Novel hydrazone derivatives in which terminal amino group is substituted with aryl or heteroaryl group, and use thereof

文档序号：327751 发布日期：2021-11-30 浏览：47次中文

阅读说明：本技术 末端胺基被芳基或杂芳基取代的新的腙衍生物及其用途 (Novel hydrazone derivatives in which terminal amino group is substituted with aryl or heteroaryl group, and use thereof ) 是由裵爱任金允经林相敏林成洙成智惠李宰旭宋知妍申瑟气郑铉静孙佑承于 2018-12-26 设计创作，主要内容包括：本发明涉及末端胺基被芳基或杂芳基取代的新的腙衍生物及其用途。(The present invention relates to novel hydrazone derivatives in which the terminal amine group is substituted with an aryl group or a heteroaryl group, and uses thereof.)

1. A compound represented by the following formula 1:

[ formula 1]

Wherein, in the above formula 1,

in the above-mentioned formula 1, the,

R₁is hydrogen or C_1-6An alkyl group;

R₂is unsubstituted or substituted C_6-14Aryl, 5-to 14-membered heteroaryl, or 5-to 14-membered heterocyclyl;

R₃-R₅i) are both hydrogen, ii) form a triple bond with one N, iii) R₃And R₄Form a double bond with NH, O or S to form an imine, oxo or thioxo, respectively, and R₅Is C_1-6Alkoxy, amino, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, or 5-to 14-membered heterocyclyl, or iv) R₃-R₅(ii) the heteroatom O, N or S is connected by a single or double bond and comprises carbon and a heteroatom attached to carbon to form an unsubstituted or substituted 5-to 14-membered heteroaryl or heterocyclyl group; and is

R₆-R₈i) Are both hydrogen, ii) form a triple bond with one N, iii) R₃And R₄Form a double bond with NH, O or S to form an imine, oxo or thioxo, respectively, and R₅Is C_1-6Alkoxy, amino, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, or 5-to 14-membered heterocyclyl, or iv) R₃-R₅(ii) the heteroatom O, N or S is connected by a single or double bond and comprises carbon and a heteroatom attached to carbon to form an unsubstituted or substituted 5-to 14-membered heteroaryl or heterocyclyl group;

wherein said heteroaryl or said heterocyclyl comprises at least one of O, N and S,

the substituted aryl, substituted heteroaryl or substituted heterocyclyl group may comprise: c_1-6An alkyl group; c_1-6An alkoxy group; halogen; c_1-6A perfluoroalkyl group; c_1-6A perfluoroalkoxy group; c_1-6A haloalkyl group; a carbamoyl group; a carboxamide group; c_6-10An aryloxy group; is prepared fromSubstituted C_6-14Aryl, 5-to 14-membered heteroaryl, or 5-to 14-membered heterocyclyl; or is selected from C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, C_1-6Alkoxycarbonyl radical, C_1-6Perfluoroalkyl radical, C_1-6Perfluoroalkoxy, C_1-6Haloalkyl, amino, C_1-6Alkylamino, di (C)_1-6Alkyl) amino and C_1-6C substituted by at least one substituent in the group consisting of alkoxycarbonyl_6-14Aryl, 5-to 14-membered heteroaryl, or 5-to 14-membered heterocyclyl, and

the carbamoyl and carboxamido groups may be selected from the group consisting of C_1-6Alkyl, and unsubstituted or substituted by C_1-6Alkoxy, hydroxy, cyano or C_1-6At least one of the group consisting of alkyl-substituted aryl and heteroaryl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof,

wherein R is₁Is hydrogen or methyl;

R₂is unsubstituted or substituted phenyl, benzothiazolyl, carbazolyl, indazolyl, quinolinyl, indolyl, pyrrolopyridyl, benzisoxazolyl, dihydrobenzothiazolyl, oxodihydrobenzothiazolyl, benzoxazolyl, oxodihydrobenzoxazolyl, benzimidazolyl, or oxodihydrobenzimidazolyl;

R₃-R₅together with the C to which it is attached form-C.ident.N, -CH₃，-CO₂Me，-CO₂Et，-CONH₂，-CSNH₂，(Here, R is₃' is C_1-6Alkyl groups); and

R₆-R₈formation of-C.ident.N, -CH₃，-CO₂Me，-CO₂Et，-CONH₂，-CSNH₂， (Here, R is₃' is C_1-6Alkyl groups);

wherein said heteroaryl and heterocyclyl contain at least one of O, N or S,

the substituted phenyl, benzothiazolyl, carbazolyl, indazolyl, quinolyl, indolyl, pyrrolopyridyl, benzisoxazolyl, dihydrobenzothiazolyl, oxodihydrobenzothiazolyl, benzoxazolyl, oxodihydrobenzoxazolyl, benzimidazolyl, or oxodihydrobenzimidazolyl group may comprise methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, fluorine, chlorine, bromine, morpholinyl, carbamoyl, carboxamido, phenoxy, or phenyl, piperidinyl, thiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazolyl, or oxodihydrobenzimidazolyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of methyl, ethyl, ethynyl, methoxy, fluorine, chlorine, bromine, nitro, dimethylamino, methoxycarbonyl, ethoxycarbonyl, and trifluoromethyl, Pyrazolyl, benzothiazolyl, naphthyl, pyrazolopyrimidinyl, imidazopyrimidinyl, quinoxalinyl, imidazopyridinyl, isoquinolinyl, indazolyl, indolyl, furyl, thienyl, oxotetrahydropyridazinyl or oxodihydropyridazinyl, and

the carbamoyl group and the carboxamide group may be substituted by at least one selected from the group consisting of a methyl group, an ethyl group, and a phenyl group, a pyridyl group, a pyrimidinyl group, and a pyrazinyl group, which are unsubstituted or substituted by a methyl group, a methoxy group, a hydroxy group, or a cyano group.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof,

wherein the compound is represented by the following formula 2:

[ formula 2]

In the above-mentioned formula 2, the first,

R₁is hydrogen or C_1-6An alkyl group;

R₂' and R₂Each independently is hydrogen, C_1-6Alkyl radical, C_1-6Alkoxy, halogen, C_1-6Perfluoroalkyl radical, C_1-6Perfluoroalkoxy, C_1-6Haloalkyl, unsubstituted or substituted by C_1-6An alkyl-substituted carbamoyl group; or unsubstituted or selected from the group consisting of C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, C_1-6Alkoxycarbonyl radical, C_1-6Perfluoroalkyl radical, C_1-6Perfluoroalkoxy, C_1-6Haloalkyl, amino, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, C_1-6Alkoxycarbonyl and C_6-10C substituted by at least one of aryloxy_6-14Aryl, 5-to 14-membered heteroaryl, or 5-to 14-membered heterocyclyl.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof,

wherein R is₁Is hydrogen or methyl;

R₂' is hydrogen, fluoro, methoxy or morpholinyl; and is

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

5. The compound according to claim 3 or a pharmaceutically acceptable salt thereof,

wherein the compound is represented by the following formula 3:

[ formula 3]

In the above-mentioned formula 3, the,

R₁is hydrogen or C_1-6An alkyl group;

cy is unsubstituted or substituted 5-to 14-membered heteroaryl or 5-to 14-membered heterocyclyl: and is

The substituted 5-to 14-membered heteroaryl or 5-to 14-membered heterocyclyl is unsubstituted or substituted with: c_1-6An alkyl group; c_1-6An alkoxy group; halogen; c_1-6A perfluoroalkyl group; c_1-6A perfluoroalkoxy group; c_1-6A haloalkyl group; unsubstituted or substituted by C_1-6An alkyl-substituted carbamoyl group; c_6-10An aryloxy group; or unsubstituted or selected from the group consisting of C_1-6Alkyl, halogen and di (C)_1-6Alkyl) amino group_6-14Aryl, 5-to 14-membered heteroaryl or 5-to 14-membered heterocyclyl.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof,

wherein R is₁Is hydrogen;

cy is unsubstituted or substituted benzothiazolyl, carbazolyl, indazolyl, quinolinyl, indolyl, pyrrolopyridinyl, oxodihydrobenzothiazolyl, oxodihydrobenzoxazolyl, or oxodihydrobenzimidazolyl; and is

The substituted 5-to 14-membered heteroaryl or 5-to 14-membered heterocyclyl is unsubstituted or substituted with: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoroethyl, difluoromethyl, trifluoromethoxy, dimethylcarbamoyl, phenoxy, or phenyl, pyridyl, furyl or thienyl unsubstituted or substituted by at least one selected from the group consisting of methyl, fluoro and dimethylamino.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof,

wherein the compound is represented by the following formula 4:

[ formula 4]

In the above-mentioned formula 4, the,

X₁-X₃each selected from C, N, O and S, different from each other, and each linked to a carboxamide group through a C-site;

R₁is hydrogen or C_1-6An alkyl group; and is

R₂"' is C_1-6Alkyl, unsubstituted or selected from C_1-6Alkoxy, hydroxy, cyano and C_1-6At least one substituted aryl or heteroaryl group from the group consisting of alkyl groups.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof,

wherein, X₁-X₃N, C and S or O, N and C in that order, and is linked to the carboxamide group via the C site;

R₁is hydrogen; and is

R₂"' is methyl, or phenyl, pyridyl, pyrazinyl or pyrimidinyl, unsubstituted or substituted with at least one member selected from the group consisting of methoxy, hydroxy, cyano and methyl.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof,

wherein the compound is represented by the following formula 5:

[ formula 5]

In the above-mentioned formula 5, the,

R₁is hydrogen or C_1-6An alkyl group;

R₂"" is unsubstituted or substituted by C_1-6An alkyl-substituted 5-to 14-membered heteroaryl or 5-to 14-membered heterocyclyl; and is

R₃-R₅i) Are both hydrogen, ii) form a triple bond with one N, iii) R₃And R₄Form a double bond with NH, O or S to form an imine, oxo or thioxo, respectively, and R₅Is C_1-6Alkoxy, amino, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, or 5-to 14-membered heterocyclyl, or iv) R₃-R₅The heteroatom O, N or S is connected by a single or double bond and comprises carbon and a heteroatom attached to carbon to form an unsubstituted or substituted 5-to 14-membered heteroaryl or heterocyclyl group.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof,

wherein R is₁Is hydrogen;

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

R₃-R₅together with the C to which it is attached form-C.ident.N, -CH₃，-CO₂Me，-CO₂Et，-CONH₂，-CSNH₂，(Here, R is₃' is methyl).

