)pyrazine-2-carboxamide

[0811] By conducting a reaction in the same manner as in Step 86-1 of Example 86, except that pyrazine-2-carboxylic acid (3.65 mmol) was used instead of 4-methoxybenzoic acid, 870 mg (71% yield) of the title compound was obtained.

[0812] Step 92-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)pyrazine-2-carboxamide

[0813] By conducting a reaction in the same manner as in Step 86-2 of Example 86, except using N-(6-nitrobenzo[d]thiazol-2-yl)pyrazine-2-carboxamide instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide, 155 mg (87% yield) of the title compound was obtained.

[0814] Step 92-3: Preparation of (2-(pyrazine-2-carboxamido)benzo[d]thiazol-6-yl)carbazone dinitrile

[0815] The reaction was carried out in the same manner as in 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, to give 55 mg (43% yield) of the title compound.

[0816] Example 93: Preparation of (2-(5-methylpyrazine-2-carboxamido)benzo[d]thiazol-6-yl)carbohydrazine dinitrile (Compound 93) Step 93-1: Preparation of 5-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)pyrazine-2-carboxamide

[0817] By conducting a reaction in the same manner as in Step 86-1 of Example 86, except that 5-methylpyrazine-2-carboxylic acid (3.65 mmol) was used instead of 4-methoxybenzoic acid, 766 mg (67% yield) of the title compound was obtained.

[0818] Step 93-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-5-methylpyrazine-2-carboxamide

[0819] By conducting a reaction in the same manner as in Step 86-2 of Example 86, except using 5-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)pyrazine-2-carboxamide instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide, 165 mg (92% yield) of the title compound was obtained.

[0820] Step 93-3: Preparation of (2-(5-methylpyrazine-2-carboxamido)benzo[d]thiazol-6-yl)carbazone dinitrile

[0821] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that N-(6-aminobenzo[d]thiazol-2-yl)-5-methylpyrazine-2-carboxamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 20 mg (16% yield) of the title compound.

[0822] Example 94: Preparation of (2-(pyrimidine-5-carboxamido)benzo[d]thiazol-6-yl)carbohydrazine dinitrile (Compound 94)

[0823] Step 94-1: Preparation of N-(6-nitrobenzo[d]thiazol-2-yl)pyrimidine-5-carboxamide

[0824] By conducting a reaction in the same manner as in Step 86-1 of Example 86, except that pyrimidine-5-carboxylic acid (3.65 mmol) was used instead of 4-methoxybenzoic acid, 510 mg (70% yield) of the title compound was obtained.

[0825] Step 94-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)pyrimidine-5-carboxamide

[0826] By conducting a reaction in the same manner as in Step 86-2 of Example 86, except using N-(6-nitrobenzo[d]thiazol-2-yl)pyrimidine-5-carboxamide instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide, 113 mg (83% yield) of the title compound was obtained.

[0827] Step 94-3: Preparation of (2-(pyrimidine-5-carboxamido)benzo[d]thiazol-6-yl)carbazone dinitrile

[0828] The reaction was carried out in the same manner as in 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, to give 15 mg (24% yield) of the title compound.

[0829] Example 95: Preparation of (2-(2-methylpyrimidine-5-carboxamido)benzo[d]thiazol-6-yl)carbohydrazine dinitrile (Compound 95) Step 95-1: Preparation of 2-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)pyrimidine-5-carboxamide

[0830] By conducting a reaction in the same manner as in Step 86-1 of Example 86, except that 2-methylpyrimidine-5-carboxylic acid (3.65 mmol) was used instead of 4-methoxybenzoic acid, 414 mg (61% yield) of the title compound was obtained.

[0831] Step 95-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-2-methylpyrimidine-5-carboxamide

[0832] By conducting a reaction in the same manner as in Step 86-2 of Example 86, except using 2-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)pyrimidine-5-carboxamide instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide, 119 mg (88% yield) of the title compound was obtained.

[0833] Step 95-3: Preparation of (2-(2-methylpyrimidine-5-carboxamido)benzo[d]thiazol-6-yl)carbazone dinitrile

[0834] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that N-(6-aminobenzo[d]thiazol-2-yl)-2-methylpyrimidine-5-carboxamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 21 mg (21% yield) of the title compound.

[0835] Example 96: Preparation of (2-(4-methylpyrimidine-5-carboxamido)benzo[d]thiazol-6-yl)carbohydrazine dinitrile (Compound 96) Step 96-1: Preparation of 4-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)pyrimidine-5-carboxamide

[0836] By conducting a reaction in the same manner as in Step 86-1 of Example 86, except that 4-methylpyrimidine-5-carboxylic acid (3.65 mmol) was used instead of 4-methoxybenzoic acid, 327 mg (72% yield) of the title compound was obtained.

[0837] Step 96-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-4-methylpyrimidine-5-carboxamide

[0838] By conducting a reaction in the same manner as in Step 86-2 of Example 86, except using 4-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)pyrimidine-5-carboxamide instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide, 131 mg (96% yield) of the title compound was obtained.

[0839] Step 96-3: Preparation of (2-(4-methylpyrimidine-5-carboxamido)benzo[d]thiazol-6-yl)carbazone dinitrile

[0840] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that N-(6-aminobenzo[d]thiazol-2-yl)-4-methylpyrimidine-5-carboxamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 28 mg (28% yield) of the title compound.

[0841] Example 97: Preparation of (2-(3-methylpyrazine-2-carboxamido)benzo[d]thiazol-6-yl)carbohydrazine dinitrile (Compound 97) Step 97-1: Preparation of 3-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)pyrazine-2-carboxamide

[0842] By conducting a reaction in the same manner as in Step 86-1 of Example 86, except that 3-methylpyrazine-2-carboxylic acid (3.65 mmol) was used instead of 4-methoxybenzoic acid, 542 mg (79% yield) of the title compound was obtained.

[0843] Step 97-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-3-methylpyrazine-2-carboxamide

[0844] By conducting a reaction in the same manner as in Step 86-2 of Example 86, except using 3-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)pyrazine-2-carboxamide instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide, 158 mg (88% yield) of the title compound was obtained.

[0845] Step 97-3: Preparation of (2-(3-methylpyrazine-2-carboxamido)benzo[d]thiazol-6-yl)carbazone dinitrile

[0846] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that N-(6-aminobenzo[d]thiazol-2-yl)-3-methylpyrazine-2-carboxamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 86 mg (68% yield) of the title compound.

[0847] Example 98: Preparation of (2-(6-methylpyrazine-2-carboxamido)benzo[d]thiazol-6-yl)carbohydrazine dinitrile (Compound 98) Step 98-1: Preparation of 6-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)pyrazine-2-carboxamide

[0848] By conducting a reaction in the same manner as in Step 86-1 of Example 86, except that 6-methylpyrazine-2-carboxylic acid (3.65 mmol) was used instead of 4-methoxybenzoic acid, 542 mg (79% yield) of the title compound was obtained.

[0849] Step 98-2: Preparation of N-(6-aminobenzo[d]thiazol-2-yl)-6-methylpyrazine-2-carboxamide

[0850] By conducting a reaction in the same manner as in Step 86-2 of Example 86, except using 6-methyl-N-(6-nitrobenzo[d]thiazol-2-yl)pyrazine-2-carboxamide instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide, 105 mg (58% yield) of the title compound was obtained.

[0851] Step 98-3: Preparation of (2-(6-methylpyrazine-2-carboxamido)benzo[d]thiazol-6-yl)carbazone dinitrile

[0852] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that N-(6-aminobenzo[d]thiazol-2-yl)-6-methylpyrazine-2-carboxamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 54 mg (53% yield) of the title compound.

[0853] Example 99: Preparation of (2-(pyrazine-2-carboxamido)benzo[d]thiazol-5-yl)carbazone dinitrile (Compound 99)

[0854] Step 99-1: Preparation of N-(5-nitrobenzo[d]thiazol-2-yl)pyrazine-2-carboxamide

[0855] The reaction was carried out in the same manner as in 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 was used instead of 6-nitrobenzo[d]thiazol-2-amine, to give 486 mg (67% yield) of the title compound.

[0856] Step 99-2: Preparation of N-(5-aminobenzo[d]thiazol-2-yl)pyrazine-2-carboxamide

[0857] By conducting a reaction in the same manner as in Step 86-2 of Example 86, except using N-(5-nitrobenzo[d]thiazol-2-yl)pyrazine-2-carboxamide instead of 4-methoxy-N-(6-nitrobenz[d]thiazol-2-yl)benzamide, 110 mg (81% yield) of the title compound was obtained.

[0858] Step 99-3: Preparation of (2-(pyrazine-2-carboxamido)benzo[d]thiazol-5-yl)carbazone dinitrile

[0859] The reaction was carried out in the same manner as in 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, to give 22 mg (21% yield) of the title compound.

[0860] Example 100: Preparation of (2-(5-methylpyrazine-2-carboxamido)benzo[d]thiazol-5-yl)carbazone dinitrile (Compound 100)

[0861] Step 100-1: Preparation of 5-methyl-N-(5-nitrobenzo[d]thiazol-2-yl)pyrazine-2-carboxamide

[0862] The reaction was carried out in the same manner as in Step 86-1 of Example 86, except that 5-methylpyrazine-2-carboxylic acid (3.65 mmol) was used instead of 4-methoxybenzoic acid, and 5-nitrobenzo[d]thiazol-2-amine was used instead of 6-nitrobenzo[d]thiazol-2-amine, to give 512 mg (75% yield) of the title compound.

[0863] Step 100-2: Preparation of N-(5-aminobenzo[d]thiazol-2-yl)-5-methylpyrazine-2-carboxamide

[0864] By conducting a reaction in the same manner as in Step 86-2 of Example 86, except using 5-methyl-N-(5-nitrobenzo[d]thiazol-2-yl)pyrazine-2-carboxamide instead of 4-methoxy-N-(6-nitrobenzo[d]thiazol-2-yl)benzamide, 83 mg (65% yield) of the title compound was obtained.

[0865] Step 100-3: Preparation of (2-(5-methylpyrazine-2-carboxamido)benzo[d]thiazol-5-yl)carbazone dinitrile

[0866] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that N-(5-aminobenzo[d]thiazol-2-yl)-5-methylpyrazine-2-carboxamide was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 102 mg (80% yield) of the title compound.

[0867] Example 101: Preparation of (2-phenylbenzo[d]thiazol-6-yl)carbazone dinitrile (Compound 101)

[0868] Step 101-1: Preparation of 2-bromo-6-nitrobenzo[d]thiazole

[0869] 6-nitrobenz[d]thiazole-2-amine (500mg, 2.56mmol) is dissolved in water, then CuBr (55mg, 0.38mmol) and 48% HBr (5mL) are added to obtain reaction mixture. Then, sodium nitrite (1.41g, 20.48mmol) is added to reaction mixture at 0 ℃, and the obtained mixture is stirred at room temperature for 1 hour. After reaction is complete, the reaction product is extracted twice with saturated NaCl aqueous solution and ethyl acetate, and moisture is dried over anhydrous magnesium sulfate, then filtered. The filtrate is concentrated under reduced pressure, and the concentrated solution is solidified and filtered with methanol to obtain the title compound of 564mg (85% yield) solid state.

