Novel carbohydrazonoyl dinitrile compounds containing two or more aryl or heteroaryl groups connected by a linker and their uses

Abstract

The present invention relates to: a carbohydrazonoyl dinitrile compound, the compound comprising at least two aryl or heteroaryl groups linked by a novel linker; and its use.

Description

Technical Field

[0001] The present invention relates to novel carbonohydrazonoyl dicyanide compounds and their uses, said compounds comprising two or more aryl or heteroaryl groups linked by a linker. 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 is used to stabilize microtubules and exhibits molecular diversity through phosphorylation. In humans, tau protein forms six subtypes by inserting 29 or 58 amino acid residues at the N-terminus and selectively splicing 3 or 4 repeating structures (called microtubule-binding domains) of mRNA at the C-terminus.

[0003] In healthy nerves, tau protein stabilizes microtubules by promoting axonal growth and neuronal polarization. When pathological hyperphosphorylation occurs, tau protein dissociates from microtubules, generating insoluble aggregates. In addition, a structural scaffold for inducing tau protein aggregation has been proposed, and evidence has been provided that insoluble filaments are formed from 10 soluble monomers, and these filaments bind into a higher-dimensional structure called neurofibrillary tangles (NFT). Full-length human tau protein includes a microtubule-binding domain consisting of four repeated conserved sequences. Among these repeating sequences, positively charged residues play an important role in binding to highly negatively charged microtubules (20 to 30 electrons per αβ-tubulin dimer). The binding affinity of tau to microtubules is also actively regulated by phosphorylation of tau protein, which causes dynamic rearrangement of the microtubule network. When tau protein is abnormally hyperphosphorylated, the balance of this dynamic rearrangement is disrupted, and the affinity for microtubules rapidly decreases.

[0004] Hyperphosphorylation and / or aggregation of tau protein leads to abnormal aggregation of these tau proteins in nerve cells, which is considered to be the cause of various neurodegenerative diseases and the like. Tau protein aggregates mainly exist in the cell bodies and dendrites of nerve cells, and these tau protein aggregates are called neurofibrillary tangles (NFT) and neuropil threads. Examination of the microstructure of neurofibrillary tangles (NFT) shows that its microstructure consists of paired helical filaments (PHF), in which tau protein is tangled like a thin thread and aggregated and hyperphosphorylated, which is different from normal tau protein. Abnormal tau protein aggregation also occurs in tauopathies. In this case, although it is not exactly known what role tau protein aggregation plays in the progression of tauopathies, this tau protein aggregation phenomenon seems to be similar to the aggregation phenomenon commonly seen in general neurodegenerative diseases.

[0005] Thus, although it is known that hyperphosphorylation and / or aggregation of tau protein cause various neurodegenerative diseases, including Alzheimer's disease and tauopathies, the specific mechanisms by which these abnormal tau species cause changes in signaling pathways and trigger neurotoxicity have not been confirmed, and there are no effective therapeutic methods or therapeutic agents available for treating these diseases. SUMMARY OF THE INVENTION

[0006] TECHNICAL PROBLEM

[0007] The present inventors have made extensive efforts to develop novel small molecule compounds capable of inhibiting tau protein aggregation and / or hyperphosphorylation. As a result, the present inventors have discovered a series of novel carbohydrazide dinitrile compounds, which comprise two or more aryl or heteroaryl groups linked by a linker, and which are effective in inhibiting tau protein aggregation at effective concentrations without exhibiting cytotoxicity, thereby completing the present invention.

[0008] TECHNICAL SOLUTION

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

[0010] [Formula 1]

[0011]

[0012] In the above formula 1,

[0013] L is -NHCO-, -CONH-, -NHSO2-, -SO2NH- or -(linear or branched C 0-3 alkylene)′-O-(linear or branched C 0-3 alkylene)″-;

[0014] R1 is hydrogen, C 1-6 alkyl or C 1-6 alkylcarbonyl;

[0015] (Het)Ar1 is C 6–10 arylene or a 5- to 10-membered heteroarylene; and

[0016] (Het)Ar2 is C 6–10 aryl or a 5- to 10-membered heteroaryl;

[0017] wherein the C 6–10 (sub)arylene and 5- to 10-membered (sub)heteroarylene are each independently unsubstituted or substituted with at least one group selected from the group consisting of C 1–6 alkyl, C 1–6 alkoxy, halogen, cyano, C 1–6 haloalkyl and C1–6 Halogenated alkoxy group.

[0018] Another object of the present invention is to provide a method for preparing the above-mentioned compound.

[0019] Another object of the present invention is to provide a composition for inhibiting tau protein aggregation, which comprises the above-mentioned compound as an active ingredient.

[0020] Another object of the present invention is to provide a composition for inhibiting tau protein hyperphosphorylation, which comprises the above-mentioned compound as an active ingredient.

[0021] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases caused by tau protein aggregation or hyperphosphorylation, which comprises the above-mentioned compound as an active ingredient.

[0022] Another object of the present invention is to provide a method for preventing or treating diseases caused by tau protein aggregation or hyperphosphorylation, the method comprising administering the above-mentioned pharmaceutical composition to a subject in need thereof.

[0023] Beneficial effects

[0024] The novel carbohydrazonoyl dinitrile compound of the present invention containing two or more aryl or heteroaryl groups linked by a linker can effectively inhibit tau protein aggregation and / or hyperphosphorylation, and thus can be effectively used for preventing or treating diseases caused thereby, such as Alzheimer's disease and various tauopathies. Detailed embodiments

[0025] The first aspect of the present invention provides a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof:

[0026] [Formula 1]

[0027]

[0028] In the above formula 1,

[0029] L is -NHCO-, -CONH-, -NHSO2-, -SO2NH- or -(linear or branched C 0-3 alkylene)′-O-(linear or branched C 0-3 alkylene)″-;

[0030] R1 is hydrogen, C 1-6 alkyl or C 1-6 alkylcarbonyl;

[0031] (Het)Ar1 is C 6–10 arylene or 5- to 10-membered heteroarylene; and

[0032] (Het)Ar2 is C 6–10 an aryl or a 5- to 10-membered heteroaryl;

[0033] wherein C 6–10 (substituted)aryl and 5- to 10-membered (substituted)heteroaryl are each independently unsubstituted or substituted with at least one group selected from the group consisting of C 1–6 alkyl, C 1–6 alkoxy, halogen, cyano, C 1–6 haloalkyl, and C 1–6 haloalkoxy.

[0034] For example, in the compounds of the present invention, L can be -NHCO-, -CONH-, -NHSO2-, -SO2NH-, -O-, -O-CH2-, -O-(CH2)2-, or -O-CH(CH3)-, but is not limited thereto.

[0035] For example, in the compounds of the present invention,

[0036] R1 is hydrogen, methyl, or acetyl;

[0037] (Het)Ar1 is phenylene, pyridylene, pyrazinylene, pyrimidinylene, pyrazolylene, pyridazinylene, thienylene, benzothiazolylene, thiazolopyridinylene, quinoxalinylene, thiazolylene, isoxazolylene, oxazolylene, furanylene, benzimidazolylene, benzothienylene, or benzoxazolylene; and

[0038] (Het)Ar2 is phenyl, pyridyl, pyrazyl, pyrimidyl, pyrazolyl, pyridazinyl, thienyl, benzothiazolyl, thiazolopyridinyl, quinoxalinyl, thiazolyl, isoxazolyl, oxazolyl, furanyl, benzimidazolyl, benzothienyl, or benzoxazolyl,

[0039] wherein (Het)Ar1 and (Het)Ar2 are each independently unsubstituted or substituted with at least one group selected from the group consisting of methyl, methoxy, fluorine, chlorine, cyano, and trifluoromethyl, but is not limited thereto.

[0040] Specifically, in the compounds of the present invention,

[0041] R1 is hydrogen, methyl, or acetyl;

[0042] (Het)Ar1 is phenylene, pyridylene, or thiazolopyridinylene; and

[0043] (Het)Ar2 is phenyl, pyridyl, pyrazyl, pyrimidyl, pyrazolyl, pyridazinyl, thienyl, benzothiazolyl, quinoxalinyl, thiazolyl, isoxazolyl, oxazolyl, furanyl, benzimidazolyl, benzothienyl, or benzoxazolyl,

[0044] Wherein (Het)Ar1 and (Het)Ar2 are each independently unsubstituted or substituted by at least one group selected from the group consisting of methyl, methoxy, fluoro, chloro, cyano, and trifluoromethyl, but not limited thereto.

[0045] More specifically, the compound can be:

[0046] 1. (6-(5-Methylpyrazine-2-carboxamido)pyridin-3-yl)carbamoyl dinitrile,

[0047] 2. (4-(5-Methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile,

[0048] 3. (2-Fluoro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile,

[0049] 4. (2-Methoxy-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile,

[0050] 5. (2-Chloro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile,

[0051] 6. (2-Methyl-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile,

[0052] 7. (3-Fluoro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile,

[0053] 8. (3-Methyl-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile,

[0054] 9. Methyl (3-methyl-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile,

[0055] 10. (3-Methoxy-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile,

[0056] 11. (3-Chloro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile,

[0057] 12. (5-Methyl-6-(5-methylpyrazine-2-carboxamido)pyridin-3-yl)carbamoyl dinitrile,

[0058] 13. (4-Methyl-6-(5-methylpyrazine-2-carboxamido)pyridin-3-yl)carbamoyl dinitrile,

[0059] 14. (5-(5-Methylpyrazine-2-carboxamido)pyridin-2-yl)carbamoyl dinitrile,

[0060] 15. (6-Benzamidopyridin-3-yl)carbazic di-nitrile,

[0061] 16. (6-(4-Fluorobenzamidopyridin-3-yl)carbazic di-nitrile,

[0062] 17. (6-(2-Fluorobenzamidopyridin-3-yl)carbazic di-nitrile,

[0063] 18. (6-(3-Fluorobenzamidopyridin-3-yl)carbazic di-nitrile,

[0064] 19. (6-(3-Fluoro-5-methylbenzamidopyridin-3-yl)carbazic di-nitrile,

[0065] 20. (6-(2-Fluoro-3-methylbenzamidopyridin-3-yl)carbazic di-nitrile,

[0066] 21. (6-(4-Fluoro-3-methylbenzamidopyridin-3-yl)carbazic di-nitrile,

[0067] 22. (6-(3-Fluoro-4-methylbenzamidopyridin-3-yl)carbazic di-nitrile,

[0068] 23. (6-(4-Methylbenzamidopyridin-3-yl)carbazic di-nitrile,

[0069] 24. (6-(3-Methylbenzamidopyridin-3-yl)carbazic di-nitrile,

[0070] 25. (6-(2-Methylbenzamidopyridin-3-yl)carbazic di-nitrile,

[0071] 26. (6-(3-(Trifluoromethyl)benzamidopyridin-3-yl)carbazic di-nitrile,

[0072] 27. (6-(4-(Trifluoromethyl)benzamidopyridin-3-yl)carbazic di-nitrile,

[0073] 28. (6-(2-(Trifluoromethyl)benzamidopyridin-3-yl)carbazic di-nitrile,

[0074] 29. (6-(Pyrimidine-2-carboxamidopyridin-3-yl)carbazic di-nitrile,

[0075] 30. (6-(Thiophene-2-carboxamidopyridin-3-yl)carbazic di-nitrile,

[0076] 31. (6-(Benzo[d]thiazole-2-carboxamidopyridin-3-yl)carbazic di-nitrile,

[0077] 32. (6-(Quinoxaline-2-carboxamido)pyridin-3-yl)carbazonyldinitrile,

[0078] 33. (2-(5-Methylpyrazine-2-carboxamido)thiazolo[4,5-b]pyridin-6-yl)carbazonyldinitrile,

[0079] 34. (6-(p-Tolylcarbamoyl)pyridin-3-yl)carbazonyldinitrile,

[0080] 35. (6-(4-Methoxyphenylcarbamoyl)pyridin-3-yl)carbazonyldinitrile,

[0081] 36. (6-(5-Methylpyrazin-2-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile,

[0082] 37. (6-(4-Chlorophenylcarbamoyl)pyridin-3-yl)carbazonyldinitrile,

[0083] 38. (6-(6-Methylpyridin-3-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile,

[0084] 39. (6-(5-Methylpyridin-3-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile,

[0085] 40. (6-(Pyridin-3-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile,

[0086] 41. (6-(6-Methylpyrazin-2-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile,

[0087] 42. (6-(Pyrimidin-5-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile,

[0088] 43. (6-(Pyrimidin-2-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile,

[0089] 44. (4-(4-Methoxyphenylcarbamoyl)phenyl)carbazonyldinitrile,

[0090] 45. (4-(5-Methylpyrazin-2-ylcarbamoyl)phenyl)carbazonyldinitrile,

[0091] 46. (4-(6-Methylpyrazin-2-ylcarbamoyl)phenyl)carbazonyldinitrile,

[0092] 47. (4-(6-Methylpyridin-3-ylcarbamoyl)phenyl)carbazonyldinitrile,

[0093] 48. (4-(5-Methylpyridin-3-ylcarbamoyl)phenyl)carbazonyldinitrile,

[0094] 49. (4-(Pyridin-3-ylcarbamoyl)phenyl)carbazic diimidoyl nitrile,

[0095] 50. (4-(Pyrimidin-5-ylcarbamoyl)phenyl)carbazic diimidoyl nitrile,

[0096] 51. (2-Methoxy-4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbazic diimidoyl nitrile,

[0097] 52. (3-Methyl-4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbazic diimidoyl nitrile,

[0098] 53. (3-Methyl-4-(6-methylpyridin-3-ylcarbamoyl)phenyl)carbazic diimidoyl nitrile,

[0099] 54. (3-Methyl-4-(6-methylpyrazin-2-ylcarbamoyl)phenyl)carbazic diimidoyl nitrile,

[0100] 55. (2-Methyl-4-(6-methylpyridin-3-ylcarbamoyl)phenyl)carbazic diimidoyl nitrile,

[0101] 56. (2-Fluoro-4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbazic diimidoyl nitrile,

[0102] 57. (2-Methoxy-4-(6-methylpyridin-3-ylcarbamoyl)phenyl)carbazic diimidoyl nitrile,

[0103] 58. (6-(Phenylsulfonamido)pyridin-3-yl)carbazic diimidoyl nitrile,

[0104] 59. (6-(4-Methoxyphenylsulfonamido)pyridin-3-yl)carbazic diimidoyl nitrile,

[0105] 60. (6-(Pyridine-3-sulfonamido)pyridin-3-yl)carbazic diimidoyl nitrile,

[0106] 61. (6-(1-Methyl-1H-pyrazole-4-sulfonamido)pyridin-3-yl)carbazic diimidoyl nitrile,

[0107] 62. (6-(Thiophene-2-sulfonamido)pyridin-3-yl)carbazic diimidoyl nitrile,

[0108] 63. (6-(4-Methylphenylsulfonamido)pyridin-3-yl)carbazic diimidoyl nitrile,

[0109] 64. (6-(4-Fluorophenylsulfonamido)pyridin-3-yl)carbazic diimidoyl nitrile,

[0110] 65. (4-(N-(6-Methylpyridin-3-yl)sulfamoyl)phenyl)carbazic diimidoyl nitrile,

[0111] 66. (4-(N-(4-Methoxyphenyl)sulfamoyl)phenyl)carbazoyl dinitrile,

[0112] 67. (4-(N-(5-Methylpyrazin-2-yl)sulfamoyl)phenyl)carbazoyl dinitrile,

[0113] 68. (6-Phenoxypyridin-3-yl)carbazoyl dinitrile,

[0114] 69. (6-(3-Fluorophenoxy)pyridin-3-yl)carbazoyl dinitrile,

[0115] 70. (5-Phenoxypyridin-2-yl)carbazoyl dinitrile,

[0116] 71. (3-Fluoro-4-phenoxyphenyl)carbazoyl dinitrile,

[0117] 72. (3-Fluoro-4-(pyridin-3-yloxy)phenyl)carbazoyl dinitrile,

[0118] 73. (4-Phenoxy-3-(trifluoromethyl)phenyl)carbazoyl dinitrile,

[0119] 74. (3-Methyl-4-(pyridin-3-yloxy)phenyl)carbazoyl dinitrile,

[0120] 75. Methyl(5-phenoxypyridin-2-yl)carbazoyl dinitrile,

[0121] 76. (6-(3-Fluorophenoxy)pyridin-3-yl)(methyl)carbazoyl dinitrile,

[0122] 77. (3-Fluoro-4-phenoxyphenyl)(methyl)carbazoyl dinitrile,

[0123] 78. Methyl(4-phenoxy-3-(trifluoromethyl)phenyl)carbazoyl dinitrile,

[0124] 79. (3-Methyl-4-(pyridin-4-yloxy)phenyl)carbazoyl dinitrile,

[0125] 80. (3-Fluoro-4-(pyridin-4-yloxy)phenyl)carbazoyl dinitrile,

[0126] 81. (3-Methyl-4-(pyrimidin-5-yloxy)phenyl)carbazoyl dinitrile,

[0127] 82. (3-Fluoro-4-(pyrimidin-5-yloxy)phenyl)carbazoyl dinitrile,

[0128] 83. (4-(Pyridin-2-yloxy)phenyl)carbazoyl dinitrile,

[0129] 84. (4-(Pyrazin-2-yloxy)phenyl)carbazoyl dinitrile,

[0130] 85. (4-(Pyridin-3-yloxy)phenyl)carbazimidodinitrile,

[0131] 86. (4-(2-Cyanophenoxy)phenyl)carbazimidodinitrile,

[0132] 87. (4-(4-Cyanophenoxy)phenyl)carbazimidodinitrile,

[0133] 88. (4-(3-Cyanophenoxy)phenyl)carbazimidodinitrile,

[0134] 89. (4-(6-(Trifluoromethyl)pyridin-3-yloxy)phenyl)carbazimidodinitrile,

[0135] 90. (4-(5-(Trifluoromethyl)pyridin-2-yloxy)phenyl)carbazimidodinitrile,

[0136] 91. (4-(Pyrimidin-2-yloxy)phenyl)carbazimidodinitrile,

[0137] 92. (4-(Pyridazin-3-yloxy)phenyl)carbazimidodinitrile,

[0138] 93. (4-(2-Fluorophenoxy)phenyl)carbazimidodinitrile,

[0139] 94. (4-(3-Fluorophenoxy)phenyl)carbazimidodinitrile,

[0140] 95. (6-(Benzyloxy)pyridin-3-yl)carbazimidodinitrile,

[0141] 96. (6-(4-(Trifluoromethyl)benzyloxy)pyridin-3-yl)carbazimidodinitrile,

[0142] 97. (4-(Benzyloxy)-3-(trifluoromethyl)phenyl)carbazimidodinitrile,

[0143] 98. (3-(Trifluoromethyl)-4-(4-(trifluoromethyl)benzyloxy)phenyl)carbazimidodinitrile,

[0144] 99. (6-(4-Methylbenzyloxy)pyridin-3-yl)carbazimidodinitrile,

[0145] 100. (6-Phenethoxypyridin-3-yl)carbazimidodinitrile,

[0146] 101. (4-Phenethoxy-3-(trifluoromethyl)phenyl)carbazimidodinitrile,

[0147] 102. (6-(4-Methoxyphenethoxy)pyridin-3-yl)carbazimidodinitrile,

[0148] 103. (6-(4-(Trifluoromethyl)phenethoxy)pyridin-3-yl)carbamoyl dinitrile,

[0149] 104. (3-Methoxy-4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbamoyl dinitrile,

[0150] 105. (3-Methoxy-4-(6-methylpyrazin-2-ylcarbamoyl)phenyl)carbamoyl dinitrile,

[0151] 106. (3-Chloro-4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbamoyl dinitrile,

[0152] 107. (3-Methoxy-4-(5-methylpyridin-3-ylcarbamoyl)phenyl)carbamoyl dinitrile,

[0153] 108. (3-Methoxy-4-(p-tolylcarbamoyl)phenyl)carbamoyl dinitrile,

[0154] 109. (3-Methoxy-4-(4-methoxyphenylcarbamoyl)phenyl)carbamoyl dinitrile,

[0155] 110. (6-(Furan-3-carboxamido)pyridin-3-yl)carbamoyl dinitrile,

[0156] 111. (3-Methyl-4-(thiazole-4-carboxamido)phenyl)carbamoyl dinitrile,

[0157] 112. (6-(Thiazole-4-carboxamido)pyridin-3-yl)carbamoyl dinitrile,

[0158] 113. (6-(Oxazole-4-carboxamido)pyridin-3-yl)carbamoyl dinitrile,

[0159] 114. (6-(Oxazole-5-carboxamido)pyridin-3-yl)carbamoyl dinitrile,

[0160] 115. (6-(Isoxazole-3-carboxamido)pyridin-3-yl)carbamoyl dinitrile,

[0161] 116. (4-(Thiazol-2-yloxy)phenyl)carbamoyl dinitrile,

[0162] 117. (4-(Benzyloxy)phenyl)carbamoyl dinitrile,

[0163] 118. (4-(4-(Trifluoromethyl)benzyloxy)phenyl)carbamoyl dinitrile,

[0164] 119. (4-(4-Methylbenzyloxy)phenyl)carbamoyl dinitrile,

[0165] 120. (4-(4-Methoxyphenethoxy)phenyl)carbazoyl dinitrile,

[0166] 121. (4-(4-(Trifluoromethyl)phenethoxy)phenyl)carbazoyl dinitrile,

[0167] 122. (4-Phenethoxyphenyl)carbazoyl dinitrile,

[0168] 123. (4-(4-Chlorophenethoxy)phenyl)carbazoyl dinitrile,

[0169] 124. (4-(Pyridin-3-ylmethoxy)phenyl)carbazoyl dinitrile,

[0170] 125. (4-(Pyrazin-2-ylmethoxy)phenyl)carbazoyl dinitrile,

[0171] 126. (4-((1H-Benzimidazol-2-yl)methoxy)phenyl)carbazoyl dinitrile,

[0172] 127. (4-(Pyridazin-3-ylmethoxy)phenyl)carbazoyl dinitrile,

[0173] 128. (4-(Benzo[d]oxazol-2-ylmethoxy)phenyl)carbazoyl dinitrile,

[0174] 129. (4-(Benzo[d]thiazol-2-ylmethoxy)phenyl)carbazoyl dinitrile,

[0175] 130. (4-(Benzo[b]thiophen-2-ylmethoxy)phenyl)carbazoyl dinitrile,

[0176] 131. (6-(4-Chlorophenethoxy)pyridin-3-yl)carbazoyl dinitrile,

[0177] 132. (4-(4-Methylbenzyloxy)-3-(trifluoromethyl)phenyl)carbazoyl dinitrile,

[0178] 133. (4-(4-Chlorophenethoxy)-3-(trifluoromethyl)phenyl)carbazoyl dinitrile,

[0179] 134. (4-(4-Methoxyphenethoxy)-3-(trifluoromethyl)phenyl)carbazoyl dinitrile,

[0180] 135. (3-(Trifluoromethyl)-4-(4-(trifluoromethyl)phenethoxy)phenyl)carbazoyl dinitrile,

[0181] 136. (4-(Pyrimidin-2-ylmethoxy)phenyl)carbazoyl dinitrile,

[0182] 137. (4-((1H-Pyrazol-4-yl)methoxy)phenyl)carbazoyl dinitrile,

[0183] 138. (4 - ((5-Methylpyrazin-2-yl)methoxy)phenyl)carbamoyl dinitrile,

[0184] 139. (4-(1-(4-(Trifluoromethyl)phenyl)ethoxy)phenyl)carbamoyl dinitrile,

[0185] 140. (4-(1-(Pyridin-3-yl)ethoxy)phenyl)carbamoyl dinitrile,

[0186] 141. (4-(Benzyloxy)-3-methylphenyl)carbamoyl dinitrile,

[0187] 142. (3-Methyl-4-(4-methylbenzyloxy)phenyl)carbamoyl dinitrile,

[0188] 143. (3-Methyl-4-(Pyrimidin-2-ylmethoxy)phenyl)carbamoyl dinitrile,

[0189] 144. (3-Methyl-4-(Pyrazin-2-ylmethoxy)phenyl)carbamoyl dinitrile,

[0190] 145. (3-Methyl-4-(Pyridin-3-ylmethoxy)phenyl)carbamoyl dinitrile,

[0191] 146. (4-((1H-Benz[d]imidazol-2-yl)methoxy)-3-methylphenyl)carbamoyl dinitrile,

[0192] 147. (3-Methyl-4-((5-methylpyrazin-2-yl)methoxy)phenyl)carbamoyl dinitrile,

[0193] 148. (3-Methyl-4-(4-(Trifluoromethyl)benzyloxy)phenyl)carbamoyl dinitrile,

[0194] 149. (3-Methyl-4-(Pyridazin-3-ylmethoxy)phenyl)carbamoyl dinitrile,

[0195] 150. (4-(Benzo[b]thiophen-2-ylmethoxy)-3-methylphenyl)carbamoyl dinitrile,

[0196] 151. (4-((1H-Pyrazol-3-yl)methoxy)-3-methylphenyl)carbamoyl dinitrile,

[0197] 152. (3-Methyl-4-(Thiazol-4-ylmethoxy)phenyl)carbamoyl dinitrile,

[0198] 153. (4-(Benzyloxy)-3-methoxyphenyl)carbamoyl dinitrile,

[0199] 154. (3-Methoxy-4-(4-methylbenzyloxy)phenyl)carbamoyl dinitrile,

[0200] 155. (3-Methoxy-4-(4-(trifluoromethyl)benzyloxy)phenyl)carbamoyl dinitrile,

[0201] 156. (4-(Benzo[d]oxazol-2-ylmethoxy)-3-methylphenyl)carbamoyl dinitrile,

[0202] 157. (4-(Benzo[d]thiazol-2-ylmethoxy)-3-methylphenyl)carbamoyl dinitrile,

[0203] 158. (4-(Benzo[b]thiophen-2-ylmethoxy)-3-methoxyphenyl)carbamoyl dinitrile,

[0204] 159. (3-Methoxy-4-(pyrazin-2-ylmethoxy)phenyl)carbamoyl dinitrile,

[0205] 160. (3-Methoxy-4-(pyridin-3-ylmethoxy)phenyl)carbamoyl dinitrile,

[0206] 161. (3-Methoxy-4-(pyrimidin-2-ylmethoxy)phenyl)carbamoyl dinitrile,

[0207] 162. (3-Methoxy-4-((5-methylpyrazin-2-yl)methoxy)phenyl)carbamoyl dinitrile,

[0208] 163. (4-((1H-benzo[d]imidazol-2-yl)methoxy)-3-methoxyphenyl)carbamoyl dinitrile,

[0209] 164. (3-Methoxy-4-(pyridazin-3-ylmethoxy)phenyl)carbamoyl dinitrile,

[0210] 165. (4-(Benzo[d]thiazol-2-ylmethoxy)-3-methoxyphenyl)carbamoyl dinitrile,

[0211] 166. (4-(Benzo[d]oxazol-2-ylmethoxy)-3-methoxyphenyl)carbamoyl dinitrile,

[0212] 167. (3-Methoxy-4-(thiazol-4-ylmethoxy)phenyl)carbamoyl dinitrile,

[0213] 168. (4-((1H-pyrazol-3-yl)methoxy)-3-methoxyphenyl)carbamoyl dinitrile,

[0214] 169. (3-Methoxy-4-(pyridin-2-ylmethoxy)phenyl)carbamoyl dinitrile,

[0215] 170. (3-Methoxy-4-((6-methylpyridin-3-yl)methoxy)phenyl)carbamoyl dinitrile,

[0216] 171. (3-Methoxy-4-((2-methylthiazol-4-yl)methoxy)phenyl)carbamoyl dinitrile,

[0217] 172. (3-Methoxy-4-(thiophen-2-ylmethoxy)phenyl)carbamoyl dinitrile,

[0218] 173. (3-Methoxy-4-(thiophen-3-ylmethoxy)phenyl)carbamoyl dinitrile,

[0219] 174. (3-Methoxy-4-((1-methyl-1H-pyrazol-4-yl)methoxy)phenyl)carbamoyl dinitrile, or

[0220] 175. Acetyl(3-methyl-4-(4-methylbenzyloxy)phenyl)carbamoyl dinitrile.

[0221] In addition, these compounds may be compounds represented by the chemical formulas shown in Table 1 below.

[0222] Table 1

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236] Meanwhile, the compounds of the present invention may exist in the form of pharmaceutically acceptable salts. As salts, acid addition salts formed from pharmaceutically acceptable free acids are useful. As used herein, the term "pharmaceutically acceptable salt" refers to any organic or inorganic addition salt of the compound represented by Formula 1, which is relatively non-toxic and harmless to patients, and the side effects caused by the salt do not impair the beneficial effects of the compound.

[0237] The acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an aqueous solution of an excess of acid and precipitating the solution with a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Aqueous solutions of the same molar amounts of the compound and an acid or an alcohol (such as ethylene glycol monoethyl ether) are heated, and subsequently the mixture can be evaporated and dried, or the precipitated salt can be filtered by suction.

[0238] In this case, organic acids or inorganic acids can be used as the free acids. Hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as inorganic acids. 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 organic acids. However, the present invention is not limited thereto.

[0239] In addition, pharmaceutically acceptable metal salts can be prepared using bases. Alkali metal salts or alkaline earth metal salts are obtained by the following method: dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salts, and then evaporating and drying the filtrate. In this case, preparing sodium salts, potassium salts or calcium salts as metal salts is suitable for pharmaceutical use, but the present invention is not limited thereto. In addition, the corresponding silver salts can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (such as silver nitrate).

[0240] Unless otherwise specified, 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. 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 hydrobromide salts, sulfate salts, bisulfate salts, phosphate salts, hydrogen phosphate salts, dihydrogen phosphate salts, acetate salts, succinate salts, citrate salts, tartrate salts, lactate salts, mandelate salts, methanesulfonate salts and p-toluenesulfonate salts. These pharmaceutically acceptable salts can be prepared by methods for preparing salts known in the art.

[0241] As salts of the compounds of Formula 1 of the present invention, any salt can be used without limitation as a pharmaceutically acceptable salt as long as it exhibits the same pharmacological activity as the compounds of Formula 1, for example, it inhibits tau protein aggregation and / or hyperphosphorylation.

[0242] In addition, the compounds represented by Formula 1 according to the present invention include, but are not limited to, pharmaceutically acceptable salts thereof, as well as solvates, such as possible hydrates that can be prepared therefrom, and all possible stereoisomers. Solvates and stereoisomers of the compounds represented by Formula 1 can be prepared from the compounds represented by Formula 1 using any method known in the art.

[0243] In addition, the compounds represented by Formula 1 according to the present invention can be prepared in crystalline or amorphous form, and if prepared in crystalline form, can be optionally hydrated or solvated. In the present invention, stoichiometric hydrates of the compounds represented by Formula 1, as well as compounds containing different amounts of water, are provided. Solvates of the compounds represented by Formula 1 according to the present invention include stoichiometric solvates and non-stoichiometric solvates.

[0244] The second aspect of the present invention provides a method for preparing a compound of Formula 1.

[0245] For example, the compounds of the present invention can be prepared by a method comprising the following steps:

[0246] In the first step, in the presence of an acid, a compound represented by the following Formula 2 having a reactive amino group at one end is reacted with sodium nitrite and malononitrile to form an imine bond; and

[0247] Optionally, in the second step, when R1 is a substituent other than hydrogen, an R1 substituent is introduced into the product obtained in the previous step:

[0248] [Formula 2]

[0249] H2N-(Het)Ar1-L-(Het)Ar2

[0250] In the above Formula 2, L, (Het)Ar1, (Het)Ar2, and R1 are as defined in the first aspect above.

[0251] Specifically, the first step of the method can be carried out through a series of processes, including the following steps:

[0252] 1-1) Dissolve the compound of Formula 2 and sodium nitrite in a C 1-4 lower alcohol solvent, and add an aqueous solution of an acid thereto at a temperature of -5°C to 5°C to form a diazonium salt,

[0253] 1-2) Add malononitrile to the reaction solution containing the diazonium salt obtained in step 1-1), and carry out the reaction at a temperature of 15°C to 40°C, and

[0254] 1-3) Add an aqueous solution of a base to the reaction solution of step 1-2) to neutralize the reaction solution, but not limited thereto.

[0255] For example, the first step can be carried out by the following steps: reacting in a 1M hydrochloric acid solution at a low temperature of about 0 °C for 2 minutes to 1 hour in step 1-1), and then reacting in step 1-2) at room temperature for 2 minutes to 1 hour, but not limited thereto.

[0256] For example, the second step can be carried out by the following steps: reacting the carbonhydrazonoyl dinitrile compound (wherein R1 is not hydrogen) obtained in the previous step with a halogenated derivative of R1 in an organic solvent. Specifically, when R1 is C 1-6 alkyl, the second step can be carried out by the following steps: dissolving the carbonhydrazonoyl dinitrile compound (wherein R1 is not hydrogen) obtained in the previous step in an organic solvent such as DMF, adding an alkyl halide corresponding to R1 such as alkyl iodide to the reaction solution, and reacting at a temperature of 50 °C to 70 °C, wherein the reaction solution may further contain potassium tert-butoxide. However, the present invention is not limited thereto. Specifically, when R1 is C 1-6 alkylcarbonyl, the second step can be carried out by the following steps: dissolving the carbonhydrazonoyl dinitrile compound (wherein R1 is not hydrogen) obtained in the previous step in a lower alcohol such as methanol, then reacting with a base such as potassium hydroxide and solidifying to obtain a product, and in the presence of triethylamine, reacting the product with a haloalkylcarbonyl corresponding to C 1–6 alkylcarbonyl such as acetyl chloride in an organic solvent such as acetonitrile. However, the present invention is not limited thereto.

[0257] For example, the compound represented by Formula 2 containing a reactive amino group at one end and used for preparing the compound of the present invention can be prepared by a reduction reaction from the compound containing a nitro group represented by Formula 3 below, but not limited thereto:

[0258] [Formula 3]

[0259] O2N-(Het)Ar1-L-(Het)Ar2.

[0260] Specifically, the reduction can be carried out in the following ways: reacting in an organic solvent such as 1,4-dioxane or methanol solvent in the presence of a Pd / C catalyst, reacting with AcOH in the presence of Fe, or reacting with ammonium chloride in the presence of Fe, but not limited thereto.

[0261] For example, when L is -NHCO- or -CONH-, the compound of Formula 3 can be prepared by the following ways:

[0262] i) The reaction between the (Het)Ar1 derivative and the (Het)Ar2 derivative, wherein the (Het)Ar1 derivative includes a carboxyl group at the site connected to the nitro group and L, and the (Het)Ar2 derivative includes an amino group at the site connected to L; or

[0263] ii) The reaction between a (Het)Ar1 derivative and a (Het)Ar2 derivative, wherein the (Het)Ar1 derivative includes an amino group at the site connected to the nitro group and L, and the (Het)Ar2 derivative includes a carboxyl group at the site connected to L, but is not limited thereto.

[0264] Specifically, the compound of formula 3 can be prepared by the following method: dissolving a carboxylic acid derivative of one of (Het)Ar1 and (Het)Ar2 in an organic solvent such as MeCN, ACN, etc., adding HATU and TEA thereto, and stirring the mixture at room temperature for several hours to prepare a reaction solution; adding an amine derivative of the other of (Het)Ar1 and (Het)Ar2 to the reaction solution; and refluxing the resulting product for 12 to 48 hours, but is not limited thereto.

[0265] As another example, the compound of formula 3 can be prepared by the following method: dissolving a carboxylic acid derivative of one of (Het)Ar1 and (Het)Ar2 in anhydrous DCM as an organic solvent, adding (COCl)2 and a small amount of DMF thereto at 0 °C, and concentrating the mixture under reduced pressure with stirring for 1 hour to prepare a concentrate; and dissolving an amine derivative of the other of (Het)Ar1 and (Het)Ar2 and the concentrate in pyridine as an organic solvent; and stirring the mixture at room temperature for 3 to 24 hours, but is not limited thereto.

[0266] For example, when L is -NHSO2- or -SO2NH-, the compound of formula 3 can be prepared by the following method:

[0267] i) The reaction between a (Het)Ar1 derivative and a (Het)Ar2 derivative, wherein the (Het)Ar1 derivative includes an amino group at the site connected to the nitro group and L, and the (Het)Ar2 derivative includes a chlorosulfonyl group at the site connected to L; or

[0268] ii) The reaction between a (Het)Ar1 derivative and a (Het)Ar2 derivative, wherein the (Het)Ar1 derivative includes a halosulfonyl group at the site connected to the nitro group and L, and the (Het)Ar2 derivative includes an amino group at the site connected to L, but is not limited thereto.

[0269] Specifically, the compound of formula 3 can be prepared by dissolving an amine derivative of one of (Het)Ar1 and (Het)Ar2 in an organic solvent such as THF, lowering the reaction temperature to about 0 °C, adding sodium hydride thereto, and stirring the mixture for several minutes to several tens of minutes to prepare a reaction solution; adding a halosulfonyl derivative of the other of (Het)Ar1 and (Het)Ar2, such as a sulfonyl chloride derivative, thereto, and stirring the resulting product at room temperature for 1 to 12 hours, but not limited thereto.

[0270] For example, when L is -(linear or branched C 0–3 alkylene)′-O-(linear or branched C 0–3 alkylene)″-, the compound of formula 3 can be prepared by the following method:

[0271] i) The reaction between the (Het)Ar1 derivative and the (Het)Ar2 derivative, wherein the (Het)Ar1 derivative includes -(linear or branched C 0–3 alkylene)′-OH at the site connected to the nitro group and L, and the (Het)Ar2 derivative includes -(linear or branched C 0–3 alkylene)″-X (where X is a halogen) at the site connected to L; or

[0272] ii) The reaction between the (Het)Ar1 derivative and the (Het)Ar2 derivative, wherein the (Het)Ar1 derivative includes -(linear or branched C 0–3 alkylene)′-X at the site connected to the nitro group and L, and the (Het)Ar2 derivative includes -(linear or branched C 0–3 alkylene)″-OH at the site connected to L, but not limited thereto.

[0273] Specifically, the compound of formula 3 can be prepared by dissolving a haloalkyl (- (linear or branched C 0–3 alkylene)-X) derivative of one of (Het)Ar1 and (Het)Ar2 in an organic solvent such as DMF; adding a hydroxyalkyl (- (linear or branched C 0–3 alkylene)-OH) derivative of the other of (Het)Ar1 and (Het)Ar2 and a base such as potassium carbonate thereto; and stirring the mixture at a temperature of 130 °C to 170 °C for several minutes to several hours, but not limited thereto. In this regard, stirring can be carried out using microwaves, but not limited thereto.

[0274] For example, commercially available compounds can be used as the reactants and intermediates used in each step of the method of the present invention, or the reactants and intermediates used in each step can be synthesized individually or in combination from commercially available compounds through reactions well known in the art, but the present invention is not limited thereto.

[0275] In addition, if necessary, the method may further include the processes of separating and / or purifying the product after each reaction, and these processes may be carried out using various methods well known in the art.

[0276] The third aspect of the present invention is to provide a composition for inhibiting tau protein aggregation, which contains the compound of the present invention as an active ingredient.

[0277] The fourth aspect of the present invention is to provide a composition for inhibiting tau protein hyperphosphorylation, which contains the compound of the present invention as an active ingredient.

[0278] The fifth aspect of the present invention is to provide a pharmaceutical composition for preventing or treating diseases caused by tau protein aggregation or hyperphosphorylation, which contains the compound of the present invention as an active ingredient.

[0279] The sixth aspect of the present invention is to provide a method for preventing or treating diseases caused by tau protein aggregation or hyperphosphorylation, the method comprising administering the compound of the present invention to a subject in need thereof.

[0280] In a specific embodiment of the present invention, a total of 175 compounds numbered from 1 to 175 and represented by Formula 1 were newly synthesized, and their effects of inhibiting tau protein aggregation and hyperphosphorylation were confirmed. In addition, to confirm the possibility of being used as a pharmaceutical composition, it was confirmed that these compounds did not have cytotoxicity.

[0281] As used herein, the term "prevention" refers to any act of inhibiting or delaying the occurrence, spread, and recurrence of a disease induced by tau protein aggregation or hyperphosphorylation by administering the pharmaceutical composition of the present invention, and the term "treatment" refers to any act of improving or beneficially altering the symptoms of a disease by administering the pharmaceutical composition of the present invention.

[0282] As described above, since the compounds of the present invention not only inhibit tau protein aggregation or hyperphosphorylation, but also are not toxic to cells, a pharmaceutical composition containing the compound as an active ingredient can be used for preventing or treating diseases caused by tau protein aggregation or hyperphosphorylation. Diseases caused by tau protein aggregation or hyperphosphorylation to which the pharmaceutical composition of the present invention can be applied can be Alzheimer's disease, Parkinson's disease, vascular dementia, acute stroke, trauma, cerebrovascular disease, craniospinal trauma, spinal cord trauma, peripheral neuropathy, retinopathy, glaucoma or tauopathy. Non-limiting examples of tauopathy can include: chronic traumatic encephalopathy (CTE), primary age-related tauopathy, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, argyrophilic grain disease (AGD), frontotemporal dementia (FTD), Parkinsonism associated with chromosome 17, Lytico-bodig disease (Guam-type Parkinsonism-dementia complex), ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic Parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, pantothenate kinase-associated neurodegeneration, lipofuscinosis, post-traumatic stress disorder and traumatic brain injury.

[0283] For example, the composition of the present invention may further include a pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into various forms and used according to general methods for each purpose of use, such as oral preparations, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, and injectable drugs of sterile injection solutions, and can be administered orally or can be administered by various routes, including intravenous, intraperitoneal, subcutaneous, rectal and topical administration. Examples of suitable carriers, excipients or diluents contained in the composition can include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl paraben, propyl paraben, talc, magnesium stearate and mineral oil. The composition of the present invention may further include fillers, anti-aggregating agents, lubricants, wetting agents, flavoring agents, emulsifying agents, preservatives, etc.

[0284] Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations are formulated by mixing one or more excipients such as starch, calcium carbonate, sucrose, lactose and gelatin with the composition. At the same time, in addition to simple excipients, lubricants such as magnesium stearate or talc can also be used.

[0285] Examples of oral liquid preparations include suspensions, oral solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used as simple diluents, oral liquid preparations may include various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives.

[0286] Preparations for parenteral administration include sterile aqueous solvents, non-aqueous solvents, suspending agents, emulsifying agents, freeze-dried preparations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. can be used as non-aqueous solvents or suspending agents. Witepsol, polyethylene glycol (macrogol), twin 61, cocoa butter, laurel oil, glycerol gelatin, etc. can be used as the matrix of suppositories. At the same time, injectable preparations may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers, and preservatives.

[0287] The preparation can be prepared using conventional mixing, granulation, or coating methods and may contain the active ingredient in an amount of about 0.1 wt% to 75 wt%, preferably about 0.1 wt% to 50 wt%. The unit preparation for a mammal weighing about 50 kg to 70 kg contains about 10 mg to 200 mg of the active ingredient.

[0288] In this case, the composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and without causing side effects, and the level of the effective amount can be determined according to factors such as the patient's health condition, disease type, severity, drug activity, drug sensitivity, administration method, administration time, administration route, excretion rate, treatment period, factors including drugs used in combination or simultaneously, and other factors well known in the medical field. The composition of the present invention can be administered as a single therapeutic agent or in combination with other therapeutic agents, can be administered successively or simultaneously with conventional therapeutic agents, and can be administered in a single dose or multiple doses. Considering all the above factors, it is important to administer the minimum amount that can achieve the maximum effect without side effects, which can be easily determined by those skilled in the art.

[0289] For example, since the dose can be increased or decreased depending on the administration route, disease severity, gender, body weight, age, etc., the dose does not limit the scope of the present invention in any way.

[0290] The preferred dosage of the compounds of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the form of the drug, and the route and duration of administration, but can be appropriately selected by those skilled in the art. However, in order to achieve the desired effect, the compounds of the present invention can be administered in an amount of 0.0001 mg / kg to 100 mg / kg (body weight) per day, preferably 0.001 mg / kg to 100 mg / kg (body weight). The compound can be administered in divided doses once a day or several times a day by oral or parenteral routes.

[0291] The seventh aspect of the present invention is to provide a method for preventing or treating a disease caused by tau protein aggregation or hyperphosphorylation, the method comprising administering the pharmaceutical composition of the present invention to a subject in need thereof.

[0292] As used herein, the term "subject" refers to any animal, including monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rabbits, and guinea pigs in addition to humans, which have or may have 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 tau protein aggregation or hyperphosphorylation, a synergistic effect can be exhibited by co-administering the composition with a conventional therapeutic agent.

[0293] As used herein, the term "administer" refers to providing a predetermined substance to a patient by any suitable method, and the route of administration of the composition of the present invention can be any conventional route as long as the substance can reach the target tissue. The composition can be administered by intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, pulmonary administration, or rectal administration, but the present invention is not limited thereto. In addition, the pharmaceutical composition of the present invention can be administered by any device capable of moving the active substance to the target cell. Preferred administrations and formulations include intravenous injection drugs, subcutaneous injection drugs, intradermal injection drugs, intramuscular injection drugs, and infusion drugs. The injection drug can be prepared using an aqueous solvent such as a physiological saline solution or Ringer's solution, or a non-aqueous solvent such as vegetable oil, a higher fatty acid ester (such as ethyl oleate), or an alcohol (such as ethanol, benzyl alcohol, propylene glycol, or glycerol), and can include a drug carrier such as a stabilizer for preventing denaturation (such as ascorbic acid, sodium bisulfite, sodium metabisulfite, BHA, tocopherol, or EDTA), an emulsifier, a buffer for pH control, or a preservative for inhibiting microbial growth (such as phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, or benzyl alcohol).

[0294] Modes for Carrying Out the Invention

[0295] Hereinafter, the present invention will be described in more detail with reference to examples and experimental examples. However, these examples and experimental examples are merely illustrative of the present invention, and the scope of the present invention is not limited to these examples and experimental examples.

[0296] Example 1: Preparation of (6-(5-Methylpyrazine-2-carboxamido)pyridin-3-yl)carbonohydrazonitrile (Compound 1)

[0297] Step 1-1: Preparation of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide

[0298] Under a nitrogen atmosphere, after dissolving 5-methylpyrazine-2-carboxylic acid (500 mg, 3.62 mmol) in MeCN, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.65 g, 4.34 mmol), and triethylamine (TEA, 0.8 mL, 5.43 mmol) were added thereto, and the reaction mixture was stirred at room temperature for 4 hours. Then, 5-nitropyridin-2-amine (503 mg, 3.62 mmol) was added thereto, and the reaction mixture was refluxed for 24 hours. After completion of the reaction, the product was filtered with MeCN to obtain 476 mg (yield: 51%) of the title compound.