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof,

wherein the compound is:

a (4- (pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile,

(4- (5-fluoropyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile,

(4- (5-fluoro-4-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile,

(4- (5-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile,

(4- (pyrimidin-2-yl) carbohydrazone acyldinitrile,

(4- (4-ethylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile,

(4- (5-chloropyrimidin-2-yl) carbohydrazone acyldinitrile,

(4- (5-methoxypyrimidin-2-yl) -phenyl) carbohydrazone acyldinitrile,

(4- (2,4-dimethylthiazol-5-yl) phenyl) carbohydrazone acyldinitrile,

(4- (pyridin-2-yl) phenyl) carbohydrazone acyldinitrile,

(4- (2-methylthiazol-5-yl) phenyl) carbohydrazone acyldinitrile,

(4- (4-methylthiazol-5-yl) phenyl) carbohydrazone acyldinitrile,

13. biphenyl-4-yl carbohydrazone acyldinitrile,

(4' -methylbiphenyl-4-yl) carbohydrazone acyldinitrile,

(4- (pyridin-3-yl) phenyl) carbohydrazone acyldinitrile,

(4- (pyridin-4-yl) phenyl) carbohydrazone acyldinitrile,

(4- (pyridazin-3-yl) phenyl) carbohydrazone acyldinitrile,

(4- (5-methylthiazol-2-yl) phenyl) carbohydrazone acyldinitrile,

19.2- (4- (2- (dicyanomethylene) hydrazino) phenyl) thiazole-5-carboxylic acid ethyl ester,

(4- (thiazol-5-yl) phenyl) carbohydrazone acyldinitrile,

(3 '-fluoro-4' -nitrobiphenyl-4-yl) carbohydrazone acyldinitrile,

(4- (6-fluoropyridin-3-yl) phenyl) carbohydrazone acyldinitrile,

(2',4' -dimethylbiphenyl-4-yl) carbohydrazone acyldinitrile,

24.4' - (2- (dicyanomethylene) hydrazino) -2-fluorobiphenyl-4-carboxylic acid methyl ester,

(2 '-methyl-4' -nitrobiphenyl-4-yl) carbohydrazone acyldinitrile,

(2, 4-dichlorobiphenyl-4-yl) carbohydrazone acyldinitrile,

(2 '-methoxy-4' -methylbiphenyl-4-yl) carbohydrazone acyldinitrile,

(4- (pyrazin-2-yl) phenyl) carbohydrazone acyldinitrile,

(4- (5- (trifluoromethyl) pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile,

(4- (4,6-dimethylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile,

(4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile,

(4- (pyrimidin-5-yl) phenyl) carbohydrazone acyldinitrile,

(4- (1-methyl-1H-1,2,4-triazol-5-yl) phenyl) carbohydrazone acyldinitrile,

(4- (1-methyl-1H-1,2,4-triazol-3-yl) phenyl) carbohydrazone acyldinitrile,

(4- (1H-pyrazol-1-yl) phenyl) carbohydrazone acyldinitrile,

(4- (4-methyl-1H-pyrazol-1-yl) phenyl) carbohydrazone acyldinitrile,

(2-fluoro-4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile,

(2-fluoro-4- (pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile,

(3-fluoro-4- (pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile,

(3-fluoro-4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile,

(2-methoxy-4- (5-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile,

(2-methoxy-4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile,

(2-methoxy-4- (pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile,

(4- (5-fluoropyrimidin-2-yl) -2-morpholinophenyl) carbohydrazone acyldinitrile,

45. methyl (4- (pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile,

(3- (5-fluoropyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile,

(5- (5-fluoropyrimidin-2-yl) -2-morpholinophenyl) carbohydrazone acyldinitrile,

(4- (benzo [ d ] thiazol-6-yl) phenyl) carbohydrazone acyldinitrile,

(4- (naphthalen-2-yl) phenyl) carbohydrazone acyldinitrile,

(4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) carbohydrazone acyldinitrile,

(4- (imidazo [1,2-a ] pyrimidin-6-yl) phenyl) carbohydrazone acyldinitrile,

(4- (quinoxalin-2-yl) phenyl) carbohydrazone acyldinitrile,

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

(4- (isoquinolin-3-yl) phenyl) carbohydrazone acyldinitrile,

(4- (2-methyl-2H-indazol-4-yl) phenyl) carbohydrazone acyldinitrile,

56.(4- (2-methyl-2H-indazol-5-yl) phenyl) carbohydrazone acyldinitrile,

(4- (2-methyl-2H-indazol-7-yl) phenyl) carbohydrazone acyldinitrile,

58.(4- (1H-indol-5-yl) phenyl) carbohydrazone acyldinitrile,

(4-methoxybenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile,

60. benzo [ d ] thiazol-6-yl carbohydrazone acyldinitrile,

61. benzo [ d ] thiazol-5-yl carbohydrazone acyldinitrile,

(9-ethyl-9H-carbazol-3-yl) carbohydrazone acyldinitrile,

63. (1-methyl-1H-indazol-6-yl) carbohydrazone acyldinitrile,

64. a quinolin-3-yl carbohydrazone acyldinitrile,

65. (2-methyl-2H-indazol-6-yl) carbohydrazone acyldinitrile,

66. (1-methyl-1H-indazol-5-yl) carbohydrazone acyldinitrile,

67. quinoline-6-yl carbohydrazone acyldinitrile,

68. (1-methyl-1H-indol-5-yl) carbohydrazone acyldinitrile,

(1H-indazol-5-yl) carbohydrazone acyldinitrile,

(1H-indazol-6-yl) carbohydrazone acyldinitrile,

71. (1H-indol-5-yl) carbohydrazone acyldinitrile,

(1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile,

73. (3-methyl-1H-indazol-6-yl) carbohydrazone acyldinitrile,

(3-methyl-1H-indazol-5-yl) carbohydrazone acyldinitrile,

(1H-indol-4-yl) carbohydrazone acyldinitrile,

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

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

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

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

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

(2-methyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile,

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

(3-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile,

(4-methoxy-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile,

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

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

(2- (2-hydroxybenzamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

88. (2-acetamidobenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

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

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

(2- (3-hydroxypicolinecarboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

92.(2- (pyrazine-2-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

93.(2- (5-methylpyrazine-2-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

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

95.(2- (2-methylpyrimidine-5-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

96.(2- (4-methylpyrimidine-5-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

(2- (3-methylpyrazine-2-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

98.(2- (6-methylpyrazine-2-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

99.(2- (pyrazine-2-carboxamido) benzo [ d ] thiazol-5-yl) carbohydrazone acyldinitrile,

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

(2-phenylbenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

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

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

(2- (pyridin-3-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

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

(2- (6-fluoropyridin-3-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

(2- (furan-2-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

(2- (thien-2-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

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

(2- (5-methylpyridin-3-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

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

(2- (5-methylpyridin-3-yl) benzo [ d ] thiazol-5-yl) carbohydrazone acyldinitrile,

113. benzo [ d ] thiazol-2-yl carbohydrazone acyldinitrile,

114. (6-fluorobenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile,

115. (6-chlorobenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile,

(6-bromobenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile,

117.(6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile,

118. (4-chlorobenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile,

119 (5-chlorobenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile,

120. (5-bromobenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile,

121. (6-methoxybenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile,

122. (6-ethoxybenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile,

123.(6- (trifluoromethoxy) benzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile,

(6-methylbenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile,

(4-methylbenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile,

126.(4, 6-dimethylbenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile,

127.(5, 6-dimethylbenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile,

128. (6-phenoxybenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile,

129. (6-phenylbenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile,

130.(3- (pyrazine-2-carboxamido) benzo [ d ] isoxazol-5-yl) carbohydrazone acyldinitrile,

(3- (5-methylpyrazine-2-carboxamido) benzo [ d ] isoxazol-5-yl) carbohydrazone acyldinitrile,

132 (3- (3-cyanobenzamido) benzo [ d ] isoxazol-5-yl) carbohydrazone acyldinitrile,

133 (3- (4-methoxybenzamido) benzo [ d ] isoxazol-5-yl) carbohydrazone acyldinitrile,

a (2-oxo-2,3-dihydrobenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

(3-methyl-2-oxo-2,3-dihydrobenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

136. (2-methoxybenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

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

(3-methyl-2-oxo-2,3-dihydrobenzo [ d ] oxazol-6-yl) carbohydrazone acyldinitrile,

(2-oxo-2,3-dihydro-1H-benzo [ d ] imidazol-5-yl) carbohydrazone acyldinitrile,

140.2- (2- (4- (4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) hydrazone) malonic acid diethyl ester,

141.2-imino-N' - (4- (4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) -2- (piperazin-1-yl) acetyl hydrazone,

142.2-imino-N' - (4- (4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) -2-morpholinoacetyl hydrazone acyl nitrile,

143.2- (2- (4- (4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) hydrazone) propionic acid methyl ester,

144.2-cyano-2- (2- (4- (pyrimidin-2-yl) phenyl) hydrazone) acetic acid methyl ester,

145.2-amino-2-oxo-N' - (4- (pyrimidin-2-yl) phenyl) acetyl hydrazone acylnitrile,

146.2-cyano-2- (2- (4- (pyrimidin-2-yl) phenyl) hydrazone) ethyl acetate,

147.2-amino-N' - (4- (pyrimidin-2-yl) phenyl) -2-thioacetyl hydrazone acylnitrile,

148.4-methyl-N' - (4- (pyrimidin-2-yl) phenyl) thiazole-2-carbohydrazone acylnitrile,

149.(4- (5-ethynylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile,

(4' - (dimethylamino) -3-fluorobiphenyl-4-yl) carbohydrazone acyldinitrile,

(4' - (dimethylamino) biphenyl-4-yl) carbohydrazone acyldinitrile,

(4- (6- (dimethylamino) pyridin-3-yl) phenyl) carbohydrazone acyldinitrile,

153.(4- (6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile,

154 (4- (4-methyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile,

155 (4- (5-methyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile,

156.(4- (1-methyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile,

157 (4- (1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile,

158 (4- (1,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile,

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

(3- (difluoromethyl) -2-oxo-2,3-dihydrobenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

161. (2-isopropoxybenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

(3-isopropyl-2-oxo-2,3-dihydrobenzo [ d ] oxazol-6-yl) carbohydrazone acyldinitrile,

(3- (difluoromethyl) -2-oxo-2,3-dihydrobenzo [ d ] oxazol-6-yl) carbohydrazone acyldinitrile,

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

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

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

167 a (2- (methylamino) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

168.(2- (dimethylamino) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile,

169.(4- (6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile,

(4- (1-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile, or

A (4- (1,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile.