[0870] Step 101-2: Preparation of 2-bromobenzo[d]thiazol-6-amine

[0871] 2-Bromo-6-nitrobenzo[d]thiazole and Fe (539 mg, 9.65 mmol) obtained in step 101-1 were dissolved in acetic acid to obtain a reaction mixture, and then the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction product was extracted twice with a saturated NaCl aqueous solution and ethyl acetate, and the water 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 342 mg of the title compound (yield 69%).

[0872] Step 101-3: Preparation of 2-phenylbenzo[d]thiazol-6-amine

[0873] By conducting a reaction in the same manner as in Step 1-1 of Example 1, except replacing 2-bromopyrimidine with 2-bromobenzo[d]thiazol-6-amine, replacing 4-aminophenylboronic acid pinacol ester with phenylboronic acid pinacol ester, and replacing aqueous sodium carbonate with aqueous potassium carbonate solution, 56 mg (48% yield) of the title compound was obtained.

[0874] Step 101-4: Preparation of (2-phenylbenzo[d]thiazol-6-yl)carbazone dinitrile

[0875] By conducting a reaction in the same manner as in Step 86-3 of Example 86, except using 2-phenylbenzo[d]thiazol-6-amine instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, 46 mg (76% yield) of the title compound was obtained.

[0876] Example 102: Preparation of (2-(4-fluorophenyl)benzo[d]thiazol-6-yl)carbazone dinitrile (Compound 102)

[0877] Step 102-1: Preparation of 2-(4-fluorophenyl)benzo[d]thiazol-6-amine

[0878] By conducting a reaction in the same manner as in Step 101-3 of Example 101, except that 4-fluorophenylboronic acid pinacol ester was used instead of phenylboronic acid pinacol ester, 30 mg (28% yield) of the title compound was obtained.

[0879] Step 102-2: Preparation of (2-(4-fluorophenyl)benzo[d]thiazol-6-yl)carbazone dinitrile

[0880] The reaction was carried out in the same manner as in 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, to give 31 mg (79% yield) of the title compound.

[0881] Example 103: Preparation of (2-(4-(dimethylamino)phenyl)benzo[d]thiazol-6-yl)carbohydrazine dinitrile (Compound 103) Step 103-1: Preparation of 2-(4-(dimethylamino)phenyl)benzo[d]thiazol-6-amine

[0882] By conducting a reaction in the same manner as in Step 101-3 of Example 101, except that 4-(dimethylamino)phenylboronic acid pinacol ester was used instead of phenylboronic acid pinacol ester, 43 mg (37% yield) of the title compound was obtained.

[0883] Step 103-2: Preparation of (2-(4-(dimethylamino)phenyl)benzo[d]thiazol-6-yl)carbazone dinitrile

[0884] The reaction was carried out in the same manner as in 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, to give 31 mg (79% yield) of the title compound.

[0885] Example 104: Preparation of (2-(pyridin-3-yl)benzo[d]thiazol-6-yl)carbazone dinitrile (Compound 104)

[0886] Step 104-1: Preparation of 2-(pyridin-3-yl)benzo[d]thiazol-6-amine hydrochloride

[0887] 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 was obtained as hydrochloride from a 4M HCl solution in dioxane.

[0888] Step 104-2: Preparation of (2-(pyridin-3-yl)benzo[d]thiazol-6-yl)carbazone dinitrile

[0889] The reaction was carried out in the same manner as in 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, to give 15 mg (26% yield) of the title compound.

[0890] Example 105: Preparation of (2-(6-methylpyridin-3-yl)benzo[d]thiazol-6-yl)carbazone dinitrile (Compound 105)

[0891] Step 105-1: Preparation of 2-(6-methylpyridin-3-yl)benzo[d]thiazol-6-amine

[0892] By conducting a reaction in the same manner as in Step 101-3 of Example 101, except that 6-methylpyridin-3-ylboronic acid pinacol ester was used instead of phenylboronic acid pinacol ester, 68 mg (52% yield) of the title compound was obtained.

[0893] Step 105-2: Preparation of (2-(6-methylpyridin-3-yl)benzo[d]thiazol-6-yl)carbazone dinitrile

[0894] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that 2-(6-methylpyridin-3-yl)benzo[d]thiazol-6-amine was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 6 mg (9% yield) of the title compound.

[0895] Example 106: Preparation of (2-(6-fluoropyridin-3-yl)benzo[d]thiazol-6-yl)carbazone dinitrile (Compound 106)

[0896] Step 106-1: Preparation of 2-(6-fluoropyridin-3-yl)benzo[d]thiazol-6-amine

[0897] By conducting a reaction in the same manner as in Step 101-3 of Example 101, except that 6-fluoropyridin-3-ylboronic acid pinacol ester was used instead of phenylboronic acid pinacol ester, 25 mg (23% yield) of the title compound was obtained.

[0898] Step 106-2: Preparation of (2-(6-fluoropyridin-3-yl)benzo[d]thiazol-6-yl)carbazone dinitrile

[0899] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that 2-(6-fluoropyridin-3-yl)benzo[d]thiazol-6-amine was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 22 mg (63% yield) of the title compound.

[0900] Example 107: Preparation of (2-(Furan-2-yl)benzo[d]thiazol-6-yl)carbazone dinitrile (Compound 107)

[0901] Step 107-1: Preparation of 2-(furan-2-yl)benzo[d]thiazol-6-amine hydrochloride

[0902] The reaction was carried out in the same manner as in Step 101-3 of Example 101, except that furan-2-ylboronic acid pinacol ester was used instead of phenylboronic acid pinacol ester. 68 mg (61% yield) of the title compound was obtained as hydrochloride from a 4 M HCl solution in dioxane.

[0903] Step 107-2: Preparation of (2-(furan-2-yl)benzo[d]thiazol-6-yl)carbazone dinitrile

[0904] The reaction was carried out in the same manner as in 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, to give 53 mg (48% yield) of the title compound.

[0905] Example 108: Preparation of (2-(thiophen-2-yl)benzo[d]thiazol-6-yl)carbazone dinitrile (Compound 108)

[0906] Step 108-1: Preparation of 2-(thiophen-2-yl)benzo[d]thiazol-6-amine hydrochloride

[0907] The reaction was carried out in the same manner as in Step 101-3 of Example 101, except that thiophen-2-ylboronic acid pinacol ester was used instead of phenylboronic acid pinacol ester. 32 mg (27% yield) of the title compound was obtained as hydrochloride from a 4 M HCl solution in dioxane.

[0908] Step 108-2: Preparation of (2-(thiophen-2-yl)benzo[d]thiazol-6-yl)carbazone dinitrile

[0909] The reaction was carried out in the same manner as in 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, to give 13 mg (27% yield) of the title compound.

[0910] Example 109: Preparation of (2-(5-fluoropyridin-3-yl)benzo[d]thiazol-6-yl)carbazone dinitrile (Compound 109)

[0911] Step 109-1: Preparation of 2-(5-fluoropyridin-3-yl)benzo[d]thiazol-6-amine hydrochloride

[0912] 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 was obtained as hydrochloride from 4 M HCl solution in dioxane.

[0913] Step 109-2: Preparation of (2-(5-fluoropyridin-3-yl)benzo[d]thiazol-6-yl)carbazone dinitrile

[0914] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that 2-(5-fluoropyridin-3-yl)benzo[d]thiazol-6-amine hydrochloride was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 42 mg (57% yield) of the title compound.

[0915] Example 110: Preparation of (2-(5-methylpyridin-3-yl)benzo[d]thiazol-6-yl)carbazone dinitrile (Compound 110)

[0916] Step 110-1: Preparation of 2-(5-methylpyridin-3-yl)benzo[d]thiazol-6-amine hydrochloride

[0917] 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 was obtained as hydrochloride from 4 M HCl solution in dioxane.

[0918] Step 110-2: Preparation of (2-(5-methylpyridin-3-yl)benzo[d]thiazol-6-yl)carbazone dinitrile

[0919] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that 2-(5-methylpyridin-3-yl)benzo[d]thiazol-6-amine hydrochloride was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 9 mg (36% yield) of the title compound.

[0920] Example 111: Preparation of (2-(pyridin-3-yl)benzo[d]thiazol-5-yl)carbazone dinitrile (Compound 111)

[0921] Step 111-1: Preparation of 2-bromo-5-nitrobenzo[d]thiazole

[0922] By conducting a reaction in the same manner as in Step 101-1 of Example 101, except using 5-nitrobenz[d]thiazol-2-amine instead of 6-nitrobenz[d]thiazol-2-amine, 780 mg (59% yield) of the title compound was obtained.

[0923] Step 111-2: Preparation of 2-bromobenzo[d]thiazol-5-amine

[0924] By conducting a reaction in the same manner as in Step 101-2 of Example 101, except using 2-bromo-5-nitrobenzo[d]thiazole instead of 2-bromo-6-nitrobenzo[d]thiazole, 153 mg (58% yield) of the title compound was obtained.

[0925] Step 111-3: Preparation of 2-(pyridin-3-yl)benzo[d]thiazol-5-amine

[0926] The reaction was carried out in the same manner as in 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, to give 48 mg (48% yield) of the title compound.

[0927] Step 111-4: Preparation of (2-(pyridin-3-yl)benzo[d]thiazol-5-yl)carbazone dinitrile

[0928] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that 2-(pyridin-3-yl)benzo[d]thiazol-5-amine was used instead of 2N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 18 mg (23% yield) of the title compound.

[0929] Example 112: Preparation of (2-(5-methylpyridin-3-yl)benzo[d]thiazol-5-yl)carbazone dinitrile (Compound 112)

[0930] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that 2-(5-methylpyridin-3-yl)benzo[d]thiazol-5-amine was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 26 mg (39% yield) of the title compound.

[0931] Example 113: Preparation of benzo[d]thiazol-2-ylcarbazone dinitrile (Compound 113)

[0932] The reaction was carried out in the same manner as in 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 the solvent, to give 29 mg (19% yield) of the title compound.

[0933] Example 114: Preparation of (6-fluorobenzo[d]thiazol-2-yl)carbazone dinitrile (Compound 114)

[0934] The reaction was carried out in the same manner as in Example 113, except that 6-fluorobenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2-amine, to obtain 29 mg (19% yield) of the title compound.

[0935] Example 115: Preparation of (6-chlorobenzo[d]thiazol-2-yl)carbazone dinitrile (Compound 115)

[0936] The reaction was carried out in the same manner as in Example 113, except that 6-chlorobenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2-amine, to obtain 29 mg (21% yield) of the title compound.

[0937] Example 116: Preparation of (6-bromobenzo[d]thiazol-2-yl)carbazone dinitrile (Compound 116)

[0938] The reaction was carried out in the same manner as in Example 113, except that 6-bromobenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2-amine, to obtain 23 mg (17% yield) of the title compound.