[0299] 1 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.29–9.15 (m, 2H), 8.74 (d, J = 8.7 Hz, 2H), 8.45 (d, J = 9.2 Hz, 1H), 2.66 (s, 3H).

[0300] Step 1-2: Preparation of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide

[0301] 5-Methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide (400 mg, 1.54 mmol) obtained in the above step 1-1 and 10% Pd / C (328 mg, 0.31 mmol) were dissolved in 1,4-dioxane, and the reaction mixture was stirred at 60 °C under a hydrogen atmosphere for 2 hours. After completion of the reaction, the reaction mixture was filtered with ethyl acetate. The filtrate was concentrated under reduced pressure, solidified with diethyl ether, and filtered to obtain 47 mg (yield: 13%) of the solid title compound.

[0302] 11H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.16 (d, J = 1.4 Hz, 1H), 8.68 (d, J = 1.5 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 2.8 Hz, 1H), 7.06 (dd, J = 8.7 Hz, 2.9 Hz, 1H), 5.27 (s, 2H), 2.63 (s, 3H).

[0303] Step 1-3: Preparation of (6-(5-methylpyrazine-2-carboxamido)pyridin-3-yl)carbamoyl dinitrile

[0304] Under a nitrogen atmosphere, N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide (40 mg, 0.17 mmol) and sodium nitrite (18 mg, 0.26 mmol) obtained in the above step 1-2 were dissolved in ethanol, and 1.0 M aqueous hydrochloric acid solution (0.5 mL, 0.52 mmol) was added thereto at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes to form a diazonium salt. Malononitrile (23 mg, 0.35 mmol) was added to the reaction mixture containing the diazonium salt, and the mixture was stirred at room temperature for 10 minutes. Thereafter, the pH of the reaction mixture was adjusted to 6.0 using an aqueous sodium hydroxide solution, and the reaction mixture was stirred at room temperature for another 1 hour. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 48 mg (yield: 89%) of the title compound.

[0305] 1 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.19 (d, J = 1.4 Hz, 1H), 8.71 (d, J = 1.4 Hz, 1H), 8.49 (d, J = 2.7 Hz, 1H), 8.27 (d, J = 9.0 Hz, 1H), 7.95 (dd, J = 9.0 Hz, 2.7 Hz, 1H), 2.64 (s, 3H).

[0306] Example 2: Preparation of (4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile (Compound 2)

[0307] Step 2-1: Preparation of 5-methyl-N-(4-nitrophenyl)pyrazine-2-carboxamide

[0308] Except for using N-nitroaniline (500 mg, 3.62 mmol) instead of 5-nitropyridin-2-amine, 778 mg (yield: 83%) of the title compound was obtained in the same manner as in step 1-1 of Example 1 above.

[0309] 11H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 9.20 (d, J = 1.5 Hz, 1H), 8.74 (d, J = 1.4 Hz, 1H), 8.35–8.16 (m, 4H), 2.65 (s, 3H).

[0310] Step 2-2: Preparation of N-(4-aminophenyl)-5-methylpyrazine-2-carboxamide

[0311] Except for using 5-methyl-N-(4-nitrophenyl)pyrazine-2-carboxamide (750 mg, 2.90 mmol) obtained in Step 2-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Step 1-2 of Example 1 above, 435 mg (yield: 66%) of the title compound was obtained.

[0312] 1 1H NMR (400 MHz, DMSO-d6) δ 7.35 (d, J = 9.5 Hz, 1H), 7.11 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 9.4 Hz, 1H), 6.59 (d, J = 8.7 Hz, 2H), 5.31 (s, 2H), 2.28 (s, 3H).

[0313] Step 2-3: Preparation of (4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile

[0314] Except for using N-(4-aminophenyl)-5-methylpyrazine-2-carboxamide (284 mg, 1.24 mmol) obtained in Step 2-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Step 1-3 of Example 1 above, 113 mg (yield: 30%) of the title compound was obtained.

[0315] 1 1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 10.79 (s, 1H), 9.16 (s, 1H), 8.70 (s, 1H), 7.97 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 2.64 (s, 3H).

[0316] Example 3: Preparation of (2-fluoro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile (Compound 3)

[0317] Step 3-1: Preparation of N-(3-fluoro-4-nitrophenyl)-5-methylpyrazine-2-carboxamide

[0318] Except using 3-fluoro-4-nitroaniline (500 mg, 3.62 mmol) instead of 5-nitropyridin-2-amine, the title compound (778 mg, yield: 83%) was obtained in the same manner as in Step 1-1 of Example 1 above.

[0319] 1 H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 9.20 (d, J = 1.5 Hz, 1H), 8.74 (d, J = 1.4 Hz, 1H), 8.35–8.16 (m, 4H), 2.65 (s, 3H).

[0320] Step 3-2: Preparation of N-(4-amino-3-fluorophenyl)-5-methylpyrazine-2-carboxamide

[0321] Except using N-(3-fluoro-4-nitrophenyl)-5-methylpyrazine-2-carboxamide (350 mg, 1.27 mmol) obtained in Step 3-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (41 mg, yield: 13%) was obtained in the same manner as in Step 1-2 of Example 1 above.

[0322] 1 H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 9.12 (d, J = 1.5 Hz, 1H), 8.67 (s, 1H), 7.66 (dd, J = 13.7 Hz, 2.3 Hz, 1H), 7.48–7.34 (m, 1H), 6.74 (dd, J = 10.1 Hz, 8.6 Hz, 1H), 5.02 (s, 2H), 2.62 (s, 3H).

[0323] Step 3-3: Preparation of (2-fluoro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile

[0324] Except using N-(4-amino-3-fluorophenyl)-5-methylpyrazine-2-carboxamide (284 mg, 1.24 mmol) obtained in Step 3-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (113 mg, yield: 30%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[0325] 1 H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 10.79 (s, 1H), 9.16 (s, 1H), 8.70 (s, 1H), 7.97 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 2.64 (s, 3H).

[0326] Example 4: Preparation of (2-methoxy-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile (Compound 4)Preparation

[0327] Step 4-1: Preparation of N-(3-methoxy-4-nitrophenyl)-5-methylpyrazine-2-carboxamide

[0328] Except for using 3-methoxy-4-nitroaniline (365 mg, 2.17 mmol) instead of 5-nitropyridin-2-amine, the title compound (496 mg, yield: 79%) was obtained in the same manner as in Step 1-1 of Example 1 above.

[0329] 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.20 (s, 1H), 8.73 (s, 1H), 8.08–7.94 (m, 2H), 7.78 (dd, J = 9.0 Hz, 2.0 Hz, 1H), 3.93 (s, 3H), 2.65 (s, 3H).

[0330] Step 4-2: Preparation of N-(4-amino-3-methoxyphenyl)-5-methylpyrazine-2-carboxamide

[0331] Except for using N-(3-methoxy-4-nitrophenyl)-5-methylpyrazine-2-carboxamide (450 mg, 1.56 mmol) obtained in Step 4-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (192 mg, yield: 48%) was obtained in the same manner as in Step 1-2 of Example 1 above.

[0332] 1 H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.13 (s, 1H), 8.67 (s, 1H), 7.46 (s, 1H), 7.32–7.21 (m, 1H), 6.60 (dd, J = 8.5 Hz, 2.0 Hz, 1H), 4.68–4.60 (m, 3H), 3.77 (d, J = 2.0 Hz, 3H), 2.62 (d, J = 2.0 Hz, 3H).

[0333] Step 4-3: Preparation of (2-methoxy-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile

[0334] Except for using N-(4-amino-3-methoxyphenyl)-5-methylpyrazine-2-carboxamide (180 mg, 0.70 mmol) obtained in Step 4-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (214 mg, yield: 91%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[0335] 11H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 10.80 (s, 1H), 9.17 (d, J = 1.4 Hz, 1H), 8.71 (s, 1H), 7.86 (d, J = 2.1 Hz, 1H), 7.67 (dd, J = 8.8 Hz, 2.1 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 3.91 (s, 3H), 2.64 (s, 3H).

[0336] Example 5: Preparation of (2-chloro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile (Compound 5)

[0337] Step 5-1: Preparation of N-(3-chloro-4-nitrophenyl)-5-methylpyrazine-2-carboxamide

[0338] Except for using 3-chloro-4-nitroaniline (375 mg, 2.17 mmol) instead of 5-nitropyridin-2-amine, in the same manner as in Step 1-1 of Example 1 above, 339 mg (yield: 53%) of the title compound was obtained.

[0339] 1 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 9.19 (d, J = 1.4 Hz, 1H), 8.73 (d, J = 1.4 Hz, 1H), 8.38 (d, J = 2.1 Hz, 1H), 8.22–8.09 (m, 2H), 2.65 (s, 3H).

[0340] Step 5-2: Preparation of N-(4-amino-3-chlorophenyl)-5-methylpyrazine-2-carboxamide

[0341] Except for using N-(3-chloro-4-nitrophenyl)-5-methylpyrazine-2-carboxamide (300 mg, 1.03 mmol) obtained in Step 5-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as in Step 1-2 of Example 1 above, 489 mg (yield: 50%) of the title compound was obtained.

[0342] 1 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 9.12 (d, J = 1.4 Hz, 1H), 8.67 (d, J = 1.5 Hz, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.51 (dd, J = 8.7 Hz, 2.4 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 5.24 (s, 2H), 2.62 (s, 3H).

[0343] Step 5-3: Preparation of (2-chloro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile

[0344] Except for using N-(4-amino-3-chlorophenyl)-5-methylpyrazine-2-carboxamide (120 mg, 0.46 mmol) obtained in Step 5-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 119 mg (yield: 77%) of the title compound was obtained.

[0345] 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.17 (s, 1H), 8.71 (s, 1H), 8.18 (s, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 2.64 (s, 3H).

[0346] Example 6: Preparation of (2-methyl-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile (Compound 6)

[0347] Step 6-1: Preparation of 5-methyl-N-(3-methyl-4-nitrophenyl)pyrazine-2-carboxamide

[0348] Except for using 3-methyl-4-nitroaniline (331 mg, 2.17 mmol) instead of 5-nitropyridin-2-amine, in the same manner as Step 1-1 of Example 1 above, 489 mg (yield: 83%) of the title compound was obtained.

[0349] 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.18 (s, 1H), 8.73 (s, 1H), 8.18–7.95 (m, 3H), 2.65 (s, 3H), 2.56 (s, 3H).

[0350] Step 6-2: Preparation of N-(4-amino-3-methylphenyl)-5-methylpyrazine-2-carboxamide

[0351] Except for using 5-methyl-N-(3-methyl-4-nitrophenyl)pyrazine-2-carboxamide (480 mg, 1.69 mmol) obtained in Step 6-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Step 1-2 of Example 1 above, 268 mg (yield: 63%) of the title compound was obtained.

[0352] 11H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.11 (s, 1H), 8.66 (s, 1H), 7.46 (s, 1H), 7.40 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 6.62 (d, J = 8.5 Hz, 1H), 5.16 (s, 2H), 2.62 (s, 3H), 2.07 (s, 3H).

[0353] Step 6-3: Preparation of (2-methyl-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile

[0354] Except for using N-(4-amino-3-methylphenyl)-5-methylpyrazine-2-carboxamide (260 mg, 1.07 mmol) obtained in Step 6-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 112 mg (yield: 33%) of the title compound was obtained.

[0355] 1 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 10.71 (s, 1H), 9.16 (d, J = 1.4 Hz, 1H), 8.70 (d, J = 1.4 Hz, 1H), 7.91–7.75 (m, 2H), 7.34 (d, J = 8.5 Hz, 1H), 2.64 (s, 3H), 2.36 (s, 3H).

[0356] Example 7: Preparation of (3-fluoro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbazoyl dinitrile (Compound 7)

[0357] Step 7-1: Preparation of N-(2-fluoro-4-nitrophenyl)-5-methylpyrazine-2-carboxamide

[0358] Except for using 2-fluoro-4-nitroaniline (339 mg, 2.61 mmol) to replace 5-nitropyridin-2-amine, in the same manner as Step 1-1 of Example 1 above, 309 mg (yield: 51%) of the title compound was obtained.

[0359] 1 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.21 (s, 0H), 8.75 (s, 1H), 8.39 (t, J = 8.3 Hz, 1H), 8.29 (dd, J = 10.7 Hz, 2.6 Hz, 1H), 8.21 (dd, J = 9.1 Hz, 2.6 Hz, 1H), 2.66 (s, 3H).

[0360] Step 7-2: Preparation of N-(4-amino-2-fluorophenyl)-5-methylpyrazine-2-carboxamide

[0361] Except using N-(2-fluoro-4-nitrophenyl)-5-methylpyrazine-2-carboxamide (250 mg, 0.91 mmol) obtained in Step 7-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 97 mg (yield: 44%) of the title compound was obtained.

[0362] 1 H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.11 (d, J = 1.4 Hz, 1H), 8.67 (d, J = 1.4 Hz, 1H), 7.37 (t, J = 8.7 Hz, 1H), 6.51–6.29 (m, 2H), 5.39 (s, 2H), 2.62 (s, 3H).

[0363] Step 7-3: Preparation of (3-fluoro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile

[0364] Except using N-(4-amino-2-fluorophenyl)-5-methylpyrazine-2-carboxamide (90 mg, 0.37 mmol) obtained in Step 7-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 110 mg (yield: 93%) of the title compound was obtained.

[0365] 1 H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 10.35 (s, 1H), 9.16 (d, J = 1.4 Hz, 1H), 8.72 (d, J = 1.4 Hz, 1H), 7.95 (t, J = 8.5 Hz, 1H), 7.46–7.29 (m, 2H), 2.64 (s, 3H).

[0366] Example 8: Preparation of (3-methyl-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile (Compound 8)

[0367] Step 8-1: Preparation of 5-methyl-N-(2-methyl-4-nitrophenyl)pyrazine-2-carboxamide

[0368] Except using 2-methyl-4-nitroaniline (331 mg, 2.17 mmol) to replace 5-nitropyridin-2-amine, in the same manner as Steps 1-1 of Example 1 above, 514 mg (yield: 87%) of the title compound was obtained.

[0369] 11H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.21 (s, 1H), 8.75 (s, 1H), 8.23 (s, 1H), 8.17 (s, 2H), 2.65 (s, 3H), 2.45 (s, 3H).

[0370] Step 8-2: Preparation of N-(4-amino-2-methylphenyl)-5-methylpyrazine-2-carboxamide

[0371] Except for using 5-methyl-N-(2-methyl-4-nitrophenyl)pyrazine-2-carboxamide (460 mg, 1.69 mmol) obtained in Step 8-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 277 mg (yield: 57%) of the title compound was obtained.

[0372] 1 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 9.11 (s, 1H), 8.66 (d, J = 1.5 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 2.6 Hz, 1H), 6.41 (dd, J = 8.3 Hz, 2.6 Hz, 1H), 5.01 (s, 2H), 2.62 (s, 3H), 2.10 (s, 3H).

[0373] Step 8-3: Preparation of (3-methyl-4-(5-methylpyrazine-2-carboxamido)phenyl)carbamoyl dinitrile

[0374] Except for using N-(4-amino-2-methylphenyl)-5-methylpyrazine-2-carboxamide (260 mg, 1.07 mmol) obtained in Step 8-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 168 mg (yield: 42%) of the title compound was obtained.

[0375] 1 1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 10.21 (s, 1H), 9.15 (s, 1H), 8.70 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.46–7.22 (m, 2H), 2.63 (s, 3H), 2.30 (s, 3H).

[0376] Example 9: Preparation of Methyl (3-methyl-4-(5-methylpyrazine-2-carboxamido)phenyl)carbazonyldinitrile (Compound 9)

[0377] (3-Methyl-4-(5-methylpyrazine-2-carboxamido)phenyl)carbazoyl dinitrile (100 mg, 0.31 mmol) obtained in Example 8 above was dissolved in dimethylformamide (DMF), potassium tert-butoxide (46 mg, 0.41 mmol) was added thereto at room temperature, and then methyl iodide (39 μL, 0.63 mmol) was added thereto. The reaction mixture was stirred at 60 °C for 12 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 4 mg (yield: 3%) of the title compound.

[0378] 1 H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.16 (d, J = 1.5 Hz, 1H), 8.71 (d, J = 1.4 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 2.8 Hz, 1H), 7.38 (dd, J = 8.7 Hz, 2.8 Hz, 1H), 4.06 (s, 3H), 2.64 (s, 3H), 2.33 (s, 3H).

[0379] Example 10: Preparation of (3-Methoxy-4-(5-methylpyrazine-2-carboxamido)phenyl)carbazoyl dinitrile (Compound 10)

[0380] Step 10-1: Preparation of N-(2-methoxy-4-nitrophenyl)-5-methylpyrazine-2-carboxamide

[0381] Except that 2-methoxy-4-nitroaniline (365 mg, 2.17 mmol) was used instead of 5-nitropyridin-2-amine, in the same manner as in Step 1-1 of Example 1 above, 454 mg (yield: 75%) of the title compound was obtained.

[0382] 1 H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.23 (s, 1H), 8.74 (s, 1H), 8.66 (d, J = 9.0 Hz, 1H), 8.08–7.99 (m, 1H), 7.92 (d, J = 2.5 Hz, 1H), 4.09 (s, 3H), 2.65 (s, 3H).

[0383] Step 10-2: Preparation of N-(4-Amino-2-methoxyphenyl)-5-methylpyrazine-2-carboxamide

[0384] Except for using N-(2-methoxy-4-nitrophenyl)-5-methylpyrazine-2-carboxamide (447 mg, 1.55 mmol) obtained in Step 10-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Step 1-2 of Example 1 above, 290 mg (yield: 72%) of the title compound was obtained.

[0385] 1 H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.13 (s, 1H), 8.66 (s, 1H), 7.98 (d, J = 8.5 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 6.18 (dd, J = 8.6 Hz, 2.4 Hz, 1H), 5.11 (s, 2H), 3.82 (s, 3H), 2.62 (s, 3H).

[0386] Step 10-3: Preparation of (3-Methoxy-4-(5-methylpyrazine-2-carboxamido)phenyl)carbazic diimidate

[0387] Except for using N-(4-amino-2-methoxyphenyl)-5-methylpyrazine-2-carboxamide (280 mg, 1.08 mmol) obtained in Step 10-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Step 1-3 of Example 1 above, 181 mg (yield: 50%) of the title compound was obtained.

[0388] 1 H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 10.10 (s, 1H), 9.17 (s, 1H), 8.69 (s, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.22 (s, 1H), 7.13 (dd, J = 8.8 Hz, 2.3 Hz, 1H), 3.96 (s, 3H), 2.63 (s, 3H).

[0389] Example 11: Preparation of (3-chloro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbazoyl dinitrile (Compound 11)

[0390] Step 11-1: Preparation of N-(2-Chloro-4-nitrophenyl)-5-methylpyrazine-2-carboxamide

[0391] Under a nitrogen atmosphere, 5-methylpyrazine-2-carboxylic acid (300 mg, 2.17 mmol) was dissolved in anhydrous dichloromethane, and oxalyl chloride (0.56 mL, 6.52 mmol) and DMF (1 to 2 drops) were added thereto at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour and concentrated under reduced pressure. Under a nitrogen atmosphere, the concentrate and 2-chloro-4-nitroaniline (375 mg, 2.17 mmol) were dissolved in pyridine, and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction product was extracted with an aqueous ammonium chloride solution and dichloromethane to obtain an organic layer. The organic layer was dried over anhydrous magnesium sulfate and filtered to obtain 162 mg (yield: 25%) of the solid title compound.

[0392] 1 H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.25 (d, J = 1.4 Hz, 1H), 8.76 (d, J = 1.4 Hz, 1H), 8.66 (d, J = 9.2 Hz, 1H), 8.49 (d, J = 2.7 Hz, 1H), 8.35 (dd, J = 9.1 Hz, 2.7 Hz, 1H), 2.66 (s, 3H).

[0393] Step 11-2: Preparation of N-(4-Amino-2-chlorophenyl)-5-methylpyrazine-2-carboxamide

[0394] Except using N-(2-chloro-4-nitrophenyl)-5-methylpyrazine-2-carboxamide (150 mg, 0.51 mmol) obtained in Step 11-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 89 mg (yield: 66%) of the title compound was obtained.

[0395] 1 H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.13 (s, 1H), 8.68 (s, 1H), 7.64 (d, J = 8.7 Hz, 1H), 6.71 (d, J = 2.5 Hz, 1H), 6.57 (dd, J = 8.7 Hz, 2.5 Hz, 1H), 5.39 (s, 2H), 2.62 (s, 3H).

[0396] Step 11-3: Preparation of (3-Chloro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbazic diimidate

[0397] Except using N-(4-amino-2-chlorophenyl)-5-methylpyrazine-2-carboxamide (75 mg, 0.28 mmol) obtained in Step 11-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 86 mg (yield: 89%) of the title compound was obtained.

[0398] 1 1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 10.32 (s, 1H), 9.17 (d, J = 1.4 Hz, 1H), 8.71 (d, J = 1.4 Hz, 1H), 8.24 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 8.9 Hz, 2.5 Hz, 1H), 2.64 (s, 3H).

[0399] Example 12: Preparation of (5-Methyl-6-(5-methylpyrazine-2-carboxamido)pyridin-3-yl)carbamoyl dinitrile (Compound 12)

[0400] Step 12-1: Preparation of 5-Methyl-N-(3-methyl-5-nitropyridin-2-yl)pyrazine-2-carboxamide

[0401] Except for using 3-methyl-5-nitropyridin-2-amine (332 mg, 2.17 mmol) instead of 5-nitropyridin-2-amine, in the same manner as in Step 1-1 of Example 1 above, 410 mg (yield: 69%) of the title compound was obtained.

[0402] 1 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.17 (d, J = 1.4 Hz, 1H), 9.13 (d, J = 2.7 Hz, 1H), 8.73 (d, J = 1.4 Hz, 1H), 8.61 (d, J = 2.7 Hz, 1H), 2.65 (s, 3H), 2.40 (s, 3H).

[0403] Step 12-2: Preparation of N-(5-Amino-3-methylpyridin-2-yl)-5-methylpyrazine-2-carboxamide

[0404] Except for using 5-methyl-N-(3-methyl-5-nitropyridin-2-yl)pyrazine-2-carboxamide (400 mg, 1.46 mmol) obtained in Step 12-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as in Step 1-2 of Example 1 above, 211 mg (yield: 59%) of the title compound was obtained.

[0405] 1 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.10 (d, J = 1.6 Hz, 1H), 8.67 (s, 1H), 7.64 (d, J = 2.7 Hz, 1H), 6.86 (d, J = 2.7 Hz, 1H), 5.26 (s, 2H), 2.62 (s, 3H), 2.07 (s, 3H).

[0406] Step 12-3: Preparation of (5-Methyl-6-(5-methylpyrazine-2-carboxamido)pyridin-3-yl)carbazic diimidate

[0407] Except for using N-(5-amino-3-methylpyridin-2-yl)-5-methylpyrazine-2-carboxamide (200 mg, 0.82 mmol) obtained in Step 12-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 231 mg (yield: 88%) of the title compound was obtained.

[0408] 1 H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.14 (s, 1H), 8.71 (d, J = 1.4 Hz, 1H), 8.44 (d, J = 2.6 Hz, 1H), 7.88–7.78 (m, 1H), 2.64 (s, 3H), 2.28 (s, 3H).

[0409] Example 13: Preparation of (4-methyl-6-(5-methylpyrazine-2-carboxamido)pyridin-3-yl)carbamoyl dinitrile (Compound 13)

[0410] Step 13-1: Preparation of 5-Methyl-N-(4-methyl-5-nitropyridin-2-yl)pyrazine-2-carboxamide

[0411] Except for using 4-methyl-5-nitropyridin-2-amine (332 mg, 2.17 mmol) to replace 5-nitropyridin-2-amine, in the same manner as Step 1-1 of Example 1 above, 265 mg (yield: 45%) of the title compound was obtained.

[0412] 1 H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.22 (d, J = 1.5 Hz, 1H), 9.06 (s, 1H), 8.75 (d, J = 1.5 Hz, 1H), 8.32 (s, 1H), 2.66 (d, J = 5.6 Hz, 6H).

[0413] Step 13-2: Preparation of N-(5-Amino-4-methylpyridin-2-yl)-5-methylpyrazine-2-carboxamide

[0414] Except for using 5-methyl-N-(4-methyl-5-nitropyridin-2-yl)pyrazine-2-carboxamide (250 mg, 0.91 mmol) obtained in Step 13-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Step 1-2 of Example 1 above, 28 mg (yield: 13%) of the title compound was obtained.

[0415] 11H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 9.16 (d, J = 1.4 Hz, 1H), 8.68 (d, J = 1.4 Hz, 1H), 7.87 (s, 1H), 7.72 (s, 1H), 5.05 (s, 2H), 2.63 (s, 3H), 2.14 (s, 3H).

[0416] Step 13-3: Preparation of (4-Methyl-6-(5-methylpyrazine-2-carboxamido)pyridin-3-yl)carbazic diimidate

[0417] Except for using N-(5-amino-4-methylpyridin-2-yl)-5-methylpyrazine-2-carboxamide (25 mg, 0.10 mmol) obtained in Step 13-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 20 mg (yield: 61%) of the title compound was obtained.

[0418] 1 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 9.20 (d, J = 1.4 Hz, 1H), 8.72 (d, J = 1.5 Hz, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 2.65 (s, 3H), 2.45 (s, 3H).

[0419] Example 14: Preparation of (5-(5-methylpyrazine-2-carboxamido)pyridin-2-yl)carbamoyl dinitrile (Compound 14)

[0420] Step 14-1: Preparation of 5-Methyl-N-(6-nitropyridin-3-yl)pyrazine-2-carboxamide

[0421] Except for using 6-nitropyridin-3-amine (302 mg, 2.17 mmol) to replace 5-nitropyridin-2-amine, in the same manner as Steps 1-1 of Example 1 above, 304 mg (yield: 54%) of the title compound was obtained.

[0422] 1 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 9.22 (d, J = 1.4 Hz, 1H), 9.15 (d, J = 2.5 Hz, 1H), 8.77–8.72 (m, 2H), 8.41 (d, J = 8.9 Hz, 1H), 2.66 (s, 3H).

[0423] Step 14-2: Preparation of N-(6-Aminopyridin-3-yl)-5-methylpyrazine-2-carboxamide

[0424] Except for using 5-methyl-N-(6-nitropyridin-3-yl)pyrazine-2-carboxamide (290 mg, 1.12 mmol) obtained in Step 14-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 103 mg (yield: 40%) of the title compound was obtained.

[0425] 1 H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.12 (d, J = 1.5 Hz, 1H), 8.67 (d, J = 1.4 Hz, 1H), 8.35 (d, J = 2.6 Hz, 1H), 7.80 (dd, J = 8.8 Hz, 2.7 Hz, 1H), 6.45 (d, J = 8.8 Hz, 1H), 5.82 (s, 2H), 2.62 (s, 3H).

[0426] Step 14-3: Preparation of (5-(5-Methylpyrazine-2-carboxamido)pyridin-2-yl)carbazic diimidate

[0427] Except for using N-(6-aminopyridin-3-yl)-5-methylpyrazine-2-carboxamide (90 mg, 0.39 mmol) obtained in Step 14-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 34 mg (yield: 28%) of the title compound was obtained.

[0428] 1 H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 10.59 (s, 1H), 9.12 (d, J = 1.4 Hz, 1H), 8.68 (d, J = 1.4 Hz, 1H), 8.06 (d, J = 2.9 Hz, 1H), 7.84 (dd, J = 9.7 Hz, 2.9 Hz, 1H), 6.38 (d, J = 9.7 Hz, 1H), 2.62 (s, 3H).

[0429] Example 15: Preparation of (6-benzamidopyridin-3-yl)carbamoyl dinitrile (Compound 15)

[0430] Step 15-1: Preparation of N-(5-Nitropyridin-2-yl)benzamide

[0431] Except for using benzoic acid (300 mg, 2.46 mmol) to replace 5-methylpyrazine-2-carboxylic acid, and using 2-amino-5-nitropyridine (342 mg, 2.46 mmol) to replace 2-chloro-4-nitroaniline, in the same manner as Step 11-1 of Example 11 above, 424 mg (yield: 71%) of the title compound was obtained.

[0432] 1 1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 9.24 (d, J = 2.8 Hz, 1H), 8.67 (dd, J = 9.3 Hz, 2.9 Hz, 1H), 8.45 (d, J = 9.3 Hz, 1H), 8.14–7.94 (m, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H).

[0433] Step 15-2: Preparation of N-(5-Aminopyridin-2-yl)benzamide

[0434] Except for using N-(5-nitropyridin-2-yl)benzamide (410 mg, 1.69 mmol) obtained in Step 15-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 328 mg (yield: 91%) of the title compound was obtained.

[0435] 1 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 7.99 (d, J = 7.3 Hz, 2H), 7.81 (d, J = 8.7 Hz, 1H), 7.75 (d, J = 2.8 Hz, 1H), 7.61–7.53 (m, 1H), 7.52–7.43 (m, 2H), 7.02 (dd, J = 8.7 Hz, 2.9 Hz, 1H), 5.17 (s, 2H).

[0436] Step 15-3: Preparation of (6-Benzamidopyridin-3-yl)carbazic diimidate

[0437] Except for using N-(5-aminopyridin-2-yl)benzamide (320 mg, 1.50 mmol) obtained in Step 15-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 86 mg (yield: 89%) of the title compound was obtained.

[0438] 1 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.51 (d, J = 2.7 Hz, 1H), 8.25 (d, J = 9.0 Hz, 1H), 8.03 (d, J = 7.2 Hz, 2H), 7.93 (dd, J = 9.1 Hz, 2.7 Hz, 1H), 7.61 (t, J = 7.3 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H).

[0439] Example 16: Preparation of (6-(4-fluorobenzamido)pyridin-3-yl)carbamoyl dinitrile (Compound 16)

[0440] Step 16-1: Preparation of 4-Fluoro-N-(5-nitropyridin-2-yl)benzamide

[0441] Except for using 4-fluorobenzoic acid (300 mg, 2.14 mmol) instead of 5-methylpyrazine-2-carboxylic acid and using 2-amino-5-nitropyridine (298 mg, 2.14 mmol) instead of 2-chloro-4-nitroaniline, the title compound (369 mg, yield: 66%) was obtained in the same manner as in Step 11-1 of Example 11 above.

[0442] 1 H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 9.24 (d, J = 2.8 Hz, 1H), 8.67 (dd, J = 9.3 Hz, 2.8 Hz, 1H), 8.43 (d, J = 9.2 Hz, 1H), 8.13 (dd, J = 8.8 Hz, 5.5 Hz, 2H), 7.38 (t, J = 8.9 Hz, 2H).

[0443] Step 16-2: Preparation of N-(5-Aminopyridin-2-yl)-4-fluorobenzamide

[0444] Except for using 4-fluoro-N-(5-nitropyridin-2-yl)benzamide (350 mg, 1.34 mmol) obtained in Step 16-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (273 mg, yield: 88%) was obtained in the same manner as in Step 1-2 of Example 1 above.

[0445] 1 H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.07 (dd, J = 8.6 Hz, 5.5 Hz, 2H), 7.83–7.72 (m, 2H), 7.31 (t, J = 8.8 Hz, 2H), 7.03 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 5.18 (s, 2H).

[0446] Step 16-3: Preparation of (6-(4-Fluorobenzamido)pyridin-3-yl)carbazic diimidate

[0447] Except for using N-(5-aminopyridin-2-yl)-4-fluorobenzamide (260 mg, 1.12 mmol) obtained in Step 16-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (160 mg, yield: 46%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[0448] 11H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 11.01 (s, 1H), 8.51 (d, J = 2.7 Hz, 1H), 8.23 (d, J = 9.1 Hz, 1H), 8.11 (dd, J = 8.6 Hz, 5.5 Hz, 2H), 7.92 (dd, J = 9.0 Hz, 2.8 Hz, 1H), 7.35 (t, J = 8.8 Hz, 2H).

[0449] Example 17: Preparation of (6-(2-fluorobenzamido)pyridin-3-yl)carbamoyl dinitrile (Compound 17)

[0450] Step 17-1: Preparation of 2-Fluoro-N-(5-nitropyridin-2-yl)benzamide

[0451] Except for using 2-fluorobenzoic acid (300 mg, 2.14 mmol) instead of 5-methylpyrazine-2-carboxylic acid and using 2-amino-5-nitropyridine (298 mg, 2.14 mmol) instead of 2-chloro-4-nitroaniline, in the same manner as in Step 11-1 of Example 11 above, 358 mg (yield: 64%) of the title compound was obtained.

[0452] 1 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 9.22 (d, J = 2.8 Hz, 1H), 8.68 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 8.42 (d, J = 9.2 Hz, 1H), 7.73 (t, J = 7.4 Hz, 1H), 7.63 (q, J = 6.2 Hz, 5.8 Hz, 1H), 7.35 (q, J = 8.3 Hz, 7.1 Hz, 2H).

[0453] Step 17-2: Preparation of N-(5-Aminopyridin-2-yl)-2-fluorobenzamide

[0454] Except for using 2-fluoro-N-(5-nitropyridin-2-yl)benzamide (340 mg, 1.30 mmol) obtained in Step 17-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as in Step 1-2 of Example 1 above, 204 mg (yield: 68%) of the title compound was obtained.

[0455] 1 1H NMR (400 MHz, DMSO-d6) δ 10.42–10.03 (m, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.73–7.63 (m, 2H), 7.58–7.52 (m, 1H), 7.35–7.26 (m, 2H), 7.02 (dd, J = 8.7 Hz, 2.9 Hz, 1H), 5.18 (s, 2H).

[0456] Step 17-3: Preparation of (6-(2-Fluorobenzamido)pyridin-3-yl)carbazic diimidate

[0457] Except for using N-(5-aminopyridin-2-yl)-2-fluorobenzamide (190 mg, 0.82 mmol) obtained in Step 17-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (161 mg, yield: 63%) was obtained in the same manner as Steps 1-3 of Example 1 above.

[0458] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.49 (d, J = 2.8 Hz, 1H), 8.25 (d, J = 9.1 Hz, 1H), 7.93 (dd, J = 9.0 Hz, 2.7 Hz, 1H), 7.70 (td, J = 7.5 Hz, 1.8 Hz, 1H), 7.64–7.56 (m, 1H), 7.40–7.28 (m, 2H).

[0459] Example 18: Preparation of (6-(3-fluorobenzamido)pyridin-3-yl)carbamoyl dinitrile (Compound 18)

[0460] Step 18-1: Preparation of 3-Fluoro-N-(5-nitropyridin-2-yl)benzamide

[0461] Except for using 3-fluorobenzoic acid (300 mg, 2.14 mmol) to replace 5-methylpyrazine-2-carboxylic acid and using 2-amino-5-nitropyridine (298 mg, 2.14 mmol) to replace 2-chloro-4-nitroaniline, the title compound (288 mg, yield: 51%) was obtained in the same manner as Step 11-1 of Example 11 above.

[0462] 1 H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.25 (d, J = 2.2 Hz, 0H), 8.68 (dd, J = 9.3 Hz, 2.8 Hz, 1H), 8.43 (dd, J = 9.3 Hz, 0.7 Hz, 1H), 7.94–7.85 (m, 2H), 7.60 (td, J = 8.1 Hz, 5.9 Hz, 1H), 7.55–7.47 (m, 1H).

[0463] Step 18-2: Preparation of N-(5-Aminopyridin-2-yl)-3-fluorobenzamide

[0464] Except using 3-fluoro-N-(5-nitropyridin-2-yl)benzamide (250 mg, 0.96 mmol) obtained in Step 18-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 188 mg (yield: 85%) of the title compound was obtained.

[0465] 1 H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 7.87–7.78 (m, 3H), 7.75 (dd, J = 2.9 Hz, 0.7 Hz, 1H), 7.54 (td, J = 8.0 Hz, 5.9 Hz, 1H), 7.43–7.37 (m, 2H), 5.20 (s, 2H).

[0466] Step 18-3: Preparation of (6-(3-Fluorobenzamido)pyridin-3-yl)carbazic diimidate

[0467] Except using N-(5-aminopyridin-2-yl)-3-fluorobenzamide (150 mg, 0.65 mmol) obtained in Step 18-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 75 mg (yield: 38%) of the title compound was obtained.

[0468] 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.53 (d, J = 2.8 Hz, 1H), 8.24 (d, J = 9.0 Hz, 1H), 7.96–7.82 (m, 3H), 7.58 (td, J = 8.0 Hz, 5.8 Hz, 1H), 7.49–7.42 (m, 1H).

[0469] Example 19: Preparation of (6-(3-fluoro-5-methylbenzamido)pyridin-3-yl)carbonohydrazonitrile (Compound 19)

[0470] Step 19-1: Preparation of 3-Fluoro-5-methyl-N-(5-nitropyridin-2-yl)benzamide

[0471] Except using 3-fluoro-5-methylbenzoic acid (300 mg, 1.95 mmol) to replace 5-methylpyrazine-2-carboxylic acid, and using 2-amino-5-nitropyridine (271 mg, 1.95 mmol) to replace 2-chloro-4-nitroaniline, in the same manner as Step 11-1 of Example 11 above, 403 mg (yield: 75%) of the title compound was obtained.

[0472] 11H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 9.24 (d, J = 2.8 Hz, 1H), 8.67 (dd, J = 9.2 Hz, 2.9 Hz, 1H), 8.42 (d, J = 9.3 Hz, 1H), 7.75 (s, 1H), 7.66 (dt, J = 9.6 Hz, 2.0 Hz, 1H), 7.36–7.31 (m, 1H), 2.41 (s, 3H).

[0473] Step 19-2: Preparation of N-(5-aminopyridin-2-yl)-3-fluoro-5-methylbenzamide

[0474] Except for using 3-fluoro-5-methyl-N-(5-nitropyridin-2-yl)benzamide (380 mg, 1.38 mmol) obtained in Step 19-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (182 mg, yield: 54%) was obtained in the same manner as Steps 1-2 of Example 1 above.

[0475] 1 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 2.8 Hz, 1H), 7.69 (s, 1H), 7.59 (d, J = 9.8 Hz, 1H), 7.24 (d, J = 9.6 Hz, 1H), 7.02 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 5.19 (s, 2H), 2.38 (s, 3H).

[0476] Step 19-3: Preparation of (6-(3-fluoro-5-methylbenzamido)pyridin-3-yl)carbamoyl dinitrile

[0477] Except for using N-(5-aminopyridin-2-yl)-3-fluoro-5-methylbenzamide (150 mg, 0.61 mmol) obtained in Step 19-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (114 mg, yield: 58%) was obtained in the same manner as Steps 1-3 of Example 1 above.

[0478] 1 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.52 (d, J = 2.8 Hz, 1H), 8.23 (d, J = 9.0 Hz, 1H), 7.92 (dd, J = 9.1 Hz, 2.8 Hz, 1H), 7.73 (s, 1H), 7.63 (dt, J = 9.7 Hz, 2.1 Hz, 1H), 7.37–7.23 (m, 1H), 2.40 (s, 3H).

[0479] Example 20: Preparation of (6-(2-Fluoro-3-methylbenzamido)pyridin-3-yl)carbazic di-nitrile (Compound 20)

[0480] Step 20-1: Preparation of 2-fluoro-3-methyl-N-(5-nitropyridin-2-yl)benzamide

[0481] Except using 2-fluoro-3-methylbenzoic acid (300 mg, 1.95 mmol) instead of 5-methylpyrazine-2-carboxylic acid and using 2-amino-5-nitropyridine (271 mg, 1.95 mmol) instead of 2-chloro-4-nitroaniline, in the same manner as in Step 11-1 of Example 11 above, 396 mg (yield: 74%) of the title compound was obtained.

[0482] 1 H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 9.21 (d, J = 2.8 Hz, 1H), 8.68 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 8.42 (d, J = 9.2 Hz, 1H), 7.51 (qd, J = 7.4 Hz, 3.7 Hz, 2H), 7.22 (t, J = 7.6 Hz, 1H), 2.30 (d, J = 2.1 Hz, 3H).

[0483] Step 20-2: Preparation of N-(5-aminopyridin-2-yl)-2-fluoro-3-methylbenzamide

[0484] Except using 2-fluoro-3-methyl-N-(5-nitropyridin-2-yl)benzamide (380 mg, 1.38 mmol) obtained in Step 20-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as in Step 1-2 of Example 1 above, 268 mg (yield: 79%) of the title compound was obtained.

[0485] 1 H NMR (400 MHz, DMSO-d6) δ 10.19 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 2.8 Hz, 1H), 7.55–7.37 (m, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.01 (dd, J = 8.7 Hz, 2.9 Hz, 1H), 5.17 (s, 2H), 2.28 (d, J = 2.1 Hz, 3H).

[0486] Step 20-3: Preparation of (6-(2-fluoro-3-methylbenzamido)pyridin-3-yl)carbamoyl dinitrile

[0487] Except for using N-(5-aminopyridin-2-yl)-2-fluoro-3-methylbenzamide (250 mg, 1.02 mmol) obtained in Step 20-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 292 mg (yield: 89%) of the title compound was obtained.

[0488] 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.48 (d, J = 2.7 Hz, 1H), 8.24 (d, J = 9.1 Hz, 1H), 7.92 (dd, J = 9.1 Hz, 2.8 Hz, 1H), 7.56–7.42 (m, 2H), 7.20 (t, J = 7.6 Hz, 1H), 2.29 (d, J = 2.1 Hz, 3H).

[0489] Example 21: Preparation of (6-(4-fluorobenzamido)pyridin-3-yl)carbamoyl dinitrile (Compound 21)

[0490] Step 21-1: Preparation of 4-fluoro-3-methyl-N-(5-nitropyridin-2-yl)benzamide

[0491] Except for using 4-fluorobenzoic acid (300 mg, 1.95 mmol) instead of 5-methylpyrazine-2-carboxylic acid and using 2-amino-5-nitropyridine (271 mg, 1.95 mmol) instead of 2-chloro-4-nitroaniline, in the same manner as Step 11-1 of Example 11 above, 349 mg (yield: 65%) of the title compound was obtained.

[0492] 1 H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 9.30–9.15 (m, 1H), 8.66 (dd, J = 9.3 Hz, 2.8 Hz, 1H), 8.42 (dd, J = 9.3 Hz, 0.7 Hz, 1H), 8.05 (dd, J = 7.4 Hz, 1.5 Hz, 1H), 7.94 (ddd, J = 8.0 Hz, 5.0 Hz, 2.5 Hz, 1H), 7.30 (dd, J = 9.6 Hz, 8.6 Hz, 1H), 2.31 (d, J = 2.0 Hz, 3H).

[0493] Step 21-2: Preparation of N-(5-aminopyridin-2-yl)-4-fluoro-3-methylbenzamide

[0494] Except for using 4-fluoro-3-methyl-N-(5-nitropyridin-2-yl)benzamide (310 mg, 1.13 mmol) obtained in Step 21-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 235 mg (yield: 85%) of the title compound was obtained.

[0495] 1 H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 7.98 (dd, J = 7.3 Hz, 1.8 Hz, 1H), 7.87 (ddd, J = 7.9 Hz, 5.1 Hz, 2.4 Hz, 1H), 7.81–7.77 (m, 1H), 7.74 (dd, J = 2.8 Hz, 0.7 Hz, 1H), 7.23 (dd, J = 9.7 Hz, 8.5 Hz, 1H), 7.02 (dd, J = 8.7 Hz, 2.9 Hz, 1H), 5.17 (s, 2H), 2.29 (d, J = 2.0 Hz, 3H).

[0496] Step 21-3: Preparation of (6-(4-fluoro-3-methylbenzamido)pyridin-3-yl)carbamoyl dinitrile

[0497] Except for using N-(5-aminopyridin-2-yl)-4-fluoro-3-methylbenzamide (200 mg, 0.81 mmol) obtained in Step 21-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 145 mg (yield: 55%) of the title compound was obtained.

[0498] 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.51 (d, J = 2.7 Hz, 1H), 8.22 (d, J = 9.0 Hz, 1H), 8.01 (dd, J = 7.6 Hz, 2.4 Hz, 1H), 7.92 (dd, J = 8.9 Hz, 2.8 Hz, 2H), 7.27 (t, J = 9.1 Hz, 1H), 2.31 (d, J = 1.9 Hz, 3H).

[0499] Example 22: Preparation of (6-(3-fluoro-4-methylbenzamido)pyridin-3-yl)carbazoyl dinitrile (Compound 22)

[0500] Step 22-1: Preparation of 3-fluoro-4-methyl-N-(5-nitropyridin-2-yl)benzamide

[0501] Except for using 3-fluoro-4-methylbenzoic acid (300 mg, 1.95 mmol) instead of 5-methylpyrazine-2-carboxylic acid, and using 2-amino-5-nitropyridine (271 mg, 1.95 mmol) instead of 2-chloro-4-nitroaniline, the title compound (380 mg, yield: 71%) was obtained in the same manner as in Step 11-1 of Example 11 above.

[0502] 1 H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 9.24 (dd, J = 2.9 Hz, 0.7 Hz, 1H), 8.66 (dd, J = 9.3 Hz, 2.9 Hz, 1H), 8.42 (dd, J = 9.2 Hz, 0.7 Hz, 1H), 8.04–7.72 (m, 2H), 7.51–7.35 (m, 1H), 2.32 (d, J = 1.9 Hz, 3H).

[0503] Step 22-2: Preparation of N-(5-aminopyridin-2-yl)-3-fluoro-4-methylbenzamide

[0504] Except for using 3-fluoro-4-methyl-N-(5-nitropyridin-2-yl)benzamide (350 mg, 1.27 mmol) obtained in Step 22-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (259 mg, yield: 83%) was obtained in the same manner as in Step 1-2 of Example 1 above.

[0505] 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.85–7.72 (m, 4H), 7.40 (t, J = 7.8 Hz, 1H), 7.02 (dd, J = 8.7 Hz, 2.9 Hz, 1H), 5.18 (s, 2H), 2.30 (d, J = 2.1 Hz, 3H).