12. A process for preparing the compound of claim 1 comprising reacting sodium nitrite, R₂Amino derivative (R) of (A)₂-NH₂) Anda step of reacting in the presence of an acid to form an imine bond.

13. A process for preparing the compound of claim 3, comprising the steps of:

a1) preparation of aryl or heteroaryl, which is unsubstituted or substituted by R₂' or R₂"substituted-substituted aniline derivativesAnd

a2) reacting sodium nitrite, said aniline derivativeWith malononitrile in the presence of an acid to form an imine bond.

14. The method of claim 13, wherein the first and second light sources are selected from the group consisting of,

wherein when R is₁Is C_1-6In the case of an alkyl group, after the step of forming the imine bond, the method further includes a step of alkylation by reaction with an alkyl halide in an organic solvent in the presence of potassium tert-butoxide or sodium hydride.

15. The method of claim 13, wherein the first and second light sources are selected from the group consisting of,

wherein, by aryl or heteroaryl-said aryl or heteroaryl is unsubstituted or substituted by R₂' or R₂Said aniline derivative "substituted-substituted" is unsubstituted or substituted by R by using Pd (II) catalyst₂' boronic acid pinacol ester derivatives of substituted anilines with unsubstituted or substituted R₂"substituted haloaryl or heteroaryl derivatives are synthesized by reaction in the presence of a base.

16. A method of preparing the compound of claim 5, comprising the step of reacting sodium nitrite, a 5 to 14 membered heteroaryl or 5 to 14 membered heterocyclyl derivative containing an amine group, and malononitrile in the presence of an acid to form an imine bond.

17. The method of claim 16, wherein the first and second light sources are selected from the group consisting of,

wherein, when the 5-to 14-membered heteroaryl or 5-to 14-membered heterocyclic group contains a nitrogen other than an amine group which may be bonded thereto, it contains a protecting group at the nitrogen site, and after the step of forming the imine bond, the method further comprises a step of removing the protecting group.

18. The method of claim 16, wherein the first and second light sources are selected from the group consisting of,

wherein the 5-to 14-membered heteroaryl or 5-to 14-membered heterocyclyl is prepared by reduction of a nitrophenyl derivative comprising a nitro group instead of an amine group in the same backbone.

19. A process for preparing the compound of claim 7, comprising the steps of:

make R₂"' with carboxylic acids or anhydrides thereof(here, Y is an unprotected or protected amine group or nitro group) to form an amide bond; and is

Reacting sodium nitrite, malononitrile with a compound comprising R linked to the carboxamide group obtained in the preceding step₂The heterocyclic derivative of ""' reacts in the presence of an acid to form an imine bond.

20. The method of claim 19, wherein the first and second portions are selected from the group consisting of,

wherein, when Y is a protected amine group or nitro group, the method further comprises a step of converting the protected amine group or nitro group into an amine group before the step of forming an imine group.

21. A process for preparing the compound of claim 9, comprising the steps of:

sodium nitrite, R₂Amino derivative (R) of (A)₂-NH₂Andreacting to form an imine bond; and is

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

22. A composition for inhibiting tau protein aggregation comprising as an active ingredient a compound according to any one of claims 1 to 11.

23. A composition for inhibiting hyperphosphorylation of tau protein comprising as an active ingredient a compound according to any one of claims 1 to 11.

24. A pharmaceutical composition for preventing or treating a disease caused by tau protein aggregation or hyperphosphorylation, comprising the compound according to any one of claims 1 to 11 as an active ingredient.

25. The pharmaceutical composition according to claim 24, wherein the compound of formula (I),

wherein the disease caused by tau protein aggregation or hyperphosphorylation is selected from the group consisting of: alzheimer's disease, Parkinson's disease, vascular dementia, acute stroke, trauma, cerebrovascular disease, cerebrospinal trauma, spinal cord trauma, peripheral neuropathy, retinopathy, glaucoma and tauopathies.

26. The pharmaceutical composition according to claim 25, wherein the pharmaceutically acceptable salt of the compound,

wherein the tauopathy is selected from the group consisting of: non-limiting examples of the tauopathies may include: chronic Traumatic Encephalopathy (CTE), primary age-related tauopathies, progressive supranuclear palsy, corticobasal degeneration, pick's disease, Argentophilic Granulosis (AGD), frontotemporal dementia (FTD), parkinson's disease associated with chromosome 17, muscular dystrophy (guam parkinsonism-dementia complex of guam), ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinson's disease, subacute sclerosing panencephalitis, plumbaginous encephalopathy, tuberous sclerosis, pantothenic acid kinase-related neurodegeneration, lipofuscinosis, and traumatic brain injury.

Technical Field

The present invention relates to novel hydrazone derivatives in which the terminal amine group is substituted with an aryl group or a heteroaryl group, and uses thereof.

Background

Tau protein (Tau protein) is a microtubule-associated protein (MAP) that is mainly expressed in axons of nerve cells, has a molecular weight of 50,000 to 70,000, functions to stabilize microtubules, and exhibits molecular diversity through phosphorylation. In humans, tau proteins form six isoforms by insertion of 29 or 58 amino acid residues at the N-terminus and alternative splicing of mRNA of 3 or 4 repeats, termed microtubule binding domains, at the C-terminus.

In healthy nerves, tau protein stabilizes microtubules by promoting axon growth and nerve cell polarization. When pathological hyperphosphorylation occurs, tau protein separates from microtubules, resulting in insoluble aggregation. Furthermore, a structural scaffold has been proposed that induces tau protein aggregation, and there is evidence that insoluble filaments are formed from 10 soluble monomers and these filaments associate into a high dimensional structure known as neurofibrillary tangles (NFTs). Human full-length tau protein contains a microtubule binding domain consisting of four repeats of a conserved sequence. In these repeats, positively charged residues play an important role in binding to highly negatively charged microtubules (20-30 electrons per α β -tubulin dimer). The binding affinity for tau microtubules is also actively regulated by phosphorylation of tau proteins, and this phosphorylation leads to dynamic rearrangement of the microtubule network. When tau proteins are abnormally hyperphosphorylated, this equilibrium of dynamic rearrangements is broken and the affinity for microtubules decreases rapidly.

Hyperphosphorylation and/or aggregation of tau proteins leads to abnormal accumulation of these tau proteins in nerve cells, which is indicated as a cause of various neurodegenerative diseases and the like. tau aggregates are found primarily in the soma and dendrites of nerve cells, and these tau aggregates are called neurofibrillary tangles (NFTs) and neuropil filaments. Examination of the microstructure of neurofibrillary tangles (NFT) indicates that this microstructure consists of Paired Helical Filaments (PHFs) in which tau proteins are tangled together like thin threads and aggregated and hyperphosphorylated, unlike normal tau proteins. Abnormal tau aggregation also occurs in tauopathies. In this case, although it is not known precisely what role tau aggregation plays in the development of tauopathies, this tau aggregation phenomenon appears to be similar to that common in general neurodegenerative diseases.

Thus, although hyperphosphorylation and/or aggregation of tau is known to lead to various neurodegenerative diseases, including alzheimer's disease and tauopathies, the specific mechanisms of how these abnormal tau species lead to changes in signaling pathways and induce neurotoxicity have not been validated, and there is no effective therapeutic approach or agent to treat these diseases.

Disclosure of Invention

Technical problem

The present inventors have made many efforts to find novel small molecule compounds capable of inhibiting aggregation and/or hyperphosphorylation of tau proteins. As a result, they found that a series of hydrazone derivatives in which the terminal amine group is substituted with an aryl group or a heteroaryl group effectively inhibit the aggregation of tau protein and do not exhibit cytotoxicity at effective concentrations. Based on this finding, the present invention has been completed.

Technical scheme

A first aspect of the present invention provides a compound represented by the following formula 1:

[ formula 1]

In the above-mentioned formula 1, the,

R₁is hydrogen or C_1-6An alkyl group;

R₂is unsubstituted or substituted C_6-14Aryl, 5-to 14-membered heteroaryl, or 5-to 14-membered heterocyclyl;

R₆-R₈i) Are both hydrogen, ii) form a triple bond with one N, iii) R₆And R₇Form a double bond with NH, O or S to form an imine, oxo or thioxo, respectively, and R₈Is C_1-6Alkoxy, amino, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, or 5-to 14-membered heterocyclyl, or iv) R₆-R₈(ii) the heteroatom O, N or S is connected by a single or double bond and comprises carbon and a heteroatom attached to carbon to form an unsubstituted or substituted 5-to 14-membered heteroaryl or heterocyclyl group;

wherein said heteroaryl or said heterocyclyl comprises at least one of O, N and S,

the substituted aryl, the substituted heteroaryl, or the substituted heterocyclyl may comprise: c_1-6An alkyl group; c_1-6An alkoxy group; halogen; c_1-6A perfluoroalkyl group; c_1-6A perfluoroalkoxy group; c_1-6A haloalkyl group; carbamoyl (carbamoyl); carboxamido (carboxamido); c_6-10An aryloxy group; unsubstituted C_6-14Aryl, 5-to 14-membered heteroaryl, or 5-to 14-membered heterocyclyl; or is selected from C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, C_1-6Alkoxycarbonyl radical, C_1-6Perfluoroalkyl radical, C_1-6Perfluoroalkoxy, C_1-6Haloalkyl, amino, C_1-6Alkylamino, di (C)_1-6Alkyl) amino and C_1-6C substituted by at least one substituent in the group consisting of alkoxycarbonyl_6-14Aryl, 5-to 14-membered heteroaryl, or 5-to 14-membered heterocyclyl, and

A second aspect of the invention provides a process for preparing a compound of the first aspect comprising contacting sodium nitrite, R₂Amino derivative (R) of (A)₂-NH₂) Anda step of reacting in the presence of an acid to form an imine bond.