[0939] Example 117: Preparation of (6-(trifluoromethyl)benzo[d]thiazol-2-yl)carbazone dinitrile (Compound 117)

[0940] The reaction was carried out in the same manner as in Example 113, except that 6-(trifluoromethyl)benzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2-amine, to obtain 27 mg (20% yield) of the title compound.

[0941] Example 118: Preparation of (4-chlorobenzo[d]thiazol-2-yl)carbohydrazine dinitrile (Compound 118)

[0942] The reaction was carried out in the same manner as in Example 113, except that 4-chlorobenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2-amine, to obtain 20 mg (15% yield) of the title compound.

[0943] Example 119: Preparation of (5-chlorobenzo[d]thiazol-2-yl)carbazone dinitrile (Compound 119)

[0944] By conducting the reaction in the same manner as in Example 113, except using 5-chlorobenzo[d]thiazol-2-amine instead of benzo[d]thiazol-2-amine, 11 mg (8% yield) of the title compound was obtained.

[0945] Example 120: Preparation of (5-bromobenzo[d]thiazol-2-yl)carbazone dinitrile (Compound 120)

[0946] By conducting the reaction in the same manner as in Example 113, except using 5-bromobenzo[d]thiazol-2-amine instead of benzo[d]thiazol-2-amine, 18 mg (7% yield) of the title compound was obtained.

[0947] Example 121: Preparation of (6-methoxybenzo[d]thiazol-2-yl)carbazone dinitrile (Compound 121)

[0948] The reaction was carried out in the same manner as in Example 113, except that 6-methoxybenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2-amine, to obtain 26 mg (18% yield) of the title compound.

[0949] Example 122: Preparation of (6-ethoxybenzo[d]thiazol-2-yl)carbazone dinitrile (Compound 122)

[0950] The reaction was carried out in the same manner as in Example 113, except that 6-ethoxybenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2-amine, to obtain 40 mg (29% yield) of the title compound.

[0951] Example 123: Preparation of (6-(trifluoromethoxy)benzo[d]thiazol-2-yl)carbazone dinitrile (Compound 123)

[0952] By conducting the reaction in the same manner as in Example 113, except using 6-(trifluoromethoxy)benzo[d]thiazol-2-amine instead of benzo[d]thiazol-2-amine, 15 mg (10% yield) of the title compound was obtained.

[0953] Example 124: Preparation of (6-methylbenzo[d]thiazol-2-yl)carbohydrazine dinitrile (Compound 124)

[0954] The reaction was carried out in the same manner as in Example 113, except that 6-methylbenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2-amine, to obtain 36 mg (24% yield) of the title compound.

[0955] Example 125: Preparation of (4-methylbenzo[d]thiazol-2-yl)carbohydrazine dinitrile (Compound 125)

[0956] The reaction was carried out in the same manner as in Example 113, except that 4-methylbenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2-amine, to obtain 68 mg (46% yield) of the title compound.

[0957] Example 126: Preparation of (4,6-dimethylbenzo[d]thiazol-2-yl)carbohydrazine dinitrile (Compound 126)

[0958] The reaction was carried out in the same manner as in Example 113, except that 4,6-dimethylbenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2-amine, to obtain 41 mg (29% yield) of the title compound.

[0959] Example 127: Preparation of (5,6-dimethylbenzo[d]thiazol-2-yl)carbohydrazine dinitrile (Compound 127)

[0960] The reaction was carried out in the same manner as in Example 113, except that 5,6-dimethylbenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2-amine, to obtain 32 mg (22% yield) of the title compound.

[0961] Example 128: Preparation of (6-phenoxybenzo[d]thiazol-2-yl)carbohydrazine dinitrile (Compound 128)

[0962] The reaction was carried out in the same manner as in Example 113, except that 6-phenoxybenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2-amine, to obtain 6 mg (4% yield) of the title compound.

[0963] Example 129: Preparation of (6-phenylbenzo[d]thiazol-2-yl)carbazone dinitrile (Compound 129)

[0964] Step 129-1: Preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine

[0965] In the presence of nitrogen, 6-bromobenzo[d]thiazole-2-amine (50mg, 0.22mmol) was dissolved in dioxane, and then Pd(dppf)Cl2-DCM (36mg, 0.04mmol), bis(pinacolato)diboron (84mg, 0.33mmol), and potassium acetate (65mg, 0.66mmol) were added to obtain a reaction mixture. The reaction mixture was stirred at 90°C for 3 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 38mg (yield 62%) of the title compound.

[0966] Step 129-2: Preparation of 6-phenylbenzo[d]thiazol-2-amine

[0967] The reaction was carried out in the same manner as in 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, to give 81 mg (50% yield) of the title compound.

[0968] Step 129-3: Preparation of (6-phenylbenzo[d]thiazol-2-yl)carbazone dinitrile

[0969] By conducting the reaction in the same manner as in Example 113, except that 6-phenylbenzo[d]thiazol-2-amine was used instead of benzo[d]thiazol-2-amine, 6 mg (5% yield) of the title compound was obtained.

[0970] Example 130: Preparation of (3-(pyrazine-2-carboxamido)benzo[d]isoxazol-5-yl)carbonyl dinitrile (Compound 130) Step 130-1: Preparation of 5-(tert-butoxycarbonyl)amino-2-fluorobenzonitrile and 5-di(tert-butoxycarbonyl)amino-2-fluorobenzonitrile

[0971] In the presence of nitrogen, 5-amino-2-fluorobenzonitrile (1 g, 7.35 mmol) and DMAP (4-dimethylaminopyridine, 90 mg, 0.74 mmol) were dissolved in DCM, and then di-tert-butyl dicarbonate ((Boc)2O, 2.4 g, 11.02 mmol) was added to obtain a reaction mixture. The reaction mixture was refluxed for 12 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to obtain 1.8 g of the title compound (5-(tert-butoxycarbonyl)amino-2-fluorobenzonitrile and 5-di(tert-butoxycarbonyl)amino-2-fluorobenzonitrile).

[0972] Step 130-2: Preparation of tert-butyl 3-aminobenzo[d]isoxazol-5-ylcarbamate

[0973] In the presence of nitrogen, potassium carbonate (8.34 g, 60.36 mmol) and acetohydroxamic acid (2.27 g, 30.18 mmol) were dissolved in DCM / H2O, and then a mixture of 5-(tert-butoxycarbonyl)amino-2-fluorobenzonitrile and 5-di(tert-butoxycarbonyl)amino-2-fluorobenzonitrile (1.44 g) prepared according to step 130-1 was added to obtain a reaction mixture. The reaction mixture was stirred for 12 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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.

[0974] Step 130-3: Preparation of tert-butyl 3-(pyrazine-2-carboxamido)benzo[d]isoxazol-5-ylcarbamate

[0975] In the presence of nitrogen, pyrazine-2-carboxylic acid (200mg, 1.61mmol) is dissolved in DCM, then oxalyl chloride (0.25mL, 2.93mmol) and a drop of DMF are added to obtain a reaction mixture. The reaction mixture is stirred at room temperature for 2 hours. Then, 3-aminobenzo [d] isoxazole-5-ylcarbamic acid tert-butyl ester (365mg, 1.47mmol) and pyridine prepared according to step 130-2 are added, and the reaction mixture is stirred for 12 hours. After the reaction is complete, the reaction product is extracted with distilled water and ethyl acetate to obtain an organic layer, and the organic layer is dried over anhydrous magnesium sulfate and then filtered. The filtrate is concentrated under reduced pressure, and the concentrated solution is solidified with methanol, then filtered, and 225mg (yield 43%) title compound is obtained.

[0976] Step 130-4: Preparation of 3-(pyrazine-2-carboxamido)benzo[d]isoxazol-5-aminium 2,2,2-trifluoroacetate

[0977] In the presence of nitrogen, tert-butyl 3-(pyrazine-2-formamido)benzo[d]isoxazole-5-ylcarbamate (100mg, 0.28mmol) prepared according to step 130-3 is dissolved in DCM, then trifluoroacetic acid (0.43mL, 5.63mmol) is added to obtain a reaction mixture. The reaction mixture is stirred at room temperature for 6 hours. After the reaction is complete, the reaction product is concentrated under reduced pressure and then dried for 4 hours. The filtrate is concentrated under reduced pressure, and the concentrated solution is solidified with methanol, then filtered to obtain 225mg (yield 43%) title compound. Then, the concentrated solution is solidified with ethyl acetate, then filtered to obtain 97mg (yield 93%) title compound.

[0978] Step 130-5: Preparation of (3-(pyrazine-2-carboxamido)benzo[d]isoxazol-5-yl)carbazone dinitrile

[0979] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that 3-(pyrazine-2-carboxamido)benzo[d]isoxazol-5-aminium 2,2,2-trifluoroacetate was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 29 mg (63% yield) of the title compound.

[0980] Example 131: Preparation of (3-(5-methylpyrazine-2-carboxamido)benzo[d]isoxazol-5-yl)carbazone dinitrile (Compound 131)

[0981] Step 131-1: Preparation of tert-butyl 3-(5-methylpyrazine-2-carboxamido)benzo[d]isoxazol-5-ylcarbamate

[0982] By conducting a reaction in the same manner as in Step 130-3 of Example 130, except that 5-methylpyrazine-2-carboxylic acid was used instead of pyrazine-2-carboxylic acid, 209 mg (43% yield) of the title compound was obtained.

[0983] Step 131-2: Preparation of 3-(5-methylpyrazine-2-carboxamido)benzo[d]isoxazol-5-ammonium 2,2,2-trifluoroacetate

[0984] The reaction was carried out in the same manner as in 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-(pyrazine-2-carboxamido)benzo[d]isoxazol-5-ylcarbamate, to give 84 mg (81% yield) of the title compound.

[0985] Step 131-3: Preparation of (3-(5-methylpyrazine-2-carboxamido)benzo[d]isoxazol-5-yl)carbazone dinitrile

[0986] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that 3-(5-methylpyrazine-2-carboxamido)benzo[d]isoxazol-5-aminium 2,2,2-trifluoroacetate was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 34 mg (75% yield) of the title compound.

[0987] Example 132: Preparation of (3-(3-cyanobenzamido)benzo[d]isoxazol-5-yl)carbazone dinitrile (Compound 132) Step 132-1: Preparation of tert-butyl 3-(3-cyanobenzamido)benzo[d]isoxazol-5-ylcarbamate

[0988] By conducting a reaction in the same manner as in Step 130-3 of Example 130, except that 3-cyanobenzoic acid was used instead of pyrazine-2-carboxylic acid, 203 mg (43% yield) of the title compound was obtained.

[0989] Step 132-2: Preparation of N-(5-aminobenzo[d]isoxazol-3-yl)-3-cyanobenzamide

[0990] In the presence of nitrogen, tert-butyl 3-(3-cyanobenzamido)benzo[d]isoxazole-5-ylcarbamate prepared according to step 132-1 is dissolved in DCM, and trifluoroacetic acid is then added to obtain a reaction mixture. The reaction mixture is stirred at room temperature for 6 hours. After the reaction is complete, the reaction product is extracted with distilled water and ethyl acetate to obtain an organic layer, which is dried over anhydrous magnesium sulfate and then filtered. The filtrate is concentrated under reduced pressure and dried for 4 hours. Then, the concentrate is solidified with ethyl acetate and then filtered to obtain 71 mg (yield 96%) of the title compound.