[0506] Step 22-3: Preparation of (6-(3-fluoro-4-methylbenzamido)pyridin-3-yl)carbamoyl dinitrile

[0507] Except for using N-(5-aminopyridin-2-yl)-3-fluoro-4-methylbenzamide (240 mg, 0.98 mmol) obtained in Step 22-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (18 mg, yield: 6%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[0508] 11H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.51 (d, J = 2.7 Hz, 1H), 8.23 (d, J = 9.1 Hz, 1H), 7.92 (dd, J = 9.1 Hz, 2.8 Hz, 1H), 7.85–7.77 (m, 2H), 7.44 (t, J = 7.8 Hz, 1H), 2.31 (d, J = 1.9 Hz, 3H).

[0509] Example 23: Preparation of (6-(4-methylbenzamido)pyridin-3-yl)carbamoyl dinitrile (Compound 23)

[0510] Step 23-1: Preparation of 4-methyl-N-(5-nitropyridin-2-yl)benzamide

[0511] Except for using p-toluic acid (300 mg, 2.20 mmol) instead of 5-methylpyrazine-2-carboxylic acid and 2-amino-5-nitropyridine (306 mg, 2.20 mmol) instead of 2-chloro-4-nitroaniline, the title compound (412 mg, yield: 73%) was obtained in the same manner as in Step 11-1 of Example 11 above.

[0512] 1 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 9.23 (d, J = 2.8 Hz, 1H), 8.65 (dd, J = 9.3 Hz, 2.8 Hz, 1H), 8.44 (d, J = 9.3 Hz, 1H), 7.97 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 2.40 (s, 3H).

[0513] Step 23-2: Preparation of N-(5-aminopyridin-2-yl)-4-methylbenzamide

[0514] Except for using 4-methyl-N-(5-nitropyridin-2-yl)benzamide (400 mg, 1.55 mmol) obtained in Step 23-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (265 mg, yield: 75%) was obtained in the same manner as in Step 1-2 of Example 1 above.

[0515] 1 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.80 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 2.8 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.01 (dd, J = 8.7 Hz, 2.9 Hz, 1H), 5.15 (s, 2H), 2.37 (s, 3H).

[0516] Step 23-3: Preparation of (6-(4-methylbenzamido)pyridin-3-yl)carbamoyl dinitrile

[0517] Except for using N-(5-aminopyridin-2-yl)-4-methylbenzamide (250 mg, 1.10 mmol) obtained in Step 23-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 269 mg (yield: 80%) of the title compound was obtained.

[0518] 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.50 (d, J = 2.7 Hz, 1H), 8.23 (d, J = 9.1 Hz, 1H), 7.98–7.89 (m, 3H), 7.32 (d, J = 8.0 Hz, 2H), 2.38 (s, 3H).

[0519] Example 24: Preparation of (6-(3-methylbenzamido)pyridin-3-yl)carbamoyl dinitrile (Compound 24)

[0520] Step 24-1: Preparation of 3-methyl-N-(5-nitropyridin-2-yl)benzamide

[0521] Except for using m-toluic acid (300 mg, 2.20 mmol) to replace 5-methylpyrazine-2-carboxylic acid, and using 2-amino-5-nitropyridine (306 mg, 2.20 mmol) to replace 2-chloro-4-nitroaniline, in the same manner as Step 11-1 of Example 11 above, 432 mg (yield: 76%) of the title compound was obtained.

[0522] 1 H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 9.23 (d, J = 2.8 Hz, 1H), 8.66 (dd, J = 9.3 Hz, 2.8 Hz, 1H), 8.44 (d, J = 9.3 Hz, 1H), 7.97–7.78 (m, 2H), 7.52–7.37 (m, 2H), 2.40 (s, 3H).

[0523] Step 24-2: Preparation of N-(5-aminopyridin-2-yl)-3-methylbenzamide

[0524] Except for using 3-methyl-N-(5-nitropyridin-2-yl)benzamide (400 mg, 1.55 mmol) obtained in Step 24-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 308 mg (yield: 87%) of the title compound was obtained.

[0525] 11H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 7.84–7.73 (m, 3H), 7.36 (d, J = 5.2 Hz, 1H), 7.02 (dd, J = 8.7 Hz, 2.9 Hz, 1H), 5.16 (s, 2H), 2.37 (s, 3H).

[0526] Step 24-3: Preparation of (6-(3-methylbenzamido)pyridin-3-yl)carbamoyl dinitrile

[0527] Except for using N-(5-aminopyridin-2-yl)-3-methylbenzamide (280 mg, 1.23 mmol) obtained in Step 24-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 370 mg (yield: 99%) of the title compound was obtained.

[0528] 1 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.51 (d, J = 2.7 Hz, 1H), 8.24 (d, J = 9.1 Hz, 1H), 7.92 (dd, J = 9.1 Hz, 2.8 Hz, 1H), 7.86 (s, 1H), 7.83–7.80 (m, 1H), 7.40 (d, J = 6.2 Hz, 2H), 2.39 (s, 3H).

[0529] Example 25: Preparation of (6-(2-methylbenzamido)pyridin-3-yl)carbamoyl dinitrile (Compound 25)

[0530] Step 25-1: Preparation of 2-methyl-N-(5-nitropyridin-2-yl)benzamide

[0531] Except for using o-toluic acid (300 mg, 2.20 mmol) to replace 5-methylpyrazine-2-carboxylic acid and using 2-amino-5-nitropyridine (306 mg, 2.20 mmol) to replace 2-chloro-4-nitroaniline, in the same manner as Step 11-1 of Example 11 above, 396 mg (yield: 70%) of the title compound was obtained.

[0532] 1 1H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 9.20 (d, J = 2.7 Hz, 1H), 8.66 (dd, J = 9.2 Hz, 2.9 Hz, 1H), 8.44 (d, J = 9.3 Hz, 1H), 7.56–7.51 (m, 1H), 7.42 (td, J = 7.5 Hz, 1.4 Hz, 1H), 7.34–7.27 (m, 2H), 2.40 (s, 3H).

[0533] Step 25-2: Preparation of N-(5-aminopyridin-2-yl)-2-methylbenzamide

[0534] Except for using 2-methyl-N-(5-nitropyridin-2-yl)benzamide (370 mg, 1.44 mmol) obtained in Step 25-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 260 mg (yield: 79%) of the title compound was obtained.

[0535] 1 H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 2.8 Hz, 1H), 7.44–7.39 (m, 1H), 7.34 (td, J = 7.4 Hz, 1.5 Hz, 1H), 7.28–7.21 (m, 2H), 7.01 (dd, J = 8.7 Hz, 2.9 Hz, 1H), 5.13 (s, 2H), 2.37 (s, 3H).

[0536] Step 25-3: Preparation of (6-(2-methylbenzamido)pyridin-3-yl)carbamoyl dinitrile

[0537] Except for using N-(5-aminopyridin-2-yl)-2-methylbenzamide (250 mg, 1.10 mmol) obtained in Step 25-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 226 mg (yield: 68%) of the title compound was obtained.

[0538] 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.47 (d, J = 2.7 Hz, 1H), 8.24 (d, J = 9.1 Hz, 1H), 7.92 (dd, J = 9.1 Hz, 2.8 Hz, 1H), 7.50–7.46 (m, 1H), 7.39 (td, J = 7.5 Hz, 1.4 Hz, 1H), 7.33–7.25 (m, 2H), 2.39 (s, 3H).

[0539] Example 26: Preparation of (6-(3-(trifluoromethyl)benzamido)pyridin-3-yl)carbamoyl dinitrile (Compound 26)

[0540] Step 26-1: Preparation of N-(5-nitropyridin-2-yl)-3-(trifluoromethyl)benzamide

[0541] Except for using 3-(trifluoromethyl)benzoic acid (300 mg, 1.58 mmol) instead of 5-methylpyrazine-2-carboxylic acid, and using 2-amino-5-nitropyridine (219 mg, 1.58 mmol) instead of 2-chloro-4-nitroaniline, in the same manner as in Step 11-1 of Example 11 above, the title compound was obtained, and the solvent was removed therefrom. The title compound was used in the next step without further purification.

[0542] Step 26-2: Preparation of N-(5-aminopyridin-2-yl)-3-(trifluoromethyl)benzamide

[0543] Except for using N-(5-nitropyridin-2-yl)-3-(trifluoromethyl)benzamide (230 mg, 0.74 mmol) obtained in Step 26-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as in Step 1-2 of Example 1 above, 134 mg (yield: 65%) of the title compound was obtained.

[0544] 1 H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.34 (s, 1H), 8.28 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.78–7.70 (m, 2H), 7.04 (dd, J = 8.7 Hz, 2.9 Hz, 1H), 5.22 (s, 2H).

[0545] Step 26-3: Preparation of (6-(3-(trifluoromethyl)benzamido)pyridin-3-yl)carbamoyl dinitrile

[0546] Except for using N-(5-aminopyridin-2-yl)-3-(trifluoromethyl)benzamide (120 mg, 0.43 mmol) obtained in Step 26-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as in Step 1-3 of Example 1 above, 133 mg (yield: 87%) of the title compound was obtained.

[0547] 1 H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.53 (d, J = 2.7 Hz, 1H), 8.38 (s, 1H), 8.31 (d, J = 7.8 Hz, 1H), 8.26 (d, J = 9.1 Hz, 1H), 8.01–7.91 (m, 2H), 7.77 (t, J = 7.8 Hz, 1H).

[0548] Example 27: Preparation of (6-(4-(trifluoromethyl)benzamido)pyridin-3-yl)carbamimidodinitrile (Compound 27)

[0549] Step 27-1: Preparation of N-(5-nitropyridin-2-yl)-4-(trifluoromethyl)benzamide

[0550] Except for using 4-(trifluoromethyl)benzoic acid (300 mg, 1.58 mmol) instead of 5-methylpyrazine-2-carboxylic acid, and using 2-amino-5-nitropyridine (219 mg, 1.58 mmol) instead of 2-chloro-4-nitroaniline, the title compound was obtained in the same manner as in Step 11-1 of Example 11 above, and the solvent was removed therefrom. The title compound was used in the next step without further purification.

[0551] Step 27-2: Preparation of N-(5-aminopyridin-2-yl)-4-(trifluoromethyl)benzamide

[0552] Except for using N-(5-nitropyridin-2-yl)-4-(trifluoromethyl)benzamide (250 mg, 0.80 mmol) obtained in Step 27-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (130 mg, yield: 58%) was obtained in the same manner as in Step 1-2 of Example 1 above.

[0553] 1 H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.16 (d, J = 8.1 Hz, 2H), 7.84 (dd, J = 14.0 Hz, 8.4 Hz, 3H), 7.76 (d, J = 2.8 Hz, 1H), 7.03 (dd, J = 8.7 Hz, 2.9 Hz, 1H), 5.22 (s, 2H).

[0554] Step 27-3: Preparation of (6-(4-(trifluoromethyl)benzamido)pyridin-3-yl)carbamoyl dinitrile

[0555] Except for using N-(5-aminopyridin-2-yl)-4-(trifluoromethyl)benzamide (110 mg, 0.39 mmol) obtained in Step 27-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (138 mg, yield: 98%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[0556] 1 H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 8.53 (d, J = 2.8 Hz, 1H), 8.26 (d, J = 9.1 Hz, 1H), 8.20 (d, J = 8.1 Hz, 2H), 7.94 (dd, J = 9.0 Hz, 2.8 Hz, 1H), 7.89 (d, J = 8.1 Hz, 2H).

[0557] Preparation of Example 28: (6-(2-(Trifluoromethyl)benzamido)pyridin-3-yl)carbazic di-nitrile (Compound 28)

[0558] Step 28-1: Preparation of N-(5-nitropyridin-2-yl)-2-(trifluoromethyl)benzamide

[0559] Except for using 2-(trifluoromethyl)benzoic acid (300 mg, 1.58 mmol) instead of 5-methylpyrazine-2-carboxylic acid and using 2-amino-5-nitropyridine (219 mg, 1.58 mmol) instead of 2-chloro-4-nitroaniline, in the same manner as in Step 11-1 of Example 11 above, 138 mg (yield: 28%) of the title compound was obtained.

[0560] 1 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.21 (d, J = 2.8 Hz, 1H), 8.68 (dd, J = 9.2 Hz, 2.9 Hz, 1H), 8.39 (d, J = 9.2 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.82–7.71 (m, 3H).

[0561] Step 28-2: Preparation of N-(5-aminopyridin-2-yl)-2-(trifluoromethyl)benzamide

[0562] Except for using N-(5-nitropyridin-2-yl)-2-(trifluoromethyl)benzamide (120 mg, 0.39 mmol) obtained in Step 28-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as in Step 1-2 of Example 1 above, 84 mg (yield: 78%) of the title compound was obtained.

[0563] 1 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.76–7.59 (m, 4H), 7.02 (dd, J = 8.8 Hz, 2.9 Hz, 1H), 5.17 (s, 2H).

[0564] Step 28-3: Preparation of (6-(4-(Trifluoromethyl)benzamido)pyridin-3-yl)carbazonyldinitrile

[0565] Except for using N-(5-aminopyridin-2-yl)-2-(trifluoromethyl)benzamide (75 mg, 0.27 mmol) obtained in Step 28-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as in Step 1-3 of Example 1 above, 58 mg (yield: 61%) of the title compound was obtained.

[0566] 11H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.48 (d, J = 2.8 Hz, 1H), 8.21 (d, J = 9.1 Hz, 1H), 7.93 (dd, J = 9.1 Hz, 2.8 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.80–7.67 (m, 3H).

[0567] Example 29: Preparation of (6-(Pyrimidine-2-carboxamido)pyridin-3-yl)carbonohydrazonitrile (Compound 29)

[0568] Step 29-1: Preparation of N-(5-Nitropyridin-2-yl)pyrimidine-2-carboxamide

[0569] Except for using pyrimidine-2-carboxylic acid (300 mg, 2.42 mmol) instead of 5-methylpyrazine-2-carboxylic acid and 2-amino-5-nitropyridine (336 mg, 2.42 mmol) instead of 2-chloro-4-nitroaniline, the title compound (180 mg, yield: 30%) was obtained in the same manner as in Step 11-1 of Example 11 above.

[0570] 1 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.25 (d, J = 2.8 Hz, 1H), 9.09 (d, J = 4.9 Hz, 2H), 8.74 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 8.48 (d, J = 9.2 Hz, 1H), 7.82 (t, J = 4.9 Hz, 1H).

[0571] Step 29-2: Preparation of N-(5-Aminopyridin-2-yl)pyrimidine-2-carboxamide

[0572] Except for using N-(5-nitropyridin-2-yl)pyrimidine-2-carboxamide (150 mg, 0.61 mmol) obtained in Step 29-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (52 mg, yield: 40%) was obtained in the same manner as in Step 1-2 of Example 1 above.

[0573] 1 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.03 (d, J = 4.9 Hz, 2H), 7.96 (d, J = 8.7 Hz, 1H), 7.83–7.67 (m, 2H), 7.07 (dd, J = 8.8 Hz, 2.9 Hz, 1H), 5.27 (s, 2H).

[0574] Step 29-3: Preparation of (6-(Pyrimidine-2-carboxamido)pyridin-3-yl)carbazonyldinitrile

[0575] Except for using N-(5-aminopyridin-2-yl)pyrimidine-2-carboxamide (40 mg, 0.19 mmol) obtained in Step 29-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (36 mg, yield: 67%) was obtained in the same manner as Steps 1-3 of Example 1 above.

[0576] 1 H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.06 (d, J = 4.9 Hz, 2H), 8.50 (d, J = 2.7 Hz, 1H), 8.31 (d, J = 9.0 Hz, 1H), 7.96 (dd, J = 9.0 Hz, 2.7 Hz, 1H), 7.78 (t, J = 4.9 Hz, 1H).

[0577] Example 30: Preparation of (6-(thiophene-2-carboxamido)pyridin-3-yl)carbamoyl dinitrile (Compound 30)

[0578] Step 30-1: Preparation of N-(5-Nitropyridin-2-yl)thiophene-2-carboxamide

[0579] Except for using thiophene-2-carboxylic acid (300 mg, 2.34 mmol) to replace 5-methylpyrazine-2-carboxylic acid and 2-amino-5-nitropyridine (326 mg, 2.34 mmol) to replace 2-chloro-4-nitroaniline, the title compound (459 mg, yield: 79%) was obtained in the same manner as Step 11-1 of Example 11 above.

[0580] 1 H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.24 (d, J = 2.8 Hz, 1H), 8.65 (dd, J = 9.3 Hz, 2.8 Hz, 1H), 8.39 (d, J = 9.3 Hz, 1H), 8.33 (dd, J = 3.8 Hz, 1.1 Hz, 1H), 7.98 (dd, J = 5.0 Hz, 1.1 Hz, 1H), 7.25 (dd, J = 5.0 Hz, 3.8 Hz, 1H).

[0581] Step 30-2: Preparation of N-(5-Aminopyridin-2-yl)thiophene-2-carboxamide

[0582] Except for using N-(5-nitropyridin-2-yl)thiophene-2-carboxamide (430 mg, 1.72 mmol) obtained in Step 30-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (244 mg, yield: 64%) was obtained in the same manner as Steps 1-2 of Example 1 above.

[0583] 11H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.13 (dd, J = 3.8 Hz, 1.1 Hz, 1H), 7.81 (dd, J = 5.0 Hz, 1.1 Hz, 1H), 7.78–7.69 (m, 2H), 7.17 (dd, J = 5.0 Hz, 3.8 Hz, 1H), 7.01 (dd, J = 8.7 Hz, 3.0 Hz, 1H), 5.18 (s, 2H).

[0584] Step 30-3: Preparation of (6-(Thiophene-2-carboxamido)pyridin-3-yl)carbazonyldinitrile

[0585] Except for using N-(5-aminopyridin-2-yl)thiophene-2-carboxamide (100 mg, 0.46 mmol) obtained in Step 30-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 130 mg (yield: 96%) of the title compound was obtained.

[0586] 1 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.52 (d, J = 2.7 Hz, 1H), 8.24 (d, J = 3.8 Hz, 1H), 8.19 (d, J = 9.1 Hz, 1H), 7.96–7.86 (m, 2H), 7.22 (dd, J = 5.0 Hz, 3.7 Hz, 1H).

[0587] Example 31: Preparation of (6-(benzothiazole-2-carboxamido)pyridin-3-yl)carbamoyl dinitrile (Compound 31)

[0588] Step 31-1: Preparation of N-(5-Nitropyridin-2-yl)benzo[d]thiazole-2-carboxamide

[0589] Except for using benzothiazole-2-carboxylic acid (300 mg, 1.67 mmol) to replace 5-methylpyrazine-2-carboxylic acid and using 2-amino-5-nitropyridine (233 mg, 1.67 mmol) to replace 2-chloro-4-nitroaniline, in the same manner as Step 11-1 of Example 11 above, 112 mg (yield: 22%) of the title compound was obtained.

[0590] 1 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.27 (d, J = 2.8 Hz, 1H), 8.74 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 8.37 (d, J = 9.2 Hz, 1H), 8.33–8.24 (m, 2H), 7.80–7.58 (m, 2H).

[0591] Step 31-2: Preparation of N-(5-Aminopyridin-2-yl)benzo[d]thiazole-2-carboxamide

[0592] Except for using N-(5-nitropyridin-2-yl)benzo[d]thiazole-2-carboxamide (100 mg, 0.33 mmol) obtained in Step 31-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 55 mg (yield: 61%) of the title compound was obtained.

[0593] 1 H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.32–8.16 (m, 2H), 7.85–7.77 (m, 2H), 7.72–7.58 (m, 2H), 7.07 (dd, J = 8.7 Hz, 2.9 Hz, 1H), 5.34 (s, 2H).

[0594] Step 31-3: Preparation of (6-(Benzo[d]thiazole-2-carboxamido)pyridin-3-yl)carbazonyldinitrile

[0595] Except for using N-(5-aminopyridin-2-yl)benzo[d]thiazole-2-carboxamide (40 mg, 0.15 mmol) obtained in Step 31-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 34 mg (yield: 66%) of the title compound was obtained.

[0596] 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.53 (d, J = 2.7 Hz, 1H), 8.37–8.15 (m, 3H), 7.96 (dd, J = 9.1 Hz, 2.7 Hz, 1H), 7.66 (dt, J = 20.0 Hz, 7.3 Hz, 2H).

[0597] Example 32: Preparation of (6-(quinoxaline-2-carboxamido)pyridin-3-yl)carbamoyl dinitrile (Compound 32)

[0598] Step 32-1: Preparation of N-(5-Nitropyridin-2-yl)quinoxaline-2-carboxamide

[0599] Except for using quinoxaline-2-carboxylic acid (300 mg, 1.72 mmol) to replace 5-methylpyrazine-2-carboxylic acid, and using 2-amino-5-nitropyridine (240 mg, 1.72 mmol) to replace 2-chloro-4-nitroaniline, in the same manner as Steps 11-1 of Example 11 above, 183 mg (yield: 36%) of the title compound was obtained.

[0600] 11H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.61 (s, 1H), 9.29 (d, J = 2.8 Hz, 1H), 8.77 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 8.52 (d, J = 9.2 Hz, 1H), 8.41–8.33 (m, 1H), 8.30–8.19 (m, 1H), 8.09–8.03 (m, 2H).

[0601] Step 32-2: Preparation of N-(5-Aminopyridin-2-yl)quinoxaline-2-carboxamide

[0602] Except for using N-(5-nitropyridin-2-yl)quinoxaline-2-carboxamide (170 mg, 0.58 mmol) obtained in Step 32-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 37 mg (yield: 24%) of the title compound was obtained.

[0603] 1 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.58 (s, 1H), 8.36–8.29 (m, 1H), 8.27–8.19 (m, 1H), 8.09–7.95 (m, 3H), 7.79 (d, J = 2.8 Hz, 1H), 7.10 (dd, J = 8.7 Hz, 2.8 Hz, 1H), 5.31 (s, 2H).

[0604] Step 32-3: Preparation of (6-(Quinoxaline-2-carboxamido)pyridin-3-yl)carbazonyldinitrile

[0605] Except for using N-(5-aminopyridin-2-yl)quinoxaline-2-carboxamide (30 mg, 0.11 mmol) obtained in Step 32-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 34 mg (yield: 88%) of the title compound was obtained.

[0606] 1 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.56 (s, 1H), 8.51 (s, 1H), 8.31 (t, J = 8.0 Hz, 2H), 8.25–8.17 (m, 1H), 8.06–8.00 (m, 2H), 7.94 (d, J = 9.0 Hz, 1H).

[0607] Example 33: Preparation of (2-(5-methylpyrazine-2-carboxamido)thiazolo[4,5-b]pyridin-6-yl)carbamoyl dinitrile (Compound 33)

[0608] Step 33-1: Preparation of 5-Methyl-N-(6-nitrothiazolo[4,5-b]pyridin-2-yl)pyrazine-2-carboxamide

[0609] Under a nitrogen atmosphere, after dissolving 5-methylpyrazine-2-carboxylic acid (211 mg, 1.53 mmol) in MeCN, HATU (698 mg, 1.84 mmol) and TEA (0.26 mL, 1.84 mmol) were added thereto, and the reaction mixture was stirred at room temperature for 2 hours. Thereafter, 6-nitrothiazolo[4,5-b]pyridin-2-amine (300 mg, 1.53 mmol) was added thereto, and the reaction mixture was refluxed for 24 hours. After completion of the reaction, the reaction product was filtered with MeCN to obtain 413 mg (yield: 85%) of the title compound.

[0610] 1 1H NMR (400 MHz, DMSO-d6) δ 13.50 (s, 1H), 9.46 (d, J = 2.8 Hz, 1H), 9.40 (d, J = 2.8 Hz, 1H), 9.26 (s, 1H), 8.79 (s, 1H), 2.57 (s, 3H).

[0611] Step 33-2: Preparation of N-(6-Aminothiazolo[4,5-b]pyridin-2-yl)-5-methylpyrazine-2-carboxamide

[0612] 5-Methyl-N-(6-nitrothiazolo[4,5-b]pyridin-2-yl)pyrazine-2-carboxamide (200 mg, 0.63 mmol) obtained in Step 33-1 and 10% Pd / C (135 mg, 0.13 mmol) were dissolved in DMF, and the reaction mixture was stirred at 60 °C under a hydrogen atmosphere for 2 hours. After completion of the reaction, the reaction product was filtered with DMF, and the filtrate was concentrated under reduced pressure. Then, the product was solidified with ethyl acetate and filtered to obtain 101 mg (yield: 56%) of the title compound as a solid.

[0613] 1 1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 9.19 (d, J = 1.3 Hz, 1H), 8.74 (s, 1H), 8.00 (d, J = 2.6 Hz, 1H), 7.51 (d, J = 2.6 Hz, 1H), 5.45 (s, 2H), 2.65 (s, 3H).

[0614] Step 33-3: Preparation of (2-(5-Methylpyrazine-2-carboxamido)thiazolo[4,5-b]pyridin-6-yl)carbazonyldinitrile Preparation

[0615] Except for using N-(6-aminothiazolo[4,5-b]pyridin-2-yl)-5-methylpyrazine-2-carboxamide (70 mg, 0.37 mmol) obtained in Step 33-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 52 mg (yield: 60%) of the title compound was obtained.

[0616] 1 H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.74 (s, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.96 (dd, J = 8.6 Hz, 2.5 Hz, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 2.29 (s, 3H).

[0617] Example 34: Preparation of (6-(p-tolylcarbamoyl)pyridin-3-yl)carbamoyl dinitrile (Compound 34)

[0618] Step 34-1: Preparation of 5-Nitro-N-p-tolylpyridinecarboxamide

[0619] Under a nitrogen atmosphere, after dissolving 5-nitrocholic acid (300 mg, 1.78 mmol) in acetonitrile (18 mL), HATU (814 mg, 2.14 mmol), TEA (376 μL, 2.68 mmol), and p-toluidine (191 mg, 1.78 mmol) were successively added thereto, and the reaction mixture was refluxed for 16 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by recrystallization from ethyl acetate to obtain 401 mg (yield: 87%) of the title compound.

[0620] 1 H NMR (400 MHz, chloroform-d6) δ 9.83 (s, 1H), 9.43 (d, J = 2.4 Hz, 1H), 8.69 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 8.52 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 2.37 (s, 3H).

[0621] Step 34-2: Preparation of 5-Amino-N-p-tolylpyridinecarboxamide

[0622] Dissolve 5-nitro-N-p-tolylpicolinamide (200 mg, 0.78 mmol) and 10% Pd / C (92 mg, 0.08 mmol) obtained in Step 34-1 in DMF (5 mL), and stir the reaction mixture under a hydrogen atmosphere at 60 °C for 1 hour. After the reaction is completed, filter the reaction mixture through diatomaceous earth to remove the catalyst from the reaction mixture. Concentrate the filtrate under reduced pressure to obtain 169 mg (yield: 96%) of the title compound.

[0623] 1 H NMR (400 MHz, chloroform-d) δ 9.70 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 2.7 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 7.07 (dd, J = 8.5 Hz, 2.8 Hz, 1H), 4.05 (s, 2H), 2.33 (s, 3H).

[0624] Step 34-3: Preparation of (6-(p-Tolylcarbamoyl)pyridin-3-yl)carbazonyldinitrile

[0625] Except for using 5-amino-N-p-tolylpicolinamide (40 mg, 0.18 mmol) obtained in Step 34-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 4 mg (yield: 7%) of the title compound was obtained.

[0626] 1 H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.74 (s, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.96 (dd, J = 8.6 Hz, 2.5 Hz, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 2.29 (s, 3H).

[0627] Example 35: Preparation of (6-(4-methoxyphenylcarbamoyl)pyridin-3-yl)carbazodinitrile (Compound 35)

[0628] Step 35-1: Preparation of N-(4-Methoxyphenyl)-5-nitropyridinecarboxamide

[0629] Except for using p-methoxyaniline (147 mg, 1.19 mmol) instead of p-toluidine, in the same manner as Step 34-1 of Example 34 above, 267 mg (yield: 82%) of the title compound was obtained.

[0630] 11H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.44 (d, J = 2.5 Hz, 1H), 8.82 (dd, J = 8.6 Hz, 2.5 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 3.76 (s, 3H).

[0631] Step 35-2: Preparation of 5-Amino-N-(4-methoxyphenyl)pyridinecarboxamide

[0632] Except for using N-(4-methoxyphenyl)-5-nitropyridinecarboxamide (150 mg, 0.55 mmol) obtained in Step 35-1 to replace 5-nitro-N-p-tolylpyridinecarboxamide, in the same manner as Step 34-2 of Example 34 above, 124 mg (yield: 93%) of the title compound was obtained.

[0633] 1 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.01 (dd, J = 2.6 Hz, 0.7 Hz, 1H), 7.85–7.81 (m, 1H), 7.77 (d, J = 9.1 Hz, 2H), 7.04 (dd, J = 8.5 Hz, 2.7 Hz, 1H), 6.91 (d, J = 9.0 Hz, 1H), 6.07 (s, 2H), 3.75 (s, 3H).

[0634] Step 35-3: Preparation of (6-(4-Methoxyphenylcarbamoyl)pyridin-3-yl)carbazonyldinitrile

[0635] Except for using 5-amino-N-(4-methoxyphenyl)pyridinecarboxamide (124 mg, 0.51 mmol) obtained in Step 35-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 9 mg (yield: 5%) of the title compound was obtained.

[0636] 1 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.73 (d, J = 2.5 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 7.96 (dd, J = 8.6 Hz, 2.4 Hz, 1H), 7.81 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 3.75 (s, 3H).

[0637] Example 36: Preparation of (6-(5-methylpyrazin-2-ylcarbamoyl)pyridin-3-yl)carbonohydrazonitrile (Compound 36)

[0638] Step 36-1: Preparation of N-(5-Methylpyrazin-2-yl)-5-nitropyridinecarboxamide

[0639] Except for using 5-methylpyrazin-2-amine (101 mg, 0.92 mmol) instead of p-toluidine, the title compound (91 mg, yield: 38%) was obtained in the same manner as in Step 34-1 of Example 34 above.

[0640] 1 H NMR (400 MHz, chloroform-d) δ 10.29 (s, 1H), 9.61 (d, J = 1.5 Hz, 1H), 9.47 (d, J = 2.5 Hz, 1H), 8.73 (dd, J = 8.6 Hz, 2.5 Hz, 1H), 8.54 (dd, J = 8.6 Hz, 0.8 Hz, 1H), 8.24 (d, J = 1.5 Hz, 1H), 2.59 (s, 3H).

[0641] Step 36-2: Preparation of 5-Amino-N-(5-methylpyrazin-2-yl)pyridinecarboxamide

[0642] Except for using N-(5-methylpyrazin-2-yl)-5-nitropyridinecarboxamide (110 mg, 0.42 mmol) obtained in Step 36-1 instead of 5-nitro-N-p-tolylpyridinecarboxamide, the title compound (78 mg, yield: 81%) was obtained in the same manner as in Step 34-2 of Example 34 above.

[0643] 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.36 (d, J = 1.5 Hz, 1H), 8.32 (t, J = 1.0 Hz, 1H), 8.00 (d, J = 2.6 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.06 (dd, J = 8.6 Hz, 2.6 Hz, 1H), 6.30 (s, 2H), 2.47 (s, 3H).

[0644] Step 36-3: Preparation of (6-(5-Methylpyrazin-2-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile

[0645] Except for using 5-amino-N-(5-methylpyrazin-2-yl)pyridinecarboxamide (75 mg, 0.65 mmol) obtained in Step 36-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (13 mg, yield: 13%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[0646] 11H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.37 (d, J = 1.5 Hz, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.36 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.79 (dd, J = 8.5 Hz, 2.4 Hz, 1H), 2.49 (s, 3H).

[0647] Example 37: Preparation of (6-(4-Chlorophenylcarbamoyl)pyridin-3-yl)carbazodicarbonitrile (Compound 37)

[0648] Step 37-1: Preparation of N-(4-Chlorophenyl)-5-nitropyridinecarboxamide

[0649] Except using 4-chloroaniline (152 mg, 1.19 mmol) instead of p-toluidine, in the same manner as Step 34-1 of Example 34 above, 267 mg (yield: 81%) of the title compound was obtained.

[0650] 1 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.45 (d, J = 2.5 Hz, 1H), 8.83 (dd, J = 8.6 Hz, 2.5 Hz, 1H), 8.39 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 8.9 Hz, 2H), 7.45 (d, J = 8.9 Hz, 2H).

[0651] Step 37-2: Preparation of 5-Amino-N-(4-chlorophenyl)pyridinecarboxamide

[0652] Except using N-(4-chlorophenyl)-5-nitropyridinecarboxamide (267 mg, 0.96 mmol) obtained in Step 37-1 instead of 5-nitro-N-p-tolylpyridinecarboxamide, and using 1,4-dioxane instead of DMF as the solvent, in the same manner as Step 34-2 of Example 34 above, 174 mg (yield: 73%) of the title compound was obtained.

[0653] 1 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.92 (d, J = 8.9 Hz, 2H), 7.84 (d, J = 8.5 Hz, 1H), 7.37 (d, J = 8.9 Hz, 2H), 7.04 (dd, J = 8.5 Hz, 2.7 Hz, 1H), 6.13 (s, 2H).

[0654] Step 37-3: Preparation of (6-(4-Chlorophenylcarbamoyl)pyridin-3-yl)carbazonyldinitrile

[0655] Except for using 5-amino-N-(4-chlorophenyl)picolinamide (167 mg, 0.67 mmol) obtained in Step 37-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 14 mg (yield: 6%) of the title compound was obtained.

[0656] 1 H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 8.9 Hz, 2H), 7.85 (dd, J = 8.6 Hz, 2.5 Hz, 1H), 7.41 (d, J = 8.9 Hz, 2H).

[0657] Example 38: Preparation of (6-(6-methylpyridin-3-ylcarbamoyl)pyridin-3-yl)carbamoyl dinitrile (Compound 38)

[0658] Step 38-1: Preparation of N-(6-methylpyridin-3-yl)-5-nitropyridinecarboxamide

[0659] Except for using 6-methylpyridin-3-amine (129 mg, 1.19 mmol) to replace p-toluidine, in the same manner as Step 34-1 of Example 34 above, 202 mg (yield: 66%) of the title compound was obtained.

[0660] 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.45 (d, J = 2.5 Hz, 1H), 8.95 (d, J = 2.5 Hz, 1H), 8.83 (dd, J = 8.6 Hz, 2.6 Hz, 1H), 8.39 (d, J = 8.6 Hz, 1H), 8.19 (dd, J = 8.4 Hz, 2.6 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 2.46 (s, 3H).

[0661] Step 38-2: Preparation of 5-amino-N-(6-methylpyridin-3-yl)pyridinecarboxamide

[0662] Except for using N-(6-methylpyridin-3-yl)-5-nitropicolinamide (198 mg, 0.77 mmol) obtained in Step 38-1 to replace 5-nitro-N-p-tolylpicolinamide, in the same manner as Step 34-2 of Example 34 above, 120 mg (yield: 69%) of the title compound was obtained.

[0663] 11H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.89 (d, J = 2.5 Hz, 1H), 8.15 (dd, J = 8.4 Hz, 2.6 Hz, 1H), 8.02 (d, J = 2.7 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.04 (dd, J = 8.5 Hz, 2.6 Hz, 1H), 6.13 (s, 2H), 2.42 (s, 3H).

[0664] Step 38-3: Preparation of (6-(6-methylpyridin-3-ylcarbamoyl)pyridin-3-yl)carbazic dihydrazide

[0665] Except for using 5-amino-N-(6-methylpyridin-3-yl)pyridine-2-carboxamide (115 mg, 0.50 mmol) obtained in Step 38-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 8 mg (yield: 5%) of the title compound was obtained.

[0666] 1 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.14 (d, J = 2.5 Hz, 1H), 8.62 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.84 (dd, J = 8.6 Hz, 2.4 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 2.56 (s, 3H).

[0667] Example 39: Preparation of (6-(5-methylpyridin-3-ylcarbamoyl)pyridin-3-yl) carbohydrazononitrile (Compound 39)

[0668] Step 39-1: Preparation of N-(5-methylpyridin-3-yl)-5-nitropyridinecarboxamide

[0669] Except for using 5-methylpyridin-3-amine (129 mg, 1.19 mmol) to replace p-toluidine, in the same manner as Step 34-1 of Example 34 above, 148 mg (yield: 48%) of the title compound was obtained.

[0670] 1 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.46 (d, J = 2.5 Hz, 1H), 8.87 (d, J = 2.3 Hz, 1H), 8.84 (dd, J = 8.6 Hz, 2.6 Hz, 1H), 8.40 (d, J = 8.5 Hz, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 2.33 (s, 3H).

[0671] Step 39-2: Preparation of 5-amino-N-(5-methylpyridin-3-yl)pyridinecarboxamide

[0672] Except for using N-(5-methylpyridin-3-yl)-5-nitropyridinecarboxamide (143 mg, 0.55 mmol) obtained in Step 39-1 in place of 5-nitro-N-p-tolylpyridinecarboxamide, the title compound (85 mg, yield: 67%) was obtained in the same manner as in Step 34-2 of Example 34 above.

[0673] 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.81 (d, J = 2.3 Hz, 1H), 8.14 (s, 1H), 8.12 (s, 1H), 8.02 (d, J = 2.6 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.04 (dd, J = 8.5 Hz, 2.7 Hz, 1H), 6.15 (s, 2H), 2.30 (s, 3H).

[0674] Step 39-3: Preparation of (6-(5-methylpyridin-3-ylcarbamoyl)pyridin-3-yl)carbazic dihydrazide

[0675] Except for using 5-amino-N-(5-methylpyridin-3-yl)pyridinecarboxamide (85 mg, 0.37 mmol) obtained in Step 39-2 in place of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (47 mg, yield: 28%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[0676] 1 H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.15–9.11 (m, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.39 (s, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.90 (dd, J = 8.6 Hz, 2.4 Hz, 1H), 2.43 (s, 3H).

[0677] Example 40: Preparation of (6-(pyridin-3-ylcarbamoyl)pyridin-3-yl) carbohydrazonitrile (Compound 40)

[0678] Step 40-1: Preparation of 5-nitro-N-(pyridin-3-yl)pyridinecarboxamide

[0679] Except for using 5-methylpyridin-3-amine (112 mg, 1.19 mmol) in place of p-toluidine, the title compound (161 mg, yield: 55%) was obtained in the same manner as in Step 34-1 of Example 34 above.

[0680] 11H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.49–9.44 (m, 1H), 9.12–9.07 (m, 1H), 8.85 (dd, J = 8.6 Hz, 2.6 Hz, 1H), 8.42 (dd, J = 8.6 Hz, 0.7 Hz, 1H), 8.41–8.30 (m, 2H), 7.44 (ddd, J = 8.3 Hz, 4.7 Hz, 0.8 Hz, 1H), 2.70 (s, 3H).

[0681] Step 40-2: Preparation of 5-amino-N-(pyridin-3-yl)pyridinecarboxamide

[0682] Except for using 5-nitro-N-(pyridin-3-yl)picolinamide (161 mg, 0.66 mmol) obtained in Step 40-1 to replace 5-nitro-N-p-tolylpicolinamide, in the same manner as Step 34-2 of Example 34 above, 79 mg (yield: 56%) of the title compound was obtained.

[0683] 1 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.04 (d, J = 2.5 Hz, 1H), 8.33–8.25 (m, 2H), 8.04 (d, J = 2.6 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.37 (dd, J = 8.3 Hz, 4.7 Hz, 1H), 7.06 (dd, J = 8.5 Hz, 2.7 Hz, 1H), 6.16 (s, 2H).

[0684] Step 40-3: Preparation of (6-(pyridin-3-ylcarbamoyl)pyridin-3-yl)carbazic dihydrazide

[0685] Except for using 5-amino-N-(pyridin-3-yl)picolinamide (79 mg, 0.37 mmol) obtained in Step 40-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 30 mg (yield: 27%) of the title compound was obtained.

[0686] 1 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.32–9.26 (m, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.64 (ddd, J = 8.5 Hz, 2.5 Hz, 1.4 Hz, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H), 7.93 (dd, J = 8.6 Hz, 2.4 Hz, 1H), 7.73 (dd, J = 8.5 Hz, 5.1 Hz, 1H).

[0687] Preparation of Example 41: (6-(6-Methylpyrazin-2-ylcarbamoyl)pyridin-3-yl)carbamoyl dinitrile (Compound 41)

[0688] Step 41-1: Preparation of N-(6-methylpyrazin-2-yl)-5-nitropyridinecarboxamide

[0689] Except for using 6-methylpyrazin-2-amine (130 mg, 1.19 mmol) instead of p-toluidine, the title compound (161 mg, yield: 55%) was obtained in the same manner as in Step 34-1 of Example 34 above.

[0690] 1 H NMR (400 MHz, chloroform-d) δ 10.28 (s, 1H), 9.54 (s, 1H), 9.47 (d, J = 2.5 Hz, 1H), 8.73 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 8.55 (d, J = 8.5 Hz, 1H), 8.33 (s, 1H), 2.55 (s, 3H).

[0691] Step 41-2: Preparation of 5-amino-N-(6-methylpyrazin-2-yl)pyridinecarboxamide

[0692] Except for using N-(6-methylpyrazin-2-yl)-5-nitropyridinecarboxamide (165 mg, 0.64 mmol) obtained in Step 41-1 instead of 5-nitro-N-p-tolylpyridinecarboxamide, the title compound (134 mg, yield: 92%) was obtained in the same manner as in Step 34-2 of Example 34 above.

[0693] 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.30 (s, 1H), 8.30 (s, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.07 (dd, J = 8.5 Hz, 2.6 Hz, 1H), 6.32 (s, 2H), 2.46 (s, 3H).

[0694] Step 41-3: Preparation of (6-(6-methylpyrazin-2-ylcarbamoyl)pyridin-3-yl)carbazic dihydrazide

[0695] Except for using 5-amino-N-(6-methylpyrazin-2-yl)pyridinecarboxamide (130 mg, 0.57 mmol) obtained in Step 41-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (35 mg, yield: 20%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[0696] 11H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.32 (s, 1H), 8.55 (d, J = 2.3 Hz, 1H), 8.34 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.79 (dd, J = 8.5 Hz, 2.4 Hz, 1H), 2.48 (s, 3H).

[0697] Example 42: Preparation of (6-(Pyrimidin-5-ylcarbamoyl)pyridin-3-yl)carbamoyl dinitrile (Compound 42)

[0698] Step 42-1: Preparation of 5-nitro-N-(pyrimidin-5-yl)pyridinecarboxamide

[0699] Except for using pyrimidin-5-amine (113 mg, 1.19 mmol) instead of p-toluidine, in the same manner as Step 34-1 of Example 34 above, 192 mg (yield: 65%) of the title compound was obtained.

[0700] 1 1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 9.48 (dd, J = 2.6 Hz, 0.7 Hz, 1H), 9.33 (s, 2H), 8.99 (s, 1H), 8.87 (dd, J = 8.6 Hz, 2.6 Hz, 1H), 8.43 (dd, J = 8.6 Hz, 0.7 Hz, 1H).

[0701] Step 42-2: Preparation of 5-amino-N-(pyrimidin-5-yl)pyridinecarboxamide

[0702] Except for using 5-nitro-N-(pyrimidin-5-yl)pyridinecarboxamide (173 mg, 0.71 mmol) obtained in Step 42-1 instead of 5-nitro-N-p-tolylpyridinecarboxamide, in the same manner as Step 34-2 of Example 34 above, 117 mg (yield: 76%) of the title compound was obtained.

[0703] 1 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.28 (s, 2H), 8.88 (s, 1H), 8.05 (d, J = 2.6 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.05 (dd, J = 8.5 Hz, 2.6 Hz, 1H), 6.22 (s, 2H).

[0704] Step 42-3: Preparation of (6-(pyrimidin-5-ylcarbamoyl)pyridin-3-yl)carbazic dihydrazide

[0705] Except using 5-amino-N-(pyrimidin-5-yl)picolinamide (115 mg, 0.53 mmol) obtained in Step 42-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 33 mg (yield: 21%) of the title compound was obtained.

[0706] 1 H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.31 (s, 2H), 8.93 (s, 1H), 8.75 (d, J = 2.5 Hz, 1H), 8.17 (d, J = 8.6 Hz, 1H), 7.96 (dd, J = 8.6 Hz, 2.5 Hz, 1H).

[0707] Example 43: Preparation of (6-(pyrimidin-2-ylcarbamoyl)pyridin-3-yl)carbamoyl dinitrile (Compound 43)

[0708] Step 43-1: Preparation of 5-nitro-N-(pyrimidin-2-yl)pyridinecarboxamide

[0709] Except using pyrimidin-2-amine (113 mg, 1.19 mmol) to replace p-toluidine, in the same manner as Step 34-1 of Example 34 above, 194 mg (yield: 66%) of the title compound was obtained.

[0710] 1 H NMR (400 MHz, chloroform-d) δ 10.58 (s, 1H), 9.47 (d, J = 2.5 Hz, 1H), 8.78–8.68 (m, 3H), 8.59 (dd, J = 8.6 Hz, 0.8 Hz, 1H), 7.14 (t, J = 4.8 Hz, 1H).

[0711] Step 43-2: Preparation of 5-amino-N-(pyrimidin-2-yl)pyridinecarboxamide

[0712] Except using 5-nitro-N-(pyrimidin-2-yl)picolinamide (165 mg, 0.67 mmol) obtained in Step 43-1 to replace 5-nitro-N-p-tolylpicolinamide, in the same manner as Step 34-2 of Example 34 above, 98 mg (yield: 67%) of the title compound was obtained.

[0713] 11H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.70 (d, J = 4.8 Hz, 2H), 7.99 (dd, J = 2.7 Hz, 0.6 Hz, 1H), 7.90–7.84 (m, 1H), 7.22 (t, J = 4.8 Hz, 1H), 7.06 (dd, J = 8.6 Hz, 2.7 Hz, 1H), 6.27 (s, 2H).

[0714] Step 43-3: Preparation of (6-(pyrimidin-2-ylcarbamoyl)pyridin-3-yl)carbazic dihydrazide

[0715] Except for using 5-amino-N-(pyrimidin-2-yl)picolinamide (97 mg, 0.45 mmol) obtained in Step 43-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 25 mg (yield: 19%) of the title compound was obtained.

[0716] 1 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.81–8.73 (m, 3H), 8.20 (dd, J = 8.7 Hz, 0.7 Hz, 1H), 8.02 (dd, J = 8.6 Hz, 2.5 Hz, 1H), 7.29 (t, J = 4.8 Hz, 1H).