A third aspect of the present invention provides a process for the preparation of a compound according to the first aspect, comprising the steps of:

a1) preparation of substituted or unsubstituted₂' or R₂"substituted aryl-or heteroaryl-substituted aniline derivatives

a2) Reacting sodium nitrite, said aniline derivativeWith malononitrile in the presence of an acid to form an imine bond.

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

A fifth aspect of the present invention provides a process for the preparation of a compound according to the first aspect, comprising the steps of:

make R₂"' with carboxylic acids or anhydrides thereof(here, Y is an unprotected or protected amine group or nitro group) to form an amide bond; and

linking sodium nitrite, R comprising carboxamide group obtained in previous step₂The heterocyclic derivative of "", reacts with malononitrile in the presence of an acid to form an imine bond.

A sixth aspect of the present invention provides a process for the preparation of a compound according to the first aspect, comprising the steps of:

sodium nitrite, R₂Amino derivative (R) of (A)₂-NH₂) Andreacting to form an imine bond; and is

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

The seventh aspect of the present invention provides a composition for inhibiting tau protein aggregation comprising as an active ingredient a compound according to the present invention.

An eighth aspect of the invention provides a composition for inhibiting hyperphosphorylation of tau protein, comprising as an active ingredient a compound according to the invention.

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

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

Advantageous effects

According to the present invention, since the novel hydrazone derivative in which the terminal amine group is substituted with an aryl group or a heteroaryl group is effective in inhibiting aggregation and/or hyperphosphorylation of tau protein, such hydrazone derivative can be effectively used for the prevention or treatment of diseases caused thereby, such as alzheimer's disease and various tauopathies.

Detailed Description

A first aspect of the present invention provides a compound represented by the following formula 1:

[ formula 1]

In the above-mentioned formula 1, the,

R₁is hydrogen or C_1-6An alkyl group;

R₂is unsubstituted or substituted C_6-14Aryl, 5-to 14-membered heteroaryl, or 5-to 14-membered heterocyclyl;

wherein said heteroaryl or said heterocyclyl comprises at least one of O, N and S,

the substituted aryl, the substituted heteroaryl, or the substituted heterocyclyl may comprise: c_1-6An alkyl group; c_1-6An alkoxy group; halogen; c_1-6A perfluoroalkyl group; c_1-6A perfluoroalkoxy group; c_1-6A haloalkyl group; a carbamoyl group; a carboxamide group; c_6-10An aryloxy group; unsubstituted C_6-14Aryl, 5-to 14-membered heteroaryl or 5-to 14-membered heterocyclyl; or is selected from C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, C_1-6Alkoxycarbonyl radical, C_1-6Perfluoroalkyl radical, C_1-6Perfluoroalkoxy, C_1-6Haloalkyl, amino, C_1-6Alkylamino, di (C)_1-6Alkyl) amino and C_1-6C substituted by at least one substituent in the group consisting of alkoxycarbonyl_6-14Aryl, 5-to 14-membered heteroaryl, or 5-to 14-membered heterocyclyl, and

the carbamoyl and carboxamido groups may be selected from the group consisting of C_1-6Alkyl, and unsubstituted or substituted by C_1-6Alkoxy, hydroxy, cyano or C_1-6Of the group consisting of alkyl-substituted aryl and heteroaryl groupsAt least one substitution.

Specifically, among the compounds of the present invention,

R₁is hydrogen or methyl;

R₃-R₅together with the C to which it is attached form-C.ident.N, -CH₃，-CO₂Me，-CO₂Et，-CONH₂，-CSNH₂，(Here, R is₃' is C_1-6Alkyl groups); and

R₆-R₈formation of-C.ident.N, -CH₃，-CO₂Me，-CO₂Et，-CONH₂，-CSNH₂， (Here, R is₃' is C_1-6Alkyl groups);

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

the substituted phenyl, benzothiazolyl, carbazolyl, indazolyl, quinolyl, indolyl, pyrrolopyridyl, benzisoxazolyl, dihydrobenzothiazolyl, oxodihydrobenzothiazolyl, benzoxazolyl, oxodihydrobenzoxazolyl, benzimidazolyl, or oxodihydrobenzimidazolyl group may comprise methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, fluorine, chlorine, bromine, morpholinyl, carbamoyl, carboxamido, phenoxy, or phenyl, piperidinyl, thiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazolyl, or oxodihydrobenzimidazolyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of methyl, ethyl, ethynyl, methoxy, fluorine, chlorine, bromine, nitro, dimethylamino, methoxycarbonyl, ethoxycarbonyl, and trifluoromethyl, Pyrazolyl, benzothiazolyl, naphthyl, pyrazolopyrimidinyl, imidazopyrimidinyl, quinoxalinyl, imidazopyridinyl, isoquinolinyl, indazolyl, indazolylindolyl, furyl, thienyl, oxotetrahydropyridazinyl or oxodihydropyridazinyl, and

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

[ formula 2]

In the above-mentioned formula 2, the first,

R₁is hydrogen or C_1-6An alkyl group;

R₂' and R₂Each independently is hydrogen, C_1-6Alkyl radical, C_1-6Alkoxy, halogen, C_1-6Perfluoroalkyl radical, C_1-6Perfluoroalkoxy, C_1-6Haloalkyl, unsubstituted or substituted by C_1-6Carbamoyl substituted by alkyl, or unsubstituted or selected from C_1-6Alkyl radical, C_1-6Alkoxy, halogen, nitro, C_1-6Alkoxycarbonyl radical, C_1-6Perfluoroalkyl radical, C_1-6Perfluoroalkoxy, C_1-6Haloalkyl, amino, C_1-6Alkylamino, di (C)_1-6Alkyl) amino, C_1-6Alkoxycarbonyl and C_6-10C substituted by at least one of aryloxy_6-14Aryl, 5-to 14-membered heteroaryl, or 5-to 14-membered heterocyclyl.

Specifically, in the above formula 2,

R₁is hydrogen or methyl;

R₂' is hydrogen, fluoro, methoxy or morpholinyl; and is

For example, the compound of the present invention may be represented by the following formula 3:

[ formula 3]

In the above-mentioned formula 3, the,

R₁is hydrogen or C_1-6An alkyl group;

cy is unsubstituted or substituted 5-to 14-membered heteroaryl or 5-to 14-membered heterocyclyl: and is

Specifically, in the above formula 3,

R₁is hydrogen;

cy is unsubstituted or substituted benzothiazolyl, carbazolyl, indazolyl, quinolinyl, indolyl, pyrrolopyridinyl, oxodihydrobenzothiazolyl, oxodihydrobenzoxazolyl, or oxodihydrobenzimidazolyl; and is

For example, the compound of the present invention may be represented by the following formula 4:

[ formula 4]

In the above-mentioned formula 4, the,

X₁-X₃each selected from C, N, O and S, different from each other, and each linked to a carboxamide group through a C-site;

R₁is hydrogen or C_1-6An alkyl group; and is

R₂"' is C_1-6Alkyl, unsubstituted or selected from C_1-6Alkoxy, hydroxy, cyano and C_1-6At least one substituted aryl or heteroaryl group from the group consisting of alkyl groups.

Specifically, in the above formula 4,

X₁-X₃n, C and S or O, N and C in that order, and is linked to the carboxamide group via the C site;

R₁is hydrogen; and is

R₂"' is methyl, or unsubstituted or substitutedAt least one substituted phenyl, pyridyl, pyrazinyl or pyrimidinyl selected from the group consisting of methoxy, hydroxy, cyano and methyl.

For example, the compound of the present invention may be represented by the following formula 5:

[ formula 5]

In the above-mentioned formula 5, the,

R₁is hydrogen or C_1-6An alkyl group;

R₂"' is unsubstituted or substituted by C_1-6An alkyl-substituted 5-to 14-membered heteroaryl or 5-to 14-membered heterocyclyl; and is

Specifically, in the above formula 5,

R₁is hydrogen;

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

R₃-R₅together with the C to which it is attached form-C.ident.N, -CH₃，-CO₂Me，-CO₂Et，-CONH₂，-CSNH₂，(Here, R is₃' is methyl).

More specifically, the compound may be

(4- (pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile ((4- (pyrimidin-2-yl) phenyl) carbohydrazolyl dicaryide),

(4- (5-fluoropyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile ((4- (5-fluoropyrimidin-2-yl) phenyl) carbohydrazolyl dicaryide),

(4- (5-fluoro-4-methylpyrimidin-2-yl) phenyl) carbohydrazonoyl dinitrile ((4- (5-fluoro-4-methylpyrimidin-2-yl) phenyl) carbohydrazonoyl dicarbamide),

4.(4- (5-methylpyrimidin-2-yl) phenyl) carbohydrazonoyl dinitrile ((4- (5-methylpyrimidin-2-yl) phenyl) carbohydrazonoyl dicarbamide),

(4- (5-ethylpyrimidin-2-yl) phenyl) carbohydrazonoyl dinitrile ((4- (5-ethylpyrimidin-2-yl) phenyl) carbohydrazonoyl dicarbamide),

(4- (4-ethylpyrimidin-2-yl) phenyl) carbohydrazonoyl dinitrile ((4- (4-ethylpyrimidin-2-yl) phenyl) carbohydrazonoyl dicarbamide),

(4- (5-chloropyrimidin-2-yl) carbohydrazone diacyldinitrile ((4- (5-chloropyrimidin-2-yl) carbohydrazolyl diacylcyanide),

(4- (5-methoxypyrimidin-2-yl) -phenyl) carbohydrazone acyldinitrile ((4- (5-methoxypyrimidin-2-yl) -phenyl) carbohydrazolyl dicaryide),

(4- (2,4-dimethylthiazol-5-yl) phenyl) carbohydrazonoyl dinitrile ((4- (2,4-dimethylthiazol-5-yl) phenyl) carbohydrazonoyl dicarbamide),

(4- (pyridin-2-yl) phenyl) carbohydrazone acyldinitrile (4- (pyridin-2-yl) phenyl) carbohydrazolyl dicaryide),