[0991] Step 132-3: Preparation of (3-(3-cyanobenzamido)benzo[d]isoxazol-5-yl)carbazone dinitrile

[0992] The reaction was carried out in the same manner as in 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, to give 42 mg (65% yield) of the title compound.

[0993] Example 133: Preparation of (3-(4-methoxybenzamido)benzo[d]isoxazol-5-yl)carbazone dinitrile (Compound 133)

[0994] Step 133-1: Preparation of tert-butyl 3-(4-methoxybenzamido)benzo[d]isoxazol-5-ylcarbamate

[0995] By conducting a reaction in the same manner as in Step 130-3 of Example 130, except that 4-methoxybenzoic acid was used instead of pyrazine-2-carboxylic acid, 312 mg (68% yield) of the title compound was obtained.

[0996] Step 133-2: Preparation of N-(5-aminobenzo[d]isoxazol-3-yl)-4-methoxybenzamide

[0997] The reaction was carried out in the same manner as in Step 132-3 of Example 132, except that tert-butyl 3-(4-methoxybenzamido)benzo[d]isoxazol-5-ylcarbamate was used instead of tert-butyl 3-(3-cyanobenzamido)benzo[d]isoxazol-5-ylcarbamate, to give 116 mg (78% yield) of the title compound.

[0998] Step 133-3: Preparation of (3-(4-methoxybenzamido)benzo[d]isoxazol-5-yl)carbazone dinitrile

[0999] The reaction was carried out in the same manner as in 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, to give 38 mg (58% yield) of the title compound.

[1000] Example 134: Preparation of (2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbazone dinitrile (Compound 134)

[1001] Step 134-1: Preparation of 6-aminobenzo[d]thiazol-2(3H)-one

[1002] In the presence of nitrogen, 6-nitrobenzo[d]thiazole-2(3H)-one (200 mg, 1.02 mmol) was dissolved in ethanol / water, and then Fe (228 mg, 4.08 mmol) and ammonium chloride (545 mg, 10.19 mmol) were added to obtain a reaction mixture. The reaction mixture was stirred at 80°C for 1 hour. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 (yield 49%) of the title compound.

[1003] Step 134-2: Preparation of (2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbazone dinitrile

[1004] By conducting a reaction in the same manner as in Step 86-3 of Example 86, except using 6-aminobenzo[d]thiazol-2(3H)-one instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, 34 mg (47% yield) of the title compound was obtained.

[1005] Example 135: Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbohydrazine dinitrile (Compound 135) Step 135-1: Preparation of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one

[1006] In the presence of nitrogen, 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, and then iodomethane (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 obtain a reaction mixture. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with methanol to obtain 68 mg (64% yield) of the title compound.

[1007] Step 135-2: Preparation of 6-amino-3-methylbenzo[d]thiazol-2(3H)-one

[1008] 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 obtain a reaction mixture. The reaction mixture was stirred at room temperature for 1 hour in the presence of hydrogen. After the reaction was complete, the reaction product was filtered and the filtrate was then concentrated under reduced pressure to obtain 79 mg (91% yield) of the title compound.

[1009] Step 135-3: Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbazone dinitrile

[1010] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that 6-amino-3-methylbenzo[d]thiazol-2(3H)-one was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 94 mg (83% yield) of the title compound.

[1011] Example 136: Preparation of (2-methoxybenzo[d]thiazol-6-yl)carbazone dinitrile (Compound 136)

[1012] Step 136-1: Preparation of 2-methoxy-6-nitrobenzo[d]thiazole

[1013] In the presence of nitrogen, 60% sodium hydride (45 mg, 1.12 mmol) and methanol (0.05 mL, 1.12 mmol) were dissolved in THF at 0°C, and then 2-chloro-6-nitrobenz[d]thiazole (200 mg, 0.93 mmol) was added to obtain a reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 (yield 49%) of the title compound.

[1014] Step 136-2: Preparation of 2-methoxybenzo[d]thiazol-6-amine

[1015] By conducting a reaction in the same manner as in Step 86-3 of Example 86, except using 2-methoxy-6-nitrobenzo[d]thiazole instead of 3-methyl-6-nitrobenzo[d]thiazole-2(3H)-one, 69 mg (90% yield) of the title compound were obtained.

[1016] Step 136-3: Preparation of (2-methoxybenzo[d]thiazol-6-yl)carbazone dinitrile

[1017] By conducting a reaction in the same manner as in Step 135-2 of Example 135, except using 2-methoxybenzo[d]thiazol-6-amine instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, 60 mg (61% yield) of the title compound was obtained.

[1018] Example 137: Preparation of (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbazone dinitrile (Compound 137)

[1019] Step 137-1: Preparation of 6-aminobenzo[d]oxazol-2(3H)-one

[1020] By conducting a reaction in the same manner as in Step 135-2 of Example 135, except using 6-nitrobenzo[d]oxazol-2(3H)-one instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one, 131 mg (78% yield) of the title compound was obtained.

[1021] Step 137-2: Preparation of (2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbazone dinitrile

[1022] By conducting a reaction in the same manner as in Step 86-3 of Example 86, except using 6-aminobenzo[d]oxazol-2(3H)-one instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, 115 mg (76% yield) of the title compound was obtained.

[1023] Example 138: Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbazone dinitrile (Compound 138) Step 138-1: Preparation of 3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one

[1024] By conducting a reaction in the same manner as in Step 135-1 of Example 135, except using 6-nitrobenzo[d]oxazol-2(3H)-one instead of 6-nitrobenzo[d]thiazol-2(3H)-one, 111 mg (88% yield) of the title compound was obtained.

[1025] Step 138-2: Preparation of 6-amino-3-methylbenzo[d]oxazol-2(3H)-one

[1026] By conducting a reaction in the same manner as in Step 135-2 of Example 135, except using 3-methyl-6-nitrobenzo[d]oxazol-2(3H)-one instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one, 282 mg (87% yield) of the title compound was obtained.

[1027] Step 138-3: Preparation of (3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbazone dinitrile

[1028] By conducting a reaction in the same manner as in Step 86-3 of Example 86, except using 6-amino-3-methylbenzo[d]oxazol-2(3H)-one instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, 107 mg (73% yield) of the title compound was obtained.

[1029] Example 139: Preparation of (2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile (Compound 139) Step 139-1: Preparation of 5-amino-1H-benzo[d]imidazol-2(3H)-one

[1030] By conducting a reaction in the same manner as in Step 135-2 of Example 135, except using 5-nitro-1H-benzo[d]imidazol-2(3H)-one instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one, 122 mg (73% yield) of the title compound was obtained.

[1031] Step 139-2: Preparation of (2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile

[1032] By conducting a reaction in the same manner as in Step 86-3 of Example 86, except using 5-amino-1H-benzo[d]imidazol-2(3H)-one instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, 15 mg (10% yield) of the title compound was obtained.

[1033] Example 140: Preparation of diethyl 2-(2-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)hydrazono)malonate (Compound 140)

[1034] In the presence of nitrogen, 6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (50mg, 0.25mmol) and sodium nitrite (40mg, 0.29mmol) were dissolved in ethanol, and then 1.0M aqueous hydrochloric acid solution (0.74mL, 0.74mmol) was added to obtain a reaction mixture. The reaction mixture was stirred at 0 ° C for 10 minutes to form a diazonium salt. After the diazonium salt is formed, diethyl malonate (80μL, 0.50mmol) is added, followed by stirring at room temperature for 10 minutes. Then, the pH value of the reaction mixture is adjusted using sodium acetate aqueous solution, and the reaction mixture is further stirred at room temperature for 1 hour. After the reaction is complete, the reaction product is extracted with distilled water and ethyl acetate to obtain an organic layer, which is dried over anhydrous magnesium sulfate and then filtered. The filtrate is concentrated under reduced pressure, and the concentrate is purified by column chromatography to obtain the title compound 17mg (yield 18%).

[1035] Example 141: Preparation of 2-imino-N'-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)-2-(piperazin-1-yl)acetylhydrazonenitrile (Compound 141)

[1036] (4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbonyl dinitrile (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. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with ethanol to obtain 50 mg (76% yield) of the title compound.

[1037] Example 142: Preparation of 2-imino-N'-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)-2-morpholinoacetylhydrazone nitrile (Compound 142)

[1038] By conducting the reaction in the same manner as in Example 141, except that morpholine was used instead of piperazine, 61 mg (93% yield) of the title compound was obtained.

[1039] Example 143: Preparation of methyl 2-(2-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)hydrazono)propanoate (Compound 143)

[1040] 6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (200 mg, 0.98 mmol), sodium nitrite (81.4 mg, 1.18 mmol), and 1.0 M aqueous hydrochloric acid solution (2.9 mL, 2.95 mmol) were mixed to obtain a reaction mixture, and the reaction mixture was stirred at 0°C for 10 minutes. Then, tin (II) chloride hydrate (666 mg, 2.95 mmol) and 1.0 M aqueous hydrochloric acid solution (0.68 mL) were added, followed by stirring at 0°C for 10 minutes; then methyl pyruvate (0.18 mL, 1.97 mmol) was added, followed by stirring at room temperature for 30 minutes. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with ethanol to obtain 177 mg (60% yield) of the title compound.

[1041] Example 144: Preparation of methyl 2-cyano-2-(2-(4-(pyrimidin-2-yl)phenyl)hydrazono)acetate (Compound 144)

[1042] In the presence of nitrogen, 4-(pyrimidine-2-yl)aniline (50mg, 0.29mmol) and sodium nitrite (24mg, 0.35mmol) were dissolved in ethanol, and then 1.0M aqueous hydrochloric acid solution (0.88mL, 0.88mmol) 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 (80μL, 0.50mmol) was added, followed by stirring at room temperature for 10 minutes. Methyl 2-cyanoacetate (31μL, 0.35mmol) was added, followed by stirring at room temperature for 10 minutes. The pH value of the reaction mixture was adjusted to 6.0 using aqueous sodium hydroxide solution, and the reaction mixture was further stirred at room temperature for 1 hour. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 the title compound 25mg (yield 64%).

[1043] Example 145: Preparation of 2-amino-2-oxo-N'-(4-(pyrimidin-2-yl)phenyl)acetylhydrazone nitrile (Compound 145)

[1044] By conducting the reaction in the same manner as in Example 144, except that 2-cyanoacetamide was used instead of methyl 2-cyanoacetate, 14 mg (18% yield) of the title compound was obtained.

[1045] Example 146: Preparation of ethyl 2-cyano-2-(2-(4-(pyrimidin-2-yl)phenyl)hydrazono)acetate (Compound 146)

[1046] By conducting the reaction in the same manner as in Example 144, except that 2-cyanoacetamide was used instead of methyl 2-cyanoacetate, 24 mg (30% yield) of the title compound was obtained.