[0717] Example 44: Preparation of (4-(4-methoxyphenylcarbamoyl)phenyl)carbazodicarbonitrile (Compound 44)

[0718] Step 44-1: Preparation of N-(4-methoxyphenyl)-4-nitrobenzamide

[0719] Except for using 4-nitrobenzoic acid (200 mg, 1.20 mmol) to replace 5-nitrocholic acid and using p-methoxyaniline (147 mg, 1.20 mmol) to replace p-toluidine, in the same manner as Step 34-1 of Example 34 above, 174 mg (yield: 53%) of the title compound was obtained.

[0720] 1 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.37 (d, J = 8.8 Hz, 2H), 8.18 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 3.76 (s, 3H).

[0721] Step 44-2: Preparation of 4-amino-N-(4-methoxyphenyl)benzamide

[0722] Except for using N-(4-methoxyphenyl)-4-nitrobenzamide (168 mg, 0.62 mmol) obtained in Step 44-1 to replace 5-nitro-N-p-tolylpicolinamide, in the same manner as Step 34-2 of Example 34 above, 137 mg (yield: 92%) of the title compound was obtained.

[0723] 1 H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 6.59 (d, J = 8.6 Hz, 2H), 5.71 (s, 2H), 3.74 (s, 3H).

[0724] Step 44-3: Preparation of (4-(4-methoxyphenylcarbamoyl)phenyl)carbazic dihydrazide

[0725] Except for using 4-amino-N-(4-methoxyphenyl)benzamide (135 mg, 0.56 mmol) obtained in Step 44-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Step 1-3 of Example 1 above, 20 mg (yield: 11%) of the title compound was obtained.

[0726] 1 H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 10.13 (s, 1H), 8.02 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 9.0 Hz, 2H), 3.76 (s, 3H).

[0727] Example 45: Preparation of (4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbamoyl dinitrile (Compound 45)

[0728] Step 45-1: Preparation of N-(5-methylpyrazin-2-yl)-4-nitrobenzamide

[0729] Except for using 5-methylpyrazin-2-amine (131 mg, 1.20 mmol) to replace p-methoxyaniline, in the same manner as Step 44-1 of Example 44 above, 84 mg (yield: 13%) of the title compound was obtained.

[0730] 1 H NMR (400 MHz, chloroform-d) δ 9.59–9.54 (m, 1H), 8.47 (s, 1H), 8.42–8.34 (m, 2H), 8.21–8.16 (m, 1H), 8.15–8.07 (m, 2H), 2.59 (s, 3H).

[0731] Step 45-2: Preparation of 4-amino-N-(5-methylpyrazin-2-yl)benzamide

[0732] Except for using N-(5-methylpyrazin-2-yl)-4-nitrobenzamide (76 mg, 0.29 mmol) obtained in Step 45-1 to replace 5-nitro-N-p-tolylpicolinamide, in the same manner as Step 34-2 of Example 34 above, 56 mg (yield: 84%) of the title compound was obtained.

[0733] 1 H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.26 (d, J = 1.5 Hz, 1H), 8.31 (d, J = 1.5 Hz, 1H), 7.85–7.77 (m, 2H), 6.63–6.54 (m, 2H), 5.87 (s, 2H), 2.46 (s, 3H).

[0734] Step 45-3: Preparation of (4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbazic dihydrazide

[0735] Except for using 4-amino-N-(5-methylpyrazin-2-yl)benzamide (46 mg, 0.20 mmol) obtained in Step 45-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Step 1-3 of Example 1 above, 37 mg (yield: 59%) of the title compound was obtained.

[0736] 1 H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 10.99 (s, 1H), 9.28 (d, J = 1.5 Hz, 1H), 8.37 (d, J = 1.5 Hz, 1H), 8.14–8.08 (m, 2H), 7.60–7.54 (m, 2H), 2.49 (s, 3H).

[0737] Example 46: Preparation of (4-(6-methylpyrazin-2-ylcarbamoyl)phenyl)carbonohydrazonitrile (Compound 46)

[0738] Step 46-1: Preparation of N-(6-methylpyrazin-2-yl)-4-nitrobenzamide

[0739] Except for using 6-methylpyrazin-2-amine (196 mg, 1.80 mmol) to replace p-methoxyaniline, in the same manner as Step 44-1 of Example 44 above, 156 mg (yield: 33%) of the title compound was obtained.

[0740] 11H NMR (400 MHz, chloroform-d) δ 9.49 (s, 1H), 8.46 (s, 1H), 8.42–8.35 (m, 2H), 8.33 (s, 1H), 8.16–8.08 (m, 2H), 2.52 (d, J = 0.7 Hz, 3H).

[0741] Step 46-2: Preparation of 4-amino-N-(6-methylpyrazin-2-yl)benzamide

[0742] Except for using N-(6-methylpyrazin-2-yl)-4-nitrobenzamide (154 mg, 0.60 mmol) obtained in Step 46-1 in place of 5-nitro-N-p-tolylpicolinamide, in the same manner as Step 34-2 of Example 34 above, 135 mg (yield: 99%) of the title compound was obtained.

[0743] 1 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.21 (s, 1H), 8.24 (s, 1H), 7.86–7.78 (m, 2H), 6.62–6.54 (m, 2H), 5.88 (s, 2H), 2.46 (s, 3H).

[0744] Step 46-3: Preparation of (4-(6-methylpyrazin-2-ylcarbamoyl)phenyl)carbazic dihydrazide

[0745] Except for using 4-amino-N-(6-methylpyrazin-2-yl)benzamide (105 mg, 0.46 mmol) obtained in Step 46-2 in place of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Step 1-3 of Example 1 above, 25 mg (yield: 18%) of the title compound was obtained.

[0746] 1 1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 11.05 (s, 1H), 9.25 (s, 1H), 8.32 (s, 1H), 8.12 (d, 2H), 7.57 (d, 2H), 2.50 (s, 3H).

[0747] Example 47: Preparation of (4-(6-methylpyridin-3-ylcarbamoyl)phenyl)carbazic diimidoyl (Compound 47)

[0748] Step 47-1: Preparation of N-(6-methylpyridin-3-yl)-4-nitrobenzamide

[0749] Except for using 6-methylpyridin-3-amine (129 mg, 1.20 mmol) in place of p-methoxyaniline, in the same manner as Step 44-1 of Example 44 above, 157 mg (yield: 51%) of the title compound was obtained.

[0750] 1 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.80 (d, J = 2.6 Hz, 1H), 8.39 (d, 2H), 8.21 (d, 2H), 8.08 (dd, J = 8.4 Hz, 2.6 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 2.46 (s, 3H).

[0751] Step 47-2: Preparation of 4-amino-N-(6-methylpyridin-3-yl)benzamide

[0752] Except for using N-(6-methylpyridin-3-yl)-4-nitrobenzamide (157 mg, 0.61 mmol) obtained in Step 47-1 to replace 5-nitro-N-p-tolylpyridinecarboxamide, in the same manner as Step 34-2 of Example 34 above, 95 mg (yield: 68%) of the title compound was obtained.

[0753] 1 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.76 (d, J = 2.5 Hz, 1H), 8.03 (dd, J = 8.4 Hz, 2.6 Hz, 1H), 7.72 (d, 2H), 7.20 (d, J = 8.4 Hz, 1H), 6.60 (d, 2H), 5.79 (s, 2H), 2.42 (s, 3H).

[0754] Step 47-3: Preparation of (4-(6-methylpyridin-3-ylcarbamoyl)phenyl)carbamoyl dinitrile

[0755] Except for using 4-amino-N-(6-methylpyridin-3-yl)benzamide (92 mg, 0.40 mmol) obtained in Step 47-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Step 1-3 of Example 1 above, 91 mg (yield: 73%) of the title compound was obtained.

[0756] 1 1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.91 (d, J = 2.5 Hz, 1H), 8.21 (dd, J = 8.5 Hz, 2.6 Hz, 1H), 8.02 (d, 2H), 7.55 (d, 2H), 7.43 (d, J = 8.5 Hz, 1H), 3.45 (m, 3H).

[0757] Example 48: Preparation of (4-(5-methylpyridin-3-ylcarbamoyl)phenyl)carbazic diimidoyl dinitrile (Compound 48)

[0758] Step 48-1: Preparation of N-(5-methylpyridin-3-yl)-4-nitrobenzamide

[0759] The title compound (195 mg, yield: 63%) was obtained in the same manner as in Step 44-1 of Example 44 above, except that 5-methylpyridin-3-amine (129 mg, 1.20 mmol) was used instead of p-methoxyaniline.

[0760] 1 H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.40 (d, 2H), 8.21 (d, 3H), 8.05 (t, J = 2.3 Hz, 1H), 2.33 (s, 3H).

[0761] Step 48-2: Preparation of 4-amino-N-(5-methylpyridin-3-yl)benzamide

[0762] The title compound (78 mg, yield: 49%) was obtained in the same manner as in Step 34-2 of Example 34 above, except that N-(5-methylpyridin-3-yl)-4-nitrobenzamide (179 mg, 0.70 mmol) obtained in Step 48-1 was used instead of 5-nitro-N-p-tolylpyridinecarboxamide.

[0763] 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.72 (d, J = 2.3 Hz, 1H), 8.10 (dd, J = 2.0 Hz, 0.9 Hz, 1H), 8.06–8.00 (m, 1H), 7.75 (d, 2H), 6.61 (d, 2H), 5.82 (s, 2H), 2.29 (s, 3H).

[0764] Step 48-3: Preparation of (4-(5-methylpyridin-3-ylcarbamoyl)phenyl)carbamoyl dinitrile

[0765] The title compound (44 mg, yield: 46%) was obtained in the same manner as in Step 1-3 of Example 1 above, except that 4-amino-N-(5-methylpyridin-3-yl)benzamide (71 mg, 0.31 mmol) obtained in Step 48-2 was used instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide.

[0766] 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.04 (d, J = 2.2 Hz, 1H), 8.41 (dt, J = 4.2 Hz, 1.8 Hz, 2H), 8.10 (d, 2H), 7.62 (d, 2H), 2.43 (s, 3H).

[0767] Example 49: Preparation of (4-(pyridin-3-ylcarbamoyl)phenyl)carbamoyl dinitrile (Compound 49)

[0768] Step 49-1: Preparation of 4-nitro-N-(pyridin-3-yl)benzamide

[0769] Except using pyridin-3-amine (112 mg, 1.20 mmol) to replace p-methoxyaniline, in the same manner as step 44-1 of Example 44 above, 272 mg (yield: 93%) of the title compound was obtained.

[0770] 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.94 (dd, J = 2.6 Hz, 0.7 Hz, 1H), 8.40 (d, 2H), 8.36 (dd, J = 4.7 Hz, 1.5 Hz, 1H), 8.26–8.17 (m, 3H), 7.44 (ddd, J = 8.3 Hz, 4.7 Hz, 0.8 Hz, 1H).

[0771] Step 49-2: Preparation of 4-amino-N-(pyridin-3-yl)benzamide

[0772] Except using 4-nitro-N-(pyridin-3-yl)benzamide (272 mg, 1.12 mmol) obtained in step 49-1 to replace 5-nitro-N-p-tolylpyridinecarboxamide, in the same manner as step 34-2 of Example 34 above, 145 mg (yield: 60%) of the title compound was obtained.

[0773] 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (d, J = 3.8 Hz, 1H), 8.91 (t, J = 3.3 Hz, 1H), 8.26 (td, J = 4.4 Hz, 1.6 Hz, 1H), 8.17 (dp, J = 6.2 Hz, 1.8 Hz, 1H), 7.74 (ddd, J = 8.0 Hz, 4.9 Hz, 2.9 Hz, 2H), 7.36 (dt, J = 8.5 Hz, 4.2 Hz, 1H), 6.62 (ddd, J = 8.1 Hz, 5.0 Hz, 2.9 Hz, 2H), 5.82 (d, J = 3.9 Hz, 2H).

[0774] Step 49-3: Preparation of (4-(pyridin-3-ylcarbamoyl)phenyl)carbamoyl dinitrile

[0775] Except using 4-amino-N-(pyridin-3-yl)benzamide (145 mg, 0.68 mmol) obtained in step 49-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as step 1-3 of Example 1 above, 42 mg (yield: 21%) of the title compound was obtained.

[0776] 11H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.99 (d, J = 2.4 Hz, 1H), 8.36 (dd, J = 4.8 Hz, 1.5 Hz, 1H), 8.26 (dt, J = 8.4 Hz, 1.9 Hz, 1H), 8.04 (d, 2H), 7.58 (d, 2H), 7.49 (dd, J = 8.4 Hz, 4.8 Hz, 1H).

[0777] Example 50: Preparation of (4-(pyrimidin-5-ylcarbamoyl)phenyl)carbazoyl dinitrile (Compound 50)

[0778] Step 50-1: Preparation of 4-nitro-N-(pyrimidin-5-yl)benzamide

[0779] Except for using 4-nitrobenzoic acid (200 mg, 1.20 mmol) instead of 5-nitrocholic acid and using 5-aminopyrimidine (114 mg, 1.20 mmol) instead of p-toluidine, the title compound (230 mg, yield: 112%) was obtained in the same manner as in Step 34-1 of Example 34 above.

[0780] 1 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.18 (s, 2H), 8.98 (s, 1H), 8.46–8.38 (m, 2H), 8.27–8.19 (m, 2H).

[0781] Step 50-2: Preparation of 4-amino-N-(pyrimidin-5-yl)benzamide

[0782] Except for using 4-nitro-N-(pyrimidin-5-yl)benzamide (292 mg, 1.20 mmol) obtained in Step 50-1 instead of 5-nitro-N-p-tolylpicolinamide, the title compound (44 mg, yield: 17%) was obtained in the same manner as in Step 34-2 of Example 34 above.

[0783] 1 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.16 (s, 2H), 8.88 (s, 1H), 7.80–7.72 (m, 2H), 6.67–6.59 (m, 2H), 5.90 (s, 2H).

[0784] Step 50-3: Preparation of (4-(pyrimidin-5-ylcarbamoyl)phenyl)carbamoyl dinitrile

[0785] Except for using 4-amino-N-(pyrimidin-5-yl)benzamide (44 mg, 0.21 mmol) obtained in Step 50-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 51 mg (yield: 84%) of the title compound was obtained.

[0786] 1 H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 10.64 (s, 1H), 9.18 (s, 2H), 8.95 (s, 1H), 8.12–8.04 (m, 2H), 7.67–7.59 (m, 2H).

[0787] Example 51: Preparation of (2-methoxy-4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbamoyl dinitrile (Compound 51)

[0788] Step 51-1: Preparation of 3-methoxy-N-(5-methylpyrazin-2-yl)-4-nitrobenzamide

[0789] Except for using 3-methoxy-4-nitrobenzoic acid (200 mg, 1.01 mmol) to replace 5-nitrocholic acid, and using 5-methylpyrazin-2-amine (111 mg, 1.01 mmol) to replace p-toluidine, in the same manner as Step 34-1 of Example 34 above, 174 mg (yield: 59%) of the title compound was obtained.

[0790] 1 H NMR (400 MHz, chloroform-d) δ 9.56 (d, J = 1.5 Hz, 1H), 8.40 (s, 1H), 8.19 (dd, J = 1.5 Hz, 0.7 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 1.7 Hz, 1H), 7.48 (dd, J = 8.3 Hz, 1.7 Hz, 1H), 4.06 (s, 3H), 2.59 (s, 3H).

[0791] Step 51-2: Preparation of 4-amino-3-methoxy-N-(5-methylpyrazin-2-yl)benzamide

[0792] Except for using 3-methoxy-N-(5-methylpyrazin-2-yl)-4-nitrobenzamide (174 mg, 0.60 mmol) obtained in Step 51-1 to replace 5-nitro-N-p-tolylpyridine amide, in the same manner as Step 34-2 of Example 34 above, 132 mg (yield: 84%) of the title compound was obtained.

[0793] 11H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.28 (d, J = 1.5 Hz, 1H), 8.34–8.29 (m, 1H), 7.55 (d, J = 7.9 Hz, 2H), 6.66 (d, J = 8.0 Hz, 1H), 5.51 (s, 2H), 3.86 (s, 3H), 2.47 (s, 3H).

[0794] Step 51-3: Preparation of (2-methoxy-4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbamoyl dinitrile

[0795] Except for using 4-amino-3-methoxy-N-(5-methylpyrazin-2-yl)benzamide (132 mg, 0.51 mmol) obtained in Step 51-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 35 mg (yield: 20%) of the title compound was obtained.

[0796] 1 1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 11.09 (s, 1H), 9.30 (d, J = 1.5 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 7.86 (d, J = 1.8 Hz, 1H), 7.75 (dd, J = 8.4 Hz, 1.8 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 4.03 (s, 3H), 2.49 (s, 3H).

[0797] Example 52: Preparation of Methyl-4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbazodinitrile (Compound 52)

[0798] Step 52-1: Preparation of 2-methyl-N-(5-methylpyrazin-2-yl)-4-nitrobenzamide

[0799] Except for using 2-methyl-4-nitrobenzoic acid (200 mg, 1.10 mmol) instead of 5-nitrocholic acid, and using 5-methylpyrazin-2-amine (121 mg, 1.10 mmol) instead of p-toluidine, in the same manner as Step 34-1 of Example 34 above, 105 mg (yield: 35%) of the title compound was obtained.

[0800] 1 1H NMR (400 MHz, chloroform-d) δ 9.53 (s, 1H), 8.32 (s, 1H), 8.19–8.08 (m, 2H), 8.04 (d, J = 1.5 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 2.63 (s, 3H), 2.55 (s, 3H).

[0801] Step 52-2: Preparation of 4-amino-2-methyl-N-(5-methylpyrazin-2-yl)benzamide

[0802] Except for using 2-methyl-N-(5-methylpyrazin-2-yl)-4-nitrobenzamide (105 mg, 0.39 mmol) obtained in Step 52-1 to replace 5-nitro-N-p-tolylpyridineamide, in the same manner as Step 34-2 of Example 34 above, 73 mg (yield: 78%) of the title compound was obtained.

[0803] 1 H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.23 (d, J = 1.6 Hz, 1H), 8.29 (d, J = 1.6 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 6.45–6.37 (m, 2H), 5.58 (s, 2H), 2.46 (s, 3H), 2.35 (s, 3H).

[0804] Step 52-3: Preparation of (3-methyl-4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbamoyl dinitrile

[0805] Except for using 4-amino-2-methyl-N-(5-methylpyrazin-2-yl)benzamide (73 mg, 0.30 mmol) obtained in Step 52-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Step 1-3 of Example 1 above, 82 mg (yield: 85%) of the title compound was obtained.

[0806] 1 H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 10.97 (s, 1H), 9.28 (d, J = 1.5 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.41–7.32 (m, 2H), 2.48 (s, 3H), 2.43 (s, 3H).

[0807] Example 53: Preparation of (3-methyl-4-(6-methylpyridin-3-ylcarbamoyl)phenyl)carbazodinitrile (Compound 53)

[0808] Step 53-1: Preparation of 2-methyl-N-(6-methylpyridin-3-yl)-4-nitrobenzamide

[0809] Except for using 2-methyl-4-nitrobenzoic acid (200 mg, 1.10 mmol) to replace 5-nitrocholic acid, and using 5-amino-2-methylpyridine (119 mg, 1.10 mmol) to replace p-toluidine, in the same manner as Step 34-1 of Example 34 above, 270 mg (yield: 90%) of the title compound was obtained.

[0810] 11H NMR (400 MHz, chloroform-d) δ 8.52 (d, J = 2.6 Hz, 1H), 8.15–8.08 (m, 3H), 8.05 (dd, J = 8.3 Hz, 2.3 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 2.58 (s, 3H), 2.52 (s, 3H).

[0811] Step 53-2: Preparation of 4-amino-2-methyl-N-(6-methylpyridin-3-yl)benzamide

[0812] Except for using 2-methyl-N-(6-methylpyridin-3-yl)-4-nitrobenzamide (270 mg, 1.00 mmol) obtained in Step 53-1 to replace 5-nitro-N-p-tolylpyridinecarboxamide, in the same manner as Step 34-2 of Example 34 above, 135 mg (yield: 56%) of the title compound was obtained.

[0813] 1 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.72 (dd, J = 2.6 Hz, 0.7 Hz, 1H), 8.02 (dd, J = 8.4 Hz, 2.6 Hz, 1H), 7.30 (d, J = 8.9 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.47–6.40 (m, 2H), 5.50 (s, 2H), 2.42 (s, 3H), 2.32 (s, 3H).

[0814] Step 53-3: Preparation of (3-methyl-4-(6-methylpyridin-3-ylcarbamoyl)phenyl)carbamoyl dinitrile

[0815] Except for using 4-amino-2-methyl-N-(6-methylpyridin-3-yl)benzamide (135 mg, 0.56 mmol) obtained in Step 53-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Step 1-3 of Example 1 above, 55 mg (yield: 31%) of the title compound was obtained.

[0816] 1 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.85 (d, J = 2.6 Hz, 1H), 8.15 (dd, J = 8.5 Hz, 2.6 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.43–7.33 (m, 3H), 2.50 (s, 3H), 2.44 (s, 3H).

[0817] Example 54: Preparation of (3-methyl-4-(6-methylpyrazin-2-ylcarbamoyl)phenyl)carbazodinitrile (Compound 54)

[0818] Step 54-1: Preparation of 2-methyl-N-(6-methylpyrazin-2-yl)-4-nitrobenzamide

[0819] Except for using 2-methyl-4-nitrobenzoic acid (200 mg, 1.10 mmol) instead of 5-nitrocholic acid and using 6-methylpyrazin-2-amine (121 mg, 1.10 mmol) instead of p-toluidine, the title compound (97 mg, yield: 32%) was obtained in the same manner as in Step 34-1 of Example 34 above.

[0820] 1 H NMR (400 MHz, chloroform-d) δ 9.44 (s, 1H), 8.32 (s, 1H), 8.20–8.11 (m, 3H), 7.70 (d, J = 8.3 Hz, 1H), 2.63 (s, 3H), 2.50 (s, 3H).

[0821] Step 54-2: Preparation of 4-amino-2-methyl-N-(6-methylpyrazin-2-yl)benzamide

[0822] Except for using 2-methyl-N-(6-methylpyrazin-2-yl)-4-nitrobenzamide (97 mg, 0.36 mmol) obtained in Step 54-1 instead of 5-nitro-N-p-tolylpyridinecarboxamide, the title compound (81 mg, yield: 94%) was obtained in the same manner as in Step 34-2 of Example 34 above.

[0823] 1 H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.19 (s, 1H), 8.23 (s, 1H), 7.38 (d, J = 8.2 Hz, 1H), 6.45–6.36 (m, 2H), 5.59 (s, 2H), 2.45 (s, 3H), 2.35 (s, 3H).

[0824] Step 54-3: Preparation of (3-methyl-4-(6-methylpyrazin-2-ylcarbamoyl)phenyl)carbamoyl dinitrile

[0825] Except for using 4-amino-2-methyl-N-(6-methylpyrazin-2-yl)benzamide (80 mg, 0.33 mmol) obtained in Step 54-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (90 mg, yield: 85%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[0826] 11H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 11.04 (s, 1H), 9.24 (s, 1H), 8.31 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.41–7.32 (m, 2H), 2.47 (s, 3H), 2.44 (s, 3H).

[0827] Example 55: Preparation of (2-Methyl-4-(6-methylpyridin-3-ylcarbamoyl)phenyl)carbamoyl dinitrile (Compound 55)

[0828] Step 55-1: Preparation of 3-methyl-N-(6-methylpyridin-3-yl)-4-nitrobenzamide

[0829] Except for using 3-Methyl-4-nitrobenzoic acid (200 mg, 1.10 mmol) instead of 5-nitrocholic acid and 5-Amino-2-methylpyridine (119 mg, 1.10 mmol) instead of p-toluidine, the title compound (166 mg, yield: 55%) was obtained in the same manner as in Step 34-1 of Example 34 above.

[0830] 1 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.79 (d, J = 2.6 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.09–8.03 (m, 2H), 7.98 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 2.59 (s, 3H), 2.45 (s, 3H).

[0831] Step 55-2: Preparation of 4-amino-3-methyl-N-(6-methylpyridin-3-yl)benzamide

[0832] Except for using 3-Methyl-N-(6-methylpyridin-3-yl)-4-nitrobenzamide (160 mg, 0.60 mmol) obtained in Step 55-1 instead of 5-nitro-N-p-tolylpyridineamide, the title compound (78 mg, yield: 54%) was obtained in the same manner as in Step 34-2 of Example 34 above.

[0833] 1 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.79–8.74 (m, 1H), 8.05 (dd, J = 8.4 Hz, 2.6 Hz, 1H), 7.67–7.58 (m, 2H), 7.20 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 5.56 (s, 2H), 2.43 (s, 3H), 2.13 (s, 3H).

[0834] Step 55-3: Preparation of (2-methyl-4-(6-methylpyridin-3-ylcarbamoyl)phenyl)carbamoyl dinitrile

[0835] Except for using 4-amino-3-methyl-N-(6-methylpyridin-3-yl)benzamide (78 mg, 0.32 mmol) obtained in Step 55-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 55 mg (yield: 26%) of the title compound was obtained.

[0836] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.23 (d, J = 2.4 Hz, 1H), 8.68 (dd, J = 8.9 Hz, 2.4 Hz, 1H), 7.99 (s, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 2.70 (s, 3H), 2.48 (s, 3H).

[0837] Example 56: Preparation of (2-fluoro-4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbazoyl dinitrile (Compound 56)

[0838] Step 56-1: Preparation of 3-fluoro-N-(5-methylpyrazin-2-yl)-4-nitrobenzamide

[0839] Except for using 3-fluoro-4-nitrobenzoic acid (200 mg, 1.08 mmol) to replace 5-nitrocholic acid and using 5-methylpyrazin-2-amine (118 mg, 1.08 mmol) to replace p-toluidine, in the same manner as Step 34-1 of Example 34 above, 232 mg (yield: 77%) of the title compound was obtained.

[0840] 1 H NMR (400 MHz, chloroform-d) δ 9.53 (d, J = 1.5 Hz, 1H), 8.41 (s, 1H), 8.25–8.16 (m, 2H), 7.90 (dd, J = 10.7 Hz, 1.9 Hz, 1H), 7.83 (ddd, J = 8.4 Hz, 1.9 Hz, 1.0 Hz, 1H), 2.59 (s, 3H).

[0841] Step 56-2: Preparation of 4-amino-3-fluoro-N-(5-methylpyrazin-2-yl)benzamide

[0842] Except for using 3-fluoro-N-(5-methylpyrazin-2-yl)-4-nitrobenzamide (230 mg, 0.83 mmol) obtained in Step 56-1 to replace 5-nitro-N-p-tolylpyridineamide, in the same manner as Step 34-2 of Example 34 above, 171 mg (yield: 83%) of the title compound was obtained.

[0843] 1 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 9.25 (d, J = 1.5 Hz, 1H), 8.33 (d, J = 1.5 Hz, 1H), 7.78 (dd, J = 12.9 Hz, 2.0 Hz, 1H), 7.71 (dd, J = 8.4 Hz, 2.1 Hz, 1H), 6.79 (t, J = 8.7 Hz, 1H), 5.95 (s, 2H), 2.47 (s, 3H).

[0844] Step 56-3: Preparation of (2-Fluoro-4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbazic di-nitrile

[0845] Except for using 4-amino-3-fluoro-N-(5-methylpyrazin-2-yl)benzamide (171 mg, 0.69 mmol) obtained in Step 56-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 19 mg (yield: 8%) of the title compound was obtained.

[0846] 1 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.28 (d, J = 1.5 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.00 (dd, J = 12.3 Hz, 2.0 Hz, 1H), 7.93 (dd, J = 8.5 Hz, 1.9 Hz, 1H), 7.61 (t, J = 8.3 Hz, 1H), 2.50 (s, 3H).

[0847] Example 57: Preparation of (2-methoxy-4-(6-methylpyridin-3-ylcarbamoyl)phenyl)carbazic diimidoyl (Compound 57)

[0848] Step 57-1: Preparation of 3-Methoxy-N-(6-methylpyridin-3-yl)-4-nitrobenzamide

[0849] Except for using 3-methoxy-4-nitrobenzoic acid (200 mg, 1.01 mmol) instead of 5-nitrocholic acid, and using 5-amino-2-methylpyridine (110 mg, 1.01 mmol) instead of p-toluidine, in the same manner as Step 34-1 of Example 34 above, 229 mg (yield: 78%) of the title compound was obtained.

[0850] 11H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.79 (d, J = 2.6 Hz, 1H), 8.10–8.02 (m, 2H), 7.84 (d, J = 1.7 Hz, 1H), 7.68 (dd, J = 8.4 Hz, 1.7 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 4.04 (s, 3H), 2.47 (s, 3H).

[0851] Step 57-2: Preparation of 4-Amino-3-methoxy-N-(6-methylpyridin-3-yl)benzamide

[0852] Except for using 3-methoxy-N-(6-methylpyridin-3-yl)-4-nitrobenzamide (229 mg, 0.80 mmol) obtained in Step 57-1 to replace 5-nitro-N-p-tolylpicolinamide, in the same manner as Step 34-2 of Example 34 above, 122 mg (yield: 59%) of the title compound was obtained.

[0853] 1 1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.77 (d, J = 2.6 Hz, 1H), 8.03 (dd, J = 8.4, 2.6 Hz, 1H), 7.47 (dd, J = 8.2, 1.9 Hz, 1H), 7.43 (d, J = 1.9 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 5.45 (s, 2H), 3.86 (s, 3H), 2.44 (s, 3H).

[0854] Step 57-3: Preparation of (2-Methoxy-4-(6-methylpyridin-3-ylcarbamoyl)phenyl)carbazic di-nitrile

[0855] Except for using 4-amino-3-methoxy-N-(6-methylpyridin-3-yl)benzamide (60 mg, 0.23 mmol) obtained in Step 57-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Step 1-3 of Example 1 above, 46 mg (yield: 59%) of the title compound was obtained.

[0856] 1 1H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 9.27 (d, J = 2.4 Hz, 1H), 8.76 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.78 (dd, J = 8.4 Hz, 1.8 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 4.07 (s, 3H), 2.70 (s, 3H).

[0857] Example 58: Preparation of (6-(phenylsulfonamido)pyridin-3-yl)carbazic di-nitrile (Compound 58)

[0858] Step 58-1: Preparation of N-(5-Nitropyridin-2-yl)benzenesulfonamide

[0859] Dissolve 5-nitropyridin-2-amine (100 mg, 0.72 mmol) in THF (8 mL), lower the reaction temperature to 0 °C, and then add sodium hydride (35 mg, 1.44 mmol) thereto. After stirring the reaction mixture at 0 °C for 20 minutes, add benzenesulfonyl chloride (111 μL, 0.86 mmol) thereto, and stir the reaction mixture at room temperature for 4.5 hours. After completion of the reaction, extract the reaction product with dichloromethane and distilled water to obtain an organic layer, dry the organic layer with anhydrous magnesium sulfate and filter. Concentrate the filtrate under reduced pressure and purify the crude material by column chromatography to obtain 105 mg (yield: 52%) of the title compound.

[0860] 1 H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.99 (d, J = 2.7 Hz, 1H), 8.46 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 8.00 (dd, J = 7.3 Hz, 1.9 Hz, 2H), 7.69–7.65 (m, 1H), 7.62 (d, 2H), 7.18 (d, J = 9.2 Hz, 1H).

[0861] Step 58-2: Preparation of N-(5-Aminopyridin-2-yl)benzenesulfonamide

[0862] Dissolve N-(5-nitropyridin-2-yl)benzenesulfonamide (105 mg, 0.37 mmol) and 10% Pd / C (45 mg, 0.04 mmol) obtained in Step 58-1 in methanol (4 mL), and stir the reaction mixture at room temperature for 1 hour under a hydrogen atmosphere. After completion of the reaction, filter the reaction mixture through diatomaceous earth to remove the catalyst from the reaction mixture. Concentrate the filtrate under reduced pressure and purify the crude material by column chromatography to obtain 94 mg (yield: 52%) of the title compound.

[0863] 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.80–7.73 (m, 2H), 7.62–7.54 (m, 1H), 7.57–7.48 (m, 2H), 7.47 (t, J = 1.7 Hz, 1H), 6.98–6.88 (m, 2H), 5.08 (s, 2H).

[0864] Step 58-3: Preparation of (6-(Phenylsulfonamido)pyridin-3-yl)carbazic di-nitrile

[0865] Except for using N-(5-aminopyridin-2-yl)benzenesulfonamide (42 mg, 0.17 mmol) obtained in Step 58-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (24 mg, yield: 44%) was obtained in the same manner as Steps 1-3 of Example 1 above.

[0866] 1 H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.22 (s, 1H), 7.90 (d, 2H), 7.77 (dd, J = 9.0 Hz, 2.8 Hz, 1H), 7.63 (d, 1H), 7.57 (d, 2H), 7.16 (d, J = 9.0 Hz, 1H).

[0867] Example 59: Preparation of (6-(4-methoxyphenylsulfonamido)pyridin-3-yl)carbonohydrazonitrile (Compound 59)

[0868] Step 59-1: Preparation of 4-Methoxy-N-(5-nitropyridin-2-yl)benzenesulfonamide

[0869] Except for using 4-methoxybenzene-1-sulfonyl chloride (411 mg, 2.15 mmol) instead of benzenesulfonyl chloride, the title compound (191 mg, yield: 43%) was obtained in the same manner as Step 58-1 of Example 58 above.

[0870] 1 H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 9.01 (dt, J = 8.5 Hz, 3.5 Hz, 1H), 8.45 (td, J = 8.8 Hz, 3.3 Hz, 1H), 7.95 (dt, J = 14.1 Hz, 5.8 Hz, 2H), 7.14 (dt, J = 14.5 Hz, 8.6 Hz, 3H), 3.84 (t, J = 6.3 Hz, 3H).

[0871] Step 59-2: Preparation of N-(5-Aminopyridin-2-yl)-4-methoxybenzenesulfonamide

[0872] Except for using 4-methoxy-N-(5-nitropyridin-2-yl)benzenesulfonamide (285 mg, 0.92 mmol) obtained in Step 59-1 instead of N-(5-nitropyridin-2-yl)benzenesulfonamide, the title compound (193 mg, yield: 75%) was obtained in the same manner as Step 58-2 of Example 58 above.

[0873] 11H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 7.69 (d, 2H), 7.50 (t, J = 1.8 Hz, 1H), 7.04 (d, 2H), 6.91 (d, J = 1.7 Hz, 2H), 5.06 (s, 2H), 3.80 (s, 3H).

[0874] Step 59-3: Preparation of (6-(4-Methoxyphenylsulfonamido)pyridin-3-yl)carbazic di-nitrile

[0875] Except for using N-(5-aminopyridin-2-yl)-4-methoxybenzenesulfonamide (176 mg, 0.63 mmol) obtained in Step 59-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 20 mg (yield: 9%) of the title compound was obtained.

[0876] 1 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.25 (d, J = 2.7 Hz, 1H), 7.83 (d, 2H), 7.76 (dd, J = 9.0 Hz, 2.8 Hz, 1H), 7.14 (d, J = 9.0 Hz, 1H), 7.08 (d, 2H), 3.81 (s, 3H).

[0877] Example 60: Preparation of (6-(pyridine-3-sulfonamido)pyridin-3-yl)carbonohydrazonitrile (Compound 60)

[0878] Step 60-1: Preparation of N-(5-Nitropyridin-2-yl)pyridine-3-sulfonamide

[0879] Except for using pyridine-3-sulfonyl chloride (270 mg, 1.52 mmol) instead of benzenesulfonyl chloride, in the same manner as Step 58-1 of Example 58 above, 115 mg (yield: 40%) of the title compound was obtained.

[0880] 1 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 2H), 9.14 (d, J = 2.4 Hz, 2H), 9.00 (d, J = 2.8 Hz, 2H), 8.83 (dd, J = 4.9 Hz, 1.6 Hz, 2H), 8.45 (dd, J = 9.2 Hz, 2.8 Hz, 2H), 8.38 (dt, J = 8.2 Hz, 2.0 Hz, 2H), 7.65 (dd, J = 8.1 Hz, 4.8 Hz, 2H), 7.15 (d, J = 9.2 Hz, 2H).

[0881] Step 60-2: Preparation of N-(5-Aminopyridin-2-yl)pyridine-3-sulfonamide

[0882] Except using 4-methoxy-N-(5-nitropyridin-2-yl)pyridine-3-sulfonamide (115 mg, 0.41 mmol) obtained in Step 60-1 to replace N-(5-nitropyridin-2-yl)benzenesulfonamide, in the same manner as Step 58-2 of Example 58 above, 56 mg (yield: 54%) of the title compound was obtained.

[0883] 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.89 (dd, J = 2.4 Hz, 0.8 Hz, 1H), 8.74 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 8.13 (ddd, J = 8.0 Hz, 2.3 Hz, 1.6 Hz, 1H), 7.58 (ddd, J = 8.1 Hz, 4.8 Hz, 0.9 Hz, 1H), 7.43 (d, J = 2.8 Hz, 1H), 7.02 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 5.15 (s, 2H).

[0884] Step 60-3: Preparation of (6-(Pyridine-3-sulfonamido)pyridin-3-yl)carbazic di-nitrile

[0885] Except using N-(5-aminopyridin-2-yl)pyridine-3-sulfonamide (55 mg, 0.22 mmol) obtained in Step 60-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Step 1-3 of Example 1 above, 4 mg (yield: 5%) of the title compound was obtained.

[0886] 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 2.4 Hz, 2H), 8.77 (dd, J = 4.8 Hz, 1.6 Hz, 2H), 8.25 (dt, J = 8.1 Hz, 2.1 Hz, 2H), 8.06 (s, 2H), 7.78 (dd, J = 9.0 Hz, 2.7 Hz, 2H), 7.60 (dd, J = 8.1 Hz, 4.8 Hz, 2H), 7.17 (d, J = 9.1 Hz, 2H), 11.70 (s, 1H).

[0887] Example 61: Preparation of (6-(1-methyl-1H-pyrazole-4-sulfonamido)pyridin-3-yl)carbonohydrazonitrile (Compound 61)

[0888] Step 61-1: Preparation of 1-Methyl-N-(5-nitropyridin-2-yl)-1H-pyrazole-4-sulfonamide

[0889] Except for using 1-methyl-1H-pyrazole-4-sulfonyl chloride (390 mg, 2.16 mmol) instead of benzenesulfonyl chloride, the title compound (187 mg, yield: 45%) was obtained in the same manner as in Step 58-1 of Example 58 above.

[0890] 1 H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 9.12 (d, J = 2.8 Hz, 1H), 8.51 (s, 1H), 8.46 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.95 (d, J = 0.8 Hz, 1H), 7.15–7.09 (m, 1H), 3.87 (s, 3H).

[0891] Step 61-2: Preparation of N-(5-Aminopyridin-2-yl)-1-methyl-1H-pyrazole-4-sulfonamide

[0892] Except for using 1-methyl-N-(5-nitropyridin-2-yl)-1H-pyrazole-4-sulfonamide (185 mg, 0.65 mmol) obtained in Step 61-1 instead of N-(5-nitropyridin-2-yl)benzenesulfonamide, the title compound (125 mg, yield: 75%) was obtained in the same manner as in Step 58-2 of Example 58 above.

[0893] 1 H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.17 (s, 1H), 7.64 (d, J = 0.7 Hz, 1H), 7.60–7.54 (m, 1H), 6.96 (dd, J = 8.7 Hz, 2.7 Hz, 1H), 6.92 (dd, J = 8.7 Hz, 0.8 Hz, 1H), 5.09 (s, 2H), 3.84 (s, 3H).

[0894] Step 61-3: Preparation of (6-(1-Methyl-1H-pyrazole-4-sulfonamido)pyridin-3-yl)carbazic di-nitrile

[0895] Except for using N-(5-aminopyridin-2-yl)-1-methyl-1H-pyrazole-4-sulfonamide (124 mg, 0.49 mmol) obtained in Step 61-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (27 mg, yield: 16%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[0896] 11H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 11.00 (s, 1H), 8.36 (s, 1H), 8.33 (d, J = 2.6 Hz, 1H), 7.81 (d, J = 0.8 Hz, 1H), 7.78 (dd, J = 9.0 Hz, 2.8 Hz, 1H), 7.12 (d, J = 9.0 Hz, 1H), 3.85 (s, 3H).

[0897] Example 62: Preparation of (6-(Thiophene-2-sulfonamido)pyridin-3-yl)carbonohydrazonitrile (Compound 62)

[0898] Step 62-1: Preparation of N-(5-Nitropyridin-2-yl)thiophene-2-sulfonamide

[0899] Except for using 2-thiophenesulfonyl chloride (341 mg, 1.87 mmol) instead of benzenesulfonyl chloride, in the same manner as Step 58-1 of Example 58 above, 156 mg (yield: 38%) of the title compound was obtained.

[0900] 1 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.09–9.04 (m, 1H), 8.50 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.99 (dd, J = 5.0 Hz, 1.4 Hz, 1H), 7.86 (dd, J = 3.8 Hz, 1.4 Hz, 1H), 7.26–7.20 (m, 1H), 7.18 (dd, J = 5.0 Hz, 3.8 Hz, 1H).

[0901] Step 62-2: Preparation of N-(5-Aminopyridin-2-yl)thiophene-2-sulfonamide

[0902] Except for using N-(5-nitropyridin-2-yl)thiophene-2-sulfonamide (148 mg, 0.52 mmol) obtained in Step 62-1 instead of N-(5-nitropyridin-2-yl)benzenesulfonamide, in the same manner as Step 58-2 of Example 58 above, 49 mg (yield: 37%) of the title compound was obtained.

[0903] 1 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.81 (dd, J = 5.0 Hz, 1.4 Hz, 1H), 7.53–7.44 (m, 2H), 7.14–7.01 (m, 2H), 7.00 (d, J = 8.7 Hz, 1H), 5.14 (s, 2H).

[0904] Step 62-3: Preparation of (6-(Thiophene-2-sulfonamido)pyridin-3-yl)carbazic di-nitrile

[0905] Except for using N-(5-aminopyridin-2-yl)thiophene-2-sulfonamide (49 mg, 0.19 mmol) obtained in Step 62-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 6 mg (yield: 9%) of the title compound was obtained.

[0906] 1 H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.26 (s, 1H), 7.91 (dd, J = 5.0 Hz, 1.4 Hz, 1H), 7.84 (dd, J = 9.1 Hz, 2.8 Hz, 1H), 7.70 (dd, J = 3.8 Hz, 1.4 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 7.14 (dd, J = 5.0 Hz, 3.7 Hz, 1H).

[0907] Example 63: Preparation of (6-(4-methylphenylsulfonamido)pyridin-3-yl)carbonohydrazonitrile (Compound 63)

[0908] Step 63-1: Preparation of 4-Methyl-N-(5-nitropyridin-2-yl)benzenesulfonamide

[0909] Except for using p-toluenesulfonyl chloride (356 mg, 1.87 mmol) instead of benzenesulfonyl chloride, in the same manner as Step 58-1 of Example 58 above, 121 mg (yield: 29%) of the title compound was obtained.

[0910] 1 H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 8.99 (d, J = 2.7 Hz, 1H), 8.45 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.92–7.84 (m, 2H), 7.45–7.38 (m, 2H), 7.17 (d, J = 9.2 Hz, 1H), 2.37 (s, 3H).

[0911] Step 63-2: Preparation of N-(5-Aminopyridin-2-yl)-4-methylbenzenesulfonamide

[0912] Except for using 4-methyl-N-(5-nitropyridin-2-yl)benzenesulfonamide (121 mg, 0.41 mmol) obtained in Step 63-1 instead of N-(5-nitropyridin-2-yl)benzenesulfonamide, in the same manner as Step 58-2 of Example 58 above, 63 mg (yield: 58%) of the title compound was obtained.

[0913] 11H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.68–7.60 (m, 2H), 7.48 (t, J = 1.8 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 6.91 (d, J = 1.7 Hz, 2H), 5.06 (s, 2H), 2.34 (s, 3H).

[0914] Step 63-3: Preparation of (6-(4-Methylphenylsulfonamido)pyridin-3-yl)carbazic di-nitrile

[0915] Except for using N-(5-aminopyridin-2-yl)-4-methylbenzenesulfonamide (60 mg, 0.27 mmol) obtained in Step 63-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (2 mg, yield: 2%) was obtained in the same manner as Steps 1-3 of Example 1 above.

[0916] 1 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.22 (s, 1H), 7.77 (dd, J = 12.2 Hz, 9.2 Hz, 3H), 7.37 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 9.0 Hz, 1H), 2.36 (s, 3H).

[0917] Example 64: Preparation of (6-(4-fluorobenzenesulfonamido)pyridin-3-yl)carbonohydrazonitrile (Compound 64)

[0918] Step 64-1: Preparation of 4-Fluoro-N-(5-nitropyridin-2-yl)benzenesulfonamide

[0919] Except for using 4-fluorobenzenesulfonyl chloride (420 mg, 2.16 mmol) instead of benzenesulfonyl chloride, the title compound (204 mg, yield: 38%) was obtained in the same manner as Step 58-1 of Example 58 above.

[0920] 1 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.01 (d, J = 2.8 Hz, 1H), 8.47 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 8.13–8.02 (m, 2H), 7.51–7.41 (m, 2H), 7.17 (d, J = 9.2 Hz, 1H).

[0921] Step 64-2: Preparation of N-(5-Aminopyridin-2-yl)-4-fluorobenzenesulfonamide

[0922] Except for using 4-fluoro-N-(5-nitropyridin-2-yl)benzenesulfonamide (204 mg, 0.69 mmol) obtained in Step 64-1 to replace N-(5-nitropyridin-2-yl)benzenesulfonamide, in the same manner as Step 58-2 of Example 58 above, 153 mg (yield: 83%) of the title compound was obtained.

[0923] 1 H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 7.87–7.77 (m, 2H), 7.48 (d, J = 2.6 Hz, 1H), 7.42–7.29 (m, 2H), 7.02–6.88 (m, 2H), 5.10 (s, 2H).

[0924] Step 64-3: Preparation of (6-(4-Fluorophenylsulfonamido)pyridin-3-yl)carbazic di-nitrile

[0925] Except for using N-(5-aminopyridin-2-yl)-4-fluorobenzenesulfonamide (150 mg, 0.56 mmol) obtained in Step 64-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Step 1-3 of Example 1 above, 58 mg (yield: 29%) of the title compound was obtained.