(4- (2-methylthiazol-5-yl) phenyl) carbohydrazonoyl diacyl cyanide ((4- (2-methylthiazol-5-yl) phenyl) carbohydrazonoyl diacyl cyanide),

(4- (4-methylthiazol-5-yl) phenyl) carbohydrazonoyl diacyl cyanide ((4- (4-methylthiazol-5-yl) phenyl) carbohydrazonoyl diacyl cyanide),

13. biphenyl-4-yl carbohydrazone acyldinitrile (biphenyl-4-yl carbohydryl dicaryide),

(4 '-methylbiphenyl-4-yl) carbohydrazone dinitrile ((4' -methylbiphenyl-4-yl) carbohydrazoloyl dicaryide),

(4- (pyridin-3-yl) phenyl) carbohydrazone acyldinitrile ((4- (pyridin-3-yl) phenyl) carbohydrazolyl dicaryide),

(4- (pyridin-4-yl) phenyl) carbohydrazone acyldinitrile (4- (pyridin-4-yl) phenyl) carbohydrazolyl dicaryide),

(4- (pyridazin-3-yl) phenyl) carbohydrazonoyl dinitrile, (4- (pyridazin-3-yl) phenyl) carbohydrazonoyl dicarbamide),

(4- (5-methylthiazol-2-yl) phenyl) carbohydrazonoyl diacyl cyanide ((4- (5-methylthiazol-2-yl) phenyl) carbohydrazonoyl diacyl cyanide),

19.2- (4- (2- (dicyanomethylene) hydrazino) phenyl) thiazole-5-carboxylic acid ethyl ester (ethyl2- (4- (2- (dicyanomethylene) hydrazinyl) phenyl) thiazole-5-carboxylate),

(4- (thiazol-5-yl) phenyl) carbohydrazonoyl diacyl nitrile ((4- (thiazole-5-yl) phenyl) carbohydrazonoyl diacyl cyanide),

(3 '-fluoro-4' -nitrobiphenyl-4-yl) carbohydrazonoacyldinitrile ((3 '-fluoro-4' -nitrobenzoyl-4-yl) carbohydrazoloyl dichloride),

(4- (6-fluoropyridin-3-yl) phenyl) carbohydrazone acyldinitrile ((4- (6-fluoropyridin-3-yl) phenyl) carbohydrazolyl dicaryide),

(2',4' -dimethylbiphenyl-4-yl) carbohydrazone diacyl nitrile ((2',4' -dimethylbishenyl-4-yl) carbohydrazonyl diacyl nitrile),

24.4'- (2- (dicyanomethylene) hydrazino) -2-fluorobiphenyl-4-carboxylic acid methyl ester (methyl 4' - (2- (dicyanomethylene) hydrazinyl) -2-fluoroobiphenyl-4-carboxylate),

(2 '-methyl-4' -nitrobiphenyl-4-yl) carbohydrazonoacyldinitrile ((2 '-methyl-4' -nitrobenzyl-4-yl) carbohydrazoloyl dicaryide),

(2',4' -dichlorobiphenyl-4-yl) carbohydrazone diacyldinitrile ((2',4' -dichlorobiphenol-4-yl) carbohydranoyl dicaryanide),

(2 '-methoxy-4' -methylbiphenyl-4-yl) carbohydrazone acyldinitrile ((2 '-methoxy-4' -methylbiphenyl-4-yl) carbohydrazolyl dicaryide),

(4- (pyrazin-2-yl) phenyl) carbohydrazone diacyldinitrile ((4- (pyrazin-2-yl) phenyl) carbohydrazolyl diacylcyanide),

(4- (5- (trifluoromethyl) pyrimidin-2-yl) phenyl) carbohydrazonoacyldinitrile ((4- (5- (trifluoromethyl) pyrimidin-2-yl) phenyl) carbohydrazonoyl dicaryide),

(4- (4,6-dimethylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile ((4- (4,6-dimethylpyrimidin-2-yl) phenyl) carbohydrazolyl dicaride),

(4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazonoyl dinitrile (4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazonoyl dicarbamide),

(4- (pyrimidin-5-yl) phenyl) carbohydrazone acyldinitrile ((4- (pyrimidin-5-yl) phenyl) carbohydrazolyl dicaryide),

(4- (1-methyl-1H-1,2,4-triazol-5-yl) phenyl) carbohydrazone acyldinitrile ((4- (1-methyl-1H-1,2,4-triazol-5-yl) phenyl) carbohydranoyl dicaryide),

(4- (1-methyl-1H-1,2,4-triazol-3-yl) phenyl) carbohydrazone acyldinitrile ((4- (1-methyl-1H-1,2,4-triazol-3-yl) phenyl) carbohydranoyl dinitride),

(4- (1H-pyrazol-1-yl) phenyl) carbohydrazonoacyldinitrile ((4- (1H-pyrazol-1-yl) phenyl) carbohydrazonoyl dicarbamide),

(4- (4-methyl-1H-pyrazol-1-yl) phenyl) carbohydrazonoyl dinitrile ((4- (4-methyl-1H-pyrazol-1-yl) phenyl) carbohydrazonoyl dicarbamide),

(2-fluoro-4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazonoyl dinitrile ((2-fluoro-4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazonoyl dicarbamide),

(2-fluoro-4- (pyrimidin-2-yl) phenyl) carbohydrazonoacyldinitrile ((2-fluoro-4- (pyrimidin-2-yl) phenyl) carbohydrazoloyl dicarbamide),

(3-fluoro-4- (pyrimidin-2-yl) phenyl) carbohydrazonoyl dinitrile ((3-fluoro-4- (pyrimidin-2-yl) phenyl) carbohydrazoloyl dinitride),

(3-fluoro-4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazonoyl dinitrile ((3-fluoro-4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazonoyl dicarbamide),

(2-methoxy-4- (5-methylpyrimidin-2-yl) phenyl) carbohydrazonoyl dinitrile ((2-methoxy-4- (5-methylpyrimidin-2-yl) phenyl) carbohydrazonoyl dicarbamide),

(2-methoxy-4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazonoyl dinitrile ((2-methoxy-4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazonoyl dicarbamide),

(2-methoxy-4- (pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile ((2-methoxy-4- (pyrimidin-2-yl) phenyl) carbohydrazolyl dicaryide),

(4- (5-fluoropyrimidin-2-yl) -2-morpholinophenyl) carbohydrazonoyl dinitrile ((4- (5-fluoropyrimidin-2-yl) -2-morpholinophenyl) carbohydrazonoyl dicarbamide),

45. methyl (4- (pyrimidin-2-yl) phenyl) carbohydrazonoyl dinitrile (methyl (4- (pyrimidin-2-yl) phenyl) carbohydrazonoyl dicarbamide),

(3- (5-fluoropyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile ((3- (5-fluoropyrimidin-2-yl) phenyl) carbohydrazolyl dicaryide),

(5- (5-fluoropyrimidin-2-yl) -2-morpholinophenyl) carbohydrazonoyl dinitrile ((5- (5-fluoropyrimidin-2-yl) -2-morpholinophenyl) carbohydrazonoyl dicarbamide),

(4- (benzo [ d ] thiazol-6-yl) phenyl) carbohydrazonoyl diacyl cyanide ((4- (benzo [ d ] thiazol-6-yl) phenyl) carbohydragenoyl diacyl cyanide),

(4- (naphthalen-2-yl) phenyl) carbohydrazonoyl dinitrile ((4- (naphthalen-2-yl) phenyl) carbohydrazonoyl dicaryanide),

50.(4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) carbohydrazonoyl dinitrile ((4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) carbohydrazonoyl dicarbamide),

(4- (imidazo [1,2-a ] pyrimidin-6-yl) phenyl) carbohydrazonoyl dinitrile ((4- (imidazo [1,2-a ] pyrimidin-6-yl) phenyl) carbohydrazonoyl dicarbamide),

(4- (quinoxalin-2-yl) phenyl) carbohydrazone diacyldinitrile ((4- (quinoxalin-2-yl) phenyl) carbohydrazolyl dicaryanide),

53.(4- (imidazo [1,2-a ] pyridin-6-yl) phenyl) carbohydrazone acyldinitrile ((4- (imidazo [1,2-a ] pyridine-6-yl) phenyl) carbohydranoyl dicaryanide),

(4- (isoquinolin-3-yl) phenyl) carbohydrazone diacyldinitrile ((4- (isoquinolin-3-yl) phenyl) carbohydranoyl dicaryanide),

(4- (2-methyl-2H-indazol-4-yl) phenyl) carbohydrazonoyl diacylcyanide ((4- (2-methyl-2H-indazol-4-yl) phenyl) carbohydrazonoyl diacylcyanide),

56.(4- (2-methyl-2H-indazol-5-yl) phenyl) carbohydrazone acyldinitrile ((4- (2-methyl-2H-indazol-5-yl) phenyl) carbohydrazolyl dicaryide),

57.(4- (2-methyl-2H-indazol-7-yl) phenyl) carbohydrazonoyl diacyl nitrile ((4- (2-methyl-2H-indazol-7-yl) phenyl) carbohydrazonoyl diacyl nitrile),

58.(4- (1H-indol-5-yl) phenyl) carbohydrazone acyldinitrile ((4- (1H-indol-5-yl) phenyl) carbohydrazolyl dicaryanide),

(4-methoxybenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile ((4-methoxybenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile),

60. benzo [ d ] thiazol-6-ylcarbohydrazone acyldinitrile, 61, benzo [ d ] thiazol-5-ylcarbohydrazone acyldinitrile,

(9-Ethyl-9H-carbazol-3-yl) carbohydrazone acyldinitrile ((9-ethyl-9H-carbazol-3-yl) carbohydrazolyl dicaryide),

63. (1-methyl-1H-indazol-6-yl) carbohydrazone acyldinitrile ((1-methyl-1H-indazol-6-yl) carbohydranoyl dicaryanide),

64. quinolin-3-yl carbohydrazone acyldinitrile (quinolin-3-yl carbohydroazolyl dicaryide),

65. (2-methyl-2H-indazol-6-yl) carbohydrazone acyldinitrile ((2-methyl-2H-indazol-6-yl) carbohydranoyl dicaryanide),