[1047] Example 147: Preparation of 2-amino-N'-(4-(pyrimidin-2-yl)phenyl)-2-thioacetylhydrazone nitrile (Compound 147)

[1048] By conducting the reaction in the same manner as in Example 144, except that 2-cyanothioacetamide was used instead of methyl 2-cyanoacetate, 35 mg (43% yield) of the title compound was obtained.

[1049] Example 148: Preparation of 4-methyl-N'-(4-(pyrimidin-2-yl)phenyl)thiazole-2-carbohydrazone nitrile (Compound 148)

[1050] Step 148-1: Preparation of 2-(4-methylthiazol-2-yl)acetonitrile

[1051] 2-Cyanothioacetamide (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. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 (yield 24%) of the title compound.

[1052] Step 148-2: Preparation of 4-methyl-N'-(4-(pyrimidin-2-yl)phenyl)thiazole-2-carbazone nitrile

[1053] By conducting a reaction in the same manner as in Example 144, except that 2-(4-methylthiazol-2-yl)acetonitrile prepared according to Step 148-1 was used instead of 2-cyanothioacetamide, 18 mg (19% yield) of the title compound was obtained.

[1054] Example 149: Preparation of (4-(5-ethynylpyrimidin-2-yl)phenyl)carbazone dinitrile (Compound 149)

[1055] Step 149-1: Preparation of 4-(5-bromopyrimidin-2-yl)aniline

[1056] 2,5-dibromopyrimidine (2g, 8.41mmol) and 4-aminophenylboronic acid pinacol ester (2.3g, 10.51mmol) were dissolved in 1,4-dioxane solution, and then Pd(PPh3)4 (484mg, 0.42mmol) and 2.0M potassium phosphate aqueous solution (12.6mL, 25.2mmol) were added to obtain a reaction mixture. The reaction mixture was stirred at 90°C for 2.5 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 1.8g (yield 68%) of the title compound.

[1057] Step 149-2: Preparation of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline

[1058] 4-(5-bromopyrimidin-2-yl)aniline (220 mg, 0.88 mmol) and ethynyltrimethylsilane (1.32 mmol) prepared according to step 149-1 were dissolved in dimethylformamide, and then Pd(PPh3)2Cl2 (31 mg, 0.04 mmol), cuprous 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. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 (yield 63%) of the title compound.

[1059] Step 149-3: Preparation of (4-(5-ethynylpyrimidin-2-yl)phenyl)carbonyl dinitrile

[1060] The reaction was carried out in the same manner as in Example 144, except that malononitrile was used instead of methyl 2-cyanoacetate and 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline prepared according to Step 149-2 was used instead of 4-(pyrimidin-2-yl)aniline, to give 92 mg (22% yield) of the title compound.

[1061] Example 150: Preparation of (4'-(dimethylamino)-3-fluorobiphenyl-4-yl)carbohydrazine dinitrile (Compound 150)

[1062] Step 150-1: Preparation of 3'-fluoro-N,N-dimethyl-4'-nitrobiphenyl-4-amine

[1063] By conducting a reaction in the same manner as in 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, 134 mg (54% yield) of the title compound was obtained.

[1064] Step 150-2: 3-Fluoro-N 4 ',N 4 Preparation of '-Dimethylbiphenyl-4,4'-diamine

[1065] By conducting a reaction in the same manner as in Step 135-2 of Example 135, except using 3'-fluoro-N,N-dimethyl-4'-nitrobiphenyl-4-amine instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one, 51 mg (48% yield) of the title compound was obtained.

[1066] Step 150-3: Preparation of (4'-(dimethylamino)-3-fluorobiphenyl-4-yl)carbazone dinitrile

[1067] In addition to using 3-fluoro-N 4 ',N 4 The title compound (11 mg, 14% yield) was obtained by reacting in the same manner as in Step 149-3 of Example 149, except that '-dimethylbiphenyl-4,4'-diamine was used instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline.

[1068] Example 151: Preparation of (4'-(dimethylamino)biphenyl-4-yl)carbohydrazine dinitrile (Compound 151)

[1069] Step 151-1: Preparation of N,N-dimethyl-4'-nitrobiphenyl-4-amine

[1070] By conducting a reaction in the same manner as in Step 149-1 of Example 149, except using 4-bromo-1-nitrobenzene instead of 2,5-dibromopyrimidine and using 4-dimethylaminophenylboronic acid pinacol ester instead of 4-aminophenylboronic acid pinacol ester, 182 mg (93% yield) of the title compound was obtained.

[1071] Step 151-2: N 4 ',N 4 Preparation of '-Dimethylbiphenyl-4,4'-diamine

[1072] By conducting a reaction in the same manner as in Step 135-2 of Example 135, except using N,N-dimethyl-4′-nitrobiphenyl-4-amine instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one, 51 mg (48% yield) of the title compound was obtained.

[1073] Step 151-3: Preparation of (4'-(dimethylamino)biphenyl-4-yl)carbazone dinitrile

[1074] In addition to using N 4 ',N 4 The title compound (10 mg, 6% yield) was obtained by reacting in the same manner as in Step 149-3 of Example 149, except that '-dimethylbiphenyl-4,4'-diamine was used instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline.

[1075] Example 152: Preparation of (4-(6-(dimethylamino)pyridin-3-yl)phenyl)carbazone dinitrile (Compound 152)

[1076] Step 152-1: Preparation of 5-(4-aminophenyl)-N,N-dimethylpyridin-2-amine

[1077] By conducting a reaction in the same manner as in Step 149-1 of Example 149, except using 5-bromo-N,N-dimethylpyridin-2-amine instead of 2,5-dibromopyrimidine, 127 mg (60% yield) of the title compound was obtained.

[1078] Step 152-2: Preparation of (4-(6-(dimethylamino)pyridin-3-yl)phenyl)carbonyl dinitrile

[1079] By conducting a reaction in the same manner as in Step 149-3 of Example 149, except using 5-(4-aminophenyl)-N,N-dimethylpyridin-2-amine instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline, 16 mg (38% yield) of the title compound was obtained.

[1080] Example 153: Preparation of (4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazone dinitrile (Compound 153)

[1081] Step 153-1: Preparation of 6-chloropyridazin-3(2H)-one

[1082] 3,6-Dichloropyridazine (1 g, 6.71 mmol) was dissolved in acetic acid (26 mL) to obtain a reaction mixture, and the reaction mixture was stirred at 110° C. for 12 hours. After the reaction was completed, the reaction product was concentrated, and an aqueous sodium bicarbonate solution was added, and then the reaction product was stirred at room temperature to solidify and concentrated under reduced pressure to obtain 420 mg (yield 48%) of the title compound.

[1083] Step 153-2: Preparation of 6-(4-aminophenyl)pyridazin-3(2H)-one

[1084] 6-Chloropyridazine-3 (2H) -one (100mg, 0.77mmol) and 4-aminophenylboronic acid pinacol ester (168mg, 0.77mmol) were dissolved in 1,4-dioxane solution, and then Pd (PPh3) 4 (89mg, 0.08mmol) and potassium carbonate aqueous solution (423mg, 3.06mmol) were added to obtain a reaction mixture. The reaction mixture was stirred at 160 ° C for 1.5 hours in a microwave. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 36mg (yield 25%) of the title compound.

[1085] Step 153-3: Preparation of (4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazone dinitrile

[1086] By conducting a reaction in the same manner as in Step 149-3 of Example 149, except using 6-(4-aminophenyl)pyridazin-3(2H)-one instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline, 96 mg (68% yield) of the title compound was obtained.

[1087] Example 154: Preparation of (4-(4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazone dinitrile (Compound 154) Step 154-1: Preparation of 6-chloro-5-methylpyridazin-3(2H)-one and 6-chloro-4-methylpyridazin-3(2H)-one

[1088] 3,6-dichloro-4-methylpyridazine (500mg, 3.07mmol) was dissolved in acetic acid (13mL) to obtain a reaction mixture, and the reaction mixture was stirred at 110°C for 12 hours. After the reaction was complete, the reaction product was concentrated, and an aqueous sodium bicarbonate solution was added, and the reaction product was stirred at room temperature. Then, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 the title compound 184mg (yield 41%) 6-chloro-5-methylpyridazine-3 (2H) -one and 31mg (yield 7%) 6-chloro-4-methylpyridazine-3 (2H) -one.

[1089] Step 154-2: Preparation of 6-(4-aminophenyl)-5-methylpyridazin-3(2H)-one

[1090] By conducting a reaction in the same manner as in 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, 122 mg (44% yield) of the title compound was obtained.

[1091] Step 154-3: Preparation of (4-(4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazone dinitrile

[1092] By conducting a reaction in the same manner as in Step 149-3 of Example 149, except using 6-(4-aminophenyl)-5-methylpyridazin-3(2H)-one instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline, 96 mg (70% yield) of the title compound was obtained.

[1093] Example 155: Preparation of (4-(5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazone dinitrile (Compound 155) Step 155-1: Preparation of 6-(4-aminophenyl)-4-methylpyridazin-3(2H)-one

[1094] By conducting a reaction in the same manner as in 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, 87 mg (62% yield) of the title compound was obtained.

[1095] Step 155-2: Preparation of (4-(5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazone dinitrile

[1096] By conducting a reaction in the same manner as in Step 149-3 of Example 149, except using 6-(4-aminophenyl)-4-methylpyridazin-3(2H)-one instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline, 60 mg (87% yield) of the title compound was obtained.

[1097] Example 156: Preparation of (4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazone dinitrile (Compound 156) Step 156-1: Preparation of 6-chloro-2-methylpyridazin-3(2H)-one

[1098] 6-Chloropyridazine-3 (2H) -one (100mg, 0.77mmol), iodomethane (95μL, 1.53mmol), and potassium carbonate (212mg, 1.53mmol) were dissolved in dimethylformamide to obtain a reaction mixture, and the reaction mixture was then stirred at room temperature for 4 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to obtain 82mg (yield 74%) of the title compound.

[1099] Step 156-2: Preparation of 6-(4-aminophenyl)-2-methylpyridazin-3(2H)-one

[1100] By conducting a reaction in the same manner as in Step 153-2 of Example 153, except using 6-chloro-2-methylpyridazin-3(2H)-one instead of 6-chloropyridazin-3(2H)-one, 86 mg (95% yield) of the title compound was obtained.

[1101] Step 156-3: Preparation of (4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazone dinitrile

[1102] By conducting a reaction in the same manner as in Step 149-3 of Example 149, except using 6-(4-aminophenyl)-2-methylpyridazin-3(2H)-one instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline, 41 mg (59% yield) of the title compound was obtained.

[1103] Example 157: Preparation of (4-(1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazone dinitrile (Compound 157)

[1104] Step 157-1: Preparation of 6-chloro-2,5-dimethylpyridazin-3(2H)-one

[1105] By conducting a reaction in the same manner as in Step 156-1 of Example 156, except using 6-chloro-5-methylpyridazin-3(2H)-one instead of 6-chloropyridazin-3(2H)-one, 53 mg (49% yield) of the title compound was obtained.