[0926] 1 H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 11.30 (s, 3H), 8.25 (d, J = 2.7 Hz, 2H), 8.03–7.91 (m, 4H), 7.79 (dd, J = 9.0 Hz, 2.8 Hz, 2H), 7.47–7.37 (m, 4H), 7.15 (d, J = 9.0 Hz, 2H).

[0927] Example 65: Preparation of (4-(N-(6-methylpyridin-3-yl)sulfamoyl)phenyl)carbamoyl dinitrile (Compound 65)

[0928] Step 65-1: Preparation of N-(6-Methylpyridin-3-yl)-4-nitrobenzenesulfonamide

[0929] 5-Amino-2-methylpyridine (49 mg, 0.45 mmol) was dissolved in dichloromethane (5 mL), and the reaction temperature was lowered to 0 °C. Then, pyridine (55 μL, 0.68 mmol) was added thereto. After the reaction mixture was stirred at 0 °C for 5 minutes, 4-nitrobenzenesulfonyl chloride (100 mg, 0.45 mmol) was added thereto, and the reaction mixture was stirred at 0 °C for 1.5 hours. After the reaction was completed, the reaction product was extracted with dichloromethane and distilled water to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 70 mg (yield: 52%) of the title compound.

[0930] 1 H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.42–8.35 (m, 2H), 8.14 (d, J = 2.7 Hz, 1H), 8.01–7.94 (m, 2H), 7.40 (dd, J = 8.4 Hz, 2.7 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 2.37 (s, 3H).

[0931] Step 65-2: Preparation of 4-Amino-N-(6-methylpyridin-3-yl)benzenesulfonamide

[0932] N-(6-Methylpyridin-3-yl)-4-nitrobenzenesulfonamide (142 mg, 0.48 mmol) obtained in Step 65-1 and 10% Pd / C (57 mg, 0.05 mmol) were dissolved in ethyl acetate (6 mL), and the reaction mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth to remove the catalyst from the reaction mixture. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 107 mg (yield: 84%) of the title compound.

[0933] 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.10 (dd, J = 2.7 Hz, 0.7 Hz, 1H), 7.39–7.30 (m, 3H), 7.11 (d, J = 8.3 Hz, 1H), 6.57–6.49 (m, 2H), 6.00 (s, 2H), 2.35 (s, 3H).

[0934] Step 65-3: Preparation of (4-(N-(6-Methylpyridin-3-yl)sulfamoyl)phenyl)carbazic di-nitrile

[0935] Except for using 4-amino-N-(6-methylpyridin-3-yl)benzenesulfonamide (105 mg, 0.40 mmol) obtained in Step 65-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (115 mg, yield: 84%) was obtained in the same manner as Steps 1-3 of Example 1 above.

[0936] 1 H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.16 (d, J = 2.6 Hz, 1H), 7.78–7.70 (m, 2H), 7.59–7.51 (m, 2H), 7.48 (dd, J = 8.4 Hz, 2.7 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 2.40 (s, 3H).

[0937] Example 66: Preparation of (4-(N-(4-methoxyphenyl)sulfamoyl)phenyl)carbamoyl dinitrile (Compound 66)

[0938] Step 66-1: Preparation of N-(4-methoxyphenyl)-4-nitrobenzenesulfonamide

[0939] Except for using 4-methoxyaniline (150 mg, 1.22 mmol) instead of 5-amino-2-methylpyridine, the title compound (182 mg, yield: 48%) was obtained in the same manner as Step 65-1 of Example 65 above.

[0940] 1 H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.42–8.34 (m, 2H), 7.96–7.88 (m, 2H), 7.03–6.95 (m, 2H), 6.88–6.79 (m, 2H), 3.69 (s, 3H).

[0941] Step 66-2: Preparation of 4-amino-N-(4-methoxyphenyl)benzenesulfonamide

[0942] Except for using N-(4-methoxyphenyl)-4-nitrobenzenesulfonamide (180 mg, 0.58 mmol) obtained in Step 66-1 instead of N-(6-methylpyridin-3-yl)-4-nitrobenzenesulfonamide, the title compound (149 mg, yield: 91%) was obtained in the same manner as Step 65-2 of Example 65 above.

[0943] 11H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.34–7.26 (m, 2H), 6.99–6.91 (m, 2H), 6.82–6.73 (m, 2H), 6.55–6.47 (m, 2H), 5.91 (s, 2H), 3.66 (s, 3H).

[0944] Step 66-3: Preparation of (4-(N-(4-methoxyphenyl)sulfamoyl)phenyl)carbamoyl dinitrile

[0945] Except for using 4-amino-N-(4-methoxyphenyl)benzenesulfonamide (145 mg, 0.52 mmol) obtained in Step 66-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 42 mg (yield: 22%) of the title compound was obtained.

[0946] 1 1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 9.86 (s, 1H), 7.72–7.64 (m, 2H), 7.58–7.50 (m, 2H), 7.00–6.92 (m, 2H), 6.84–6.76 (m, 2H), 3.67 (s, 3H).

[0947] Example 67: Preparation of (4-(N-(5-methylpyrazin-2-yl)sulfamoyl)phenyl)carbamoyl dinitrile (Compound 67)

[0948] Step 67-1: Preparation of N-(5-methylpyrazin-2-yl)-4-nitrobenzenesulfonamide

[0949] Except for using 5-methylpyrazin-2-amine (74 mg, 0.68 mmol) to replace 5-amino-2-methylpyridine, in the same manner as Step 65-1 of Example 65 above, 41 mg (yield: 20%) of the title compound was obtained.

[0950] 1 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 8.44–8.36 (m, 2H), 8.29 (d, J = 1.5 Hz, 1H), 8.22–8.14 (m, 2H), 8.12 (d, J = 1.5 Hz, 1H), 2.37 (s, 3H).

[0951] Step 67-2: Preparation of 4-amino-N-(5-methylpyrazin-2-yl)benzenesulfonamide

[0952] Except for using N-(5-methylpyrazin-2-yl)-4-nitrobenzenesulfonamide (166 mg, 0.56 mmol) obtained in Step 67-1 in place of N-(6-methylpyridin-3-yl)-4-nitrobenzenesulfonamide, in the same manner as Step 65-2 of Example 65 above, 66 mg (yield: 44%) of the title compound was obtained.

[0953] 1 H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.25 (d, J = 1.5 Hz, 1H), 8.12 (d, J = 1.5 Hz, 1H), 7.57–7.49 (m, 2H), 6.61–6.53 (m, 2H), 6.05 (s, 2H), 2.36 (s, 3H).

[0954] Step 67-3: Preparation of (4-(N-(5-methylpyrazin-2-yl)sulfamoyl)phenyl)carbamoyl dinitrile

[0955] Except for using 4-amino-N-(4-methylpyrazin-2-yl)benzenesulfonamide (65 mg, 0.25 mmol) obtained in Step 67-2 in place of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Step 1-3 of Example 1 above, 5 mg (yield: 5%) of the title compound was obtained.

[0956] 1 H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.27 (d, J = 1.5 Hz, 1H), 8.12 (d, J = 1.5 Hz, 1H), 7.96–7.88 (m, 2H), 7.63–7.54 (m, 2H), 2.36 (s, 3H).

[0957] Example 68: Preparation of (6-phenoxypyridin-3-yl)carbonohydrazonitrile (Compound 68)

[0958] Step 68-1: Preparation of 5-nitro-2-phenoxypyridine

[0959] 2-Chloro-5-nitropyridine (200 mg, 1.26 mmol) was dissolved in DMF, and phenol (133 μL, 1.51 mmol) and potassium carbonate (698 mg, 1.84 mmol) were added thereto. The reaction mixture was stirred in a microwave at 150 °C for 1 hour. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 121 mg (yield: 44%) of the title compound.

[0960] 11H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 2.8 Hz, 1H), 8.63 (dd, J = 9.1 Hz, 2.9 Hz, 1H), 7.48 (dd, J = 8.4 Hz, 7.3 Hz, 2H), 7.34–7.22 (m, 4H).

[0961] Step 68-2: Preparation of 6-phenoxypyridin-3-amine

[0962] Except for using 5-nitro-2-phenoxypyridine (100 mg, 0.46 mmol) obtained in Step 68-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (64 mg, yield: 74%) was obtained in the same manner as Steps 1-2 of Example 1 above.

[0963] 1 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 2.8 Hz, 1H), 8.63 (dd, J = 9.1 Hz, 2.9 Hz, 1H), 7.48 (dd, J = 8.4 Hz, 7.3 Hz, 2H), 7.34–7.20 (m, 4H).

[0964] Step 68-3: Preparation of (6-phenoxypyridin-3-yl)carbamoyl dinitrile

[0965] Except for using 6-phenoxypyridin-3-amine (50 mg, 0.27 mmol) obtained in Step 68-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (14 mg, yield: 19%) was obtained in the same manner as Steps 1-3 of Example 1 above.

[0966] 1 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 2.8 Hz, 1H), 7.92 (dd, J = 8.9 Hz, 2.8 Hz, 1H), 7.43 (t, J = 7.9 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H), 7.13 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 8.9 Hz, 1H).

[0967] Example 69: Preparation of (6-(3-fluorophenoxy)pyridin-3-yl)carbamoyl dinitrile (Compound 69)

[0968] Step 69-1: Preparation of 2-(3-fluorophenoxy)-5-nitropyridine

[0969] Except for using 3-fluorophenol instead of phenol, the title compound (267 mg, yield: 90%) was obtained in the same manner as Step 68-1 of Example 68 above.

[0970] 1 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.65 (d, J = 9.2 Hz, 1H), 7.52 (q, J = 7.4 Hz, 6.5 Hz, 2H), 7.31 (d, J = 9.1 Hz, 1H), 7.24–7.09 (m, 3H).

[0971] Step 69-2: Preparation of 6-(3-fluorophenoxy)pyridin-3-amine

[0972] Except for using 2-(3-fluorophenoxy)-5-nitropyridine (260 mg, 1.11 mmol) obtained in Step 69-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 172 mg (yield: 76%) of the title compound was obtained.

[0973] 1 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 2.9 Hz, 1H), 7.41–7.31 (m, 1H), 7.10 (dd, J = 8.6 Hz, 3.0 Hz, 1H), 6.96–6.88 (m, 1H), 6.85–6.73 (m, 3H), 5.18 (s, 2H).

[0974] Step 69-3: Preparation of (6-(3-fluorophenoxy)pyridin-3-yl)carbamoyl dinitrile

[0975] Except for using 6-(3-fluorophenoxy)pyridin-3-amine (150 mg, 0.73 mmol) obtained in Step 69-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 92 mg (yield: 44%) of the title compound was obtained.

[0976] 1 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 2.8 Hz, 1H), 7.94 (dd, J = 8.9 Hz, 2.8 Hz, 1H), 7.51–7.39 (m, 1H), 7.15 (d, J = 8.9 Hz, 1H), 7.11–7.03 (m, 2H), 7.02–6.95 (m, 1H).

[0977] Example 70: Preparation of (5-phenoxypyridin-2-yl)carbamoyl dinitrile (Compound 70)

[0978] Step 70-1: Preparation of 2-nitro-5-phenoxypyridine

[0979] Except that 5-chloro-2-nitropyridine (300 mg, 1.89 mmol) was used instead of 2-chloro-5-nitropyridine, the title compound (73 mg, yield: 18%) was obtained in the same manner as in Step 68-1 of Example 68 above.

[0980] 1 H NMR (400 MHz, DMSO-d6) δ 9.06–9.00 (m, 1H), 8.63 (dd, J = 9.1 Hz, 2.9 Hz, 1H), 7.53–7.45 (m, 2H), 7.34–7.22 (m, 4H).

[0981] Step 70-2: Preparation of 5-phenoxypyridin-2-amine

[0982] Except that 2-nitro-5-phenoxypyridine (150 mg, 0.69 mmol) obtained in Step 70-1 was used instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (73 mg, yield: 56%) was obtained in the same manner as in Step 1-2 of Example 1 above.

[0983] 1 H NMR (400 MHz, DMSO-d6) δ 7.55 (d, J = 2.7 Hz, 1H), 7.37–7.27 (m, 2H), 7.11–7.05 (m, 2H), 6.97–6.91 (m, 2H), 6.76 (d, J = 8.6 Hz, 1H), 5.10 (s, 2H).

[0984] Step 70-3: Preparation of (5-phenoxypyridin-2-yl)carbamoyl dinitrile

[0985] Except that 5-phenoxypyridin-2-amine (150 mg, 0.80 mmol) obtained in Step 70-2 was used instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (132 mg, yield: 62%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[0986] 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 2.8 Hz, 1H), 7.91 (dd, J = 8.9 Hz, 2.8 Hz, 1H), 7.46–7.38 (m, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.16–7.07 (m, 3H).

[0987] Example 71: Preparation of (3-fluoro-4-phenoxyphenyl)carbamoyl dinitrile (Compound 71)

[0988] Step 71-1: Preparation of 2-fluoro-4-nitro-1-phenoxybenzene

[0989] Except for using 1,2-difluoro-4-nitrobenzene (0.30 mL, 2.71 mmol) instead of 2-chloro-5-nitropyridine, the title compound (619 mg, yield: 98%) was obtained in the same manner as in Step 68-1 of Example 68 above.

[0990] 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (dd, J = 10.8 Hz, 2.8 Hz, 1H), 8.10 (dt, J = 9.3 Hz, 1.5 Hz, 1H), 7.50 (t, J = 7.7 Hz, 2H), 7.35–7.27 (m, 1H), 7.21 (d, J = 8.7 Hz, 2H), 7.15 (t, J = 8.7 Hz, 1H).

[0991] Step 71-2: Preparation of 3-fluoro-4-phenoxyaniline

[0992] Except for using 2-fluoro-4-nitro-1-phenoxybenzene (630 mg, 2.70 mmol) obtained in Step 71-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (536 mg, yield: 98%) was obtained in the same manner as in Step 1-2 of Example 1 above.

[0993] 1 H NMR (400 MHz, DMSO-d6) δ 7.34–7.26 (m, 2H), 7.01 (t, J = 7.3 Hz, 1H), 6.91 (t, J = 9.0 Hz, 1H), 6.84 (d, J = 8.2 Hz, 2H), 6.49 (dd, J = 13.3 Hz, 2.6 Hz, 1H), 6.40 (dd, J = 8.7 Hz, 2.6 Hz, 1H), 5.34 (s, 2H).

[0994] Step 71-3: Preparation of (3-fluoro-4-phenoxyphenyl)carbamoyl dinitrile

[0995] Except for using 3-fluoro-4-phenoxyaniline (300 mg, 1.48 mmol) obtained in Step 71-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (275 mg, yield: 66%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[0996] 11H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 7.45 (dd, J = 12.1 Hz, 2.5 Hz, 1H), 7.42–7.30 (m, 3H), 7.23 (t, J = 8.8 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 6.99 (d, J = 7.6 Hz, 2H).

[0997] Example 72: Preparation of (3-Fluoro-4-(pyridin-3-yloxy)phenyl)carbamoyl dinitrile (Compound 72)

[0998] Step 72-1: Preparation of 3-(2-fluorophenoxy)-5-nitropyridine

[0999] Except using 1,2-difluoro-4-nitrobenzene (0.20 mL, 1.81 mmol) instead of 2-chloro-5-nitropyridine and using 3-hydroxypyridine (206 mg, 2.17 mmol) instead of phenol, the title compound was obtained in the same manner as in Step 68-1 of Example 68 above and used for the next step without further purification.

[1000] Step 72-1: Preparation of 3-(2-fluorophenoxy)-5-nitropyridine

[1001] Except using 3-(2-fluoro-4-nitrophenoxy)pyridine (400 mg, 1.71 mmol) obtained in Step 72-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, 295 mg (yield: 84%) of the title compound was obtained in the same manner as in Step 1-2 of Example 1 above.

[1002] 1 1H NMR (400 MHz, DMSO-d6) δ 8.34–8.21 (m, 2H), 7.34 (dd, J = 8.5 Hz, 4.6 Hz, 1H), 7.25–7.17 (m, 1H), 6.98 (t, J = 9.1 Hz, 1H), 6.51 (dd, J = 13.3 Hz, 2.6 Hz, 1H), 6.41 (dd, J = 8.6 Hz, 2.5 Hz, 1H), 5.41 (s, 2H).

[1003] Step 72-3: Preparation of (3-fluoro-4-(pyridin-3-yloxy)phenyl)carbamoyl dinitrile

[1004] Except using 3-fluoro-4-(pyridin-3-yloxy)aniline (280 mg, 1.37 mmol) obtained in Step 72-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, 361 mg (yield: 94%) of the title compound was obtained in the same manner as in Step 1-3 of Example 1 above.

[1005] 11H NMR (400 MHz, DMSO-d6) δ 8.42 (t, J = 1.9 Hz, 1H), 8.38 (t, J = 3.0 Hz, 1H), 7.50–7.43 (m, 3H), 7.33 (dd, J = 4.2 Hz, 2.2 Hz, 2H).

[1006] Example 73: Preparation of (4-Phenoxy-3-(trifluoromethyl)phenyl)carbamoyl dinitrile (Compound 73)

[1007] Step 73-1: Preparation of 4-nitro-1-phenoxy-2-(trifluoromethyl)benzene

[1008] Except for using 1-Fluoro-4-nitro-2-(trifluoromethyl)benzene (0.20 mL, 1.46 mmol) instead of 2-Chloro-5-nitropyridine, in the same manner as Step 68-1 of Example 68 above, 404 mg (yield: 98%) of the title compound was obtained.

[1009] 1 1H NMR (400 MHz, DMSO-d6) δ 8.55–8.44 (m, 2H), 7.55 (t, J = 7.9 Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 9.2 Hz, 1H).

[1010] Step 73-2: Preparation of 4-phenoxy-3-(trifluoromethyl)aniline

[1011] Except for using 4-Nitro-1-phenoxy-2-(trifluoromethyl)benzene (350 mg, 1.24 mmol) obtained in Step 73-1 instead of 5-Methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Step 1-2 of Example 1 above, 305 mg (yield: 97%) of the title compound was obtained.

[1012] 1 1H NMR (400 MHz, DMSO-d6) δ 7.32 (t, J = 7.9 Hz, 2H), 7.04 (t, J = 7.3 Hz, 1H), 6.93 (d, J = 2.6 Hz, 1H), 6.89–6.80 (m, 4H), 5.46 (s, 2H).

[1013] Step 73-3: Preparation of (4-phenoxy-3-(trifluoromethyl)phenyl)carbamoyl dinitrile

[1014] Except for using 4-Phenoxy-3-(trifluoromethyl)aniline (200 mg, 0.79 mmol) obtained in Step 73-2 instead of N-(5-Aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Step 1-3 of Example 1 above, 206 mg (yield: 79%) of the title compound was obtained.

[1015] 1 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 2.7 Hz, 1H), 7.71 (dd, J = 9.0 Hz, 2.7 Hz, 1H), 7.50–7.38 (m, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.13–7.04 (m, 3H).

[1016] Example 74: Preparation of (3-Methyl-4-(pyridin-3-yloxy)phenyl)carbamoyl dinitrile (Compound 74)

[1017] Step 74-1: Preparation of 3-(2-methyl-4-nitrophenoxy)pyridine

[1018] The title compound was obtained in the same manner as in Step 68-1 of Example 68 above, except that 2-fluoro-5-nitrotoluene (200 mg, 1.29 mmol) was used instead of 2-chloro-5-nitropyridine, and 3-hydroxypyrimidine (147 mg, 1.55 mmol) was used instead of phenol, and was used in the next step without further purification.

[1019] Step 74-2: Preparation of 3-methyl-4-(pyridin-3-yloxy)aniline

[1020] The title compound (215 mg, yield: 99%) was obtained in the same manner as in Step 1-2 of Example 1 above, except that 3-(2-methyl-4-nitrophenoxy)pyridine (250 mg, 1.09 mmol) obtained in Step 74-1 was used instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide.

[1021] 1 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 2H), 7.31 (dd, J = 8.5 Hz, 4.6 Hz, 1H), 7.09 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 6.53–6.42 (m, 2H), 5.00 (s, 2H), 1.98 (s, 3H).

[1022] Step 74-3: Preparation of (3-methyl-4-(pyridin-3-yloxy)phenyl)carbamoyl dinitrile

[1023] The title compound (226 mg, yield: 82%) was obtained in the same manner as in Step 1-3 of Example 1 above, except that 3-methyl-4-(pyridin-3-yloxy)aniline (200 mg, 0.10 mmol) obtained in Step 74-2 was used instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide.

[1024] 11H NMR (400 MHz, DMSO-d6) δ 8.39–8.30 (m, 2H), 7.51–7.39 (m, 2H), 7.37–7.29 (m, 2H), 7.02 (d, J = 8.7 Hz, 1H).

[1025] Example 75: Preparation of Methyl (5-phenoxypyridin-2-yl)carbazonyldinitrile (Compound 75)

[1026] Under a nitrogen atmosphere, (5-phenoxypyridin-2-yl)carbazonyldinitrile (50 mg, 0.19 mmol) prepared in Example 70 was dissolved in DMF. Potassium tert-butoxide (28 mg, 0.25 mmol) was added to the reaction solution at room temperature, and methyl iodide (24 μL, 0.38 mmol) was added thereto. Then the reaction mixture was stirred at 60 °C for 12 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 8 mg (yield: 15%) of the title compound.

[1027] 1 1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 2.6 Hz, 1H), 8.22 (dd, J = 9.3 Hz, 2.6 Hz, 1H), 7.60 (t, J = 7.9 Hz, 2H), 7.44 (dd, J = 12.1 Hz, 7.7 Hz, 3H), 7.01 (d, J = 9.3 Hz, 1H), 4.19 (s, 3H).

[1028] Example 76: Preparation of (6-(3-fluorophenoxy)pyridin-3-yl)(methyl)carbazonyldinitrile (Compound 76)

[1029] Except for using (6-(3-fluorophenoxy)pyridin-3-yl)carbazonyldinitrile (50 mg, 0.18 mmol) obtained in Example 69 instead of (5-phenoxypyridin-2-yl)carbazonyldinitrile, in the same manner as in Example 75 above, 7 mg (yield: 13%) of the title compound was obtained.

[1030] 1 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 2.6 Hz, 1H), 8.22 (dd, J = 9.3 Hz, 2.6 Hz, 1H), 7.69–7.59 (m, 1H), 7.43 (dt, J = 9.7 Hz, 2.4 Hz, 1H), 7.36–7.28 (m, 2H), 7.15 (d, J = 9.3 Hz, 1H), 4.18 (s, 3H).

[1031] Preparation of Example 77: (3-Fluoro-4-phenoxyphenyl)(methyl)carbazoyl dinitrile (Compound 77)

[1032] Except for using (3-fluoro-4-phenoxyphenyl)carbazoyl dinitrile (100 mg, 0.36 mmol) prepared in Example 71 instead of (5-phenoxypyridin-2-yl)carbazoyl dinitrile, in the same manner as in Example 75 above, 66 mg (yield: 63%) of the title compound was obtained.

[1033] 1 H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 12.0 Hz, 1H), 7.40 (t, J = 7.9 Hz, 3H), 7.27 (t, J = 8.8 Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 8.0 Hz, 2H), 4.02 (s, 3H).

[1034] Preparation of Example 78: Methyl (4-phenoxy-3-(trifluoromethyl)phenyl)carbazoyl dinitrile (Compound 78)

[1035] Except for using (4-phenoxy-3-(trifluoromethyl)phenyl)carbazoyl dinitrile (100 mg, 0.30 mmol) prepared in Example 73 instead of (5-phenoxypyridin-2-yl)carbazoyl dinitrile, in the same manner as in Example 75 above, 52 mg (yield: 50%) of the title compound was obtained.

[1036] 1 H NMR (400 MHz, DMSO-d6) δ 7.94–7.72 (m, 2H), 7.45 (t, J = 8.0 Hz, 2H), 7.24 (t, J = 7.4 Hz, 1H), 7.16–7.06 (m, 3H), 4.04 (s, 3H).

[1037] Preparation of Example 79: (3-Methyl-4-(pyridin-4-yloxy)phenyl)carbazoyl dinitrile (Compound 79)

[1038] Step 79-1: Preparation of 4-(2-methyl-4-nitrophenoxy)pyridine

[1039] Except for using 2-fluoro-5-nitrotoluene (200 mg, 1.29 mmol) instead of 2-chloro-5-nitropyridine, and using 4-hydroxypyrimidine (147 mg, 1.55 mmol) instead of phenol, in the same manner as in Step 68-1 of Example 68 above, 61 mg (yield: 20%) of the title compound was obtained.

[1040] 11H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 2.7 Hz, 1H), 8.21 (dd, J = 8.6 Hz, 2.7 Hz, 1H), 7.81–7.76 (m, 2H), 7.70 (d, J = 8.7 Hz, 1H), 6.23 (d, J = 7.8 Hz, 2H), 2.32 (s, 3H).

[1041] Step 79-2: Preparation of 3-methyl-4-(pyridin-4-yloxy)aniline

[1042] Except for using 4-(2-methyl-4-nitrophenoxy)pyridine (50 mg, 0.202 mmol) obtained in Step 79-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 31 mg (yield: 72%) of the title compound was obtained.

[1043] 1 1H NMR (400 MHz, DMSO-d6) δ 7.59–7.52 (m, 2H), 6.96 (d, J = 8.3 Hz, 1H), 6.52–6.42 (m, 2H), 6.15–6.09 (m, 2H).

[1044] Step 79-3: Preparation of (3-methyl-4-(pyridin-4-yloxy)phenyl)carbamoyl dinitrile

[1045] Except for using 3-methyl-4-(pyridin-4-yloxy)aniline (30 mg, 0.15 mmol) obtained in Step 79-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 22 mg (yield: 46%) of the title compound was obtained.

[1046] 1 1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 7.1 Hz, 2H), 7.51–7.35 (m, 3H), 6.55 (d, J = 7.1 Hz, 2H), 2.16 (s, 3H).

[1047] Example 80: Preparation of (3-fluoro-4-(pyridin-4-yloxy)phenyl)carbamoyl dinitrile (Compound 80)

[1048] Step 80-1: Preparation of 4-(2-fluorophenoxy)pyridine

[1049] Except using 1,2-difluoro-4-nitrobenzene (0.20 mL, 1.81 mmol) instead of 2-chloro-5-nitropyridine and using 4-hydroxypyrimidine (206 mg, 2.17 mmol) instead of phenol, the title compound (353 mg, yield: 42%) was obtained in the same manner as in Step 68-1 of Example 68 above.

[1050] 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (dd, J = 10.6 Hz, 2.5 Hz, 1H), 8.29–8.22 (m, 1H), 7.99–7.89 (m, 3H), 6.28 (d, J = 7.9 Hz, 2H).

[1051] Step 80-2: Preparation of 3-fluoro-4-(pyridin-4-yloxy)aniline

[1052] Except using 4-(2-fluoro-4-nitrophenoxy)pyridine (340 mg, 1.45 mmol) obtained in Step 80-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (94 mg, yield: 32%) was obtained in the same manner as in Step 1-2 of Example 1 above.

[1053] 1 H NMR (400 MHz, DMSO-d6) δ 7.69–7.61 (m, 2H), 7.18 (t, J = 8.9 Hz, 1H), 6.56–6.39 (m, 2H), 6.15 (d, J = 7.6 Hz, 2H), 5.78 (s, 2H).

[1054] Step 80-3: Preparation of (3-fluoro-4-(pyridin-5-yloxy)phenyl)carbamoyl dinitrile

[1055] Except using 3-fluoro-4-(pyridin-4-yloxy)aniline (80 mg, 0.39 mmol) obtained in Step 80-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (105 mg, yield: 95%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[1056] 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 7.1 Hz, 2H), 7.67 (t, J = 8.6 Hz, 1H), 7.50–7.30 (m, 2H), 6.67 (d, J = 7.1 Hz, 2H).

[1057] Example 81: Preparation of (3-methyl-4-(pyrimidin-5-yloxy)phenyl)carbamoyl dinitrile (Compound 81)

[1058] Step 81-1: Preparation of 5-(2-methyl-4-nitrophenoxy)pyrimidine

[1059] Except for using 2-fluoro-5-nitrotoluene (200 mg, 1.29 mmol) instead of 2-chloro-5-nitropyridine and using 5-hydroxypyrimidine (149 mg, 1.55 mmol) instead of phenol, the title compound (121 mg, yield: 41%) was obtained in the same manner as in Step 68-1 of Example 68 above.

[1060] 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.76 (s, 2H), 8.30 (dd, J = 2.8 Hz, 0.9 Hz, 1H), 8.08 (dd, J = 9.0 Hz, 2.7 Hz, 1H), 7.11 (d, J = 9.0 Hz, 1H), 2.41 (s, 3H).

[1061] Step 81-2: Preparation of 3-methyl-4-(pyrimidin-5-yloxy)aniline

[1062] Except for using 5-(2-methyl-4-nitrophenoxy)pyrimidine (100 mg, 0.43 mmol) obtained in Step 81-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (80 mg, yield: 92%) was obtained in the same manner as in Step 1-2 of Example 1 above.

[1063] 1 H NMR (400 MHz, DMSO-d6) δ 8.91–8.76 (m, 1H), 8.35 (s, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.47 (dd, J = 24.4 Hz, 5.5 Hz, 2H), 5.04 (s, 2H), 1.99 (s, 3H).

[1064] Step 81-3: Preparation of (3-fluoro-4-(pyrimidin-5-yloxy)phenyl)carbamoyl dinitrile

[1065] Except for using 3-fluoro-4-(pyrimidin-5-yloxy)aniline (150 mg, 0.73 mmol) obtained in Step 81-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (65 mg, yield: 67%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[1066] 11H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 8.97 (s, 1H), 8.53 (s, 2H), 7.48 (d, J = 2.7 Hz, 1H), 7.36 (dd, J = 8.8 Hz, 2.7 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 2.24 (s, 3H).

[1067] Example 82: Preparation of (3-Fluoro-4-(pyrimidin-5-yloxy)phenyl)carbonohydrazonitrile (Compound 82)

[1068] Step 82-1: Preparation of 5-(2-fluoro-4-nitrophenoxy)pyrimidine

[1069] Except for using 1,2-difluoro-4-nitrobenzene (0.20 mL, 1.81 mmol) instead of 2-chloro-5-nitropyridine and using 5-hydroxypyrimidine (208 mg, 2.17 mmol) instead of phenol, 346 mg (yield: 81%) of the title compound was obtained in the same manner as in Step 68-1 of Example 68 above.

[1070] 1 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.86 (s, 2H), 8.41 (dd, J = 10.7 Hz, 2.7 Hz, 1H), 8.12 (ddd, J = 9.2 Hz, 2.7 Hz, 1.5 Hz, 1H), 7.46 (dd, J = 9.1 Hz, 8.2 Hz, 1H).

[1071] Step 82-2: Preparation of 3-fluoro-4-(pyrimidin-5-yloxy)aniline

[1072] Except for using 5-(2-fluoro-4-nitrophenoxy)pyrimidine (300 mg, 1.28 mmol) obtained in Step 82-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, 180 mg (yield: 69%) of the title compound was obtained in the same manner as in Step 1-2 of Example 1 above.

[1073] 1 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.48 (s, 2H), 7.05 (t, J = 9.1 Hz, 1H), 6.52 (dd, J = 13.4 Hz, 2.6 Hz, 1H), 6.42 (ddd, J = 8.7 Hz, 2.6 Hz, 1.1 Hz, 1H), 5.46 (s, 2H).

[1074] Step 82-3: Preparation of (3-fluoro-4-(pyrimidin-5-yloxy)phenyl)carbamoyl dinitrile

[1075] Except for using 3-fluoro-4-(pyrimidin-5-yloxy)aniline (150 mg, 0.73 mmol) obtained in Step 82-2 in place of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (93 mg, yield: 45%) was obtained in the same manner as Steps 1-3 of Example 1 above.

[1076] 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.65 (s, 2H), 7.49 (dd, J = 12.2 Hz, 2.5 Hz, 1H), 7.42 (t, J = 8.7 Hz, 1H), 7.35 (dd, J = 9.0 Hz, 1.5 Hz, 1H).

[1077] Example 83: Preparation of (4-(pyridin-2-yloxy)phenyl)carbamoyl dinitrile (Compound 83)

[1078] Step 83-1: Preparation of 4-(pyridin-2-yloxy)aniline

[1079] After dissolving 4-aminophenol (200 mg, 1.83 mmol) in dimethyl sulfoxide, 2-fluoropyridine (158 μL, 1.83 mmol) and cesium carbonate (716 mg, 2.20 mmol) were added thereto, and the reaction mixture was stirred at 80 °C for 12 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain the title compound (113 mg, yield: 33%).

[1080] 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (ddd, J = 4.9 Hz, 2.1 Hz, 0.8 Hz, 1H), 7.76 (ddd, J = 8.3 Hz, 7.2 Hz, 2.0 Hz, 1H), 7.03 (ddd, J = 7.2 Hz, 4.9 Hz, 1.0 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.81–6.76 (m, 2H), 6.63–6.53 (m, 2H), 4.97 (s, 2H).

[1081] Step 83-2: Preparation of (4-(pyridin-2-yloxy)phenyl)carbamoyl dinitrile

[1082] Except for using 4-(pyridin-2-yloxy)aniline (100 mg, 0.54 mmol) obtained in Step 83-1 in place of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (67 mg, yield: 48%) was obtained in the same manner as Steps 1-3 of Example 1 above.

[1083] 1 1H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 8.15 (d, J = 4.9 Hz, 1H), 7.91–7.82 (m, 1H), 7.51 (d, J = 9.1 Hz, 1H), 7.21–7.12 (m, 3H), 7.05 (d, J = 8.3 Hz, 1H).

[1084] Example 84: Preparation of (4-(pyrazin-2-yloxy)phenyl)carbamoyl dinitrile (Compound 84)

[1085] Step 84-1: Preparation of 4-(pyrazin-2-yloxy)aniline

[1086] Except for using 2-fluoropyrazine (148 μL, 1.83 mmol) instead of 2-fluoropyridine, in the same manner as Step 83-1 of Example 83 above, 268 mg (yield: 78%) of the title compound was obtained.

[1087] 1 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 1.4 Hz, 1H), 8.29 (d, J = 2.7 Hz, 1H), 8.16 (dd, J = 2.7 Hz, 1.4 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 6.59 (d, J = 8.7 Hz, 2H), 5.04 (s, 2H).

[1088] Step 84-2: Preparation of (4-(pyrazin-2-yloxy)phenyl)carbamoyl dinitrile

[1089] Except for using 4-(pyrazin-2-yloxy)aniline (200 mg, 1.07 mmol) obtained in Step 84-1 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 66 mg (yield: 23%) of the title compound was obtained.

[1090] 1 1H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 8.56 (d, J = 1.4 Hz, 1H), 8.39 (d, J = 2.7 Hz, 1H), 8.21 (dd, J = 2.8 Hz, 1.4 Hz, 1H), 7.53 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 8.9 Hz, 2H).

[1091] Example 85: Preparation of (4-(pyridin-3-yloxy)phenyl)carbamoyl dinitrile (Compound 85)

[1092] Step 85-1: Preparation of 4-(pyridin-3-yloxy)aniline

[1093] Except for using 3-fluoropyridine (158 μL, 1.83 mmol) instead of 2-fluoropyridine, the title compound (62 mg, yield: 18%) was obtained in the same manner as in Step 83-1 of Example 83 above.

[1094] 1 H NMR (400 MHz, DMSO-d6) δ 8.32–8.18 (m, 2H), 7.33 (ddd, J = 8.5 Hz, 4.6 Hz, 0.7 Hz, 1H), 7.21 (ddd, J = 8.5 Hz, 2.9 Hz, 1.4 Hz, 1H), 6.81 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.8 Hz, 2H), 5.04 (s, 2H).

[1095] Step 85-2: Preparation of (4-(pyridin-3-yloxy)phenyl)carbamoyl dinitrile

[1096] Except for using 4-(pyridin-3-yloxy)aniline (50 mg, 0.27 mmol) obtained in Step 85-1 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (18 mg, yield: 25%) was obtained in the same manner as in Steps 1-3 of Example 1 above.

[1097] 1 H NMR (400 MHz, DMSO-d6) δ 8.48–8.34 (m, 2H), 7.60–7.42 (m, 4H), 7.15 (d, J = 9.0 Hz, 2H).

[1098] Example 86: Preparation of (4-(2-cyanophenoxy)phenyl)carbamoyl dinitrile (Compound 86)

[1099] Step 86-1: 2-(4-aminophenoxy)benzonitrile

[1100] Except for using 2-fluorobenzonitrile (195 μL, 1.83 mmol) instead of 2-fluoropyridine, the title compound (308 mg, yield: 80%) was obtained in the same manner as in Step 83-1 of Example 83 above.

[1101] 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (dd, J = 7.7 Hz, 1.7 Hz, 1H), 7.59 (ddd, J = 8.8 Hz, 7.4 Hz, 1.7 Hz, 1H), 7.17 (td, J = 7.6 Hz, 1.0 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.77 (d, J = 8.6 Hz, 1H), 6.64 (d, J = 8.8 Hz, 2H), 5.15 (s, 2H).

[1102] Step 86-2: Preparation of (4-(2-cyanophenoxy)phenyl)carbamoyl dinitrile

[1103] Except for using 2-(4-aminophenoxy)benzonitrile (250 mg, 1.19 mmol) obtained in Step 86-1 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 246 mg (yield: 72%) of the title compound was obtained.

[1104] 1 H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 7.91 (dd, J = 7.8 Hz, 1.7 Hz, 1H), 7.69 (ddd, J = 8.7 Hz, 7.5 Hz, 1.7 Hz, 1H), 7.60–7.52 (m, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.26–7.18 (m, 2H), 7.00 (d, J = 8.5 Hz, 1H).

[1105] Example 87: Preparation of (4-(4-cyanophenoxy)phenyl)carbazonyldinitrile (Compound 87)

[1106] Step 87-1: Preparation of 4-(4-aminophenoxy)benzonitrile

[1107] Except for using 4-fluorobenzonitrile (222 mg, 1.83 mmol) to replace 2-fluoropyridine, in the same manner as Step 83-1 of Example 83 above, 295 mg (yield: 76%) of the title compound was obtained.

[1108] 1 H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 6.63 (d, J = 8.7 Hz, 2H), 5.12 (s, 2H).

[1109] Step 87-2: Preparation of (4-(4-cyanophenoxy)phenyl)carbamoyl dinitrile

[1110] Except for using 4-(4-aminophenoxy)benzonitrile (250 mg, 1.19 mmol) obtained in Step 87-1 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 196 mg (yield: 57%) of the title compound was obtained.

[1111] 11H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.9 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H).

[1112] Example 88: Preparation of (4-(3-cyanophenoxy)phenyl)carbamoyl dinitrile (Compound 88)

[1113] Step 88-1: Preparation of 3-(4-aminophenoxy)benzonitrile

[1114] Except for using 3-chlorobenzyl cyanide (252 mg, 1.83 mmol) instead of 2-fluoropyridine, in the same manner as Step 83-1 of Example 83 above, 46 mg (yield: 12%) of the title compound was obtained.

[1115] 1 1H NMR (400 MHz, DMSO-d6) δ 7.55–7.45 (m, 2H), 7.27 (s, 1H), 7.20 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.5 Hz, 2H), 6.62 (d, J = 8.5 Hz, 2H), 5.10 (s, 2H).

[1116] Step 88-2: Preparation of (4-(3-cyanophenoxy)phenyl)carbamoyl dinitrile

[1117] Except for using 3-(4-aminophenoxy)benzyl cyanide (46 mg, 0.22 mmol) obtained in Step 88-1 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 25 mg (yield: 40%) of the title compound was obtained.

[1118] 1 1H NMR (400 MHz, DMSO-d6) δ 7.66–7.57 (m, 2H), 7.54 (d, J = 9.0 Hz, 3H), 7.37 (dt, J = 7.3 Hz, 2.4 Hz, 1H), 7.17 (d, J = 8.9 Hz, 2H).

[1119] Example 89: Preparation of (4-(6-(trifluoromethyl)pyridin-3-yloxy)phenyl)carbamoyl dinitrile (Compound 89)

[1120] Step 89-1: Preparation of 4-(6-(trifluoromethyl)pyridin-3-yloxy)aniline

[1121] Except for using 5-fluoro-2-(trifluoromethyl)pyridine (221 μL, 1.83 mmol) instead of 2-fluoropyridine, the title compound (250 mg, yield: 54%) was obtained in the same manner as in Step 83-1 of Example 83 above.

[1122] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.36 (dd, J = 8.7 Hz, 2.9 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 8.7 Hz, 2H), 5.15 (s, 2H).

[1123] Step 89-2: Preparation of (4-(6-(trifluoromethyl)pyridin-3-yloxy)phenyl)carbamoyl dinitrile

[1124] Except for using 4-(6-(trifluoromethyl)pyridin-3-yloxy)aniline (200 mg, 0.79 mmol) obtained in Step 89-1 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (51 mg, yield: 19%) was obtained in the same manner as in Steps 1-3 of Example 1 above.

[1125] 1 H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.56 (d, J = 2.8 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.63–7.51 (m, 3H), 7.28 (d, J = 9.0 Hz, 2H).

[1126] Example 90: Preparation of (4-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)carbamoyl dinitrile (Compound 90)

[1127] Step 90-1: Preparation of 4-(5-(trifluoromethyl)pyridin-2-yloxy)aniline

[1128] Except for using 2-fluoro-5-(trifluoromethyl)pyridine (221 μL, 1.83 mmol) instead of 2-fluoropyridine, the title compound (396 mg, yield: 85%) was obtained in the same manner as in Step 83-1 of Example 83 above.

[1129] 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (dd, J = 1.7 Hz, 0.9 Hz, 1H), 8.15 (dd, J = 8.8 Hz, 2.6 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 6.90–6.78 (m, 2H), 6.69–6.56 (m, 2H), 5.06 (s, 2H).

[1130] Step 90-2: Preparation of (4-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)carbamoyl dinitrile

[1131] Except for using 4-(5-(trifluoromethyl)pyridin-2-yloxy)aniline (300 mg, 1.18 mmol) obtained in Step 90-1 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 241 mg (yield: 62%) of the title compound was obtained.

[1132] 1 H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.57 (d, J = 1.9 Hz, 0H), 8.25 (dd, J = 8.8 Hz, 2.7 Hz, 1H), 7.61–7.50 (m, 2H), 7.33–7.16 (m, 3H).

[1133] Example 91: Preparation of (4-(pyrimidin-2-yloxy)phenyl)carbamoyl dinitrile (Compound 91)

[1134] Step 91-1: Preparation of 4-(pyrimidin-2-yloxy)aniline

[1135] Except for using 2-fluoropyrimidine (115 μL, 1.83 mmol) to replace 2-fluoropyridine, in the same manner as Step 83-1 of Example 83 above, 142 mg (yield: 41%) of the title compound was obtained.

[1136] 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 4.7 Hz, 2H), 7.19 (t, J = 4.7 Hz, 1H), 6.90–6.76 (m, 2H), 6.64–6.53 (m, 2H), 5.00 (s, 2H).

[1137] Step 91-2: Preparation of (4-(pyrimidin-2-yloxy)phenyl)carbamoyl dinitrile

[1138] Except for using 4-(pyrimidin-2-yloxy)aniline (100 mg, 0.53 mmol) obtained in Step 91-1 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 118 mg (yield: 84%) of the title compound was obtained.

[1139] 1 H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.66 (d, J = 4.8 Hz, 2H), 7.61–7.47 (m, 2H), 7.33–7.22 (m, 3H).

[1140] Example 92: Preparation of (4-(pyridazin-3-yloxy)phenyl)carbamoyl dinitrile (Compound 92)

[1141] Step 92-1: Preparation of 4-(pyridazin-3-yloxy)aniline

[1142] Except that 2-chloropyridazine (161 μL, 1.83 mmol) was used instead of 2-fluoropyridine, 120 mg (yield: 35%) of the title compound was obtained in the same manner as in Step 83-1 of Example 83 above.

[1143] 1 H NMR (400 MHz, DMSO-d6) δ 8.99–8.91 (m, 1H), 7.69 (dd, J = 9.0 Hz, 4.5 Hz, 1H), 7.27 (dd, J = 9.0 Hz, 1.3 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.61 (d, J = 8.7 Hz, 2H), 5.06 (s, 2H).

[1144] Step 92-2: Preparation of (4-(pyridazin-3-yloxy)phenyl)carbamoyl dinitrile

[1145] Except that 4-(pyridazin-3-yloxy)aniline (100 mg, 0.53 mmol) obtained in Step 92-1 was used instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, 79 mg (yield: 56%) of the title compound was obtained in the same manner as in Steps 1-3 of Example 1 above.

[1146] 1 H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 9.08 (dd, J = 4.6 Hz, 1.3 Hz, 1H), 7.88 (dd, J = 9.0 Hz, 4.6 Hz, 1H), 7.63–7.53 (m, 3H), 7.31 (d, J = 9.0 Hz, 2H).

[1147] Example 93: Preparation of (4-(2-fluorophenoxy)phenyl)carbamoyl dinitrile (Compound 93)

[1148] Step 93-1: Preparation of 4-(2-fluorophenoxy)aniline

[1149] Except that 1,2-difluorobenzene (181 μL, 1.83 mmol) was used instead of 2-fluoropyridine, 113 mg (yield: 30%) of the title compound was obtained in the same manner as in Step 83-1 of Example 83 above.

[1150] 11H NMR (400 MHz, DMSO-d6) δ 7.31 (ddd, J = 11.5 Hz, 7.8 Hz, 1.9 Hz, 1H), 7.15–7.04 (m, 2H), 6.89 (td, J = 8.2 Hz, 2.0 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 6.59 (d, J = 8.6 Hz, 1H), 4.99 (s, 2H).

[1151] Step 93-2: Preparation of (4-(2-fluorophenoxy)phenyl)carbamoyl dinitrile

[1152] Except for using 4-(2-fluorophenoxy)aniline (110 mg, 0.54 mmol) obtained in Step 93-1 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 38 mg (yield: 25%) of the title compound was obtained.

[1153] 1 1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 7.49 (d, J = 9.1 Hz, 2H), 7.45–7.39 (m, 1H), 7.32–7.19 (m, 3H), 7.05 (d, J = 9.0 Hz, 2H).