66. (1-methyl-1H-indazol-5-yl) carbohydrazone acyldinitrile ((1-methyl-1H-indazol-5-yl) carbohydranoyl dicaryanide),

67. quinolin-6-yl carbohydrazone acyldinitrile (quinoline-6-ylcarbohydrazonyl dicaryide),

68. (1-methyl-1H-indol-5-yl) carbohydrazone acyldinitrile ((1-methyl-1H-indol-5-yl) carbohydrazolyl dicaryanide),

(1H-indazol-5-yl) carbohydrazonoyl dinitrile ((1H-indazol-5-yl) carbohydrazonoyl dicaryanide),

(1H-indazol-6-yl) carbohydrazonoyl dinitrile ((1H-indazol-6-yl) carbohydrazonoyl dicaryanide),

71. (1H-indol-5-yl) carbohydrazonoyl dinitrile ((1H-indol-5-yl) carbohydrazonoyl dicaryanide),

(1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile (1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazolyl dicaryide),

73. (3-methyl-1H-indazol-6-yl) carbohydrazone acyldinitrile ((3-methyl-1H-indazol-6-yl) carbohydranoyl dicaryanide),

(3-methyl-1H-indazol-5-yl) carbohydrazone acyldinitrile ((3-methyl-1H-indazol-5-yl) carbohydrazolyl dicaryide),

(1H-indol-4-yl) carbohydrazonoyl dinitrile ((1H-indol-4-yl) carbohydrazonoyl dicaryide),

76. (1-methyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile ((1-methyl-1H-pyrolo [2,3-b ] pyridin-5-yl) carbohydrazoloyl dinitride),

77. (1-propyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile ((1-propyl-1H-pyrolo [2,3-b ] pyridin-5-yl) carbohydrazoloyl dinitride),

78. (1-isopropyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile ((1-isoproyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbonohydrazonyl dinitride),

79. (1-ethyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile ((1-ethyl-1H-pyrolo [2,3-b ] pyridin-5-yl) carbohydrazoloyl dinitride),

80.(1- (2,2,2-trifluoroethyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile ((1- (2,2,2-trifluoroethyl) -1H-pyrolo [2,3-b ] pyridin-5-yl) carbohydrazoloyl dinitride),

(2-methyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile ((2-methyl-1H-pyrolo [2,3-b ] pyridine-5-yl) carbohydranoyl dicaryanide),

82. (3-methyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile ((3-methyl-1H-pyrolo [2,3-b ] pyridin-5-yl) carbohydranoyl dicaryanide),

(3-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile ((3-chloro-1H-pyrolo [2,3-b ] pyridine-5-yl) carbohydranoyl dicaryanide),

(4-methoxy-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile ((4-methoxy-1H-pyrolo [2,3-b ] pyridin-5-yl) carbohydranoyl dicaryanide),

85.(2- (dimethylcarbamoyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile ((2- (dimethylcarbazoyl) -1H-pyro [2,3-b ] pyridine-5-yl) carbohydrazoloyl dinitride),

86.(2- (4-methoxybenzamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile ((2- (4-methoxybenzamido) benzo [ d ] thiazol-6-yl) carbohydranoyl dicaryanide),

(2- (2-hydroxybenzamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile ((2- (2-hydroxybenzamido) benzo [ d ] thiazol-6-yl) carbohydroazoyl dicaryanide),

88. (2-acetamidobenzo [ d ] thiazol-6-yl) carbohydrazonoyl diacyl nitrile ((2-acetamidobenzo [ d ] thiazol-6-yl) carbohydrazoloyl diacyl cyanide),

89.(2- (3-cyanobenzamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile ((2- (3-cyanobenzamid) benzo [ d ] thiazol-6-yl) carbohydrazolyl dicaryanide),

90.(2- (5-methylnicotinamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile ((2- (5-methylnicotinamido) benzo [ d ] thiazol-6-yl) carbohydrazolyl dicaryanide),

91.(2- (3-hydroxypicolinamido) benzo [ d ] thiazol-6-yl) carbohydrazonoacyldinitrile ((2- (3-hydroxypicolinonamide) benzo [ d ] thiazol-6-yl) carbohydrazonoyl dicaryanide),

92.(2- (pyrazine-2-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile ((2- (pyrazine-2-carboxamido) benzo [ d ] thiazol-6-yl) carbohydranoyl dicaryanide),

93.(2- (5-methylpyrazine-2-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile ((2- (5-methylpyrazine-2-carboxamido) benzo [ d ] thiazole-6-yl) carbohydroazonyl dicaryanide),

94.(2- (pyrimidine-5-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile ((2- (pyrimidine-5-carboxamido) benzo [ d ] thiazol-6-yl) carbohydranoyl dicaryanide),

95.(2- (2-methylpyrimidine-5-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile ((2- (2-methylpyrimidine-5-carboxamido) benzo [ d ] thiazole-6-yl) carbohydroazonyl dicaryanide),

96.(2- (4-methylpyrimidine-5-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile ((2- (4-methylpyrimidine-5-carboxamido) benzo [ d ] thiazole-6-yl) carbohydroazonyl dicaryanide),

97.(2- (3-methylpyrazine-2-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile ((2- (3-methylpyrazine-2-carboxamido) benzo [ d ] thiazole-6-yl) carbohydrazone dicaryanide),

98.(2- (6-methylpyrazine-2-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile ((2- (6-methylpyrazine-2-carboxamido) benzo [ d ] thiazole-6-yl) carbohydroazonyl dicaryanide),

99.(2- (pyrazine-2-carboxamido) benzo [ d ] thiazol-5-yl) carbohydrazone acyldinitrile ((2- (pyrazine-2-carboxamido) benzo [ d ] thiazol-5-yl) carbohydranoyl dicaryanide),

100.(2- (5-methylpyrazine-2-carboxamido) benzo [ d ] thiazol-5-yl) carbohydrazone acyldinitrile ((2- (5-methylpyrazine-2-carboxamido) benzo [ d ] thiazole-5-yl) carbohydrazone dicaryanide),

101. (2-phenylbenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile ((2-phenylbenzo [ d ] thiazol-6-yl) carbohydrazolyl dicaryide),

102.(2- (4-fluorophenyl) benzo [ d ] thiazol-6-yl) carbohydrazonoyl diacyl cyanide ((2- (4-fluorophenyl) benzo [ d ] thiazol-6-yl) carbohydrazonoyl diacyl cyanide),

103.(2- (4- (dimethylamino) phenyl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile ((2- (4- (dimethylamino) phenyl) benzo [ d ] thiazol-6-yl) carbonohydrazonyl dicaryide),

104 ((2- (pyridin-3-yl) benzo [ d ] thiazol-6-yl) carbohydrazonyl diacyl cyanide),

105.(2- (6-methylpyridin-3-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile ((2- (6-methylpyridin-3-yl) benzo [ d ] thiazole-6-yl) carbonohydrazonyl dicaryide),

106.(2- (6-fluoropyridin-3-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile ((2- (6-fluoropyridin-3-yl) benzo [ d ] thiazole-6-yl) carbohydranoyl dicaryanide),

107.(2- (furan-2-yl) benzo [ d ] thiazol-6-yl) carbohydrazonoyl diacyl nitrile ((2- (furan-2-yl) benzo [ d ] thiazole-6-yl) carbohydrazonoyl diacyl nitrile),

(2- (thien-2-yl) benzo [ d ] thiazol-6-yl) carbohydrazonoyl diacyl nitrile ((2- (thiophen-2-yl) benzo [ d ] thiazol-6-yl) carbohydrazonoyl diacyl nitrile),

109.(2- (5-fluoropyridin-3-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile ((2- (5-fluoropyridin-3-yl) benzo [ d ] thiazole-6-yl) carbohydranoyl dicaryanide),

110.(2- (5-methylpyridin-3-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile ((2- (5-methylpyridin-3-yl) benzo [ d ] thiazole-6-yl) carbonohydrazonyl dicaryide),

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

(2- (5-methylpyridin-3-yl) benzo [ d ] thiazol-5-yl) carbohydrazone acyldinitrile ((2- (5-methylpyridin-3-yl) benzo [ d ] thiazole-5-yl) carbonohydrazonyl dicaryide),

113. benzo [ d ] thiazol-2-ylcarbohydrazone diacyl nitrile (benzo [ d ] thiazole-2-ylcarbohydrazonyl dicaryide),

(6-fluorobenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile ((6-fluorobenzol [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile),

115. (6-chlorobenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile ((6-chlorobenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile),

(6-bromobenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile ((6-bromobenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile),

117.(6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile ((6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile),

118. (4-chlorobenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile ((4-chlorobenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile),

119. (5-chlorobenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile ((5-chlorobenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile),

120. (5-bromobenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile ((5-bromobenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile),

(6-methoxybenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile ((6-methoxybenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile),

122. (6-ethoxybenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile ((6-ethoxybenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile),

123.(6- (trifluoromethoxy) benzo [ d ] thiazol-2-yl) carbohydrazonoacyldinitrile ((6- (trifluoromethloxy) benzo [ d ] thiazol-2-yl) carbohydrazonoyl dicaryide),

(6-methylbenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile ((6-methylbenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile),

125 ((4-methylbenzo [ d ] thiazol-2-yl) carbohydrazonoyl dinitrile),

126.(4, 6-dimethylbenzo [ d ] thiazol-2-yl) carbohydrazonoyl dinitrile ((4, 6-dimethylbenzol [ d ] thiazol-2-yl) carbohydrazonoyl dicarbamide),

127.(5, 6-dimethylbenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile ((5,6-dimethylbenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile),

128. (6-phenoxybenzo [ d ] thiazol-2-yl) carbohydrazonoyl diacyl nitrile ((6-phenoxybenzo [ d ] thiazol-2-yl) carbonohydrazonoyl diacyl nitrile),

129. (6-phenylbenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile ((6-phenylbenzo [ d ] thiazol-2-yl) carbohydrazolyl dicaryide),

130.(3- (pyrazine-2-carboxamido) benzo [ d ] isoxazol-5-yl) carbohydrazone acyldinitrile ((3- (pyrazine-2-carboxamido) benzo [ d ] isoxazol-5-yl) carbohydrazone diacylcyanide),