[1106] Step 157-2: Preparation of 6-(4-aminophenyl)-2,5-dimethylpyridazin-3(2H)-one

[1107] By conducting a reaction in the same manner as in Step 153-2 of Example 153, except using 6-chloro-2,5-dimethylpyridazin-3(2H)-one instead of 6-chloropyridazin-3(2H)-one, 51 mg (76% yield) of the title compound was obtained.

[1108] Step 157-3: Preparation of (4-(1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazone dinitrile

[1109] By conducting a reaction in the same manner as in Step 149-3 of Example 149, except using 6-(4-aminophenyl)-2,5-dimethylpyridazin-3(2H)-one instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline, 37 mg (77% yield) of the title compound was obtained.

[1110] Example 158: Preparation of (4-(1,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazone dinitrile (Compound 158)

[1111] Step 158-1: Preparation of 6-chloro-2,4-dimethylpyridazin-3(2H)-one

[1112] By conducting a reaction in the same manner as in Step 156-1 of Example 156, except using 6-chloro-4-methylpyridazin-3(2H)-one instead of 6-chloropyridazin-3(2H)-one, 50 mg (65% yield) of the title compound was obtained.

[1113] Step 158-2: Preparation of 6-(4-aminophenyl)-2,4-dimethylpyridazin-3(2H)-one

[1114] By conducting a reaction in the same manner as in Step 153-2 of Example 153, except using 6-chloro-2,4-dimethylpyridazin-3(2H)-one instead of 6-chloropyridazin-3(2H)-one, 47 mg (70% yield) of the title compound was obtained.

[1115] Step 158-3: Preparation of (4-(1,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)carbazone dinitrile

[1116] By conducting a reaction in the same manner as in Step 149-3 of Example 149, except using 6-(4-aminophenyl)-2,4-dimethylpyridazin-3(2H)-one instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline, 11 mg (22% yield) of the title compound was obtained.

[1117] Example 159: Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbazone dinitrile (Compound 159)

[1118] Step 159-1: Preparation of 3-isopropyl-6-nitrobenzo[d]thiazol-2(3H)-one

[1119] By conducting a reaction in the same manner as in Step 135-1 of Example 135, except that 2-iodopropane was used instead of iodomethane, 162 mg (44% yield) of the title compound was obtained.

[1120] Step 159-2: Preparation of 6-amino-3-isopropylbenzo[d]thiazol-2(3H)-one

[1121] By conducting a reaction in the same manner as in Step 135-2 of Example 135, except using 3-isopropyl-6-nitrobenzo[d]thiazol-2(3H)-one instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one, 112 mg (85% yield) of the title compound was obtained.

[1122] Step 159-3: Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbazone dinitrile

[1123] By the same reaction as in Step 86-3 of Example 86, except using 6-amino-3-isopropylbenzo[d]thiazol-2(3H)-one instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, 109 mg (80% yield) of the title compound was obtained.

[1124] Example 160: Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbazone dinitrile (Compound 160)

[1125] Step 160-1: Preparation of 3-(difluoromethyl)-6-nitrobenzo[d]thiazol-2(3H)-one

[1126] In the presence of nitrogen, 6-nitrobenzo[d]thiazole-2(3H)-one (300 mg, 1.53 mmol) was dissolved in DMF, and then 2-chloro-2,2-difluoroacetic acid sodium (467 mg, 3.06 mmol) and DBU (0.46 mL, 3.06 mmol) were added to obtain a reaction mixture, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with methanol to obtain 176 mg (47% yield) of the title compound.

[1127] Step 160-2: Preparation of 6-amino-3-(difluoromethyl)benzo[d]thiazol-2(3H)-one

[1128] By conducting a reaction in the same manner as in Step 135-2 of Example 135, except using 3-(difluoromethyl)-6-nitrobenzo[d]thiazol-2(3H)-one instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one, 125 mg (95% yield) of the title compound was obtained.

[1129] Step 160-3: Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbazone dinitrile

[1130] The reaction was carried out in the same manner as in Step 86-3 of Example 86, except that 6-amino-3-(difluoromethyl)benzo[d]thiazol-2(3H)-one was used instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, to give 85 mg (63% yield) of the title compound.

[1131] Example 161: Preparation of (2-isopropoxybenzo[d]thiazol-6-yl)carbazone dinitrile (Compound 161)

[1132] Step 161-1: Preparation of 2-isopropoxy-6-nitrobenzo[d]thiazole

[1133] In the presence of nitrogen, 60% sodium hydride (84 mg, 2.10 mmol) and isopropanol (0.16 mL, 2.10 mmol) were dissolved in THF at 0°C, and then 2-chloro-6-nitrobenz[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. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 of the title compound (yield 55%).

[1134] Step 161-2: Preparation of 2-isopropoxybenzo[d]thiazol-6-amine

[1135] By conducting a reaction in the same manner as in Step 135-2 of Example 135, except using 2-isopropoxy-6-nitrobenzo[d]thiazole instead of 3-methyl-6-nitrobenzo[d]thiazole-2(3H)-one, 126 mg (96% yield) of the title compound was obtained.

[1136] Step 161-3: Preparation of (2-isopropoxybenzo[d]thiazol-6-yl)carbazone dinitrile

[1137] The reaction was carried out in the same manner as in 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, to give 30 mg (22% yield) of the title compound.

[1138] Example 162: Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbazone dinitrile (Compound 162)

[1139] Step 162-1: Preparation of 3-isopropyl-6-nitrobenzo[d]oxazol-2(3H)-one

[1140] By conducting a reaction in the same manner as in Step 135-1 of Example 135, except using 6-nitrobenzo[d]oxazol-2(3H)-one instead of 6-nitrobenzo[d]thiazol-2(3H)-one and 2-iodopropane instead of iodomethane, 201 mg (54% yield) of the title compound was obtained.

[1141] Step 162-2: Preparation of 6-amino-3-isopropylbenzo[d]oxazol-2(3H)-one

[1142] By conducting a reaction in the same manner as in Step 135-2 of Example 135, except using 3-isopropyl-6-nitrobenzo[d]thiazol-2(3H)-one instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one, 124 mg (85% yield) of the title compound was obtained.

[1143] Step 162-3: Preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbazone dinitrile

[1144] By conducting a reaction in the same manner as in Step 86-3 of Example 86, except using 6-amino-3-isopropylbenzo[d]oxazol-2(3H)-one instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, 99 mg (59% yield) of the title compound was obtained.

[1145] Example 163: Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbazone dinitrile (Compound 163)

[1146] Step 163-1: Preparation of 3-(difluoromethyl)-6-nitrobenzo[d]oxazol-2(3H)-one

[1147] By conducting a reaction in the same manner as in Step 160-1 of Example 160, except using 6-nitrobenzo[d]oxazol-2(3H)-one instead of 6-nitrobenzo[d]thiazol-2(3H)-one, 144 mg (38% yield) of the title compound was obtained.

[1148] Step 163-2: Preparation of 6-amino-3-(difluoromethyl)benzo[d]oxazol-2(3H)-one

[1149] By conducting a reaction in the same manner as in Step 135-2 of Example 135, except using 3-(difluoromethyl)-6-nitrobenzo[d]oxazol-2(3H)-one instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one, 110 mg (98% yield) of the title compound was obtained.

[1150] Step 163-3: Preparation of (3-(difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbazone dinitrile

[1151] By conducting a reaction in the same manner as in Step 86-3 of Example 86, except using 6-amino-3-(difluoromethyl)benzo[d]oxazol-2(3H)-one instead of N-(6-aminobenzo[d]thiazol-2-yl)-4-methoxybenzamide, 85 mg (63% yield) of the title compound was obtained.

[1152] Example 164: Preparation of (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile (Compound 164)

[1153] Step 164-1: Preparation of 1,3-dimethyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[1154] By conducting a reaction in the same manner as in Step 135-1 of Example 135, except using 5-nitro-1H-benzo[d]imidazol-2(3H)-one instead of 6-nitrobenzo[d]thiazol-2(3H)-one, 207 mg (64% yield) of the title compound was obtained.

[1155] Step 164-2: Preparation of 5-amino-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one

[1156] The reaction was carried out in the same manner as in 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, to give 105 mg (82% yield) of the title compound.

[1157] Step 164-3: Preparation of (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile

[1158] The reaction was carried out in the same manner as in 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, to give 11 mg (8% yield) of the title compound.

[1159] Example 165: Preparation of (1,3-diisopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile (Compound 165)

[1160] Step 165-1: Preparation of 1,3-diisopropyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[1161] By conducting a reaction in the same manner as in Step 135-1 of Example 135, except replacing 6-nitrobenzo[d]thiazol-2(3H)-one with 5-nitro-1H-benzo[d]imidazol-2(3H)-one and replacing iodomethane with 2-iodopropane, 204 mg (46% yield) of the title compound was obtained.

[1162] Step 165-2: Preparation of 5-amino-1,3-diisopropyl-1H-benzo[d]imidazol-2(3H)-one

[1163] The reaction was carried out in the same manner as in 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, to give 118 mg (89% yield) of the title compound.

[1164] Step 165-3: Preparation of (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile

[1165] The reaction was carried out in the same manner as in 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, to give 12 mg (10% yield) of the title compound.

[1166] Example 166: Preparation of (1,3-bis(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile (Compound 166)

[1167] Step 166-1: Preparation of 1,3-bis(difluoromethyl)-5-nitro-1H-benzo[d]imidazol-2(3H)-one

[1168] By conducting a reaction in the same manner as in Step 160-1 of Example 160, except using 5-nitro-1H-benzo[d]imidazol-2(3H)-one instead of 6-nitrobenzo[d]thiazol-2(3H)-one, 179 mg (38% yield) of the title compound was obtained.

[1169] Step 166-2: Preparation of 5-amino-1,3-bis(difluoromethyl)-1H-benzo[d]imidazol-2(3H)-one

[1170] The reaction was carried out in the same manner as in 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, to give 69 mg (96% yield) of the title compound.

[1171] Step 166-3: Preparation of (1,3-bis(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile

[1172] The reaction was carried out in the same manner as in 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, to give 45 mg (58% yield) of the title compound.

[1173] Example 167: Preparation of (2-(methylamino)benzo[d]thiazol-6-yl)carbazone dinitrile (Compound 167)

[1174] Step 167-1: Preparation of N-methyl-6-nitrobenzo[d]thiazol-2-amine

[1175] In the presence of nitrogen, 2-chloro-6-nitrobenz[d]thiazole (500 mg, 2.33 mmol) was dissolved in THF at room temperature, and then 2.0 M methylamine (2.56 mL, 5.13 mmol) dissolved in THF was added to obtain a reaction mixture, and the reaction mixture was stirred at room temperature for 15 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 obtain 442 mg (91% yield) of the title compound.