[1154] Example 94: Preparation of (4-(3-fluorophenoxy)phenyl)carbamoyl dinitrile (Compound 94)

[1155] Step 94-1: Preparation of 4-(3-fluorophenoxy)aniline

[1156] Except for using 1,3-difluorobenzene (180 μL, 1.83 mmol) instead of 2-fluoropyridine, in the same manner as Step 83-1 of Example 83 above, 175 mg (yield: 47%) of the title compound was obtained.

[1157] 1 1H NMR (400 MHz, DMSO-d6) δ 7.38–7.28 (m, 1H), 6.88–6.76 (m, 3H), 6.73–6.58 (m, 4H), 5.06 (s, 2H).

[1158] Step 94-2: Preparation of (4-(3-fluorophenoxy)phenyl)carbamoyl dinitrile

[1159] Except for using 4-(3-fluorophenoxy)aniline (170 mg, 0.84 mmol) obtained in Step 94-1 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 45 mg (yield: 19%) of the title compound was obtained.

[1160] 1 1H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 7.53 (d, J = 9.0 Hz, 2H), 7.49–7.37 (m, 1H), 7.15 (d, J = 9.0 Hz, 2H), 7.00 (td, J = 8.5 Hz, 2.5 Hz, 1H), 6.90 (dt, J = 10.4 Hz, 2.4 Hz, 1H), 6.85 (dd, J = 8.2 Hz, 2.3 Hz, 1H).

[1161] Example 95: Preparation of (6-(Benzyloxy)pyridin-3-yl)carbamoyl dinitrile (Compound 95)

[1162] Step 95-1: Preparation of 2-(benzyloxy)-5-nitropyridine

[1163] Under a nitrogen atmosphere, benzyl alcohol (300 mg, 2.77 mmol) was dissolved in THF, and 60% NaH (133 mg, 3.32 mmol) was added thereto. The reaction mixture was stirred at 0 °C for 1 hour. Then, 2-chloro-5-nitropyridine (439 mg, 2.77 mmol) was added thereto, and the reaction mixture was stirred for another 2 hours. After the reaction was completed, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, solidified with diethyl ether, and filtered to obtain 217 mg (yield: 34%) of the solid title compound.

[1164] 1 1H NMR (400 MHz, DMSO-d6) δ 9.106–9.114 (d, J = 3.2 Hz, 1H), 8.491–8.521 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.354–7.490 (m, 5H), 7.097–7.120 (d, J = 9.2 Hz, 1H), 5.496 (s, 2H).

[1165] Step 95-2: Preparation of 5-(benzyloxy)pyridin-3-amine

[1166] After dissolving 2-(Benzyloxy)-5-nitropyridine (100 mg, 0.43 mmol) obtained in Step 95-1 in THF, NH4Cl (92 mg, 1.72 mmol) was added thereto, and the reaction mixture was refluxed at 75 °C for 30 minutes. Then, Fe (96.06 mg, 1.72 mmol) was added thereto, and the reaction mixture was refluxed at 75 °C for another 4 hours. After the reaction was completed, the reaction product was filtered through diatomaceous earth, extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 61 mg (yield: 71%) of the title compound.

[1167] 1 1H NMR (400 MHz, CDCl3) δ 7.666–7.659 (d, J = 2.8 Hz, 1H), 7.452–7.277 (m, 5H), 7.046–7.017 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 6.674–6.652 (d, J = 8.8 Hz, 1H), 5.288 (s, 2H), 3.378 (s, 2H).

[1168] Step 95-3: Preparation of (6-(benzyloxy)pyridin-3-yl)carbamoyl dinitrile

[1169] Except for using 6-(benzyloxy)pyridin-3-amine (100 mg, 0.5 mmol) obtained in Step 95-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 21 mg (yield: 15%) of the title compound was obtained.

[1170] 1 1H NMR (400 MHz, CDCl3) δ 9.708 (s, 1H), 8.149–8.143 (d, J = 2.4 Hz, 1H), 7.694–7.664 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 7.462–7.335 (m, 5H), 6.910–6.888 (d, J = 8.8 Hz, 1H), 5.393 (s, 1H).

[1171] Example 96: Preparation of (6-(4-(trifluoromethyl)benzyloxy)pyridin-3-yl)carbamoyl dinitrile (Compound 96)

[1172] Step 96-1: Preparation of 5-nitro-2-(4-(trifluoromethyl)benzyloxy)pyridine

[1173] Except for using (4-(trifluoromethyl)phenyl)methanol (300 mg, 1.7 mmol) to replace benzyl alcohol, in the same manner as Step 95-1 of Example 95 above, 253.7 mg (yield: 60%) of the title compound was obtained.

[1174] 1 1H NMR (400 MHz, DMSO-d6) δ 9.103–9.096 (d, J = 2.8 Hz, 1H), 8.546–8.516 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.781–7.760 (d, J = 8.4 Hz, 2H), 7.708–7.688 (d, J = 8 Hz, 2H), 7.173–7.150 (d, J = 9.2 Hz, 1H), 5.607 (s, 2H).

[1175] Step 96-2: Preparation of 6-(4-(trifluoromethyl)benzyloxy)pyridin-3-amine

[1176] Except for using 5-nitro-2-(4-(trifluoromethyl)benzyloxy)pyridine (200 mg, 0.67 mmol) obtained in Step 96-1 instead of 2-(benzyloxy)-5-nitropyridine, in the same manner as Step 95-2 of Example 95 above, 158 mg (yield: 88%) of the title compound was obtained.

[1177] 1 H NMR (400 MHz, CDCl3) δ 7.651–7.644 (d, J = 2.8 Hz, 1H), 7.622–7.602 (d, J = 8.0 Hz, 2H), 7.557–7.536 (d, J = 8.4 Hz, 2H), 7.074–7.045 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 6.697–6.675 (d, J = 8.8 Hz, 1H), 5.357, 2H), 3.389 (s, 2H).

[1178] Step 96-3: Preparation of (6-(4-(Trifluoromethyl)benzyloxy)pyridin-3-yl)carbonohydrazonitrile

[1179] Except for using 6-(4-(trifluoromethyl)benzyloxy)pyridin-3-amine (40 mg, 0.15 mmol) obtained in Step 96-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Step 1-3 of Example 1 above, 12 mg (yield: 24%) of the title compound was obtained.

[1180] 1 H NMR (400 MHz, CDCl3) δ 9.828 (s, 1H), 8.149–8.142 (d, J = 2.8 Hz, 1H), 7.718–7.688 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.648–7.627 (d, J = 8.4 Hz, 2H), 7.570–7.550 (d, J = 8 Hz, 2H), 6.936–6.913 (d, J = 9.2 Hz, 1H), 5.456 (s, 2H).

[1181] Example 97: Preparation of (4-(benzyloxy)-3-(trifluoromethyl)phenyl)carbazonyldinitrile (Compound 97)

[1182] Step 97-1: Preparation of 1-(Benzyloxy)-4-nitro-2-(trifluoromethyl)benzene

[1183] In the same manner as step 68-1 of Example 68 above, 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (0.2 mL, 1.4 mmol) was dissolved in dimethylformamide. Benzyl alcohol (174 μL, 1.68 mmol) and potassium carbonate (290 mg, 2.1 mmol) were added thereto, and the reaction mixture was stirred at 150 °C for 1 hour using a microwave. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 305 mg (yield: 73%) of the title compound.

[1184] 1 H NMR (400 MHz, CDCl3) δ 8.533–8.526 (d, J = 2.8 Hz 1H), 8.394–8.364 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.424–7.350 (m, 5H), 7.143–7.120 (d, J = 9.2 Hz, 1H), 5.327 (s, 2H).

[1185] Step 97-2: Preparation of 4-(Benzyloxy)-3-(trifluoromethyl)aniline

[1186] In the same manner as step 96-2 of Example 96 above, 1-(benzyloxy)-4-nitro-2-(trifluoromethyl)benzene (150 mg, 0.5 mmol) was dissolved in THF, and NH4Cl (216 mg, 4.04 mmol) was added thereto. The reaction mixture was refluxed at 75 °C for 1 hour. After 1 hour, Fe (226 mg, 4.04 mmol) was added thereto, and the reaction mixture was refluxed at 75 °C for 15 hours. After completion of the reaction, the reaction product was filtered through diatomaceous earth, extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 71 mg (yield: 53%) of the title compound.

[1187] 1 H NMR (400 MHz, CDCl3) δ 7.412–7.275 (m, 5H), 6.911–6.904 (d, J = 2.8 Hz 1H), 6.862–6.840 (d, J = 8.8 Hz, 1H), 6.749–6.721 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 5.065 (s, 2H), 3.515 (s, 2H).

[1188] Step 97-3: Preparation of (4-(Benzyloxy)-3-(trifluoromethyl)phenyl)carbonohydrazonitrile

[1189] In the same manner as step 34-3 of Example 34 above, 4-(benzyloxy)-3-(trifluoromethyl)aniline (50 mg, 0.19 mmol) and sodium nitrite (19 mg, 0.28 mmol) were dissolved in ethanol, and a diazonium salt was formed using 1.0 M aqueous hydrochloric acid solution (0.56 mL, 0.56 mmol). After the formation of the diazonium salt, malononitrile (25 mg, 0.38 mmol) was added thereto to obtain 37 mg (yield: 56%) of the title compound.

[1190] 1 H NMR (400 MHz, DMSO-d6) δ 13.025 (s, 1H), 7.749–7.742 (d, J = 2.8 Hz, 1H), 7.909–7.681 (dd, J = 9.0 Hz, 2.5 Hz, 1H), 7.452–7.392 (m, 5H), 7.357–7.340 (d, J = 6.8 Hz, 1H), 5.284 (s, 2H).

[1191] Example 98: Preparation of (3-(trifluoromethyl)-4-(4-(trifluoromethyl)benzyloxy)phenyl)carbonohydrazonitrile (Compound 98)

[1192] Step 98-1: Preparation of 4-Nitro-2-(trifluoromethyl)-1-((4-(trifluoromethyl)benzyl)oxy)benzene

[1193] In the same manner as step 95-1 of Example 95 above, under a nitrogen atmosphere, (4-(trifluoromethyl)phenyl)methanol (164 μL, 1.2 mmol) was dissolved in a THF solution, and 60% NaH (72 mg, 1.8 mmol) was added thereto. The reaction mixture was stirred at 0 °C for 30 minutes. After 30 minutes, 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (137 μL, 1 mmol) was added thereto, and the reaction mixture was stirred for 2 hours. After the completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 266 mg (yield: 73%) of the title compound.

[1194] 1 H NMR (400 MHz, DMSO-d6) δ 8.580–8.550 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 8.431–8.425 (d, J = 2.4 Hz, 1H), 7.836–7.816 (d, J = 8.0 Hz, 2H), 7.690–7.670 (d, J = 8.0 Hz, 2H), 7.608–7.585 (d, J = 9.2 Hz, 1H), 5.586 (s, 2H).

[1195] Step 98-2: Preparation of 3-(Trifluoromethyl)-4-((4-(trifluoromethyl)benzyl)oxy)aniline

[1196] In the same manner as steps 1-2 of Example 1 above, 4-nitro-2-(trifluoromethyl)-1-((4-(trifluoromethyl)benzyl)oxy)benzene (183 mg, 0.5 mmol) and 10% Pd / C (10.6 mg, 0.1 mmol) were dissolved in 1,4-dioxane, and 86.4 mg (yield: 52%) of the title compound was obtained under a hydrogen atmosphere.

[1197] 1 H NMR (400 MHz, DMSO-d6) δ 7.783–7.762 (d, J = 8.4 Hz, 2H), 7.640–7.620 (d, J = 8.0 Hz, 2H), 7.057–7.035 (d, J = 8.8 Hz, 1H), 6.864–6.857 (d, J = 2.8 Hz, 1H), 6.789–6.760 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 5.190 (s, 2H), 5.119 (s, 2H).

[1198] Step 98-3: Preparation of (3-(Trifluoromethyl)-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)carbonohydrazonitrile Preparation

[1199] In the same manner as steps 34-3 of Example 34 above, 3-(trifluoromethyl)-4-((4-(trifluoromethyl)benzyl)oxy)aniline (60 mg, 0.18 mmol) and sodium nitrite (19 mg, 0.28 mmol) were dissolved in ethanol, and a diazonium salt was formed using 1.0 M aqueous hydrochloric acid (0.54 mL, 0.54 mmol). After the formation of the diazonium salt, malononitrile (24 mg, 0.36 mmol) was added thereto to obtain 30 mg (yield: 41%) of the title compound.

[1200] 1 H NMR (400 MHz, DMSO-d6) δ 13.118 (s, 1H), 7.812–7.792 (d, J = 8.0 Hz, 2H), 7.758–7.752 (d, J = 2.4 Hz, 1H), 7.718–7.689 (dd, J = 9.0 Hz, 2.6 Hz, 1H), 7.666–7.646 (d, J = 8.0 Hz, 2H), 7.431–7.408 (d, J = 9.2 Hz, 1H), 5.403 (s, 2H).

[1201] Example 99: Preparation of (6-(4-methylbenzyloxy)pyridin-3-yl)carbonohydrazonitrile (Compound 99)

[1202] Step 99-1: Preparation of 2-((4-Methylbenzyl)oxy)-5-nitropyridine

[1203] In the same manner as in Step 85-1 of Example 85 above, under a nitrogen atmosphere, p-methylbenzyl alcohol (160 mg, 1.3 mmol) was dissolved in a THF solution, and 60% NaH (72 mg, 1.8 mmol) was added thereto. The reaction mixture was stirred at 0 °C for 30 minutes. After 30 minutes, 2-chloro-5-nitropyridine (160 mg, 1 mmol) was added thereto, and the reaction mixture was stirred for 2 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 140 mg (yield: 57%) of the title compound.

[1204] 1 H NMR (400 MHz, DMSO-d6) δ 9.105–9.098 (d, J = 2.8 Hz, 1H), 8.506–8.476 (dd, J = 3.0 Hz, 8.6 Hz, 1H), 7.374–7.354 (d, J = 8 Hz, 2H), 7.213–7.193 (d, J = 8 Hz, 2H), 7.091–7.068 (d, J = 9.2 Hz, 1H), 5.443 (s, 2H), 2.307 (s, 3H).

[1205] Step 99-2: Preparation of 6-(4-Methylbenzyloxy)pyridin-3-amine

[1206] In the same manner as in Step 1-2 of Example 1 above, 2-((4-methylbenzyl)oxy)-5-nitropyridine (100 mg, 0.41 mmol) and 10% Pd / C (8.71 mg, 0.08 mmol) were dissolved in 1,4-dioxane, and 60 mg (yield: 68%) of the title compound was obtained under a hydrogen atmosphere.

[1207] 1 H NMR (400 MHz, CDCl3) δ 7.669–7.662 (d, J = 2.8 Hz, 1H), 7.344–7.324 (d, J = 8 Hz, 2H), 7.179–7.159 (d, J = 8 Hz, 2H), 7.043–7.014 (dd, J = 3.0 Hz, 8.6 Hz, 1H), 6.657–6.636 (d, J = 8.4 Hz, 1H), 3.342 (s, 2H), 2.347 (s, 3H).

[1208] Step 99-3: Preparation of (6-(4-Methylbenzyloxy)pyridin-3-yl)carbonohydrazonitrile

[1209] In the same manner as in Step 34-3 of Example 34 above, 6-((4-methylbenzyl)oxy)pyridin-3-amine (54 mg, 0.25 mmol) and sodium nitrite (26 mg, 0.38 mmol) were dissolved in ethanol, and a diazonium salt was formed using 1.0 M aqueous hydrochloric acid solution (0.76 mL, 0.76 mmol). After the formation of the diazonium salt, malononitrile (33 mg, 0.5 mmol) was added thereto to obtain 19 mg (yield: 26%) of the title compound.

[1210] 1 H NMR (400 MHz, acetone-d6) δ 11.874 (s, 1H), 8.337–8.330 (d, J = 2.8 Hz, 1H), 7.909–7.879 (dd, J = 9.0 Hz, 3.0 Hz, 1H), 7.369–7.350 (d, J = 7.6 Hz, 2H), 7.201–7.183 (d, J = 7.2 Hz, 2H), 6.941–6.919 (d, J = 8.8 Hz, 1H), 5.351 (s, 2H), 2.323 (s, 3H).

[1211] Example 100: Preparation of (6-phenethoxypyridin-3-yl)carbonohydrazonitrile (Compound 100)

[1212] Step 100-1: Preparation of 5-Nitro-2-phenethylpyridine

[1213] In the same manner as in Step 95-1 of Example 95, under a nitrogen atmosphere, 2-phenylethan-1-ol (144 μL, 1.20 mmol) was dissolved in a THF solution, and 60% NaH (72 mg, 1.8 mmol) was added thereto. The reaction mixture was stirred at 0 °C for 30 minutes. After 30 minutes, 2-chloro-5-nitropyridine (158 mg, 1.0 mmol) was added thereto, and the reaction mixture was stirred for another 4 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 112 mg (yield: 50%) of the title compound.

[1214] 1 H NMR (400 MHz, DMSO-d6) δ 9.081–9.075 (d, J = 2.4 Hz, 1H), 8.476–8.446 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.317–7.213 (m, 5H), 7.016–6.993 (d, J = 9.2 Hz, 1H), 4.640–4.606 (t, J = 6.8 Hz, 2H), 3.093–3.059 (t, J = 6.8 Hz, 2H).

[1215] Step 100-2: Preparation of 6-Phenethoxypyridin-3-amine

[1216] In the same manner as steps 1-2 of Example 1 above, 5-nitro-2-phenethylpyridine (50 mg, 0.2 mmol) and 10% Pd / C (4.5 mg, 0.04 mmol) were dissolved in 1,4-dioxane, and 34 mg (yield: 80%) of the title compound was obtained under a hydrogen atmosphere.

[1217] 1 H NMR (400 MHz, acetone-d6) δ 7.525–7.519 (d, J = 2.4 Hz, 1H), 7.324–7.193 (m, 5H), 7.086–7.058 (dd, J = 8.4 Hz, 2.8 Hz, 1H), 7.710–7.688 (d, J = 8.8 Hz, 1H), 4.486–4.451 (t, J = 7.0 Hz, 2H), 3.076–3.041 (t, J = 7.0 Hz, 2H), 2.818 (s, 2H).

[1218] Step 100-3: Preparation of (6-Phenethoxypyridin-3-yl)carbonohydrazonitrile

[1219] In the same manner as steps 34-3 of Example 34 above, 6-phenethoxypyridin-3-amine (30 mg, 0.14 mmol) and sodium nitrite (15 mg, 0.21 mmol) were dissolved in ethanol, and a diazonium salt was formed using 1.0 M aqueous hydrochloric acid (0.42 mL, 0.42 mmol). After the diazonium salt was formed, malononitrile (19 mg, 0.28 mmol) was added thereto to obtain 18 mg (yield: 44%) of the title compound.

[1220] 1 H NMR (400 MHz, acetone-d6) δ 11.868 (s, 1H), 8.316–8.310 (d, J = 2.4 Hz, 1H), 7.884–7.855 (dd, J = 9.0 Hz, 2.6 Hz, 1H), 7.341–7.201 (m, 5H), 6.879–6.856 (d, J = 9.2 Hz, 1H), 4.548–4.513 (t, J = 7.0 Hz, 2H), 3.098–3.063 (t, J = 7.0 Hz, 2H).

[1221] Example 101: Preparation of (4-phenethoxy-3-(trifluoromethyl)phenyl)carbazoyl dinitrile (Compound 101)

[1222] Step 101-1: Preparation of 4-Nitro-1-phenethoxy-2-(trifluoromethyl)benzene

[1223] In the same manner as step 85-1 of Example 85 above, 2-phenylethan-1-ol (258 μL, 2.15 mmol) was dissolved in a THF solution under a nitrogen atmosphere, and 60% NaH (115 mg, 2.87 mmol) was added thereto. The reaction mixture was stirred at 0 °C for 30 minutes. After 30 minutes, 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (0.2 mL, 1.43 mmol) was added thereto, and the reaction mixture was stirred for 4 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 332 mg (yield: 74%) of the title compound.

[1224] 1 H NMR (400 MHz, DMSO-d6) δ 8.518–8.488 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 8.374–8.367 (d, J = 2.8 Hz, 1H), 7.543–7.520 (d, J = 9.2 Hz, 1H), 7.355–7.236 (m, 5H), 4.526–4.493 (t, J = 6.6 Hz, 2H), 3.120–3.087 (t, J = 6.6 Hz, 2H).

[1225] Step 101-2: Preparation of 4-Phenethoxy-3-(trifluoromethyl)aniline

[1226] In the same manner as step 1-2 of Example 1 above, 4-nitro-1-phenethoxy-2-(trifluoromethyl)benzene (250 mg, 0.8 mmol) and 10% Pd / C (17 mg, 0.16 mmol) were dissolved in 1,4-dioxane, and 194 mg (yield: 86%) of the title compound was obtained under a hydrogen atmosphere.

[1227] 1 H NMR (400 MHz, DMSO-d6) δ 7.321–7.209 (m, 5H), 6.971–6.949 (d, J = 8.8 Hz, 1H), 6.832–6.825 (d, J = 2.8 Hz, 1H), 6.783–6.755 (dd, J = 8.6 Hz, 2.6 Hz, 1H), 5.021 (s, 2H), 4.143–4.109 (t, J = 6.8 Hz, 2H), 3.001–2.967 (t, J = 6.8 Hz, 2H).

[1228] Step 101-3: Preparation of (4-Phenethoxy-3-(trifluoromethyl)phenyl)carbonohydrazonitrile

[1229] In the same manner as in Step 34-3 of Example 34 above, 4-phenethoxy-3-(trifluoromethyl)aniline (50 mg, 0.18 mmol) and sodium nitrite (19 mg, 0.27 mmol) were dissolved in ethanol, and a diazonium salt was formed using 1.0 M aqueous hydrochloric acid (0.53 mL, 0.53 mmol). After the formation of the diazonium salt, malononitrile (24 mg, 0.36 mmol) was added thereto to obtain 55 mg (yield: 85%) of the title compound.

[1230] 1 H NMR (400 MHz, CDCl3) δ 9.566 (s, 1H), 7.534–7.527 (d, J = 2.8 Hz, 1H), 7.430–7.401 (dd, J = 9.0 Hz, 2.6 Hz, 1H), 7.348–7.233 (m, 5H), 7.026–7.004 (d, J = 8.8 Hz, 1H), 4.278–4.244 (t, J = 6.8 Hz, 2H), 3.163–3.130 (t, J = 6.6 Hz, 2H).

[1231] Example 102: Preparation of (6-(4-methoxyphenethoxy)pyridin-3-yl)carbamoyl dinitrile (Compound 102)

[1232] Step 102-1: Preparation of 2-(4-Methoxyphenethoxy)-5-nitropyridine

[1233] In the same manner as in Step 95-1 of Example 95 above, under a nitrogen atmosphere, 2-(4-methoxyphenyl)ethan-1-ol (183 mg, 1.20 mmol) was dissolved in a THF solution, and 60% NaH (72 mg, 1.8 mmol) was added thereto. The reaction mixture was stirred at 0 °C for 30 minutes. After 30 minutes, 2-chloro-5-nitropyridine (160 mg, 1.0 mmol) was added thereto, and the reaction mixture was stirred for 3 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 184 mg (yield: 67%) of the title compound.

[1234] 11H NMR (400 MHz, DMSO-d6) δ 9.082–9.074 (d, J = 3.2 Hz, 1H), 8.479–8.449 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.233–7.212 (d, J = 8.4 Hz, 2H), 7.014–6.991 (d, J = 9.2 Hz, 1H), 6.882 - 6.861 (d, J = 8.4 Hz, 2H), 4.589–4.555 (t, J = 6.8 Hz, 2H), 3.723 (s, 3H), 3.023–2.989 (t, J = 6.8 Hz, 2H).

[1235] Step 102-2: Preparation of 6-(4-Methoxyphenethoxy)pyridin-3-amine

[1236] In the same manner as Steps 1-2 of Example 1 above, 2-(4-methoxyphenethoxy)-5-nitropyridine (140 mg, 0.51 mmol) and 10% Pd / C (11 mg, 0.1 mmol) were dissolved in 1,4-dioxane to obtain 62 mg (yield: 50%) of the title compound under a hydrogen atmosphere.

[1237] 1 1H NMR (400 MHz, DMSO-d6) δ 7.490–7.484 (d, J = 2.4 Hz, 1H), 7.197–7.176 (d, J = 8.4 Hz, 2H), 7.005–6.976 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 6.866–6.844 (d, J = 8.8 Hz, 2H), 6.517–6.496 (d, J = 8.4 Hz, 1H), 4.726 (s, 2H), 4.261–4.226 (t, J = 7.0 Hz, 2H), 3.719 (s, 3H), 2.906–2.871 (t, J = 7.0 Hz, 2H).

[1238] Step 102-3: Preparation of (6-(4-Methoxyphenethoxy)pyridin-3-yl)carbonohydrazonitrile

[1239] In the same manner as Steps 34-3 of Example 34 above, 6-(4-methoxyphenethoxy)pyridin-3-amine (50 mg, 0.18 mmol) and sodium nitrite (19 mg, 0.27 mmol) were dissolved in ethanol, and a diazonium salt was formed using 1.0 M aqueous hydrochloric acid (0.55 mL, 0.55 mmol). After the diazonium salt was formed, malononitrile (24 mg, 0.36 mmol) was added thereto to obtain 24 mg (yield: 41%) of the title compound.

[1240] 11H NMR (400 MHz, acetone-d6) δ 11.866 (s, 1H), 8.313–8.306 (d, J = 2.8 Hz, 1H), 7.883–7.853 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.249–7.228 (d, J = 8.4 Hz, 2H), 6.880–6.854 (m, 3H), 4.499–4.463 (t, J = 7.2 Hz, 2H), 3.767 (s, 3H), 3.026–2.991 (t, J = 7.0 Hz, 2H).

[1241] Example 103: Preparation of (6-(4-(Trifluoromethyl)phenethoxy)pyridin-3-yl)carbonohydrazonitrile (Compound 103)

[1242] Step 103-1: Preparation of 5-Nitro-2-(4-(trifluoromethyl)phenethoxy)pyridine

[1243] In the same manner as in Step 95-1 above, under a nitrogen atmosphere, 2-(4-(trifluoromethyl)phenyl)ethan-1-ol (0.18 mL, 1.20 mmol) was dissolved in a THF solution, and 60% NaH (72 mg, 1.8 mmol) was added thereto. The reaction mixture was stirred at 0 °C for 30 minutes. After 30 minutes, 2-chloro-5-nitropyridine (160 mg, 1.0 mmol) was added thereto, and the reaction mixture was stirred for 3 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 215 mg (yield: 69%) of the title compound.

[1244] 1 1H NMR (400 MHz, CDCl3-d6) δ 9.058–9.052 (d, J = 2.4 Hz, 1H), 8.358–8.329 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 7.584–7.564 (d, J = 8.0 Hz, 2H), 7.411–7.391 (d, J = 8.0 Hz, 2H), 6.816–6.794 (d, J = 8.8 Hz, 1H), 4.692–4.658 (t, J = 6.8 Hz, 2H), 3.196–3.162 (t, J = 6.8 Hz, 2H).

[1245] Step 103-2: Preparation of 6-(4-(trifluoromethyl)phenethoxy)pyridin-3-amine

[1246] In the same manner as in Step 1-2 of Example 1 above, 5-nitro-2-(4-(trifluoromethyl)phenethoxy)pyridine (160 mg, 0.51 mmol) and 10% Pd / C (11 mg, 0.1 mmol) were dissolved in 1,4-dioxane to obtain 94 mg (yield: 67%) of the title compound under a hydrogen atmosphere.

[1247] 1 H NMR (400 MHz, DMSO-d6) δ 7.674–7.654 (d, J = 8.0 Hz, 2H), 7.531–7.496 (m, 3H), 7.013–6.984 (dd, J = 8.6 Hz, 3.0 Hz, 1H), 6.524–6.502 (d, J = 8.8 Hz, 1H), 4.753 (s, 2H), 4.368–4.334 (t, J = 6.8 Hz, 2H), 3.092–3.059 (t, J = 6.6 Hz, 2H).

[1248] Step 103-3: Preparation of (6-(4-(trifluoromethyl)phenethoxy)pyridin-3-yl)carbonohydrazonitrile

[1249] In the same manner as in Step 34-3 of Example 34 above, 6-(4-(trifluoromethyl)phenethoxy)pyridin-3-amine (70 mg, 0.25 mmol) and sodium nitrite (26 mg, 0.37 mmol) were dissolved in ethanol, and a diazonium salt was formed using 1.0 M aqueous hydrochloric acid (0.74 mL, 0.74 mmol). After the formation of the diazonium salt, malononitrile (33 mg, 0.5 mmol) was added thereto to obtain 91 mg (yield: 100%) of the title compound.

[1250] 1 H NMR (400 MHz, acetone-d6) δ 11.947 (s, 1H), 8.320–8.314 (d, J = 2.4 Hz, 1H), 7.884–7.855 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 7.668–7.647 (d, J = 8.4 Hz, 2H), 7.585–7.565 (d, J = 8.0 Hz, 2H), 6.879–6.857 (d, J = 8.8 Hz, 1H), 4.606–4.573 (t, J = 6.6 Hz, 2H), 3.218–3.184 (t, J = 6.8 Hz, 2H).

[1251] Example 104: Preparation of (3-methoxy-4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbamoyl dinitrile (Compound 104)

[1252] Step 104-1: Preparation of 2-Methoxy-N-(5-methylpyrazin-2-yl)-4-nitrobenzamide

[1253] Except using 2-methoxy-4-nitrobenzoic acid (200 mg, 1.01 mmol) instead of 5-nitrocholic acid, and using 5-methylpyrazin-2-amine (111 mg, 1.01 mmol) instead of p-toluidine, in the same manner as step 34-1 of Example 34 above, 185 mg (yield: 63%) of the title compound was obtained.

[1254] 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.33 (s, 1H), 8.35 (d, J = 1.5 Hz, 1H), 7.94 (dq, J = 3.9 Hz, 2.0 Hz, 2H), 7.89 (d, J = 8.9 Hz, 1H), 4.03 (s, 3H), 2.50 (s, 3H).

[1255] Step 104-2: Preparation of 4-Amino-2-methoxy-N-(5-methylpyrazin-2-yl)benzamide

[1256] Except using 2-methoxy-N-(5-methylpyrazin-2-yl)-4-nitrobenzamide (183 mg, 0.63 mmol) obtained in step 104-1 instead of 5-nitro-N-p-tolylpyridinecarboxamide, in the same manner as step 34-2 of Example 34 above, 135 mg (yield: 82%) of the title compound was obtained.

[1257] 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.33 (s, 1H), 8.35 (d, J = 1.5 Hz, 1H), 7.94 (dq, J = 3.9 Hz, 2.0 Hz, 2H), 7.89 (d, J = 8.9 Hz, 1H), 4.03 (s, 3H), 2.50 (s, 3H).

[1258] Step 104-3: Preparation of (3-Methoxy-4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbonohydrazonitrile

[1259] Except using 4-amino-2-methoxy-N-(5-methylpyrazin-2-yl)benzamide (70 mg, 0.27 mmol) obtained in step 104-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as step 1-3 of Example 1 above, 18 mg (yield: 19%) of the title compound was obtained.

[1260] 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.33 (s, 1H), 8.35 (d, J = 1.5 Hz, 1H), 7.94 (dq, J = 3.9 Hz, 2.0 Hz, 2H), 7.89 (d, J = 8.9 Hz, 1H), 4.03 (s, 3H), 2.50 (s, 3H).

[1261] Example 105: Preparation of (3-methoxy-4-(6-methylpyrazin-2-ylcarbamoyl)phenyl)carbamoyl dinitrile (Compound 105)

[1262] Step 105-1: Preparation of 2-Methoxy-N-(6-methylpyrazin-2-yl)-4-nitrobenzamide

[1263] Except for using 2-methoxy-4-nitrobenzoic acid (200 mg, 1.01 mmol) instead of 5-nitrocholic acid and using 6-methylpyrazin-2-amine (111 mg, 1.01 mmol) instead of p-toluidine, in the same manner as in Step 34-1 of Example 34 above, 113 mg (yield: 38%) of the title compound was obtained.

[1264] 1 1H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 9.28 (s, 1H), 8.36 (s, 1H), 7.94–7.92 (m, 2H), 4.02 (s, 3H), 2.48 (s, 3H).

[1265] Step 105-2: Preparation of 4-Amino-2-methoxy-N-(6-methylpyrazin-2-yl)benzamide

[1266] Except for using 2-methoxy-N-(6-methylpyrazin-2-yl)-4-nitrobenzamide (124 mg, 0.43 mmol) obtained in Step 105-1 instead of 5-nitro-N-p-tolylpyridineamide, in the same manner as in Step 34-2 of Example 34 above, 29 mg (yield: 26%) of the title compound was obtained.

[1267] 1 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.32 (s, 1H), 8.25 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 1.6 Hz, 1H), 6.31 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 6.09 (s, 2H), 3.96 (s, 3H), 2.45 (s, 3H).

[1268] Step 105-3: Preparation of (3-Methoxy-4-(6-methylpyrazin-2-ylcarbamoyl)phenyl)carbonohydrazonitrile

[1269] Except for using 4-amino-2-methoxy-N-(6-methylpyrazin-2-yl)benzamide (27 mg, 0.11 mmol) obtained in Step 105-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 8 mg (yield: 24%) of the title compound was obtained.

[1270] 1 H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.30 (s, 1H), 8.32 (s, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.19 (dd, J = 8.6 Hz, 1.9 Hz, 1H), 4.01 (s, 3H), 2.47 (s, 3H).

[1271] Example 106: Preparation of (3-chloro-4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbonohydrazonitrile (Compound 106)

[1272] Step 106-1: Preparation of 2-chloro-N-(5-methylpyrazin-2-yl)-4-nitrobenzamide

[1273] Except for using 2-methoxy-4-nitrobenzoic acid (200 mg, 1.01 mmol) to replace 5-nitrocholic acid and using 6-methylpyrazin-2-amine (111 mg, 1.01 mmol) to replace p-toluidine, in the same manner as Step 34-1 of Example 34 above, 174 mg (yield: 59%) of the title compound was obtained.

[1274] 1 H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 9.31 (s, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.37 (s, 1H), 8.30 (dd, J = 8.4 Hz, 2.2 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 2.52 (s, 3H).

[1275] Step 106-2: Preparation of 4-amino-2-chloro-N-(5-methylpyrazin-2-yl)benzamide

[1276] Under a nitrogen atmosphere, 2-chloro-N-(5-methylpyrazin-2-yl)-4-nitrobenzamide (165 mg, 0.56 mmol) obtained in Step 106-1 was dissolved in acetic acid (6 mL), and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the iron was filtered off with ethyl acetate, and the filtrate was extracted with aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and purified by column chromatography to obtain 60 mg (yield: 40%) of the title compound.

[1277] 1 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 2H), 9.25 (d, J = 1.5 Hz, 2H), 8.31 (d, J = 1.5 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 2.1 Hz, 2H), 6.54 (dd, J = 8.4 Hz, 2.2 Hz, 2H), 5.90 (s, 2H), 2.47 (s, 3H).

[1278] Step 106-3: Preparation of (3-chloro-4-(5-methylpyrazin-2-ylcarbamoyl)phenyl)carbazic diimidate

[1279] Except for using 4-amino-2-chloro-N-(5-methylpyrazin-2-yl)benzamide (60 mg, 0.23 mmol) obtained in Step 106-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 40 mg (yield: 51%) of the title compound was obtained.

[1280] 1 1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 11.23 (s, 1H), 9.29 (s, 1H), 8.35 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.50 (dd, J = 8.5 Hz, 2.1 Hz, 1H), 2.52 (s, 3H).

[1281] Example 107: Preparation of (3-methoxy-4-(5-methylpyridin-3-ylcarbamoyl)phenyl)carbazic diimidoyl (Compound 107)

[1282] Step 107-1: Preparation of 2-methoxy-N-(5-methylpyridin-3-yl)-4-nitrobenzamide

[1283] Except for using 2-methoxy-4-nitrobenzoic acid (200 mg, 1.01 mmol) to replace 5-nitrocholic acid and using 3-amino-5-methylpyridine (110 mg, 1.01 mmol) to replace p-toluidine, in the same manner as Step 34-1 of Example 34 above, 246 mg (yield: 84%) of the title compound was obtained.

[1284] 1 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.95–8.90 (m, 1H), 8.40 (s, 1H), 8.23 (d, J = 2.1 Hz, 1H), 7.96 (dt, J = 3.9 Hz, 2.5 Hz, 2H), 7.84 (d, J = 8.9 Hz, 1H), 4.02 (s, 3H), 2.42 (s, 3H).

[1285] Step 107-2: Preparation of 4-amino-2-methoxy-N-(5-methylpyridin-3-yl)benzamide

[1286] Except for using 2-methoxy-N-(5-methylpyridin-3-yl)-4-nitrobenzamide (240 mg, 0.84 mmol) obtained in Step 107-1 to replace 5-nitro-N-p-tolylpicolinamide, in the same manner as Step 34-2 of Example 34 above, 83 mg (yield: 38%) of the title compound was obtained.

[1287] 1 H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.69 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 1.9 Hz, 1H), 8.04 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 6.33–6.23 (m, 2H), 5.93 (s, 2H), 3.94 (s, 3H), 2.31 (s, 3H).

[1288] Step 107-3: Preparation of (3-methoxy-4-(5-methylpyridin-3-ylcarbamoyl)phenyl)carbazic diimidate

[1289] Except for using 4-amino-2-methoxy-N-(5-methylpyridin-3-yl)benzamide (74 mg, 0.29 mmol) obtained in Step 107-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Step 1-3 of Example 1 above, 54 mg (yield: 55%) of the title compound was obtained.

[1290] 1 H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.84–8.79 (m, 1H), 8.24 (s, 1H), 8.14 (t, J = 2.2 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 1.9 Hz, 1H), 7.13 (dd, J = 8.4 Hz, 1.9 Hz, 1H), 3.96 (s, 3H), 2.35 (s, 3H).

[1291] Example 108: Preparation of (3-methoxy-4-(p-tolylcarbamoyl)phenyl)carbazodicarbonitrile (Compound 108)

[1292] Step 108-1: Preparation of 2-methoxy-4-nitro-N-(p-tolyl)benzamide

[1293] Except for using 2-methoxy-4-nitrobenzoic acid (150 mg, 0.76 mmol) to replace 5-nitrocholic acid, in the same manner as Step 34-1 of Example 34 above, 150 mg (yield: 68%) of the title compound was obtained.

[1294] 1 1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 7.96–7.89 (m, 2H), 7.81 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 4.00 (s, 3H), 2.30 (s, 3H).

[1295] Step 108-2: Preparation of 4-amino-2-methoxy-N-(p-tolyl)benzamide

[1296] Except for using 2-methoxy-4-nitro-N-(p-tolyl)benzamide (135 mg, 0.47 mmol) obtained in Step 108-1 to replace 5-nitro-N-p-tolylpyridinecarboxamide, in the same manner as Step 34-2 of Example 34 above, 121 mg (yield: 99%) of the title compound was obtained.

[1297] 1 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.64–7.57 (m, 2H), 7.13 (d, J = 8.2 Hz, 2H), 6.30 (d, J = 1.9 Hz, 1H), 6.26 (dd, J = 8.5 Hz, 2.0 Hz, 1H), 5.86 (s, 2H), 3.93 (s, 3H), 2.28 (s, 3H), 2.28 (s, 3H).

[1298] Step 108-3: Preparation of (3-methoxy-4-(p-tolylcarbamoyl)phenyl)carbazic diimidate

[1299] Except for using 4-amino-2-methoxy-N-(p-tolyl)benzamide (121 mg, 0.47 mmol) obtained in Step 108-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Step 1-3 of Example 1 above, 95 mg (yield: 60%) of the title compound was obtained.

[1300] 1 1H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 9.97 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 10.5 Hz, 8.3 Hz, 3H), 3.95 (s, 3H), 2.29 (s, 3H).

[1301] Example 109: Preparation of (3-Methoxy-4-(4-methoxyphenylcarbamoyl)phenyl)carbamoyl dinitrile (Compound 109)

[1302] Step 109-1: Preparation of 2-methoxy-N-(4-methoxyphenyl)-4-nitrobenzamide

[1303] Except for using 2-methoxy-4-nitrobenzoic acid (200 mg, 1.01 mmol) instead of 5-nitrocholic acid and using p-methoxyaniline (125 mg, 1.01 mmol) instead of p-toluidine, the title compound (225 mg, yield: 73%) was obtained in the same manner as in Step 34-1 of Example 34 above.

[1304] 1 H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 7.97–7.90 (m, 2H), 7.81 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.01 (s, 3H), 3.76 (s, 3H).

[1305] Step 109-2: Preparation of 4-amino-2-methoxy-N-(p-tolyl)benzamide

[1306] Except for using 2-methoxy-N-(4-methoxyphenyl)-4-nitrobenzamide (225 mg, 0.74 mmol) obtained in Step 109-1 instead of 5-nitro-N-p-tolylpicolinamide, the title compound (173 mg, yield: 85%) was obtained in the same manner as in Step 34-2 of Example 34 above.

[1307] 1 H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 7.68–7.57 (m, 3H), 6.93–6.85 (m, 2H), 6.29 (d, J = 1.9 Hz, 1H), 6.25 (dd, J = 8.5 Hz, 1.9 Hz, 1H), 5.83 (s, 2H), 3.91 (s, 3H), 3.33 (s, 1H).

[1308] Step 109-3: Preparation of (3-methoxy-4-(4-methoxyphenylcarbamoyl)phenyl)carbazic diimidate

[1309] Except for using 4-amino-2-methoxy-N-(4-methoxyphenyl)benzamide (158 mg, 0.58 mmol) obtained in Step 109-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (90 mg, yield: 44%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[1310] 11H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 9.91 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 8.5 Hz, 1.9 Hz, 1H), 6.93 (d, J = 8.6 Hz, 2H), 3.96 (s, 3H), 3.76 (s, 3H).

[1311] Example 110: Preparation of (6-(furan-3-carboxamido)pyridin-3-yl)carbamoyl dinitrile (Compound 110)

[1312] Step 110-1: Preparation of N-(5-nitropyridin-2-yl)furan-3-carboxamide

[1313] Except for using furan-3-carboxylic acid (300 mg, 2.68 mmol) instead of 5-methylpyrazine-2-carboxylic acid and using 2-amino-5-nitroaniline (372 mg, 2.68 mmol) instead of 2-chloro-4-nitroaniline, the title compound (444 mg, yield: 71%) was obtained in the same manner as in Step 11-1 of Example 11 above.

[1314] 1 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 9.22 (d, J = 2.8 Hz, 1H), 8.65 (td, J = 5.2 Hz, 4.7 Hz, 2.8 Hz, 2H), 8.42 (d, J = 9.3 Hz, 1H), 7.83 (s, 1H), 7.10 (s, 1H).

[1315] Step 110-2: Preparation of N-(5-aminopyridin-2-yl)furan-3-carboxamide

[1316] Except for using N-(5-nitropyridin-2-yl)furan-3-carboxamide (400 mg, 1.71 mmol) obtained in Step 110-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (174 mg, yield: 50%) was obtained in the same manner as in Step 1-2 of Example 1 above.

[1317] 1 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.48–8.34 (m, 1H), 7.87–7.67 (m, 3H), 7.11–6.95 (m, 2H), 5.14 (s, 2H).

[1318] Step 110-3: Preparation of (6-(furan-3-carboxamido)pyridin-3-yl)carbazic diimidate

[1319] Except for using N-(5-aminopyridin-2-yl)furan-3-carboxamide (150 mg, 0.74 mmol) obtained in Step 110-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 183 mg (yield: 89%) of the title compound was obtained.

[1320] 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.55 (s, 1H), 8.50 (d, J = 2.7 Hz, 1H), 8.22 (d, J = 9.1 Hz, 1H), 7.90 (dd, J = 9.1 Hz, 2.8 Hz, 1H), 7.79 (s, 1H).

[1321] Example 111: Preparation of (3-methyl-4-(thiazole-4-carboxamido)phenyl)carbamoyl dinitrile (Compound 111)

[1322] Step 111-1: Preparation of N-(2-methyl-4-nitrophenyl)thiazole-4-carboxamide

[1323] Except for using thiazole-4-carboxylic acid (300 mg, 2.32 mmol) instead of 5-methylpyrazine-2-carboxylic acid and using 2-methyl-4-nitroaniline (354 mg, 2.32 mmol) instead of 2-chloro-4-nitroaniline, in the same manner as Step 11-1 of Example 11 above, 204 mg (yield: 33%) of the title compound was obtained.

[1324] 1 H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.32 (d, J = 2.0 Hz, 1H), 8.61 (d, J = 1.9 Hz, 1H), 8.24–8.18 (m, 2H), 8.15 (dd, J = 9.0 Hz, 2.6 Hz, 1H), 2.44 (s, 3H).

[1325] Step 111-2: Preparation of N-(4-amino-2-methylphenyl)thiazole-4-carboxamide

[1326] Except for using N-(2-methyl-4-nitrophenyl)thiazole-4-carboxamide (150 mg, 0.57 mmol) obtained in Step 111-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 129 mg (yield: 97%) of the title compound was obtained.

[1327] 11H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.23 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.52–6.33 (m, 2H), 4.95 (s, 2H), 2.09 (s, 3H).

[1328] Step 111-3: Preparation of (3-methyl-4-(thiazole-4-carboxamido)phenyl)carbazic diimidate

[1329] Except for using N-(4-amino-2-methylphenyl)thiazole-4-carboxamide (110 mg, 0.47 mmol) obtained in Step 111-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound was obtained in the same manner as Steps 1-3 of Example 1 above in a yield of 121 mg (82%).

[1330] 1 1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 9.85 (s, 1H), 9.28 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.48–7.11 (m, 2H), 2.30 (s, 3H).

[1331] Example 112: Preparation of (6-(thiazole-4-carboxamido)pyridin-3-yl)carbamoyl dinitrile (Compound 112)

[1332] Step 112-1: Preparation of N-(5-nitropyridin-2-yl)thiazole-4-carboxamide

[1333] Except for using thiazole-4-carboxylic acid (300 mg, 2.32 mmol) instead of 5-methylpyrazine-2-carboxylic acid and 2-amino-5-nitroaniline (324 mg, 2.32 mmol) instead of 2-chloro-4-nitroaniline, the title compound was obtained in the same manner as Step 11-1 of Example 11 above in a yield of 108 mg (19%).