131.(3- (5-methylpyrazine-2-carboxamido) benzo [ d ] isoxazol-5-yl) carbohydrazone acyldinitrile ((3- (5-methylpyrazine-2-carboxamido) benzo [ d ] isoxazol-5-yl) carbohydrazolyl dicaryide),

132.(3- (3-cyanobenzamido) benzo [ d ] isoxazol-5-yl) carbohydrazone acyldinitrile ((3- (3-cyanobenzamid) benzo [ d ] isoxazol-5-yl) carbohydranoyl dicaryanide),

133.(3- (4-methoxybenzamido) benzo [ d ] isoxazol-5-yl) carbohydrazone acyldinitrile ((3- (4-methoxybenzamido) benzo [ d ] isoxazol-5-yl) carbohydrazone diacyl cyanide),

(2-oxo-2,3-dihydrobenzo [ d ] thiazol-6-yl) carbohydrazonoyl diacyl nitrile ((2-oxo-2,3-dihydrobenzo [ d ] thiazol-6-yl) carbohydrazonoyl diacyl nitrile),

(3-methyl-2-oxo-2,3-dihydrobenzo [ d ] thiazol-6-yl) carbohydrazonoyl diacyldinitrile ((3-methyl-2-oxo-2,3-dihydrobenzo [ d ] thiazol-6-yl) carbohydrazonoyl diacylcyanide),

(2-methoxybenzo [ d ] thiazol-6-yl) carbohydrazonoyl diacyl nitrile ((2-methoxybenzo [ d ] thiazol-6-yl) carbohydrazonoyl diacyl nitrile),

137. (2-oxo-2,3-dihydrobenzo [ d ] oxazol-6-yl) carbohydrazonoyl diacyl nitrile ((2-oxo-2,3-dihydrobenzo [ d ] oxazol-6-yl) carbohydrazonoyl diacyl nitrile),

(3-methyl-2-oxo-2,3-dihydrobenzo [ d ] oxazol-6-yl) carbohydrazonoyl dinitrile ((3-methyl-2-oxo-2,3-dihydrobenzo [ d ] oxazol-6-yl) carbohydroazono dicaryanide),

(2-oxo-2,3-dihydro-1H-benzo [ d ] imidazol-5-yl) carbohydrazonoacyldinitrile ((2-oxo-2,3-dihydro-1H-benzo [ d ] imidozol-5-yl) carbohydrazononyl dicaryanide),

140.2- (2- (4- (4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) hydrazone) malonic acid diethyl ester (diethyl2- (2- (4- (4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) hydroazono) malonate),

141.2-imino-N '- (4- (4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) -2- (piperazin-1-yl) acylhydrazone cyanide (2-imino-N' - (4- (4-methyl-6-oxo-1,4,5, 6-tetrahydropydazin-3-yl) phenyl) -2- (piperazin-1-yl) acetyl oxybenzonyl cyanide),

142.2-imino-N '- (4- (4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) -2-morpholinoacetyl hydrazone acylnitrile (2-imino-N' - (4- (4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) -2-morpholinoacetyl nitrile),

143.2- (2- (4- (4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) hydrazone) propionic acid methyl ester (methyl2- (2- (4- (4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) hydrazono) propanoate),

144.2-cyano-2- (2- (4- (pyrimidin-2-yl) phenyl) hydrazone) acetic acid methyl ester (methyl-2-cyano-2- (2- (4- (pyrimidin-2-yl) phenyl) hydrazo) acetate),

145.2-amino-2-oxo-N '- (4- (pyrimidin-2-yl) phenyl) acetyl hydrazone carbonitrile (2-amino-2-oxo-N' - (4- (pyrimidin-2-yl) phenyl) acetyl hydrazonyl cyamide),

146.2-cyano-2- (2- (4- (pyrimidin-2-yl) phenyl) hydrazone) ethyl acetate (ethyl-2-cyano-2- (2- (4- (pyrimidin-2-yl) phenyl) hydrazo) acetate),

147.2-amino-N '- (4- (pyrimidin-2-yl) phenyl) -2-thioacetyl hydrazone carbonitrile (2-amino-N' - (4- (pyrimidin-2-yl) phenyl) -2-thioxoacetohydroazoloyl cyanide),

148.4-methyl-N '- (4- (pyrimidin-2-yl) phenyl) thiazole-2-carbohydrazone carbonitrile (4-methyl-N' - (4- (pyrimidin-2-yl) phenyl) thiazole-2-carbohydranoyl nitrile),

149.(4- (5-ethynylpyrimidin-2-yl) phenyl) carbohydrazonoyl dinitrile ((4- (5-ethylpyrimidin-2-yl) phenyl) carbohydrazonoyl dichloride),

(4'- (dimethylamino) -3-fluorobiphenyl-4-yl) carbohydrazoloyl dinitrile ((4' - (dimethylamino) -3-fluoroobipenyl-4-yl) carbohydrazoloyl dinitride),

(4'- (dimethylamino) biphenyl-4-yl) carbohydrazonoyl dinitrile ((4' - (dimethylamino) biphenol-4-yl) carbohydragenoyl dicaryide),

(4- (6- (dimethylamino) pyridin-3-yl) phenyl) carbohydrazinoyl dinitrile, (4- (6- (dimethylamino) pyridin-3-yl) phenyl) carbohydrazonoyl dinitride),

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

154 (4- (4-methyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazonoyl dinitrile ((4- (4-methyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazoloyl dinitride),

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

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

157 (4- (1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazonoyl dinitrile ((4- (1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazoloyl dinitride),

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

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

160.(3- (difluoromethyl) -2-oxo-2,3-dihydrobenzo [ d ] thiazol-6-yl) carbohydroazoyl dinitrile ((3- (difluoromethyl) -2-oxo-2,3-dihydrobenzo [ d ] thiazol-6-yl) carbohydroazoyl dinitride),

161. (2-isopropoxybenzo [ d ] thiazol-6-yl) carbohydrazonoyl dinitrile ((2-isopropoxy [ d ] thiazol-6-yl) carbohydrazonoyl dicarbamide),

(3-isopropyl-2-oxo-2,3-dihydrobenzo [ d ] oxazol-6-yl) carbohydrazonoyl dinitrile ((3-isopropylphenyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazol-6-yl) carbohydrazononyl dicaryide),

(3- (difluoromethyl) -2-oxo-2,3-dihydrobenzo [ d ] oxazol-6-yl) carbohydrazonoyl dinitrile ((3- (difluoromethyl) -2-oxo-2,3-dihydrobenzo [ d ] oxazol-6-yl) carbohydrazononyl dicaride),

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

165.(1, 3-diisopropyl-2-oxo-2,3-dihydro-1H-benzo [ d ] imidazol-5-yl) carbohydrazone diacyl nitrile ((1, 3-diisopyropyl-2-oxo-2, 3-dihydo-1H-benzo [ d ] imidozol-5-yl) carbohydrazoloyl dicaryanide),

(1,3-bis (difluoromethyl) -2-oxo-2,3-dihydro-1H-benzo [ d ] imidazol-5-yl) carbohydrazoloyl dinitrile ((1,3-bis (difluoromethyl) -2-oxo-2, 3-dihydro-1H-benzol [ d ] imido-5-yl) carbohydrazoloyl dinitride),

167 a (2- (methylamino) benzo [ d ] thiazol-6-yl) carbohydrazonoyl dinitrile ((2- (methylamino) benzo [ d ] thiazol-6-yl) carbohydrazonoyl dinitride),

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

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

(4- (1-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) carbohydrazonoyl dinitrile ((4- (1-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) carbohydrazononyl dicaryide), or

A (4- (1,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) carbohydrazonoyl dinitrile ((4- (1,4-dimethyl-6-oxo-1,4,5, 6-tetrahydropydazin-3-yl) phenyl) carbohydrazoloyl dicaryide).

Further, these compounds may be compounds represented by the following formula.

Meanwhile, the compound of the present invention may exist in the form of a pharmaceutically acceptable salt. As the salt, an acid salt formed from a pharmaceutically acceptable free acid is effective. 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 the patient, and the side effects caused by such salt do not impair the beneficial effects of such compound.

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

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

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

Unless otherwise indicated, pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compounds of formulas 1-5. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxyl group, while other pharmaceutically acceptable salts of the amino group may include hydrobromide, sulfate, bisulfate, phosphate, bisulfate, dihydrogenphosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (methanesulfonate) and p-toluenesulfonate (toluenesulfonate). These pharmaceutically acceptable salts can be prepared by methods known in the art for the preparation of salts.

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

Further, the compounds represented by formulae 1 to 5 according to the present invention include, but are not limited to, pharmaceutically acceptable salts thereof, and solvates such as possible hydrates, and all possible stereoisomers, as may be prepared therefrom. Solvates and stereoisomers of the compounds represented by formulas 1 to 5 may be prepared from the compounds represented by formulas 1 to 5 by using methods known in the art.

In addition, the compounds represented by formulae 1 to 5 according to the present invention may be prepared in a crystalline form or an amorphous form, and if prepared in a crystalline form, may be optionally hydrated or solvated. In the present invention, stoichiometric hydrates of the compounds containing various amounts of water as well as the compounds represented by formulas 1 to 5 can be provided. The solvates of the compounds represented by formulae 1 to 5 according to the present invention include stoichiometric solvates and non-stoichiometric solvates.

In a second aspect, the present invention provides a process for preparing a compound of formula 1 comprising reacting sodium nitrite, R₂Amino derivative (R) of (A)₂-NH₂) Anda step of reacting in the presence of an acid to form an imine bond.

In the preparation method of the present invention, as the reactant used therein, commercially available compounds may be used, or may be synthesized by precisely performing one or more reactions known in the art or by changing some reaction conditions of the reactions known in the art. For example, the compound may be synthesized by sequentially performing one or more reactions in consideration of the presence, kind, and position of the reactive functional group and/or the heterogeneous element present in the backbone structure, but the present invention is not limited thereto. This process can be similarly applied to the following third to sixth aspects.

A third aspect of the present invention provides a process for preparing a compound of formula 2, comprising the steps of:

a1) preparation of aryl-or heteroaryl (unsubstituted or substituted by R)₂' or R₂"substituted) substituted aniline derivativesAnd is

a2) Reacting sodium nitrite, said aniline derivativeWith malononitrile in the presence of an acid to form an imine bond.