[1176] Step 167-2: N 2 Preparation of methylbenzo[d]thiazole-2,6-diamine

[1177] By conducting a reaction in the same manner as in Step 135-2 of Example 135, except using N-methyl-6-nitrobenzo[d]thiazol-2-amine instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one, 101 mg (78% yield) of the title compound was obtained.

[1178] Step 167-3: Preparation of (2-(methylamino)benzo[d]thiazol-6-yl)carbazone dinitrile

[1179] In addition to using N 2 The reaction was carried out in the same manner as in Example 113, except that -methylbenzo[d]thiazole-2,6-diamine was used instead of benzo[d]thiazole-2-amine, to give 5 mg (4% yield) of the title compound.

[1180] Example 168: Preparation of (2-(dimethylamino)benzo[d]thiazol-6-yl)carbazone dinitrile (Compound 168)

[1181] Step 168-1: Preparation of N,N-dimethyl-6-nitrobenzo[d]thiazol-2-amine

[1182] By conducting a reaction in the same manner as in Step 167-1 of Example 167, except that dimethylamine was used instead of methylamine, 392 mg (75% yield) of the title compound was obtained.

[1183] Step 168-2: N 2 ,N 2 Preparation of dimethylbenzo[d]thiazole-2,6-diamine

[1184] By conducting a reaction in the same manner as in Step 135-2 of Example 135, except using N,N-dimethyl-6-nitrobenzo[d]thiazol-2-amine instead of 3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one, 103 mg (80% yield) of the title compound was obtained.

[1185] Step 168-3: Preparation of (2-(dimethylamino)benzo[d]thiazol-6-yl)carbazone dinitrile

[1186] In addition to using N 2 ,N 2 By conducting the reaction in the same manner as in Example 113 except that -dimethylbenzo[d]thiazole-2,6-diamine was used instead of benzo[d]thiazole-2-amine, 11 mg (10% yield) of the title compound was obtained.

[1187] Example 169: Preparation of (4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbohydrazine dinitrile (Compound 169) Step 169-1: Preparation of N-(4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide

[1188] 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 a reaction mixture, and the reaction mixture was stirred at 90° C. for 3.5 hours. After the reaction was completed, the reaction product was filtered to obtain 47 mg (48% yield) of the title compound.

[1189] Step 169-2: Preparation of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)-one

[1190] A 1.0 M aqueous hydrochloric acid solution (21.6 mL, 21.6 mmol) was added to N-(4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide prepared according to step 169-1, and then reacted at 110° C. for 1.5 hours. Then, the reaction product was neutralized with an aqueous ammonium hydroxide solution and filtered to obtain 118 mg (28% yield) of the title compound.

[1191] Step 169-3: Preparation of (4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbazone dinitrile

[1192] By conducting a reaction in the same manner as in Step 149-3 of Example 149, except using 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)-one instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline, 66 mg (93% yield) of the title compound was obtained.

[1193] Example 170: Preparation of (4-(1-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbazone dinitrile (Compound 170)

[1194] Step 170-1: Preparation of 6-(4-aminophenyl)-2-methyl-4,5-dihydropyridazin-3(2H)-one

[1195] 6-(4-aminophenyl)-4,5-dihydropyridazine-3(2H)-one (105mg, 0.55mmol) and 60% sodium hydride (24mg, 0.61mmol) were dissolved in a mixed solvent of DMF and THF, and then iodomethane (34μL, 0.55mmol) was added to obtain a reaction mixture, and the reaction mixture was stirred at 0°C for 12 hours. After the reaction was complete, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which 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 33mg (yield 29%) of the title compound.

[1196] Step 170-2: Preparation of (4-(1-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbazone dinitrile

[1197] By conducting a reaction in the same manner as in Step 149-3 of Example 149, except using 6-(4-aminophenyl)-2-methyl-4,5-dihydropyridazin-3(2H)-one instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline, 90 mg (95% yield) of the title compound was obtained.

[1198] Example 171: Preparation of (4-(1,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbazone dinitrile (Compound 171)

[1199] Step 171-1: Preparation of 6-(4-aminophenyl)-2,5-dimethyl-4,5-dihydropyridazin-3(2H)-one

[1200] By conducting a reaction in the same manner as in Step 170-1 of Example 170, except using 6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one instead of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)-one, 131 mg (61% yield) of the title compound was obtained.

[1201] Step 171-2: Preparation of (4-(1,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)carbazone dinitrile

[1202] By conducting a reaction in the same manner as in Step 149-3 of Example 149, except using 6-(4-aminophenyl)-2,5-dimethyl-4,5-dihydropyridazin-3(2H)-one instead of 4-(5-((trimethylsilyl)ethynyl)pyrimidin-2-yl)aniline, 82 mg (76% yield) of the title compound was obtained.

[1203] Preparation Example 1: Preparation of tablets by direct compression

[1204] 5.0 mg of each active ingredient prepared in Examples 1-171 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 prepare tablets.

[1205] Preparation Example 2: Preparation of tablets by wet granulation

[1206] 5.0 mg of each active ingredient prepared in Examples 1-171 was sieved and mixed with 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg of polysorbate 80 was dissolved in pure water, and the solution was added to the mixture in an appropriate amount, followed by atomization to obtain microparticles. After drying, the microparticles were sieved, mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate, and compressed into tablets.

[1207] Preparation Example 3: Preparation of powder and capsule

[1208] 5.0 mg of each active ingredient prepared in Examples 1-171 was sieved and then mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone and 0.2 mg of magnesium stearate. The mixture was filled into a hard size 5 gelatin capsule using a suitable apparatus to prepare capsules.

[1209] Preparation Example 4: Preparation of Injectable Drugs

[1210] 100 mg of each active ingredient prepared in Examples 1-171 was mixed with 180 mg of mannitol, 26 mg of Na2HPO4·12H2O and 2974 mg of distilled water to prepare an injection medicine.

[1211] Experimental Example 1: Selecting Tau Protein Aggregation Inhibitors Using Cell Models

[1212] In order to select new tau protein aggregation inhibitory substances, a tau-BiFC cell model was used, in which the formation of tau oligomers in living cells is easily observed. Tau-BiFC cells were distributed in 384-well plates, and on the second day, the compounds prepared according to Example 1-171 were treated with 1 μM, 3 μM and 10 μM respectively with forskolin (treatment concentration 30 μM), forskolin stimulated tau phosphorylation by activating PKA and forskolin induced tau protein aggregation. After 48 hours, nicotine hexane (Hoechst) (treatment concentration 2 μg / mL) was used to stain the intracellular nuclei, and Operetta (PerkinElmer) was used to automatically quantify the BiFC fluorescence intensity to count the stained nuclei in each well from the total well plate. The group treated with forskolin alone (inducing tau protein aggregation) was set as a reference point for the 100% tau protein aggregation state, and its effect was confirmed by the formula "BiFC fluorescence intensity of the compound synthesized according to the embodiment of the present invention / (fluorescence intensity of the control group treated with forskolin alone that induces tau protein aggregation-fluorescence intensity of the untreated control group)×100". In addition, the degree of cytotoxicity induced by the newly synthesized compound was also based on the 100% survival rate of the group treated with forskolin alone, and the cytotoxicity value of the compound was calculated by the formula "the number of stained nuclei in the compound-treated group / the number of stained nuclei in the forskolin-treated group×100". According to the treatment results, substances that inhibit intracellular tau protein aggregation were selected from a series of candidate groups based on 70% or more tau protein aggregation inhibition rate and 100% cell survival rate at a compound treatment concentration of 10 μM or higher.

[1213] Experimental Example 2: Confirmation of the concentration-dependent tau protein aggregation inhibitory effect of the new compound

[1214] In order to evaluate the dose-dependent tau protein aggregation inhibitory effect of the compounds selected according to Experimental Example 1, the selected compounds were treated with forskolin (treatment concentration 30 μM), a tau protein aggregation inducing substance, at concentrations of 0.03 μM, 0.01 μM, 0.3 μM, 1 μM, 3 μM, 10 μM and 30 μM in tau-BiFC cells. After 48 hours, the tau protein aggregation reaction and cytotoxicity were analyzed by observing the cell images. The IC of the compounds was analyzed by nonlinear regression analysis using Prism software (Graph Pad). 50 The calculation results of representative compounds are shown in Table 1 below.

[1215] [Table 1]

[1216]

[1217]

[1218] Experimental Example 3: Inhibitory effect of new compounds on CYP coenzyme activity

[1219] The inhibitory effect of the compound prepared according to Example 1-171 on the activity of CYP coenzymes was confirmed. Specifically, human liver microsomes (0.25 mg / mL), 0.1 M phosphate buffer solution (pH 7.4), a substrate drug mixture of five drug metabolizing enzymes (phenacetin 50 μM, diclofenac 10 μM, S-mephenytoin 100 μM, dextromethorphan 5 μM and midazolam 2.5 μM), and the compound at a concentration of 0 μM or 10 μM were added respectively. Then, the mixture was pre-cultured at 37 ° C for 5 minutes, and then further cultured at 37 ° C for 15 minutes with the addition of NADPH generating system solution. Then, the reaction was terminated by adding an acetonitrile solution containing an internal standard substance (terfenadine), centrifuged (14,000 rpm, 4 ° C) for 5 minutes, and then the supernatant was injected into the LC-MS / MS system. The metabolites of the substrate drug were analyzed at the same time to evaluate the drug metabolism inhibition ability.

[1220] The metabolites of each CYP coenzyme indicator drug produced by the reaction were analyzed using a Shimadzu Nexera XR system and a TSQ vantage (Thermo). 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, using the gradient program shown in Table 2.

[1221] [Table 2]

[1222] Time (minutes) Flow rate (mL / min) ％A ％B 0 0.3 100 0 1.0 0.3 60 40 4.0 0.3 50 50 4.1 0.3 100 0 7.0 0.3 100 0

[1223] The generated metabolites were quantified using the MRM (Multiple Reaction Monitoring) quantitative mode, and data analysis was performed using Xcalibur (version 1.6.1). Table 3 shows the inhibitory effects of the new compounds prepared according to the examples of the present invention on the CYP coenzyme activity.

[1224] [Table 3]

[1225]

[1226]

[1227] Experimental Example 4: Confirmation of the stability of new compounds in liver microsomes

[1228] The stability of the liver microsomes of the compound prepared according to Example 1-171 was confirmed. Specifically, 4 kinds of liver microsomes (human, dog, rat and mouse, each 0.25mg / mL), 0.1M phosphate buffer solution (pH 7.4), and a compound with a concentration of 1μM were added respectively. Then, the mixture was pre-cultured at 37°C for 5 minutes, and then further cultured at 37°C for 30 minutes with the addition of NADPH generating system solution. Then, the reaction was terminated by adding an acetonitrile solution containing an internal standard substance (chloropropamide), centrifuged (14,000rpm, 4°C) for 5 minutes, and then the supernatant was injected into the LC-MS / MS system. The substrate drug was analyzed to evaluate the metabolic stability of 8 compounds.