[1334] 1 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 9.31 (d, J = 2.0 Hz, 1H), 9.23 (dd, J = 2.8 Hz, 0.7 Hz, 1H), 8.75 (d, J = 1.9 Hz, 1H), 8.71 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 8.43 (dd, J = 9.2 Hz, 0.7 Hz, 1H).

[1335] Step 112-2: Preparation of N-(5-aminopyridin-2-yl)thiazole-4-carboxamide

[1336] Except for using N-(5-nitropyridin-2-yl)thiazole-4-carboxamide (100 mg, 0.40 mmol) obtained in Step 112-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Step 1-2 of Example 1 above, 48 mg (yield: 55%) of the title compound was obtained.

[1337] 1 H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 9.25 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 1.9 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.73 (d, J = 2.8 Hz, 1H), 7.05 (dd, J = 8.7 Hz, 2.8 Hz, 1H), 5.21 (s, 2H).

[1338] Step 112-3: Preparation of (6-(thiazole-4-carboxamido)pyridin-3-yl)carbazic diimidate

[1339] Except for using N-(5-aminopyridin-2-yl)thiazole-4-carboxamide (45 mg, 0.20 mmol) obtained in Step 112-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Step 1-3 of Example 1 above, 60 mg (yield: 99%) of the title compound was obtained.

[1340] 1 H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.29 (d, J = 2.0 Hz, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 2.7 Hz, 1H), 8.26 (d, J = 9.0 Hz, 1H), 7.95 (dd, J = 9.0 Hz, 2.7 Hz, 1H).

[1341] Example 113: Preparation of (6-(oxazole-4-carboxamido)pyridin-3-yl)carbamoyl dinitrile (Compound 113)

[1342] Step 113-1: Preparation of N-(5-nitropyridin-2-yl)oxazole-4-carboxamide

[1343] Except for using oxazole-4-carboxylic acid (300 mg, 2.65 mmol) to replace 5-methylpyrazine-2-carboxylic acid, and using 2-amino-5-nitroaniline (369 mg, 2.65 mmol) to replace 2-chloro-4-nitroaniline, in the same manner as Step 11-1 of Example 11 above, 76 mg (yield: 12%) of the title compound was obtained.

[1344] 11H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 9.23 (d, J = 2.8 Hz, 1H), 9.05 (s, 1H), 8.80–8.56 (m, 2H), 8.39 (d, J = 9.2 Hz, 1H).

[1345] Step 113-2: Preparation of N-(5-aminopyridin-2-yl)oxazole-4-carboxamide

[1346] Except for using N-(5-nitropyridin-2-yl)oxazole-4-carboxamide (70 mg, 0.30 mmol) obtained in Step 113-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 58 mg (yield: 95%) of the title compound was obtained.

[1347] 1 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.84 (d, J = 1.0 Hz, 1H), 8.59 (d, J = 1.0 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.73 (d, J = 2.8 Hz, 1H), 7.04 (dd, J = 8.7 Hz, 2.9 Hz, 1H), 5.22 (s, 2H).

[1348] Step 113-3: Preparation of (6-(oxazole-4-carboxamido)pyridin-3-yl)carbazic diimidate

[1349] Except for using N-(5-aminopyridin-2-yl)oxazole-4-carboxamide (70 mg, 0.30 mmol) obtained in Step 113-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 183 mg (yield: 89%) of the title compound was obtained.

[1350] 1 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.95 (s, 1H), 8.63 (s, 1H), 8.49 (s, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.93 (dd, J = 9.0 Hz, 2.7 Hz, 1H).

[1351] Example 114: Preparation of (6-(oxazole-5-carboxamido)pyridin-3-yl)carbamoyl dinitrile (Compound 114)

[1352] Step 114-1: Preparation of N-(5-nitropyridin-2-yl)oxazole-5-carboxamide

[1353] Except for using oxazole-5-carboxylic acid (300 mg, 2.65 mmol) instead of 5-methylpyrazine-2-carboxylic acid and using 2-amino-5-nitroaniline (369 mg, 2.65 mmol) instead of 2-chloro-4-nitroaniline, the title compound (95 mg, yield: 15%) was obtained in the same manner as in Step 11-1 of Example 11 above.

[1354] 1 H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 9.25 (d, J = 2.8 Hz, 1H), 8.82–8.61 (m, 2H), 8.45–8.27 (m, 2H).

[1355] Step 114-2: Preparation of N-(5-aminopyridin-2-yl)oxazole-5-carboxamide

[1356] Except for using N-(5-nitropyridin-2-yl)oxazole-5-carboxamide (400 mg, 1.71 mmol) obtained in Step 114-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (45 mg, yield: 58%) was obtained in the same manner as in Step 1-2 of Example 1 above.

[1357] 1 H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.59 (s, 1H), 8.09 (s, 1H), 7.82–7.68 (m, 2H), 7.02 (dd, J = 8.7 Hz, 2.9 Hz, 1H), 5.23 (s, 2H).

[1358] Step 114-3: Preparation of (6-(oxazole-5-carboxamido)pyridin-3-yl)carbazic diimidate

[1359] Except for using N-(5-aminopyridin-2-yl)oxazole-5-carboxamide (40 mg, 0.20 mmol) obtained in Step 114-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (31 mg, yield: 55%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[1360] 1 H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.66 (s, 1H), 8.51 (d, J = 2.7 Hz, 1H), 8.22 (s, 1H), 8.18 (d, J = 9.1 Hz, 1H), 7.91 (dd, J = 9.1 Hz, 2.8 Hz, 1H).

[1361] Example 115: Preparation of (6-(isoxazole-3-carboxamido)pyridin-3-yl)carbamoyl dinitrile (Compound 115)

[1362] Step 115-1: Preparation of N-(5-nitropyridin-2-yl)isoxazole-3-carboxamide

[1363] Except for using isoxazole-3-carboxylic acid (300 mg, 2.65 mmol) instead of 5-methylpyrazine-2-carboxylic acid and using 2-amino-5-nitroaniline (369 mg, 2.65 mmol) instead of 2-chloro-4-nitroaniline, the title compound (222 mg, yield: 36%) was obtained in the same manner as in Step 11-1 of Example 11 above.

[1364] 1 H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 9.25 (d, J = 2.8 Hz, 1H), 9.20 (d, J = 1.7 Hz, 1H), 8.71 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 8.36 (d, J = 9.2 Hz, 1H), 7.18 (d, J = 1.7 Hz, 1H).

[1365] Step 115-2: Preparation of N-(5-aminopyridin-2-yl)furan-3-carboxamide

[1366] Except for using N-(5-nitropyridin-2-yl)isoxazole-3-carboxamide (200 mg, 0.85 mmol) obtained in Step 115-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound was obtained in the same manner as in Step 1-2 of Example 1 above and was used for the next step without additional purification.

[1367] Step 115-3: Preparation of (6-(isoxazole-3-carboxamido)pyridin-3-yl)carbamoyl dinitrile

[1368] Except for using N-(5-aminopyridin-2-yl)isoxazole-3-carboxamide (60 mg, 0.29 mmol) obtained in Step 115-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (28 mg, yield: 34%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[1369] 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.16 (s, 1H), 8.52 (s, 1H), 8.17 (d, J = 9.0 Hz, 1H), 8.01–7.87 (m, 1H), 7.12 (s, 1H).

[1370] Example 116: Preparation of (4-(thiazol-2-yloxy)phenyl)carbamoyl dinitrile (Compound 116)

[1371] Step 116-1: Preparation of 4-(thiazol-2-yloxy)aniline

[1372] After dissolving 4-aminophenyl (200 mg, 1.83 mmol) in DMSO, 2-chlorothiazole (157 μL, 1.83 mmol) and cesium carbonate (716 mg, 2.20 mmol) were added thereto, and the reaction mixture was stirred at 80 °C for 12 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 224 mg (yield: 64%) of the title compound.

[1373] 1 1H NMR (400 MHz, DMSO-d6) δ 7.24 (d, J = 3.8 Hz, 1H), 7.08 (d, J = 3.7 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.8 Hz, 2H), 5.21 (s, 2H).

[1374] Step 116-2: Preparation of (4-(thiazol-2-yloxy)phenyl)carbamoyl dinitrile

[1375] Except for using 4-(thiazol-2-yloxy)aniline (200 mg, 1.04 mmol) obtained in Step 116-1 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 116 mg (yield: 41%) of the title compound was obtained.

[1376] 1 1H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 7.55 (d, J = 9.0 Hz, 2H), 7.41 (d, J = 9.0 Hz, 2H), 7.30 (d, J = 3.8 Hz, 1H), 7.25 (d, J = 3.7 Hz, 1H).

[1377] Example 117: Preparation of (4-(benzyloxy)phenyl)carbazonyldinitrile (Compound 117)

[1378] Step 117-1: Preparation of 1-(benzyloxy)-4-nitrobenzene

[1379] Under a nitrogen atmosphere, after dissolving benzyl alcohol (0.31 mL, 2.98 mmol) in DMSO, 60% NaH (159 mg, 3.97 mmol) was added thereto, and the reaction mixture was stirred at room temperature for 30 minutes. Then, 1-fluoro-4-nitrobenzene (0.21 mL, 1.98 mmol) was added thereto, and the reaction mixture was stirred for another 3 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and solidified under reduced pressure to obtain 296 mg (yield: 65%) of the title compound.

[1380] 1 H NMR (400 MHz, DMSO-d6) δ 8.243–8.219 (d, J = 9.3 Hz, 2H), 7.496–7.371 (m, 5H), 7.256–7.233 (d, J = 9.3 Hz, 2H), 5.278 (s, 1H).

[1381] Step 117-2: Preparation of 4-(benzyloxy)aniline

[1382] Except for using 1-(benzyloxy)-4-nitrobenzene (230 mg, 1 mmol) obtained in Step 117-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 28 mg (yield: 14%) of the title compound was obtained.

[1383] 1 H NMR (400 MHz, CDCl3) δ 7.395–7.273 (m, 5H), 6.810–6.788 (d, J = 8.8 Hz, 2H), 6.622–6.600 (d, J = 8.8 Hz, 2H), 4.968 (s, 2H), 3.402 (s, 2H).

[1384] Step 117-3: Preparation of (4-(benzyloxy)phenyl)carbamoyl dinitrile

[1385] Except for using 4-(benzyloxy)aniline (25 mg, 0.13 mmol) obtained in Step 117-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 31 mg (yield: 86%) of the title compound was obtained.

[1386] 11H NMR (400 MHz, acetone-d6) δ 11.786 (s, 1H), 7.491–7.468 (d, J = 9.2 Hz, 2H), 7.485–7.319 (m, 5H), 7.124–7.102 (d, J = 9.2 Hz, 2H), 5.164 (s, 2H).

[1387] Example 118: Preparation of (4-(4-(Trifluoromethyl)benzyloxy)phenyl)carbamoyl dinitrile (Compound 118)

[1388] Step 118-1: Preparation of 1-nitro-4-(4-(trifluoromethyl)benzyloxy)benzene

[1389] Except using (4-(trifluoromethyl)phenyl)methanol (262 mg, 1.49 mmol) instead of benzyl alcohol and 1-fluoro-4-nitrobenzene (0.11 mL, 0.99 mmol) instead of 2-chloro-4-nitropyridine, in the same manner as Step 95-1 of Example 95 above, 135 mg (yield: 46%) of the title compound was obtained.

[1390] 1 1H NMR (400 MHz, CDCl3) δ 8.202–8.179 (d, J = 9.2 Hz, 2H), 7.682–7.661 (d, J = 8.4 Hz, 2H), 7.607–7.587 (d, J = 8.0 Hz, 2H), 7.085–7.062 (d, J = 9.2 Hz, 2H), 5.271 (s, 2H).

[1391] Step 118-2: Preparation of 4-(4-(trifluoromethyl)benzyloxy)aniline

[1392] Except using 1-nitro-4-((4-trifluoromethyl)benzyloxy)benzene (400 mg, 1.71 mmol) obtained in Step 118-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Step 1-2 of Example 1 above, 78 mg (yield: 67%) of the title compound was obtained.

[1393] 1 1H NMR (400 MHz, DMSO-d6) δ 7.749–7.729 (d, J = 8.0 Hz, 2H), 7.640–7.620 (d, J = 8.0 Hz, 2H), 6.743 -6.721 (d, J = 8.8 Hz, 2H), 6.521–6.499 (d, J = 8.8 Hz, 2H), 5.065 (s, 2H), 4.647 (s, 2H).

[1394] Step 118-3: Preparation of (4-(4-(trifluoromethyl)benzyloxy)phenyl)carbamoyl dinitrile

[1395] Except for using 4-(4-(trifluoromethyl)benzyloxy)aniline (70 mg, 0.26 mmol) obtained in Step 118-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (56 mg, yield: 62%) was obtained in the same manner as Steps 1-3 of Example 1 above.

[1396] 1 H NMR (400 MHz, acetone-d6) δ 12.007 (s, 1H), 7.774–7.753 (d, J = 8.4 Hz, 2H), 7.739–7.718 (d, J = 8.4 Hz, 2H), 7.503–7.480 (d, J = 9.2 Hz, 2H), 7.152–7.129 (d, J = 9.2 Hz, 2H), 5.297 (s, 2H).

[1397] Example 119: Preparation of (4-(4-methylbenzyloxy)phenyl)carbamoyl dinitrile (Compound 119)

[1398] Step 119-1: Preparation of 1-methyl-4-((4-nitrophenoxy)methyl)benzene

[1399] Except for using (4-(trifluoromethyl)phenyl)methanol (262 mg, 1.49 mmol) instead of benzyl alcohol and 1-fluoro-4-nitrobenzene (0.11 mL, 0.99 mmol) instead of 2-chloro-4-nitro pyridine, the title compound (512 mg, yield: 71%) was obtained in the same manner as Step 117-1 of Example 117 above.

[1400] 1 H NMR (400 MHz, DMSO-d6) δ 8.231–8.207 (d, J = 9.6 Hz, 2H), 7.376–7.357 (d, J = 7.6 Hz, 2H), 7.235–7.212 (m, 4H), 5.222 (s, 2H), 2.320 (s, 3H).

[1401] Step 119-2: Preparation of 4-(4-methylbenzyloxy)aniline

[1402] Except for using 1-methyl-4-((4-nitrophenoxy)methyl)benzene (240 mg, 0.99 mmol) obtained in Step 119-1 instead of 2-(benzyloxy)-5-nitropyridine and adjusting the reaction temperature to 60 °C, the title compound (68 mg, yield: 32%) was obtained in the same manner as Step 95-2 of Example 95 above.

[1403] 11H NMR (400 MHz, DMSO-d6) δ 7.296–7.276 (d, J = 8.0 Hz, 2H), 7.183–7.163 (d, J = 8.0 Hz, 2H), 6.712–6.690 (d, J = 8.8 Hz, 2H), 6.506–6.484 (d, J = 8.8 Hz, 2H), 4.887 (s, 2H), 4.598 (s, 2H), 2.301 (s, 3H).

[1404] Step 119-3: Preparation of (4-(4-methylbenzyloxy)phenyl)carbamoyl dinitrile

[1405] Except for using 4-(4-methylbenzyloxy)aniline (60 mg, 0.28 mmol) obtained in Step 119-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 25 mg (yield: 31%) of the title compound was obtained.

[1406] 1 1H NMR (400 MHz, DMSO-d6) δ 12.982 (s, 1H), 7.419–7.397 (d, J = 8.8 Hz, 2H), 7.336–7.317 (d, J = 7.6 Hz, 2H), 7.208–7.188 (d, J = 8.0 Hz, 2H), 7.068–7.046 (d, J = 8.8 Hz, 1H), 5.059 (s, 2H), 2.307 (s, 3H).

[1407] Example 120: Preparation of (4-(4-methoxyphenethoxy)phenyl)carbamoyl dinitrile (Compound 120)

[1408] Step 120-1: Preparation of 1-methoxy-4-(2-(4-nitrophenoxy)ethyl)benzene

[1409] Except for using 2-(4-methoxyphenyl)ethan-1-ol (453 mg, 2.98 mmol) to replace benzyl alcohol, in the same manner as Step 117-1 of Example 117 above, 431 mg (yield: 80%) of the title compound was obtained.

[1410] 1 1H NMR (400 MHz, DMSO-d6) δ 8.204–8.180 (d, J = 9.6 Hz, 2H), 7.259–7.238 (d, J = 8.4 Hz, 2H), 7.158–7.134 (d, J = 9.6 Hz, 2H), 6.889–6.868 (d, J = 8.4 Hz, 2H), 4.317–4.282 (t, J = 6.4 Hz, 2H), 3.726 (s, 3H), 3.027–2.993 (t, J = 6.8 Hz, 2H).

[1411] Step 120-2: Preparation of 4-(4-methoxyphenethoxy)aniline

[1412] Except for using 1-methoxy-4-(2-(4-nitrophenoxy)ethyl)benzene (270 mg, 0.99 mmol) obtained in Step 120-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 197 mg (yield: 82%) of the title compound was obtained.

[1413] 1 H NMR (400 MHz, DMSO-d6) δ 7.217–7.196 (d, J = 8.4 Hz, 2H), 6.871–6.849 (d, J = 8.8 Hz, 2H), 6.644–6.623 (d, J = 8.4 Hz, 2H), 6.506–6.485 (d, J = 8.4 Hz, 2H), 4.584 (s, 2H), 3.994–3.960 (t, J = 6.8 Hz, 2H), 3.721 (s, 3H), 2.905–2.871 (t, J = 6.8 Hz, 2H).

[1414] Step 120-3: Preparation of (4-(4-methoxyphenethoxy)phenyl)carbamoyl dinitrile

[1415] Except for using 4-(4-methoxyphenethoxy)aniline (150 mg, 0.62 mmol) obtained in Step 120-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 88 mg (yield: 44%) of the title compound was obtained.

[1416] 1 H NMR (400 MHz, DMSO-d6) δ 11.681 (s, 2H), 7.394–7.371 (d, J = 9.2 Hz, 2H), 7.247–7.226 (d, J = 8.4 Hz, 2H), 6.988–6.966 (d, J = 8.8 Hz, 2H), 6.885–6.864 (d, J = 8.4 Hz, 2H), 4.158–4.124 (t, J = 6.8 Hz, 2H), 3.728 (s, 3H), 2.978–2.944 (t, J = 6.8 Hz, 2H).

[1417] Example 121: Preparation of (4-(4-(trifluoromethyl)phenethoxy)phenyl)carbazoyl dinitrile (Compound 121)

[1418] Step 121-1: Preparation of 1-nitro-4-(4-(trifluoromethyl)phenethoxy)benzene

[1419] Except for using 2-(4-(trifluoromethyl)phenyl)ethan-1-ol (0.45 mL, 2.98 mmol) instead of benzyl alcohol, the title compound (155 mg, yield: 25%) was obtained in the same manner as in Step 117-1 of Example 117 above.

[1420] 1 H NMR (400 MHz, CDCl3) δ 8.177–8.154 (d, J = 9.2 Hz, 2H), 7.593–7.573 (d, J = 8.0 Hz, 2H), 7.429–7.409 (d, J = 8.0 Hz, 2H), 6.951–6.928 (d, J = 9.2 Hz, 2H), 4.315–4.282 (t, J = 6.6 Hz, 2H), 3.220–3.187 (t, J = 6.6 Hz, 2H).

[1421] Step 121-2: Preparation of 4-(4-(trifluoromethyl)phenethoxy)aniline

[1422] Except for using 1-nitro-4-(4-(trifluoromethyl)phenethoxy)benzene (150 mg, 0.48 mmol) obtained in Step 121-2 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (94 mg, yield: 70%) was obtained in the same manner as in Step 1-2 of Example 1 above.

[1423] 1 H NMR (400 MHz, DMSO-d6) δ 7.669–7.649 (d, J = 8.0 Hz, 2H), 7.544–7.524 (d, J = 8.0 Hz, 2H), 6.650–6.628 (d, J = 8.8 Hz, 2H), 6.507–6.485 (d, J = 8.8 Hz, 2H), 4.600 (s, 2H), 4.094–4.061 (t, J = 6.6 Hz, 2H), 3.075–3.042 (t, J = 6.6 Hz, 2H).

[1424] Step 121-3: Preparation of (4-(4-(trifluoromethyl)phenethoxy)phenyl)carbamoyl dinitrile

[1425] Except for using 4-(4-(trifluoromethyl)phenethoxy)aniline (80 mg, 0.28 mmol) obtained in Step 121-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (94 mg, yield: 93%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[1426] 11H NMR (400 MHz, DMSO-d6) δ 12.980 (s, 1H), 7.689–7.669 (d, J = 8.0 Hz, 2H), 7.574–7.554 (d, J = 8.0 Hz, 2H), 7.413–7.390 (d, J = 9.2 Hz, 2H), 7.010–6.988 (d, J = 8.8 Hz, 2H), 4.264–4.232 (t, J = 6.4 Hz, 2H), 3.155–3.122 (t, J = 6.6 Hz, 2H).

[1427] Example 122: Preparation of (4-phenethoxyphenyl)carbamoyl dinitrile (Compound 122)

[1428] Step 122-1: Preparation of 1-nitro-4-phenethoxybenzene

[1429] Except for using 2-phenylethan-1-ol (0.36 mL, 2.98 mmol) instead of benzyl alcohol, the title compound (132 mg, yield: 28%) was obtained in the same manner as in Step 117-1 of Example 117 above.

[1430] 1 1H NMR (400 MHz, DMSO-d6) δ 8.203–8.180 (d, J = 9.2 Hz, 2H), 7.370–7.218 (m, 5H), 7.164–7.141 (d, J = 9.2 Hz, 2H), 4.372–4.338 (t, J = 6.8 Hz, 2H), 3.098–3.064 (t, J = 6.8 Hz, 2H).

[1431] Step 122-2: Preparation of 4-phenethoxyaniline

[1432] Except for using 1-nitro-4-phenethoxybenzene (120 mg, 0.49 mmol) obtained in Step 122-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (85 mg, yield: 82%) was obtained in the same manner as in Step 1-2 of Example 1 above.

[1433] 1 1H NMR (400 MHz, DMSO-d6) δ 7.324–7.191 (m, 5H), 6.652–6.630 (d, J = 8.8 Hz, 2H) 6.652–6.630 (d, J = 8.8 Hz, 2H), 4.586 (s, 2H), 4.046–4.014 (t, J = 7.0 Hz, 2H), 2.976–2.941 (t, J = 7.0 Hz, 2H).

[1434] Step 122-3: Preparation of (4-phenethoxyphenyl)carbamoyl dinitrile

[1435] Except for using 4-phenethoxyaniline (80 mg, 0.38 mmol) obtained in Step 122-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound was obtained in the same manner as Steps 1-3 of Example 1 above in a yield of 83 mg (75%).

[1436] 1 H NMR (400 MHz, DMSO-d6) δ 12.977 (s, 1H), 7.412–7.390 (d, J = 8.8 Hz, 2H), 7.327–7.214 (m, 5H), 7.010–6.987 (d, J = 9.2 Hz, 2H), 4.217–4.183 (t, J = 6.8 Hz, 2H), 3.051–3.017 (t, J = 6.8 Hz, 2H).

[1437] Example 123: Preparation of (4-(4-chlorophenethoxy)phenyl)carbamoyl dinitrile (Compound 123)

[1438] Step 123-1: Preparation of 1-chloro-4-(2-(4-nitrophenoxy)ethyl)benzene

[1439] Except for using 2-(4-chlorophenyl)ethan-1-ol (0.4 mL, 2.98 mmol) instead of benzyl alcohol, the title compound was obtained in the same manner as Step 117-1 of Example 117 above in a yield of 423 mg (77%).

[1440] 1 H NMR (400 MHz, DMSO-d6) δ 8.201–8.178 (d, J = 9.2 Hz, 2H), 7.368 (s, 4H), 7.154–7.130 (d, J = 9.6 Hz, 2H), 4.360–4.326 (t, J = 6.8 Hz, 2H), 3.093–3.059 (t, J = 6.8 Hz, 2H).

[1441] Step 123-2: Preparation of 4-(4-chlorophenethoxy)aniline

[1442] Except for using 1-chloro-4-(2-(4-nitrophenoxy)ethyl)benzene (280 mg, 1.01 mmol) obtained in Step 123-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound was obtained in the same manner as Steps 1-2 of Example 1 above in a yield of 169 mg (67%).

[1443] 11H NMR (400 MHz, DMSO-d6) δ 7.363–7.292 (m, 4H), 6.645–6.623 (d, J = 8.8 Hz, 2H), 6.512–6.490 (d, J = 8.8 Hz, 2H), 4.595 (s, 2H), 4.037–4.004 (t, J = 6.6 Hz, 2H), 2.967–2.934 (t, J = 6.6 Hz, 2H).

[1444] Step 123-3: Preparation of (4-(4-chlorophenethoxy)phenyl)carbamoyl dinitrile

[1445] Except for using 4-(4-chlorophenethoxy)aniline (150 mg, 0.61 mmol) obtained in Step 123-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (59 mg, yield: 30%) was obtained in the same manner as Steps 1-3 of Example 1 above.

[1446] 1 1H NMR (400 MHz, acetone-d6) δ 11.767 (s, 1H), 7.469–7.446 (d, J = 9.2 Hz, 2H), 7.394–7.327 (m, 4H), 7.038–7.015 (d, J = 9.2 Hz, 2H), 4.270–4.236 (t, J = 6.8 Hz, 2H), 3.117–3.083 (t, J = 6.8 Hz, 2H).

[1447] Example 124: Preparation of (4-(pyridin-3-ylmethoxy)phenyl)carbamoyl dinitrile (Compound 124)

[1448] Step 124-1: Preparation of 3-((4-nitrophenoxy)methyl)pyridine

[1449] Except for using pyridin-3-ylmethanol (0.29 mL, 2.98 mmol) instead of benzyl alcohol, the title compound (236 mg, yield: 52%) was obtained in the same manner as Step 117-1 of Example 117 above.

[1450] 1 1H NMR (400 MHz, DMSO-d6) δ 8.727–8.723 (d, J = 1.6 Hz, 1H), 8.602–8.586 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 8.263–8.240 (d, J = 9.2 Hz, 2H), 7.938–7.910 (dt, J = 7.7 Hz, 1.8 Hz, 1H), 7.484–7.453 (dd, J = 7.6 Hz, 4.8 Hz, 1H), 7.288–7.265 (d, J = 9.2 Hz, 2H), 5.336 (s, 2H).

[1451] Step 124-2: Preparation of 4-(pyridin-3-ylmethoxy)aniline

[1452] Except for using 3-((4-nitrophenoxy)methyl)pyridine (200 mg, 0.87 mmol) obtained in Step 124-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 76 mg (yield: 44%) of the title compound was obtained.

[1453] 1 H NMR (400 MHz, DMSO-d6) δ 8.631 (s, 1H), 8.540–8.528 (d, J = 4.8 Hz, 1H), 7.845–7.826 (d, J = 7.6 Hz, 1H), 7.433–7.402 (dd, J = 7.6 Hz, 4.8 Hz, 1H), 6.762–6.740 (d, J = 8.8 Hz, 2H), 6.533–6.512 (d, J = 8.4 Hz, 2H), 5.004 (s, 2H), 4.657 (s, 2H).

[1454] Step 124-3: Preparation of (4-(pyridin-3-ylmethoxy)phenyl)carbamoyl dinitrile

[1455] Except for using 4-(pyridin-3-ylmethoxy)aniline (70 mg, 0.35 mmol) obtained in Step 124-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 54 mg (yield: 56%) of the title compound was obtained.

[1456] 1 H NMR (400 MHz, acetone-d6) δ 11.824 (s, 1H), 8.715 (s, 1H), 8.568–8.559 (d, J = 3.6 Hz, 1H), 7.906–7.887 (d, J = 7.6 Hz, 1H), 7.508–7.485 (d, J = 9.2 Hz, 2H), 8.430–8.398 (dd, J = 7.8 Hz, 5.0 Hz, 1H), 7.156–7.133 (d, J = 9.2 Hz, 2H), 5.225 (s, 2H).

[1457] Example 125: Preparation of (4-(pyrazin-2-ylmethoxy)phenyl)carbamoyl dinitrile (Compound 125)

[1458] Step 125-1: Preparation of 2-((4-nitrophenoxy)methyl)pyrazine

[1459] Under a nitrogen atmosphere, PPh3 (629 mg, 2.40 mmol) and DIAD (0.47 mL, 2.40 mmol) were dissolved in THF, and the reaction mixture was stirred at 0 °C for 30 minutes. Pyrazin-2-ylmethanol (220 mg, 2 mmol) and 4-nitrophenol (334 mg, 2.40 mmol) were added to the reaction mixture, and the reaction mixture was stirred at room temperature for one day. After the reaction was completed, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 147 mg (yield: 26%) of the title compound.

[1460] 1 H NMR (400 MHz, acetone-d6) δ 8.876 (s, 1H), 8.659–8.630 (m, 2H), 8.280–8.257 (dd, J = 7.0 Hz, 2.2 Hz, 2H), 7.331–7.308 (dd, J = 7.2 Hz, 2.0 Hz, 2H), 5.468 (s, 2H).

[1461] Step 125-2: Preparation of 4-(pyrazin-2-ylmethoxy)aniline

[1462] Except for using 2-((4-nitrophenoxy)methyl)pyrazine (200 mg, 0.87 mmol) obtained in Step 125-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 64 mg (yield: 36%) of the title compound was obtained.

[1463] 1 H NMR (400 MHz, DMSO-d6) δ 8.764 (s, 1H), 8.651–8.614 (d, J = 14.8 Hz, 2H), 6.777–6.756 (d, J = 8.4 Hz, 2H), 6.527–6.505 (d, J = 8.8 Hz, 2H), 5.104 (s, 2H), 4.669 (s, 2H).

[1464] Step 125-3: Preparation of (4-(pyrazin-2-ylmethoxy)phenyl)carbamoyl dinitrile

[1465] Except for using 4-(pyrazin-2-ylmethoxy)aniline (50 mg, 0.25 mmol) obtained in Step 125-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 60 mg (yield: 86%) of the title compound was obtained.

[1466] 11H NMR (400 MHz, DMSO-d6) δ 11.807 (s, 1H), 8.834 (s, 1H), 8.629–8.598 (m, 2H), 7.522–7.499 (d, J = 9.2 Hz, 2H), 7.194–7.171 (d, J = 9.2 Hz, 2H), 5.317 (s, 2H).

[1467] Example 126: Preparation of (4-((1H-benzo[d]imidazol-2-yl)methoxy)phenyl)carbamoyl dinitrile (Compound 126)

[1468] Step 126-1: Preparation of 2-((4-nitrophenoxy)methyl)-1H-benzo[d]imidazole

[1469] Except for using (1H-benzo[d]imidazol-2-yl)methanol (300 mg, 2.02 mmol) instead of benzyl alcohol, the title compound (152 mg, yield: 28%) was obtained in the same manner as in Step 117-1 of Example 117 above.

[1470] 1 1H NMR (400 MHz, DMSO-d6) δ 12.745 (s, 1H), 8.264–8.241 (d, J = 9.2 Hz, 2H), 7.648–7.629 (d, J = 7.6 Hz, 1H), 7.515–7.497 (d, J = 7.2 Hz, 1H), 7.333–7.310 (d, J = 9.2 Hz, 2H), 7.247–7.170 (m, 2H), 5.506 (s, 2H).

[1471] Step 126-2: Preparation of 4-((1H-benzo[d]imidazol-2-yl)methoxy)aniline

[1472] Except for using 2-((4-nitrophenoxy)methyl)-1H-benzo[d]imidazole (110 mg, 0.41 mmol) obtained in Step 126-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (78 mg, yield: 80%) was obtained in the same manner as in Step 1-2 of Example 1 above.

[1473] 1 1H NMR (400 MHz, DMSO-d6) δ 12.587 (s, 1H), 7.609–7.589 (d, J = 8.0 Hz, 1H), 7.481–7.461 (d, J = 8.0 Hz, 1H), 7.213–7.142 (m, 2H), 6.805–6.784 (d, J = 8.4 Hz, 2H), 6.524–6.503 (d, J = 8.4 Hz, 2H), 5.144 (s, 2H), 4.666 (s, 2H).

[1474] Step 126-3: Preparation of (4-((1H-benzo[d]imidazol-2-yl)methoxy)phenyl)carbamimidoyl dinitrile

[1475] Except for using 4-((1H-benzo[d]imidazol-2-yl)methoxy)aniline (60 mg, 0.25 mmol) obtained in Step 126-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 56 mg (yield: 71%) of the title compound was obtained.

[1476] 1 H NMR (400 MHz, DMSO-d6) δ 7.695–7.672 (dd, J = 6.0 Hz, 3.2 Hz, 2H), 7.476–7.453 (d, J = 9.2 Hz, 2H), 7.379–7.356 (dd, J = 6.0 Hz, 3.2 Hz, 2H), 7.197–7.174 (d, J = 9.2 Hz, 2H), 5.488 (s, 2H).

[1477] Example 127: Preparation of (4-(pyridazin-3-ylmethoxy)phenyl)carbamoyl dinitrile (Compound 127)

[1478] Step 127-1: Preparation of 3-((4-nitrophenoxy)methyl)pyridazine

[1479] Except for using pyridazin-3-ylmethanol (220 mg, 2.0 mmol) to replace benzyl alcohol, in the same manner as Step 117-1 of Example 117 above, 177 mg (yield: 38%) of the title compound was obtained.

[1480] 1 H NMR (400 MHz, DMSO-d6) δ 9.269–9.258 (m, 1H), 8.274–8.252 (d, J = 9.2 Hz, 2H), 7.901–7.879 (d, J = 8.8 Hz, 1H), 7.821–7.788 (m, 1H), 7.331–7.308 (d, J = 9.2 Hz, 2H), 5.597 (s, 2H).

[1481] Step 127-2: Preparation of 4-(pyridazin-3-ylmethoxy)aniline

[1482] Except for using 3-((4-nitrophenoxy)methyl)pyridazine (140 mg, 0.61 mmol) obtained in Step 127-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 62 mg (yield: 51%) of the title compound was obtained.

[1483] 11H NMR (400 MHz, DMSO-d6) δ 9.196–9.180 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 7.789–7.710 (m, 2H), 6.771–6.749 (d, J = 8.8 Hz, 2H), 6.519–6.497 (d, J = 8.8 Hz, 2H), 5.243 (s, 2H), 4.668 (s, 2H).

[1484] Step 127-3: Preparation of (4-(pyridazin-3-ylmethoxy)phenyl)carbamimidoyl dinitrile

[1485] Except for using 4-(pyridazin-3-ylmethoxy)aniline (50 mg, 0.25 mmol) obtained in Step 127-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 36 mg (yield: 52%) of the title compound was obtained.

[1486] 1 1H NMR (400 MHz, DMSO-d6) δ 12.983 (s, 1H), 9.223–9.207 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 7.837–7.736 (m, 2H), 7.335–7.313 (d, J = 8.8 Hz, 2H), 7.058–7.035 (d, J = 8.8 Hz, 2H), 5.393 (s, 2H).

[1487] Example 128: Preparation of (4-(benzo[d]oxazol-2-ylmethoxy)phenyl)carbamoyl dinitrile (Compound 128)

[1488] Step 128-1: Preparation of 2-((4-nitrophenoxy)methyl)benzo[d]oxazole

[1489] Except for using 4-nitrophenol (394 mg, 2.83 mmol) to replace benzyl alcohol, and using 2-(bromomethyl)benzo[d]oxazole (400 mg, 1.89 mmol) to replace 1-fluoro-4-nitrobenzene, in the same manner as Step 117-1 of Example 117 above, 131 mg (yield: 26%) of the title compound was obtained.

[1490] 1 1H NMR (400 MHz, DMSO-d6) δ 8.260–8.237 (d, J = 9.2 Hz, 2H), 7.804–7.769 (t, J = 7.0 Hz, 2H), 7.476–7.396 (m, 2H), 7.340–7.317 (d, J = 9.2 Hz, 2H), 5.682 (s, 2H).

[1491] Step 128-2: Preparation of 4-(benzo[d]oxazol-2-ylmethoxy)aniline

[1492] Except for using 2-((4-nitrophenoxy)methyl)benz[d]oxazole (130 mg, 0.48 mmol) obtained in Step 128-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 87 mg (yield: 76%) of the title compound was obtained.

[1493] 1 H NMR (400 MHz, DMSO-d6) δ 7.777–7.743 (t, J = 6.8 Hz, 2H), 7.452–7.372 (m, 2H), 6.793–6.771 (d, J = 8.8 Hz, 2H), 6.512–6.490 (d, J = 8.8 Hz, 2H), 5.263 (s, 2H), 4.696 (s, 2H).

[1494] Step 128-3: Preparation of (4-(benzo[d]oxazol-2-ylmethoxy)phenyl)carbamimidoyl dinitrile

[1495] Except for using 4-(benz[d]oxazol-2-ylmethoxy)aniline (80 mg, 0.33 mmol) obtained in Step 128-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 62 mg (yield: 59%) of the title compound was obtained.

[1496] 1 H NMR (400 MHz, DMSO-d6) δ 13.001 (s, 1H), 7.794–7.755 (t, J = 7.8 Hz, 2H), 7.462–7.388 (m, 4H), 7.167–7.145 (d, J = 8.8 Hz, 2H), 5.488 (s, 2H).

[1497] Example 129: Preparation of (4-(benz[d]thiazol-2-ylmethoxy)phenyl)carbamoyl dinitrile (Compound 129)

[1498] Step 129-1: Preparation of 2-((4-nitrophenoxy)methyl)benzo[d]thiazole

[1499] Except for using 4-nitrophenol (366 mg, 2.63 mmol) to replace benzyl alcohol, and using 2-(bromomethyl)benz[d]thiazole (400 mg, 1.75 mmol) to replace 1-fluoro-4-nitrobenzene, in the same manner as Step 117-1 of Example 117 above, 154 mg (yield: 31%) of the title compound was obtained.

[1500] 11H NMR (400 MHz, DMSO-d6) δ 8.265–8.242 (d, J = 9.2 Hz, 2H), 8.153–8.133 (d, J = 8.0 Hz, 1H), 8.052–8.032 (d, J = 8.0 Hz, 1H), 7.575–7.539 (t, J = 7.2 Hz, 1H), 7.499–7.464 (t, J = 7.0 Hz, 1H), 7.342–7.319 (d, J = 9.2 Hz, 2H), 5.797 (s, 2H).

[1501] Step 129-2: Preparation of 4-(benzo[d]thiazol-2-ylmethoxy)aniline

[1502] Except for using 2-((4-nitrophenoxy)methyl)benzothiazole (150 mg, 0.52 mmol) obtained in Step 129-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 80 mg (yield: 60%) of the title compound was obtained.

[1503] 1 1H NMR (400 MHz, DMSO-d6) δ 8.118–8.099 (d, J = 7.6 Hz, 1H), 8.005–7.985 (d, J = 8.0 Hz, 1H), 7.544–7.509 (t, J = 7.0 Hz, 1H), 7.466–7.431 (t, J = 7.0 Hz, 1H), 6.817–6.794 (d, J = 9.2 Hz, 2H), 6.528–6.505 (d, J = 9.2 Hz, 2H), 5.414 (s, 2H), 4.710 (s, 2H).

[1504] Step 129-3: Preparation of (4-(benzo[d]thiazol-2-ylmethoxy)phenyl)carbamimidoyl dinitrile

[1505] Except for using 4-(benzothiazol-2-ylmethoxy)aniline (80 mg, 0.31 mmol) obtained in Step 129-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 74 mg (yield: 72%) of the title compound was obtained.

[1506] 11H NMR (400 MHz, DMSO-d6) δ 13.005 (s, 1H), 8.134–8.115 (d, J = 7.6 Hz, 1H), 8.033–8.013 (d, J = 8.0 Hz, 1H), 7.562–7.527 (t, J = 7.0 Hz, 1H), 7.487–7.426 (m, 3H), 7.178–7.155 (d, J = 9.2 Hz, 2H), 5.619 (s, 2H).

[1507] Example 130: Preparation of (4-(benzo[b]thiophen-2-ylmethoxy)phenyl)carbamoyl dinitrile (Compound 130)

[1508] Step 130-1: Preparation of 2-((4-nitrophenoxy)methyl)benzo[b]thiophene

[1509] Except for using benzo[b]thiophen-2-ylmethanol (300 mg, 1.83 mmol) instead of benzyl alcohol, the title compound (500 mg, yield: 96%) was obtained in the same manner as in Step 117-1 of Example 117 above.

[1510] 1 1H NMR (400 MHz, DMSO-d6) δ 8.240–8.218 (d, J = 8.8 Hz, 2H), 7.972–7.953 (d, J = 7.6 Hz, 1H), 7.867–7.849 (d, J = 7.2 Hz, 1H), 7.587 (s, 2H), 7.412–7.351 (m, 2H), 7.303–7.280 (d, J = 9.2 Hz, 2H), 5.616 (s, 2H).

[1511] Step 130-2: Preparation of 4-(benzo[b]thiophen-2-ylmethoxy)aniline

[1512] Except for using 2-((4-nitrophenoxy)benzo[b]thiophene (400 mg, 1.40 mmol) obtained in Step 130-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (51 mg, yield: 14%) was obtained in the same manner as in Step 1-2 of Example 1 above.

[1513] 11H NMR (400 MHz, DMSO-d6) δ 7.942–7.924 (d, J = 7.2 Hz, 1H), 7.820–7.801 (d, J = 7.6 Hz, 1H), 7.432 (s, 1H), 7.382–7.315 (m, 2H), 6.771–6.750 (d, J = 8.4 Hz, 2H), 6.508–6.487 (d, J = 8.4 Hz, 2H), 5.251 (s, 2H), 4.652 (s, 2H).

[1514] Step 130-3: Preparation of (4-(benzo[b]thiophen-2-ylmethoxy)phenyl)carbamimidoyl dinitrile

[1515] Except for using 4-(benzo[b]thiophen-2-ylmethoxy)aniline (60 mg, 0.24 mmol) obtained in Step 130-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 42 mg (yield: 54%) of the title compound was obtained.

[1516] 1 1H NMR (400 MHz, DMSO-d6) δ 12.791 (s, 1H), 7.959–7.940 (d, J = 7.6 Hz, 1H), 7.843–7.827 (d, J = 6.4 Hz, 1H), 7.519 (s, 1H), 7.426–7.404 (d, J = 8.8 Hz, 2H), 7.378–7.351 (m, 2H), 7.133–7.110 (d, J = 9.2 Hz, 2H), 5.447 (s, 2H).

[1517] Example 131: Preparation of (6-(4-chlorophenethoxy)pyridin-3-yl)carbonohydrazonitrile (Compound 131)

[1518] Step 131-1: Preparation of 2-(4-chlorophenethoxy)-5-nitropyridine

[1519] Except for using 2-(4-chlorophenyl)ethanol (0.25 mL, 1.80 mmol) to replace benzyl alcohol, in the same manner as Step 95-1 of Example 95 above, 205 mg (yield: 49%) of the title compound was obtained.

[1520] 1 1H NMR (400 MHz, DMSO-d6) δ 9.08 (dd, J = 2.9 Hz, 0.6 Hz, 1H), 8.47 (dd, J = 9.2 Hz, 2.9 Hz, 1H), 7.41–7.31 (m, 4H), 7.01 (dd, J = 9.2 Hz, 0.6 Hz, 1H), 4.62 (t, J = 6.7 Hz, 2H), 3.08 (t, J = 6.7 Hz, 2H).

[1521] Step 131-2: Preparation of 6-(4-chlorophenethoxy)pyridin-3-amine

[1522] Except for using 2-(4-chlorophenethoxy)-5-nitropyridine obtained in Step 131-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 86 mg (yield: 51%) of the title compound was obtained.

[1523] 1 H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 2.3 Hz, 1H), 7.33 (q, J = 8.6 Hz, 4H), 7.00 (dd, J = 8.7 Hz, 2.9 Hz, 1H), 6.51 (d, J = 9.3 Hz, 1H), 4.75 (s, 2H), 4.30 (t, J = 6.7 Hz, 2H), 2.97 (t, J = 6.7 Hz, 2H).

[1524] Step 131-3: Preparation of (6-(4-chlorophenethoxy)pyridin-3-yl)carbamimidoyl dinitrile

[1525] Except for using 6-(4-chlorophenethoxy)pyridin-3-amine obtained in Step 131-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 67 mg (yield: 73%) of the title compound was obtained.

[1526] 1 H NMR (400 MHz, acetone-d6) δ 11.96 (s, 1H), 8.31 (d, J = 2.8 Hz, 1H), 7.87 (dd, J = 9.0 Hz, 2.9 Hz, 1H), 7.41–7.24 (m, 4H), 6.86 (d, J = 9.0 Hz, 1H), 4.53 (t, J = 6.8 Hz, 2H), 3.09 (t, J = 6.8 Hz, 2H).

[1527] Example 132: Preparation of (4-(4-methylbenzyloxy)-3-(trifluoromethyl)phenyl)carbamoyl dinitrile (Compound 132)

[1528] Step 132-1: Preparation of 1-(4-methylbenzyloxy)-4-nitro-2-(trifluoromethyl)benzene

[1529] Except for using p-methylbenzyl alcohol (263 mg, 2.15 mmol) to replace benzyl alcohol and 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (0.2 mL, 1.43 mmol) to replace 2-chloro-5-nitropyridine, in the same manner as Step 95-1 of Example 95 above, 416 mg (yield: 93%) of the title compound was obtained.

[1530] 1 1H NMR (400 MHz, DMSO-d6) δ 8.53 (dd, J = 9.2 Hz, 2.9 Hz, 1H), 8.40 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 9.3 Hz, 1H), 7.36 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 7.8 Hz, 2H), 5.41 (s, 2H), 2.32 (s, 3H).

[1531] Step 132-2: Preparation of 4-(4-methylbenzyloxy)-3-(trifluoromethyl)aniline

[1532] Except for using 1-(4-methylbenzyloxy)-4-nitro-2-(trifluoromethyl)benzene obtained in Step 132-1 to replace 2-(benzyloxy)-5-nitropyridine, in the same manner as Step 95-2 of Example 95 above, 34 mg (yield: 19%) of the title compound was obtained.

[1533] 1 1H NMR (400 MHz, DMSO-d6) δ 7.30 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 7.8 Hz, 2H), 7.04 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 2.8 Hz, 1H), 6.77 (dd, J = 8.7 Hz, 2.7 Hz, 1H), 5.05 (s, 2H), 5.02 (s, 2H), 2.31 (s, 3H).

[1534] Step 132-3: Preparation of (4-(4-methylbenzyloxy)-3-(trifluoromethyl)phenyl)carbamimidoyl dinitrile

[1535] Except for using 4-(4-methylbenzyloxy)-3-(trifluoromethyl)aniline obtained in Step 132-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Step 1-3 of Example 1 above, 29 mg (yield: 74%) of the title compound was obtained.

[1536] 1 1H NMR (400 MHz, acetone-d6) δ 11.83 (s, 1H), 7.81 (d, J = 2.8 Hz, 1H), 7.75 (dd, J = 9.0 Hz, 2.8 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.38 (d, J = 7.7 Hz, 32), 7.22 (d, J = 7.9 Hz, 2H), 5.29 (s, 2H), 2.33 (s, 3H).

[1537] Example 133: Preparation of (4-(4-chlorophenethoxy)-3-(trifluoromethyl)phenyl)carbazoyl dinitrile (Compound 133)

[1538] Step 133-1: Preparation of 1-(4-chlorophenethoxy)-4-nitro-2-(trifluoromethyl)benzene

[1539] Except for using 2-(4-chlorophenyl)ethanol (0.3 mL, 2.15 mmol) instead of benzyl alcohol and using 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (0.2 mL, 1.43 mmol) instead of 2-chloro-5-nitropyridine, the title compound (144 mg, yield: 29%) was obtained in the same manner as in Step 95-1 of Example 95 above.

[1540] 1 H NMR (400 MHz, acetone-d6) δ 8.50 (dd, J = 9.2 Hz, 2.9 Hz, 1H), 8.43 (d, J = 2.8 Hz, 1H), 7.52 (d, J = 9.2 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 4.58 (t, J = 6.5 Hz, 2H), 3.21 (t, J = 6.5 Hz, 2H).

[1541] Step 133-2: Preparation of 4-(4-chlorophenethoxy)-3-(trifluoromethyl)aniline

[1542] Except for using 1-(4-chlorophenethoxy)-4-nitro-2-(trifluoromethyl)benzene obtained in Step 133-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound (28 mg, yield: 25%) was obtained in the same manner as in Step 1-2 of Example 1 above.

[1543] 1 H NMR (400 MHz, DMSO-d6) δ 7.37–7.31 (m, 4H), 6.96 (d, J = 8.7 Hz, 1H), 6.81 (d, J = 2.8 Hz, 1H), 6.76 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 5.02 (s, 2H), 4.12 (t, J = 6.6 Hz, 2H), 2.98 (t, J = 6.5 Hz, 2H).

[1544] Step 133-3: Preparation of (4-(4-chlorophenethoxy)-3-(trifluoromethyl)phenyl)carbamimidoyl dinitrile

[1545] Except for using 4-(4-chlorophenethoxy)-3-(trifluoromethyl)aniline obtained in Step 133-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound (15 mg, yield: 47%) was obtained in the same manner as in Step 1-3 of Example 1 above.

[1546] 11H NMR (400 MHz, acetone-d6) δ 11.86 (s, 1H), 7.78 (d, J = 2.7 Hz, 1H), 7.74 (dd, J = 9.0 Hz, 2.8 Hz, 1H), 7.44–7.26 (m, 5H), 4.39 (t, J = 6.5 Hz, 2H), 3.14 (t, J = 6.5 Hz, 2H).

[1547] Example 134: Preparation of (4-(4-methoxyphenethoxy)-3-(trifluoromethyl)phenyl)carbamoyl dinitrile (Compound 134)

[1548] Step 134-1: Preparation of 1-(4-methoxyphenethoxy)-4-nitro-2-(trifluoromethyl)benzene

[1549] Except for using 2-(4-methoxyphenyl)ethanol (328 mg, 2.15 mmol) instead of benzyl alcohol and 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (0.2 mL, 1.43 mmol) instead of 2-chloro-5-nitropyridine, in the same manner as Step 95-1 of Example 95 above, 165 mg (yield: 95%) of the title compound was obtained.

[1550] 1 1H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 9.2 Hz, 2.9 Hz, 1H), 8.37 (d, J = 2.9 Hz, 1H), 7.52 (d, J = 9.3 Hz, 1H), 7.25 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.45 (t, J = 6.6 Hz, 2H), 3.73 (s, 3H), 3.03 (t, J = 6.6 Hz, 2H).

[1551] Step 134-2: Preparation of 4-(4-methoxyphenethoxy)-3-(trifluoromethyl)aniline

[1552] Except for using 1-(4-methoxyphenethoxy)-4-nitro-2-(trifluoromethyl)benzene obtained in Step 134-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Step 1-2 of Example 1 above, 226 mg (yield: 73%) of the title compound was obtained.

[1553] 11H NMR (400 MHz, DMSO-d6) δ 7.22 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.8 Hz, 1H), 6.89–6.84 (m, 2H), 6.82 (d, J = 2.8 Hz, 1H), 6.76 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 5.02 (s, 2H), 4.07 (t, J = 6.8 Hz, 2H), 3.73 (s, 3H), 2.92 (t, J = 6.8 Hz, 2H).

[1554] Step 134-3: Preparation of (4-(4-methoxyphenethoxy)-3-(trifluoromethyl)phenyl)carbamimidoyl dinitrile

[1555] Except for using 4-(4-methoxyphenethoxy)-3-(trifluoromethyl)aniline obtained in Step 134-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 156 mg (yield: 84%) of the title compound was obtained.

[1556] 1 1H NMR (400 MHz, chloroform-d) δ 9.83 (s, 1H), 7.54 (d, J = 2.8 Hz, 1H), 7.42 (dd, J = 9.0 Hz, 2.8 Hz, 1H), 7.22 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 9.0 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 4.21 (t, J = 6.7 Hz, 2H), 3.80 (s, 3H), 3.08 (t, J = 6.7 Hz, 2H).

[1557] Example 135: Preparation of (3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethoxy)phenyl) carbohydrazonodicarbonitrile (Compound 135)

[1558] Step 135-1: Preparation of 4-nitro-2-(trifluoromethyl)-1-(4-(trifluoromethyl)phenethoxy)benzene

[1559] Except for using 2-(4-(trifluoromethyl)phenyl)ethanol (0.33 mL, 2.15 mmol) to replace benzyl alcohol and 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (0.2 mL, 1.43 mmol) to replace 2-chloro-5-nitropyridine, in the same manner as Step 95-1 of Example 95 above, 298 mg (yield: 53%) of the title compound was obtained.

[1560] 11H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 9.3 Hz, 2.9 Hz, 1H), 8.37 (d, J = 2.8 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.55 (dd, J = 11.8 Hz, 8.6 Hz, 3H), 4.57 (t, J = 6.4 Hz, 2H), 3.21 (t, J = 6.3 Hz, 2H).

[1561] Step 135-2: Preparation of 3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethoxy)aniline

[1562] Except for using 4-nitro-2-(trifluoromethyl)-1-(4-(trifluoromethyl)phenethoxy)benzene obtained in Step 135-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 176 mg (yield: 73%) of the title compound was obtained.

[1563] 1 1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 7.9 Hz, 2H), 6.97 (d, J = 8.7 Hz, 1H), 6.81 (d, J = 2.7 Hz, 1H), 6.77 (dd, J = 8.9 Hz, 2.7 Hz, 1H), 5.03 (s, 2H), 4.18 (t, J = 6.4 Hz, 2H), 3.09 (t, J = 6.5 Hz, 2H).

[1564] Step 135-3: Preparation of (3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethoxy)phenyl)carbamimidoyl dinitrile

[1565] Except for using 3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethoxy)aniline obtained in Step 135-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 158 mg (yield: 86%) of the title compound was obtained.

[1566] 1 1H NMR (400 MHz, acetone-d6) δ 12.09 (s, 1H), 7.79–7.71 (m, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.9 Hz, 1H), 4.45 (t, J = 6.4 Hz, 2H), 3.26 (t, J = 6.3 Hz, 2H).

[1567] Example 136: Preparation of (4-(pyrimidin-2-ylmethoxy)phenyl)carbamoyl dinitrile (Compound 136)

[1568] Step 136-1: Preparation of 2-((4-nitrophenoxy)methyl)pyrimidine

[1569] Under a nitrogen atmosphere, triphenylphosphine (PPh3, 1.26 g, 4.80 mmol) and diisopropyl azodicarboxylate (DIAD, 0.95 mL, 4.80 mmol) were dissolved in a THF solution, and the reaction mixture was stirred at 0 °C for 30 minutes. Pyrimidin-2-ylmethanol (0.36 mL, 4 mmol) and 4-nitrophenol (667 mg, 4.80 mmol) were added to the reaction mixture, and the reaction mixture was stirred at room temperature for one day. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 365 mg (yield: 39%) of the title compound.

[1570] 1 1H NMR (400 MHz, DMSO-d6) δ 8.861–8.849 (d, J = 4.8 Hz, 2H), 8.219–8.196 (d, J = 9.2 Hz, 2H), 7.516–7.491 (t, J = 5.0 Hz, 1H), 7.215–7.192 (d, J = 9.2 Hz, 2H), 5.492 (s, 2H).

[1571] Step 136-2: Preparation of 4-(pyrimidin-2-ylmethoxy)aniline

[1572] Except for using 2-((4-nitrophenoxy)methyl)pyrimidine obtained in Step 136-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 98 mg (yield: 49%) of the title compound was obtained.

[1573] 1 1H NMR (400 MHz, DMSO-d6) δ 8.840–8.828 (d, J = 4.8 Hz, 2H), 7.478–7.454 (t, J = 4.8 Hz, 1H), 6.708–6.687 (d, J = 8.4 Hz, 2H), 6.503–6.482 (d, J = 8.4 Hz, 2H), 5.095 (s, 2H), 4.619 (s, 2H).

[1574] Step 136-3: Preparation of (4-(pyrimidin-2-ylmethoxy)phenyl)carbamoyl dinitrile

[1575] Except for using 4-(pyrimidin-2-ylmethoxy)aniline obtained in Step 136-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 70 mg (yield: 63%) of the title compound was obtained.

[1576] 1 1H NMR (400 MHz, DMSO-d6) δ 12.980 (s, 1H), 8.853–8.841 (d, J = 4.8 Hz, 2H), 7.499–7.474 (t, J = 5.0 Hz, 1H), 7.421–7.398 (d, J = 9.2 Hz, 2H), 7.060–7.037 (d, J = 9.2 Hz, 2H), 5.301 (s, 2H).

[1577] Example 137: Preparation of (4-((1H-Pyrazol-4-yl)methoxy)phenyl)carbamoyl dinitrile (Compound 137)

[1578] Step 137-1: Preparation of 2-((4-nitrophenoxy)methyl)pyrimidine

[1579] Under a nitrogen atmosphere, Cs2CO3 (2.45 g, 7.55 mmol), 4-nitrophenol (420 mg, 3.02 mmol), and 4-(chloromethyl)-1H-pyrazole (577 mg, 3.77 mmol) were dissolved in DMF, and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 186 mg (yield: 28%) of the title compound.

[1580] 1 1H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 8.21 (d, J = 8.8 Hz, 2H), 7.74 (s, 1H), 7.24 (d, J = 9.3 Hz, 2H), 6.38 (s, 1H), 5.22 (s, 2H).

[1581] Step 137-2: Preparation of 4-((1H-pyrazol-4-ylmethoxy)aniline

[1582] Except using 4-((4-nitrophenoxy)methyl)-1H-pyrazole obtained in Step 137-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 151 mg (yield: 97%) of the title compound was obtained.

[1583] 1 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 7.68 (s, 1H), 6.71 (d, J = 8.8 Hz, 2H), 6.49 (d, J = 8.8 Hz, 2H), 6.28 (d, J = 2.1 Hz, 1H), 4.87 (s, 2H), 4.59 (s, 2H).

[1584] Step 137-3: Preparation of (4-((1H-pyrazol-4-yl)methoxy)phenyl)carbamoyl dinitrile

[1585] Except for replacing N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide with 4-((1H-pyrazol-4-ylmethoxy)aniline obtained in Step 137-2, the title compound (33 mg, yield: 33%) was obtained in the same manner as Steps 1-3 of Example 1 above.

[1586] 1 H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 7.67 (s, 1H), 7.42 (d, J = 7.1 Hz, 2H), 7.08 (d, J = 7.2 Hz, 2H), 6.34 (s, 1H), 5.07 (s, 2H).

[1587] Example 138: Preparation of (4-((5-methylpyrazin-2-yl)methoxy)phenyl)carbamoyl dinitrile (Compound 138)

[1588] Step 138-1: Preparation of 2-methyl-5-((4-nitrophenoxy)methyl)pyrazine

[1589] Except for replacing benzyl alcohol with (5-methylpyrazin-2-yl)methanol (400 mg, 3.22 mmol) and 2-chloro-5-nitropyridine with 1-fluoro-4-nitrobenzene (0.84 mL, 4.83 mmol), the title compound (258 mg, yield: 33%) was obtained in the same manner as Step 95-1 of Example 95 above.

[1590] 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.58 (s, 1H), 8.23 (d, J = 9.3 Hz, 2H), 7.28 (d, J = 9.3 Hz, 2H), 5.38 (s, 2H), 2.52 (s, 3H).

[1591] Step 138-2: Preparation of 4-((5-methylpyrazin-2-yl)methoxy)aniline

[1592] Except for replacing 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide with 2-methyl-5-((4-nitrophenoxy)methyl)pyrazine obtained in Step 138-1, the title compound (108 mg, yield: 61%) was obtained in the same manner as Steps 1-2 of Example 1 above.

[1593] 11H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.53 (s, 1H), 6.75 (d, J = 7.3 Hz, 2H), 6.51 (d, J = 7.1 Hz, 2H), 5.05 (s, 2H), 4.65 (s, 2H), 1.99 (s, 3H).

[1594] Step 138-3: Preparation of (4-((5-methylpyrazin-2-yl)methoxy)phenyl)carbamoyl dinitrile

[1595] Except for using 4-((5-methylpyrazin-2-yl)methoxy)aniline obtained in Step 138-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 93 mg (yield: 69%) of the title compound was obtained.

[1596] 1 1H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H), 8.66 (s, 1H), 8.56 (s, 1H), 7.43 (d, J = 9.1 Hz, 2H), 7.11 (d, J = 9.1 Hz, 2H), 5.22 (s, 2H).

[1597] Example 139: Preparation of (4-(1-(4-(trifluoromethyl)phenyl)ethoxy)phenyl)carbamoyl dinitrile (Compound 139)

[1598] Step 139-1: Preparation of 1-nitro-4-(1-(4-(trifluoromethyl)phenyl)ethoxy)benzene

[1599] Except for using 1-(4-(trifluoromethyl)phenyl)ethanol (0.31 mL, 2 mmol) to replace pyrimidin-2-ylmethanol, in the same manner as Step 136-1 of Example 136 above, 495 mg (yield: 79%) of the title compound was obtained.

[1600] 1 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 9.1 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 9.2 Hz, 2H), 5.86 (q, J = 6.3 Hz, 1H), 1.62 (d, J = 6.3 Hz, 3H).

[1601] Step 139-2: Preparation of 4-(1-(4-(trifluoromethyl)phenyl)ethoxy)aniline

[1602] Except for using 1-nitro-4-(1-(4-(trifluoromethyl)phenyl)ethoxy)benzene obtained in Step 139-1 instead of 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, the title compound was obtained in the same manner as Steps 1-2 of Example 1 above in a yield of 159 mg (59%).

[1603] 1 H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 6.61 (d, J = 8.8 Hz, 2H), 6.41 (d, J = 8.8 Hz, 2H), 5.36 (q, J = 6.4 Hz, 1H), 4.59 (s, 2H), 1.49 (d, J = 6.4 Hz, 3H).

[1604] Step 139-3: Preparation of (4-(1-(4-(trifluoromethyl)phenyl)ethoxy)phenyl)carbamoyl dinitrile

[1605] Except for using 4-(1-(4-(trifluoromethyl)phenyl)ethoxy)aniline obtained in Step 139-2 instead of N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, the title compound was obtained in the same manner as Steps 1-3 of Example 1 above in a yield of 137 mg (72%).

[1606] 1 H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.38–7.29 (m, 2H), 7.05–6.94 (m, 2H), 5.64 (q, J = 6.3 Hz, 1H), 1.57 (d, J = 6.3 Hz, 3H).

[1607] Example 140: Preparation of (4-(1-(pyridin-3-yl)ethoxy)phenyl)carbamoyl dinitrile (Compound 140)

[1608] Step 140-1: Preparation of 4-(1-(pyridin-3-yl)ethoxy)aniline

[1609] Except for using 1-(pyridin-3-yl)ethanol (0.33 mL, 2.92 mmol) instead of pyrimidin-2-ylmethanol, the title compound was obtained in the same manner as Step 136-1 of Example 136 above in a yield of 277 mg (39%).

[1610] 11H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 2.1 Hz, 1H), 8.51 (dd, J = 4.8 Hz, 1.7 Hz, 1H), 8.15 (d, J = 9.3 Hz, 2H), 7.84 (dt, J = 7.9 Hz, 2.0 Hz, 1H), 7.40 (ddd, J = 7.9 Hz, 4.8 Hz, 0.9 Hz, 1H), 7.16 (d, J = 9.3 Hz, 2H), 5.83 (q, J = 6.4 Hz, 1H), 1.64 (d, J = 6.4 Hz, 3H).

[1611] Step 140-2: Preparation of 4-(1-pyridin-3-yl)ethoxy)aniline

[1612] Except for using 4-(1-(pyridin-3-yl)ethoxy)aniline obtained in Step 140-1 to replace 5-methyl-N-(5-nitropyridin-2-yl)pyrazine-2-carboxamide, in the same manner as Steps 1-2 of Example 1 above, 98 mg (yield: 41%) of the title compound was obtained.

[1613] 1 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 2.3 Hz, 1H), 8.45 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.35 (dd, J = 7.9 Hz, 4.8 Hz, 1H), 6.63 (d, J = 8.7 Hz, 2H), 6.42 (d, J = 8.7 Hz, 2H), 5.32 (q, J = 6.4 Hz, 1H), 4.63–4.52 (m, 2H), 1.51 (d, J = 6.4 Hz, 3H).

[1614] Step 140-3: Preparation of (4-(1-(pyridin-3-yl)ethoxy)phenyl)carbamoyl dinitrile

[1615] Except for using 4-(1-pyridin-3-yl)ethoxy)aniline obtained in Step 140-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 41 mg (yield: 34%) of the title compound was obtained.

[1616] 11H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 8.65 (d, J = 2.3 Hz, 1H), 8.49 (dd, J = 4.8 Hz, 1.7 Hz, 1H), 7.84 (dt, J = 7.9 Hz, 2.0 Hz, 1H), 7.40 (ddd, J = 7.8 Hz, 4.8 Hz, 0.8 Hz, 1H), 7.33 (d, J = 9.1 Hz, 2H), 6.99 (d, J = 9.1 Hz, 2H), 5.61 (q, J = 6.4 Hz, 1H), 1.58 (d, J = 6.4 Hz, 3H).

[1617] Example 141: Preparation of (4-(Benzyloxy)-3-methylphenyl)carbamoyl dinitrile (Compound 141)

[1618] Step 141-1: Preparation of 1-(benzyloxy)-2-methyl-4-nitrobenzene

[1619] Except for using benzyl alcohol (0.32 mL, 3.05 mmol) instead of pyrimidin-2-ylmethanol and using 2-methyl-4-nitrophenol (561 mg, 3.66 mmol) instead of 4-nitrophenol, the title compound (551 mg, yield: 74%) was obtained in the same manner as in Step 136-1 of Example 136 above.

[1620] 1 1H NMR (400 MHz, DMSO-d6) δ 8.14–8.01 (m, 2H), 7.51–7.47 (m, 2H), 7.42 (td, J = 7.2 Hz, 1.3 Hz, 2H), 7.36 (d, J = 6.4 Hz, 1H), 7.24 (d, J = 9.9 Hz, 1H), 5.29 (s, 2H), 2.28 (s, 3H).

[1621] Step 141-2: Preparation of 4-(benzyloxy)-3-methylaniline

[1622] Except for using 1-(benzyloxy)-2-methyl-4-nitrobenzene obtained in Step 141-1 instead of 2-(benzyloxy)-5-nitropyridine, the title compound (320 mg, yield: 73%) was obtained in the same manner as in Step 95-2 of Example 95 above.

[1623] 1 1H NMR (400 MHz, DMSO-d6) δ 7.46–7.27 (m, 5H), 6.70 (d, J = 8.5 Hz, 1H), 6.40 (d, J = 2.0 Hz, 1H), 6.33 (dd, J = 8.5 Hz, 2.8 Hz, 1H), 4.93 (s, 2H), 4.53 (s, 1H), 2.08 (s, 3H).

[1624] Step 141-3: Preparation of (4-(benzyloxy)-3-methylphenyl)carbamoyl dinitrile

[1625] Except for using 4-(benzyloxy)-3-methylaniline obtained in Step 141-2 to replace N-(5-aminopyridin-2-yl)-5-methylpyrazine-2-carboxamide, in the same manner as Steps 1-3 of Example 1 above, 180 mg (yield: 44%) of the title compound was obtained.

[1626] 1 H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 7.46 (d, J = 6.7 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.36–7.31 (m, 2H), 7.27 (dd, J = 8.6 Hz, 2.2 Hz, 1H), 7.06 (d, J = 8.9 Hz, 1H), 5.13 (s, 2H), 2.22 (s, 3H).

[1627] Example 142: Preparation of (3-methyl-4-(4-methylbenzyloxy)phenyl)carbamoyl dinitrile (Compound 142)

[1628] Step 142-1: Preparation of 2-methyl-1-(4-methylbenzyloxy)-4-nitrobenzene

[1629] Except for using p-methylbenzyl alcohol (360 mg, 2.95 mmol) to replace pyrimidin-2-ylmethanol and using 2-methyl-4-nitrophenol (541 mg, 3.54 mmol) to replace 4-nitrophe...

Claims

1. A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1] Among them, In Formula 1 above, L is -NHCO-, -CONH-, -NHSO2-, -SO2NH- or -(linear or branched C 0-3 alkylene)′-O-(linear or branched C 0-3 alkylene)″-; R1 is hydrogen, C 1-6 alkyl or C 1-6 alkylcarbonyl; (Het)Ar1 is C 6–10 arylene or 5- to 10-membered heteroarylene; and (Het)Ar2 is C 6–10 aryl or 5- to 10-membered heteroaryl; wherein C 6–10 (Aryl) and 5- to 10-membered (heteroaryl) are each independently unsubstituted or substituted by at least one group selected from the group consisting of: C 1–6 alkyl, C 1–6 alkoxy, halogen, cyano, C 1–6 haloalkyl, and C 1–6 haloalkoxy, wherein the compound is: (1) (6-(5-Methylpyrazine-2-carboxamido)pyridin-3-yl)carbazonyldinitrile, (2) (4-(5-Methylpyrazine-2-carboxamido)phenyl)carbazonyldinitrile, (3) (2-Fluoro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbazonyldinitrile, (4) (2-Methoxy-4-(5-methylpyrazine-2-carboxamido)phenyl)carbazonyldinitrile, (5) (2-Chloro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbazonyldinitrile, (6) (2-Methyl-4-(5-methylpyrazine-2-carboxamido)phenyl)carbazonyldinitrile, (7) (3-Fluoro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbazonyldinitrile, (8) (3-Methyl-4-(5-methylpyrazine-2-carboxamido)phenyl)carbazonyldinitrile, (9) Methyl (3-methyl-4-(5-methylpyrazine-2-carboxamido)phenyl)carbazonyldinitrile, (10) (3-Methoxy-4-(5-methylpyrazine-2-carboxamido)phenyl)carbazonyldinitrile, (11) (3-Chloro-4-(5-methylpyrazine-2-carboxamido)phenyl)carbazonyldinitrile, (12) (5-Methyl-6-(5-methylpyrazine-2-carboxamido)pyridin-3-yl)carbazonyldinitrile, (13) (4-Methyl-6-(5-methylpyrazine-2-carboxamido)pyridin-3-yl)carbazonyldinitrile, (14) (5-(5-Methylpyrazine-2-carboxamido)pyridin-2-yl)carbazonyldinitrile, (15) (6-Benzamidopyridin-3-yl)carbazonyldinitrile, (16) (6-(4-Fluorobenzamido)pyridin-3-yl)carbazonyldinitrile, (17) (6-(2-Fluorobenzamido)pyridin-3-yl)carbazonyldinitrile, (18) (6-(3-Fluorobenzamido)pyridin-3-yl)carbazonyldinitrile, (19) (6-(3-Fluoro-5-methylbenzamido)pyridin-3-yl)carbazonyldinitrile, (20) (6-(2-Fluoro-3-methylbenzamido)pyridin-3-yl)carbazonyldinitrile, (21) (6-(4-Fluoro-3-methylbenzamido)pyridin-3-yl)carbazonyldinitrile, (22) (6-(3-Fluoro-4-methylbenzamido)pyridin-3-yl)carbazonyldinitrile, (23) (6-(4-Methylbenzamido)pyridin-3-yl)carbazonyldinitrile, (24) (6-(3-Methylbenzamido)pyridin-3-yl)carbazonyldinitrile, (25) (6-(2-Methylbenzamido)pyridin-3-yl)carbazonyldinitrile, (26) (6-(3-(Trifluoromethyl)benzamido)pyridin-3-yl)carbazonyldinitrile, (27) (6-(4-(Trifluoromethyl)benzamido)pyridin-3-yl)carbazonyldinitrile, (28) (6-(2-(Trifluoromethyl)benzamido)pyridin-3-yl)carbazonyldinitrile, (29)(6-(Pyrimidin-2-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile, (30)(6-(Thiophen-2-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile, (31)(6-(Benzo[d]thiazol-2-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile, (32)(6-(Quinoxalin-2-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile, (33)(2-(5-Methylpyrazin-2-ylcarbamoyl)thiazolo[4,5-b]pyridin-6-yl)carbazonyldinitrile, (34)(6-(p-Tolylcarbamoyl)pyridin-3-yl)carbazonyldinitrile, (35)(6-(4-Methoxyphenylcarbamoyl)pyridin-3-yl)carbazonyldinitrile, (36)(6-(5-Methylpyrazin-2-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile, (37)(6-(4-Chlorophenylcarbamoyl)pyridin-3-yl)carbazonyldinitrile, (38)(6-(6-Methylpyridin-3-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile, (39)(6-(5-Methylpyridin-3-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile, (40)(6-(Pyridin-3-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile, (41)(6-(6-Methylpyrazin-2-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile, (42)(6-(Pyrimidin-5-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile, (43)(6-(Pyrimidin-2-ylcarbamoyl)pyridin-3-yl)carbazonyldinitrile, (44)(4-(4-Methoxyphenylcarbamoyl)phenyl)carbazonyldinitrile, (45)(4-(5-Methylpyrazin-2-ylcarbamoyl)phenyl)carbazonyldinitrile, (46)(4-(6-Methylpyrazin-2-ylcarbamoyl)phenyl)carbazonyldinitrile, (47)(4-(6-Methylpyridin-3-ylcarbamoyl)phenyl)carbazonyldinitrile, (48)(4-(5-Methylpyridin-3-ylcarbamoyl)phenyl)carbazonyldinitrile, (49)(4-(Pyridin-3-ylcarbamoyl)phenyl)carbazonyldinitrile, (50)(4-(Pyrimidin-5-ylcarbamoyl)phenyl)carbazonyldinitrile, (51)(2-Methoxy-4-(5-Methylpyrazin-2-ylcarbamoyl)phenyl)carbazonyldinitrile, (52)(3-Methyl-4-(5-Methylpyrazin-2-ylcarbamoyl)phenyl)carbazonyldinitrile, (53)(3-Methyl-4-(6-Methylpyridin-3-ylcarbamoyl)phenyl)carbazonyldinitrile, (54)(3-Methyl-4-(6-Methylpyrazin-2-ylcarbamoyl)phenyl)carbazonyldinitrile, (55)(2-Methyl-4-(6-Methylpyridin-3-ylcarbamoyl)phenyl)carbazonyldinitrile, (56)(2-Fluoro-4-(5-Methylpyrazin-2-ylcarbamoyl)phenyl)carbazonyldinitrile, (57) (2-Methoxy-4-(6-methylpyridin-3-ylcarbamoyl)phenyl)carbamoyl dinitrile, (58) (6-(phenylsulfonamido)pyridin-3-yl)carbamoyl dinitrile, (59) (6-(4-Methoxyphenylsulfonamido)pyridin-3-yl)carbamoyl dinitrile, (60) (6-(Pyridine-3-sulfonamido)pyridin-3-yl)carbamoyl dinitrile, (61) (6-(1-Methyl-1H-pyrazole-4-sulfonamido)pyridin-3-yl)carbamoyl dinitrile, (62) (6-(Thiophene-2-sulfonamido)pyridin-3-yl)carbamoyl dinitrile, (63) (6-(4-Methylphenylsulfonamido)pyridin-3-yl)carbamoyl dinitrile, (64) (6-(4-Fluorophenylsulfonamido)pyridin-3-yl)carbamoyl dinitrile, (65) (4-(N-(6-Methylpyridin-3-yl)sulfamoyl)phenyl)carbamoyl dinitrile, (66) (4-(N-(4-Methoxyphenyl)sulfamoyl)phenyl)carbamoyl dinitrile, (67) (4-(N-(5-Methylpyrazin-2-yl)sulfamoyl)phenyl)carbamoyl dinitrile, (68) (6-Phenoxypyridin-3-yl)carbamoyl dinitrile, (69) (6-(3-Fluorophenoxy)pyridin-3-yl)carbamoyl dinitrile, (70) (5-Phenoxypyridin-2-yl)carbamoyl dinitrile, (71) (3-Fluoro-4-phenoxyphenyl)carbamoyl dinitrile, (72) (3-Fluoro-4-(pyridin-3-yloxy)phenyl)carbamoyl dinitrile, (73) (4-Phenoxy-3-(trifluoromethyl)phenyl)carbamoyl dinitrile, (74) (3-Methyl-4-(pyridin-3-yloxy)phenyl)carbamoyl dinitrile, (75) Methyl (5-phenoxypyridin-2-yl)carbamoyl dinitrile, (76) (6-(3-Fluorophenoxy)pyridin-3-yl)(methyl)carbamoyl dinitrile, (77) (3-Fluoro-4-phenoxyphenyl)(methyl)carbamoyl dinitrile, (78) Methyl (4-phenoxy-3-(trifluoromethyl)phenyl)carbamoyl dinitrile, (79) (3-Methyl-4-(pyridin-4-yloxy)phenyl)carbamoyl dinitrile, (80) (3-Fluoro-4-(pyridin-4-yloxy)phenyl)carbamoyl dinitrile, (81) (3-Methyl-4-(pyrimidin-5-yloxy)phenyl)carbamoyl dinitrile, (82) (3-Fluoro-4-(pyrimidin-5-yloxy)phenyl)carbamoyl dinitrile, (83) (4-(Pyridin-2-yloxy)phenyl)carbamoyl dinitrile, (84) (4-(Pyrazin-2-yloxy)phenyl)carbamoyl dinitrile, (85) (4-(Pyridin-3-yloxy)phenyl)carbamoyl dinitrile, (86) (4-(2-Cyanophenoxy)phenyl)carbamoyl dinitrile, (87) (4-(4-Cyanophenoxy)phenyl)carbamoyl dinitrile, (88) (4-(3-Cyanophenoxy)phenyl)carbamoyl dinitrile, (89) (4-(6-(Trifluoromethyl)pyridin-3-yloxy)phenyl)carbamoyl dinitrile, (90)(4-(5-(Trifluoromethyl)pyridin-2-yloxy)phenyl)carbonohydrazonoyl dinitrile, (91)(4-(Pyrimidin-2-yloxy)phenyl)carbonohydrazonoyl dinitrile, (92)(4-(Pyridazin-3-yloxy)phenyl)carbonohydrazonoyl dinitrile, (93)(4-(2-Fluorophenoxy)phenyl)carbonohydrazonoyl dinitrile, (94)(4-(3-Fluorophenoxy)phenyl)carbonohydrazonoyl dinitrile, (95)(6-(Benzyloxy)pyridin-3-yl)carbonohydrazonoyl dinitrile, (96)(6-(4-(Trifluoromethyl)benzyloxy)pyridin-3-yl)carbonohydrazonoyl dinitrile, (97)(4-(Benzyloxy)-3-(trifluoromethyl)phenyl)carbonohydrazonoyl dinitrile, (98)(3-(Trifluoromethyl)-4-(4-(trifluoromethyl)benzyloxy)phenyl)carbonohydrazonoyl dinitrile, (99)(6-(4-Methylbenzyloxy)pyridin-3-yl)carbonohydrazonoyl dinitrile, (100)(6-Phenethoxypyridin-3-yl)carbonohydrazonoyl dinitrile, (101)(4-Phenethoxy-3-(trifluoromethyl)phenyl)carbonohydrazonoyl dinitrile, (102)(6-(4-Methoxyphenethoxy)pyridin-3-yl)carbonohydrazonoyl dinitrile, (103)(6-(4-(Trifluoromethyl)phenethoxy)pyridin-3-yl)carbonohydrazonoyl dinitrile, (104)(3-Methoxy-4-(5-methylpyrazine-2-ylcarbamoyl)phenyl)carbonohydrazonoyl dinitrile, (105)(3-Methoxy-4-(6-methylpyrazine-2-ylcarbamoyl)phenyl)carbonohydrazonoyl dinitrile, (106)(3-Chloro-4-(5-methylpyrazine-2-ylcarbamoyl)phenyl)carbonohydrazonoyl dinitrile, (107)(3-Methoxy-4-(5-methylpyridin-3-ylcarbamoyl)phenyl)carbonohydrazonoyl dinitrile, (108)(3-Methoxy-4-(p-tolylcarbamoyl)phenyl)carbonohydrazonoyl dinitrile, (109)(3-Methoxy-4-(4-methoxyphenylcarbamoyl)phenyl)carbonohydrazonoyl dinitrile, (110)(6-(Furan-3-carboxamido)pyridin-3-yl)carbonohydrazonoyl dinitrile, (111)(3-Methyl-4-(thiazole-4-carboxamido)phenyl)carbonohydrazonoyl dinitrile, (112)(6-(Thiazole-4-carboxamido)pyridin-3-yl)carbonohydrazonoyl dinitrile, (113)(6-(Oxazole-4-carboxamido)pyridin-3-yl)carbonohydrazonoyl dinitrile, (114)(6-(Oxazole-5-carboxamido)pyridin-3-yl)carbonohydrazonoyl dinitrile, (115)(6-(Isoxazole-3-carboxamido)pyridin-3-yl)carbonohydrazonoyl dinitrile, (116)(4-(Thiazol-2-yloxy)phenyl)carbonohydrazonoyl dinitrile, (117)(4-(Benzyloxy)phenyl)carbonohydrazonoyl dinitrile, (118)(4-(4-(Trifluoromethyl)benzyloxy)phenyl)carbonohydrazonoyl dinitrile, (119)(4-(4-Methylbenzyloxy)phenyl)carbonohydrazonoyl dinitrile, (120)(4-(4-Methoxyphenethoxy)phenyl)carbonohydrazonoyl dinitrile, (121)(4-(4-(Trifluoromethyl)phenethoxy)phenyl)carbonohydrazonoyl dinitrile, (122) (4-Phenethoxyphenyl)carbamoyl dinitrile, (123) (4-(4-Chlorophenethoxy)phenyl)carbamoyl dinitrile, (124) (4-(Pyridin-3-ylmethoxy)phenyl)carbamoyl dinitrile, (125) (4-(Pyrazin-2-ylmethoxy)phenyl)carbamoyl dinitrile, (126) (4-((1H-Benzimidazol-2-yl)methoxy)phenyl)carbamoyl dinitrile, (127) (4-(Pyridazin-3-ylmethoxy)phenyl)carbamoyl dinitrile, (128) (4-(Benzo[d]oxazol-2-ylmethoxy)phenyl)carbamoyl dinitrile, (129) (4-(Benzo[d]thiazol-2-ylmethoxy)phenyl)carbamoyl dinitrile, (130) (4-(Benzo[b]thiophen-2-ylmethoxy)phenyl)carbamoyl dinitrile, (131) (6-(4-Chlorophenethoxy)pyridin-3-yl)carbamoyl dinitrile, (132) (4-(4-Methylbenzyloxy)-3-(trifluoromethyl)phenyl)carbamoyl dinitrile, (133) (4-(4-Chlorophenethoxy)-3-(trifluoromethyl)phenyl)carbamoyl dinitrile, (134) (4-(4-Methoxyphenethoxy)-3-(trifluoromethyl)phenyl)carbamoyl dinitrile, (135) (3-(Trifluoromethyl)-4-(4-(trifluoromethyl)phenethoxy)phenyl)carbamoyl dinitrile, (136) (4-(Pyrimidin-2-ylmethoxy)phenyl)carbamoyl dinitrile, (137) (4-((1H-Pyrazol-4-yl)methoxy)phenyl)carbamoyl dinitrile, (138) (4-((5-Methylpyrazin-2-yl)methoxy)phenyl)carbamoyl dinitrile, (139) (4-(1-(4-(Trifluoromethyl)phenyl)ethoxy)phenyl)carbamoyl dinitrile, (140) (4-(1-(Pyridin-3-yl)ethoxy)phenyl)carbamoyl dinitrile, (141) (4-(Benzyloxy)-3-methylphenyl)carbamoyl dinitrile, (142) (3-Methyl-4-(4-methylbenzyloxy)phenyl)carbamoyl dinitrile, (143) (3-Methyl-4-(pyrimidin-2-ylmethoxy)phenyl)carbamoyl dinitrile, (144) (3-Methyl-4-(pyrazin-2-ylmethoxy)phenyl)carbamoyl dinitrile, (145) (3-Methyl-4-(pyridin-3-ylmethoxy)phenyl)carbamoyl dinitrile, (146) (4-((1H-Benzimidazol-2-yl)methoxy)-3-methylphenyl)carbamoyl dinitrile, (147) (3-Methyl-4-((5-methylpyrazin-2-yl)methoxy)phenyl)carbamoyl dinitrile, (148) (3-Methyl-4-(4-(trifluoromethyl)benzyloxy)phenyl)carbamoyl dinitrile, (149) (3-Methyl-4-(pyridazin-3-ylmethoxy)phenyl)carbamoyl dinitrile, (150) (4-(Benzo[b]thiophen-2-ylmethoxy)-3-methylphenyl)carbamoyl dinitrile, (151) (4-((1H-Pyrazol-3-yl)methoxy)-3-methylphenyl)carbamoyl dinitrile, (152)(3-Methyl-4-(thiazol-4-ylmethoxy)phenyl)carbazimidoyl dinitrile, (153)(4-(Benzyloxy)-3-methoxyphenyl)carbazimidoyl dinitrile, (154)(3-Methoxy-4-(4-methylbenzyloxy)phenyl)carbazimidoyl dinitrile, (155)(3-Methoxy-4-(4-(trifluoromethyl)benzyloxy)phenyl)carbazimidoyl dinitrile, (156)(4-(Benzo[d]oxazol-2-ylmethoxy)-3-methylphenyl)carbazimidoyl dinitrile, (157)(4-(Benzo[d]thiazol-2-ylmethoxy)-3-methylphenyl)carbazimidoyl dinitrile, (158)(4-(Benzo[b]thiophen-2-ylmethoxy)-3-methoxyphenyl)carbazimidoyl dinitrile, (159)(3-Methoxy-4-(pyrazin-2-ylmethoxy)phenyl)carbazimidoyl dinitrile, (160)(3-Methoxy-4-(pyridin-3-ylmethoxy)phenyl)carbazimidoyl dinitrile, (161)(3-Methoxy-4-(pyrimidin-2-ylmethoxy)phenyl)carbazimidoyl dinitrile, (162)(3-Methoxy-4-((5-methylpyrazin-2-yl)methoxy)phenyl)carbazimidoyl dinitrile, (163)(4-((1H-Benzimidazol-2-yl)methoxy)-3-methoxyphenyl)carbazimidoyl dinitrile, (164)(3-Methoxy-4-(pyridazin-3-ylmethoxy)phenyl)carbazimidoyl dinitrile, (165)(4-(Benzo[d]thiazol-2-ylmethoxy)-3-methoxyphenyl)carbazimidoyl dinitrile, (166)(4-(Benzo[d]oxazol-2-ylmethoxy)-3-methoxyphenyl)carbazimidoyl dinitrile, (167)(3-Methoxy-4-(thiazol-4-ylmethoxy)phenyl)carbazimidoyl dinitrile, (168)(4-((1H-Pyrazol-3-yl)methoxy)-3-methoxyphenyl)carbazimidoyl dinitrile, (169)(3-Methoxy-4-(pyridin-2-ylmethoxy)phenyl)carbazimidoyl dinitrile, (170)(3-Methoxy-4-((6-methylpyridin-3-yl)methoxy)phenyl)carbazimidoyl dinitrile, (171)(3-Methoxy-4-((2-methylthiazol-4-yl)methoxy)phenyl)carbazimidoyl dinitrile, (172)(3-Methoxy-4-(thiophen-2-ylmethoxy)phenyl)carbazimidoyl dinitrile, (173)(3-Methoxy-4-(thiophen-3-ylmethoxy)phenyl)carbazimidoyl dinitrile, (174)(3-Methoxy-4-((1-methyl-1H-pyrazol-4-yl)methoxy)phenyl)carbazimidoyl dinitrile, or (175)Acetyl(3-methyl-4-(4-methylbenzyloxy)phenyl)carbazimidoyl dinitrile.

2. A method for preparing the compound according to claim 1, the method comprising: In the first step, in the presence of an acid, reacting a compound having a reactive amino group at one end represented by formula 2 with sodium nitrite and malononitrile to form an imine bond; and Optionally, in the second step, when R1 is a substituent other than hydrogen, introducing the R1 substituent into the product obtained in the previous step: [Formula 2] H2N-(Het)Ar1-L-(Het)Ar2 Wherein, in Formula 2, L, (Het)Ar1, (Het)Ar2 and R1 are as defined in claim 1.

3. The method according to claim 2, wherein the first step is carried out through a series of processes, including the following steps: 1-1) Dissolve the compound of formula 2 and sodium nitrite in a C 1-4 lower alcohol solvent, and add an aqueous solution of an acid thereto at a temperature of -5°C to 5°C to form a diazonium salt; 1-2) Adding malononitrile to the reaction solution containing the diazonium salt obtained in step 1-1), and reacting at a temperature of 15 °C to 40 °C; and 1-3) Adding an aqueous solution of a base to the reaction solution of step 1-2) to neutralize the reaction solution.

4. The method according to claim 2, wherein the compound containing a reactive amino group at one end represented by Formula 2 is prepared by a reduction reaction from the nitro-containing compound represented by the following Formula 3: [Formula 3] O2N-(Het)Ar1-L-(Het)Ar2.

5. The method according to claim 4, wherein when L is -NHCO- or -CONH-, the compound of Formula 3 is prepared by the following methods: i) The reaction between a (Het)Ar1 derivative and a (Het)Ar2 derivative, wherein, i) The (Het)Ar1 derivative includes a carboxyl group at the site connected to the nitro group and L, and the (Het)Ar2 derivative includes an amino group at the site connected to L; or ii) The reaction between the (Het)Ar1 derivative and the (Het)Ar2 derivative, wherein the (Het)Ar1 derivative includes an amino group at the site connected to the nitro group and L, and the (Het)Ar2 derivative includes a carboxyl group at the site connected to L.

6. The method according to claim 4, wherein when L is -NHSO2- or -SO2NH-, the compound of Formula 3 is prepared by the following methods: i) Reaction between a (Het)Ar1 derivative and a (Het)Ar2 derivative, wherein, i) The (Het)Ar1 derivative includes an amino group at the site connected to the nitro group and L, and the (Het)Ar2 derivative includes a chlorosulfonyl group at the site connected to L; or ii) The reaction between the (Het)Ar1 derivative and the (Het)Ar2 derivative, wherein the (Het)Ar1 derivative includes a halosulfonyl group at the site connected to the nitro group and L, and the (Het)Ar2 derivative includes an amino group at the site connected to L.

7. The method according to claim 4, wherein when L is -(linear or branched C 0–3 alkylene)′-O-(linear or branched C 0–3 alkylene)″-, the compound of formula 3 is prepared by the following method: i) The reaction between a (Het)Ar1 derivative and a (Het)Ar2 derivative, wherein, The (Het)Ar1 derivative includes -(linear or branched C 0–3 alkylene)′-OH at the site connected to the nitro group and L, and the (Het)Ar2 derivative includes -(linear or branched C 0–3 alkylene)″-X (where X is a halogen) at the site connected to L; or ii) Reaction between a (Het)Ar1 derivative and a (Het)Ar2 derivative, wherein the (Het)Ar1 derivative comprises -(linear or branched C 0–3 alkylene)'-X at the site connected to the nitro group and L, and the (Het)Ar2 derivative comprises -(linear or branched C 0–3 alkylene)''-OH at the site connected to L.

8. A composition for inhibiting tau protein aggregation, which comprises the compound according to claim 1 as an active ingredient.

9. A composition for inhibiting tau protein hyperphosphorylation, which comprises the compound according to claim 1 as an active ingredient.

10. A pharmaceutical composition for preventing or treating diseases caused by tau protein aggregation or hyperphosphorylation, which comprises the compound according to claim 1 as an active ingredient.

11. The pharmaceutical composition according to claim 10, wherein the diseases caused by tau protein aggregation or hyperphosphorylation are selected from the group consisting of: Alzheimer's disease, Parkinson's disease, trauma, cerebrovascular disease, peripheral neuropathy, retinopathy, glaucoma and tauopathy.

12. The pharmaceutical composition according to claim 11, wherein the tauopathy is selected from the group consisting of: chronic traumatic encephalopathy (CTE), primary age-related tauopathy, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, argyrophilic grain disease (AGD), frontotemporal dementia (FTD), Parkinsonism associated with chromosome 17, Lytico-bodig disease (Guam-type Parkinsonism-dementia complex), ganglioglioma, gangliocytoma, meningeal hemangiomatosis, postencephalitic Parkinsonism, subacute sclerosing panencephalitis, lead poisoning encephalopathy, tuberous sclerosis, pantothenate kinase-associated neurodegeneration, lipofuscinosis, post-traumatic stress disorder, and traumatic brain injury.

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