[1229] The amount of substrate remaining after the reaction was analyzed using a Shimadzu Nexera XR system and TSQ vantage (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 were used as mobile phases. Data analysis was performed using Analyst software (version 1.6.3) and Xcalibur (version 1.6.1). The calculated results are shown in Table 4 below.

[1230] [Table 4]

[1231]

[1232] Experimental Example 5: Pharmacokinetic study of new compounds

[1233] The pharmacokinetics of the compound prepared according to Example 1-171 were studied using an experimental animal model. Specifically, 7 to 8 week-old SD rats (Core Tech, Hana Trading Co., Ltd.) weighing about 250g to 300g were purchased and managed in a small animal simple breeding room with a temperature of 22°C ± 2°C, a relative humidity of 50% ± 5%, a light period of 12 hours (lights on at 8:00 in the morning and lights off at 8:00 in the evening) and an illumination of 150lux-300lux. During the entire test period, feed was freely provided, RO water was freely provided, and fasting was performed for 16 hours before oral administration. After the drug was prepared under the conditions shown in Table 5 below, the drug was intravenously injected (IV) or orally (PO) administered. 500 μL of infused blood was collected in a tube containing sodium heparin and centrifuged at 8,000rpm for 6 minutes at 2°C-8°C to obtain plasma from the blood. The obtained plasma was added to 180 μL of acetonitrile containing an internal standard substance, vortexed, and then centrifuged at 15,000 rpm for 5 minutes at 4°C to obtain a supernatant. The obtained supernatant was analyzed by LC-MS / MS. The HPLC and MS conditions used for the analysis are shown in Tables 6 and 7 below.

[1234] [Table 5]

[1235]

[1236] [Table 6]

[1237]

[1238] [Table 7]

[1239]

[1240] The specific PK parameters were obtained using the Phoenix WinNonlin program version 6.4 (Pharsight, USA) and calculated using a non-compartmental analysis model. The results are summarized in Table 8 below:

[1241] [Table 8]

[1242]

Claims

1. A compound represented by the following formula 3 or a pharmaceutically acceptable salt thereof: [Formula 3] In the above formula 3, R1 is hydrogen; Cy is unsubstituted indolyl, pyrrolopyridinyl, oxodihydrobenzothiazolyl or oxodihydrobenzoxazolyl; or substituted benzothiazolyl, indazolyl, indolyl, pyrrolopyridinyl, oxodihydrobenzothiazolyl, oxodihydrobenzoxazolyl or oxodihydrobenzimidazolyl; and The substituted indazolyl, indolyl, pyrrolopyridinyl, oxodihydrobenzothiazolyl, oxodihydrobenzoxazolyl or oxodihydrobenzimidazolyl is substituted by methyl, ethyl, propyl, butyl, isopropyl, isobutyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoroethyl, difluoromethyl, trifluoromethoxy, dimethylaminoformyl or phenoxy; or the substituted benzothiazolyl is substituted by phenyl, pyridyl, furyl or thienyl which is unsubstituted or substituted by at least one selected from the group consisting of methyl, fluorine and dimethylamino.

2. A compound represented by the following formula 4 or a pharmaceutically acceptable salt thereof: [Formula 4] In the above formula 4, X1-X3 are S, C and N in sequence or N, C and S in sequence, and each is connected to the carboxamide group through the C position; R1 is hydrogen; and R2'" is unsubstituted or substituted phenyl, pyridyl, pyrazinyl or pyrimidinyl.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, in, The compound is: (63) (1-Methyl-1H-indazol-6-yl)carbazone dinitrile (65) (2-Methyl-2H-indazol-6-yl)carbazone dinitrile (66) (1-Methyl-1H-indazol-5-yl)carbazone dinitrile (68) (1-Methyl-1H-indol-5-yl) carbazone dinitrile (71) (1H-Indol-5-yl) carbazone dinitrile (72) (1H-Pyrrolo[2,3-b]pyridin-5-yl)carbonyl dinitrile (73) (3-Methyl-1H-indazol-6-yl)carbazone dinitrile (74) (3-Methyl-1H-indazol-5-yl) carbazone dinitrile (75) (1H-Indol-4-yl) carbazone dinitrile (76) (1-Methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile (77) (1-propyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile (78) (1-Isopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile (79) (1-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile (80) (1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile (81) (2-Methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile (82) (3-Methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile (83) (3-Chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile (84) (4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile (85) (2-(Dimethylaminoformyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)carbazone dinitrile (101) (2-phenylbenzo[d]thiazol-6-yl)carbazone dinitrile (102) (2-(4-Fluorophenyl)benzo[d]thiazol-6-yl)carbazone dinitrile (103) (2-(4-(dimethylamino)phenyl)benzo[d]thiazol-6-yl)carbazone dinitrile (104) (2-(Pyridin-3-yl)benzo[d]thiazol-6-yl)carbazone dinitrile (105) (2-(6-methylpyridin-3-yl)benzo[d]thiazol-6-yl)carbazone dinitrile (106) (2-(6-fluoropyridin-3-yl)benzo[d]thiazol-6-yl)carbazone dinitrile (107) (2-(Furan-2-yl)benzo[d]thiazol-6-yl)carbazone dinitrile (108) (2-(Thiophen-2-yl)benzo[d]thiazol-6-yl)carbazone dinitrile (109) (2-(5-fluoropyridin-3-yl)benzo[d]thiazol-6-yl)carbazone dinitrile (110) (2-(5-methylpyridin-3-yl)benzo[d]thiazol-6-yl)carbazone dinitrile (111) (2-(Pyridin-3-yl)benzo[d]thiazol-5-yl)carbazone dinitrile (112) (2-(5-methylpyridin-3-yl)benzo[d]thiazol-5-yl)carbazone dinitrile (129) (6-phenylbenzo[d]thiazol-2-yl)carbazone dinitrile (134) (2-Oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbazone dinitrile (135) (3-Methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbazone dinitrile (137) (2-Oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbazone dinitrile (138) (3-Methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbazone dinitrile (159) (3-Isopropyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbazone dinitrile (160) (3-(Difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)carbazone dinitrile (162) (3-Isopropyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbazone dinitrile (163) (3-(Difluoromethyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)carbazone dinitrile (164) (1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile (165) (1,3-Diisopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile (166) (1,3-bis(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbazone dinitrile 4. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein The compound is: (86) (2-(4-methoxybenzamido)benzo[d]thiazol-6-yl)carbazone dinitrile (87) (2-(2-Hydroxybenzamido)benzo[d]thiazol-6-yl)carbazone dinitrile (89) (2-(3-cyanobenzamido)benzo[d]thiazol-6-yl)carbazone dinitrile (90) (2-(5-Methylnicotinamido)benzo[d]thiazol-6-yl)carbazone dinitrile (91) (2-(3-Hydroxypicolinamido)benzo[d]thiazol-6-yl)carbazone dinitrile (92) (2-(Pyrazine-2-carboxamido)benzo[d]thiazol-6-yl)carbazone dinitrile (93) (2-(5-Methylpyrazine-2-carboxamido)benzo[d]thiazol-6-yl)carbazone dinitrile (94) (2-(Pyrimidine-5-carboxamido)benzo[d]thiazol-6-yl)carbazone dinitrile (95) (2-(2-Methylpyrimidine-5-carboxamido)benzo[d]thiazol-6-yl)carbazone dinitrile (96) (2-(4-Methylpyrimidine-5-carboxamido)benzo[d]thiazol-6-yl)carbazone dinitrile (97) (2-(3-Methylpyrazine-2-carboxamido)benzo[d]thiazol-6-yl)carbazone dinitrile (98) (2-(6-Methylpyrazine-2-carboxamido)benzo[d]thiazol-6-yl)carbazone dinitrile (99) (2-(Pyrazine-2-carboxamido)benzo[d]thiazol-5-yl)carbazone dinitrile (100) (2-(5-methylpyrazine-2-carboxamido)benzo[d]thiazol-5-yl)carbazone dinitrile 5. A compound represented by the following chemical formula or a pharmaceutically acceptable salt thereof: (60)Benzo[d]thiazol-6-ylcarbazolidine dinitrile (61)Benzo[d]thiazol-5-ylcarbazolidine dinitrile (64) Quinolin-3-ylcarbazide dinitrile (136) (2-methoxybenzo[d]thiazol-6-yl)carbazone dinitrile (161) (2-Isopropoxybenzo[d]thiazol-6-yl)carbazone dinitrile (167) (2-(Methylamino)benzo[d]thiazol-6-yl)carbazone dinitrile (168) (2-(Dimethylamino)benzo[d]thiazol-6-yl)carbazone dinitrile 6. A method for preparing the compound according to claim 1, comprising the step of reacting sodium nitrite, a 5- to 14-membered heteroaryl group or a 5- to 14-membered heterocyclic group containing an amine group with malononitrile in the presence of an acid to form an imine bond.

7. The method according to claim 6, in, When the 5- to 14-membered heteroaryl or 5- to 14-membered heterocyclic group contains a nitrogen other than an amine group to which it can be bonded, it comprises a protecting group at the nitrogen position, and after the step of forming the imine bond, the method further comprises the step of removing the protecting group.

8. The method according to claim 6, in, The 5- to 14-membered heteroaryl or 5- to 14-membered heterocyclic group is prepared by reducing a nitrophenyl derivative having a nitro group instead of an amine group in the same skeleton.

9. A method for preparing the compound of claim 2, comprising the steps of: The carboxylic acid or anhydride of R2″′ is reacted with The reaction forms an amide bond, wherein Y is an unprotected or protected amine or nitro group; and Sodium nitrite, malononitrile and the heterocycle comprising R2'' linked to the carboxamide group obtained in the previous step are reacted in the presence of an acid to form an imine bond.

10. The method according to claim 9, in, When Y is a protected amine group or a nitro group, before the step of forming an imine group, the method further comprises a step of converting the protected amine group or the nitro group into an amine group.

11. A composition for inhibiting tau protein aggregation, comprising the compound according to any one of claims 1 to 5 as an active ingredient.

12. A composition for inhibiting hyperphosphorylation of tau protein, comprising the compound according to any one of claims 1 to 5 as an active ingredient.

13. A pharmaceutical composition for preventing or treating a disease caused by tau protein aggregation or hyperphosphorylation, comprising the compound according to any one of claims 1 to 5 as an active ingredient.

14. The pharmaceutical composition according to claim 13, in, The disease caused by tau protein aggregation or hyperphosphorylation is selected from the group consisting of Alzheimer's disease, Parkinson's disease, vascular dementia, acute stroke, cerebrovascular disease, cerebrospinal cord trauma, spinal cord trauma, peripheral neuropathy, retinopathy, glaucoma and tauopathy.

15. The pharmaceutical composition according to claim 14, in, The tauopathy is selected from the group consisting of chronic traumatic encephalopathy, primary age-related tauopathy, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, argyrophilic grain disease, frontotemporal dementia, Parkinson's disease associated with chromosome 17, muscular dystrophy, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic Parkinson's disease, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, pantothenate kinase-related neurodegeneration, lipofuscinosis and traumatic brain injury.

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