For example, when R in the above formula₁Is C_1-6In the case of an alkyl group, after the step of forming the imine bond, the method may further include a step of alkylation by reaction with an alkyl halide in an organic solvent in the presence of potassium tert-butoxide or sodium hydride. However, the present invention is not limited thereto, and the alkylation reaction known in the art may be appropriately modified and carried out in consideration of the presence or absence of other reactive substituents or heterogeneous elements.

In particular by aryl or heteroaryl (which are unsubstituted or substituted by R)₂' or R₂Said aniline derivatives "substituted" by unsubstituted or R can be substituted by using Pd (II) catalysts₂' boronic acid pinacol ester derivatives of substituted anilines with unsubstituted or substituted R₂"substituted haloaryl or heteroaryl derivatives are synthesized by reaction in the presence of a base. However, the present invention is not limited thereto, and commercially available compounds may be used, or may be synthesized by methods known in the art.

Furthermore, the potential counteractions of substituents and/or foreign elements present in the framework of the compounds to be synthesized under the reaction conditions are taken into accountOptionally, by aryl or heteroaryl (which are unsubstituted or substituted by R)₂' or R₂"substituted") substituted said aniline derivatives can be prepared by reducing nitrophenyl derivatives containing nitro groups instead of amine groups in the same skeleton using palladium catalysts activated with carbon under hydrogen.

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

For example, when a 5-to 14-membered heteroaryl or 5-to 14-membered heterocyclyl contains a nitrogen other than an amine group that may be bonded thereto, it contains a protecting group at the nitrogen site. After the step of forming the imine bond, the method may further include a step of removing the protecting group.

Further, the 5-to 14-membered heteroaryl group or the 5-to 14-membered heterocyclic group may be prepared by reducing a nitrophenyl derivative having a nitro group instead of an amine group in the same backbone, in consideration of reactivity of functional groups and/or heterogeneous elements present in the backbone, but the present invention is not limited thereto.

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

make R₂"' with carboxylic acids or anhydrides thereof(here, Y is an unprotected or protected amine group or nitro group) to form an amide bond; and is

Linking sodium nitrite, R comprising carboxamide group obtained in previous step₂The heterocyclic derivative of "", reacts with malononitrile in the presence of an acid to form an imine bond.

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

A sixth aspect of the present invention provides a method for preparing a compound of formula 5, comprising the steps of:

sodium nitrite, R₂Amino derivative (R) of (A)₂-NH₂) Andreacting to form an imine bond; and is

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

The seventh aspect of the present invention provides a composition for inhibiting tau protein aggregation comprising as an active ingredient a compound according to the present invention.

An eighth aspect of the invention provides a composition for inhibiting hyperphosphorylation of tau protein, comprising as an active ingredient a compound according to the invention.

In a specific embodiment of the present invention, a total of 171 compounds, numbered 1-171 and represented by formula 1, were newly synthesized and their effects of inhibiting tau protein aggregation and hyperphosphorylation were confirmed. Furthermore, in order to confirm the possibility of use as a pharmaceutical composition, it was confirmed that these compounds do not exhibit toxicity to cells.

As used herein, the term "prevention" refers to any effect of inhibiting or delaying the onset, spread and recurrence of a disease induced by tau protein aggregation or hyperphosphorylation by administering a pharmaceutical composition of the invention, while the term "treatment" refers to any effect of ameliorating or advantageously altering the symptoms of a disease by administering a pharmaceutical composition of the invention.

As described above, since the compound of the present invention not only inhibits the aggregation or hyperphosphorylation of tau protein but also exhibits no toxicity to cells, a pharmaceutical composition containing such a compound as an active ingredient is useful for the prevention or treatment of diseases caused by the aggregation or hyperphosphorylation of tau protein. The disease caused by tau protein aggregation or hyperphosphorylation to which the pharmaceutical composition of the present invention is applicable may be alzheimer's disease, parkinson's disease, vascular dementia, acute stroke, trauma, cerebrovascular disease, cerebrospinal trauma, spinal cord trauma, peripheral neuropathy, retinopathy, glaucoma or tauopathy. Non-limiting examples of the tauopathies may include: chronic Traumatic Encephalopathy (CTE), primary age-related tauopathies, progressive supranuclear palsy, corticobasal degeneration, pick's disease, Argyrophilic Grain Disease (AGD), frontotemporal dementia (FTD), parkinson's disease associated with chromosome 17, muscular dystrophy (Lytico-nodal disease) (guam parkinsonism-dementia syndrome), ganglioglioma, ganglioneuroma, meningioangiomatosis, postencephalitic parkinson's disease, subacute sclerosing panencephalitis, plumbaginous encephalopathy, tuberous sclerosis, pantothenic acid kinase-associated neurodegeneration, lipofuscinosis, and traumatic brain injury.

For example, the composition of the present invention may further comprise a pharmaceutically acceptable carrier, diluent or excipient, and may be formulated and used in various forms according to the general method for each purpose of use, such as oral preparations of powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol, etc., and injections of sterile injection solution; and can be administered orally, or by various routes including intravenous, intraperitoneal, subcutaneous, rectal and topical. Examples of suitable carriers, excipients or diluents for inclusion in the composition may include: lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. The compositions of the present invention may also contain fillers, anti-aggregating agents, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, and the like.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and are formulated by mixing one or more excipients (such as starch, calcium carbonate, sucrose, lactose and gelatin) with the composition. Meanwhile, in addition to simple excipients, lubricants such as magnesium stearate or talc may be used.

As the oral liquid preparation, a suspension, an anti-solvent, an emulsion, a syrup, etc. can be cited, and the oral liquid preparation may contain various excipients such as wetting agents, sweeteners, flavors, and preservatives in addition to water and liquid paraffin, which are generally used as simple diluents.

Formulations for parenteral administration include sterilized: aqueous solvents, non-aqueous solvents, suspensions, emulsifiers, lyophilized formulations, and suppositories.

Propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), injectable esters (e.g., ethyl oleate), and the like may be used as the nonaqueous solvent or suspension. Synthetic fatty acid esters (witepsol), polyethylene glycol, tween 61(twin 61), cocoa butter, bay oil, glycerogelatin, and the like may be used as bases for suppositories. Meanwhile, the injection preparation may contain conventional additives such as solubilizing agents, isotonic agents, suspending agents, emulsifying agents, stabilizing agents and preservatives.

The formulations may be prepared by conventional mixing, granulating or coating methods and may contain the active ingredient in an amount of about 0.1 to 75 wt%, preferably about 0.1 to 50 wt%. A unit formulation for a mammal weighing about 50kg to 70kg comprises about 10mg to 200mg of the active ingredient.

In this case, the composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment without causing side effects, and the level of the effective amount may be determined according to the patient's health status, type of disease, severity, pharmaceutical activity, sensitivity to drugs, administration method, administration time, administration route, excretion rate, treatment cycle, factors including drugs used in combination or simultaneously, and other well-known factors in the medical field. The compositions of the present invention may be administered as the sole therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered in single or multiple doses. In view of all the above, it is important to be able to administer the drug in an amount that achieves the maximum effect at the minimum amount without side effects, which can be easily determined by one skilled in the art.

For example, the amount to be administered does not limit the scope of the present invention in any way, since the amount can be increased or decreased depending on the administration route, the severity of the disease, sex, body weight, age, and the like.

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

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

As used herein, the term "administering" means providing a predetermined substance to a patient by any suitable method, and the route of administration of the composition of the present invention may be by any general route, as long as it reaches the target tissue. The composition may be administered by intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, or rectal administration, but the present invention is not limited thereto. Also, the pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to the target cell. Preferred modes of administration and dosage forms include intravenous, subcutaneous, intradermal, intramuscular, and instillation. Injectable drugs can be prepared by using an aqueous solvent (such as physiological saline, or ringer's solution) or a non-aqueous solvent (such as vegetable oil, higher fatty acid ester (e.g., ethyl oleate), or alcohol (e.g., ethanol, benzyl alcohol, propylene glycol, or glycerin)), and may contain a pharmaceutical carrier, such as a stabilizer for preventing denaturation (e.g., ascorbic acid, sodium bisulfite, sodium metabisulfite, BHA, tocopherol, or EDTA), an emulsifier, a buffer for pH control, or a preservative for inhibiting microbial growth (e.g., phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, or benzyl alcohol).

Detailed description of the preferred embodiments

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

Example 1: preparation of (4- (pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 1)

Step 1-1: preparation of 4- (pyrimidin-2-yl) anilines

2-bromopyrimidine (175mg, 1.10mmol) and 4-aminophenylboronic acid pinacol ester (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline) (200mg, 0.91mmol) were dissolved in 15mL of a1, 4-dioxane solution in the presence of nitrogen, followed by addition of Pd (PPh)₃)₂Cl₂(63mg, 0.09mmol) and 1.0M aqueous sodium carbonate solution (3.64mL, 3.64mmol) to give a reaction mixture. The reaction mixture was stirred at 80 ℃ for 12 hours. After the reaction is completed, distilled water andthe reaction product was extracted with ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 115mg (yield 74%).

Step 1-2: preparation of (4- (pyrimidin-2-yl) phenyl) carbohydrazone acyldinitriles

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

Example 2: preparation of (4- (5-fluoropyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 2)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 2-chloro-5-fluoropyrimidine (1.10mmol) was used instead of 2-bromopyrimidine to obtain 71mg (41% yield) of the title compound.

Step 2-2: preparation of (4- (5-fluoropyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1 except that 4- (5-fluoropyrimidin-2-yl) aniline (1.10mmol) was used in place of 4- (pyrimidin-2-yl) aniline to obtain 30mg (43% yield) of the title compound.

Example 3: preparation of (4- (5-fluoro-4-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 3)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 2-chloro-5-fluoro-4-methylpyrimidine (1.10mmol) was used instead of 2-bromopyrimidine to obtain 139mg (75% yield) of the title compound.

Step 3-2: preparation of (4- (5-fluoro-4-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (5-fluoro-4-methylpyrimidin-2-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 40mg (29% yield) of the title compound.

Example 4: preparation of (4- (5-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 4)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 2-chloro-5-methylpyrimidine (1.10mmol) was used instead of 2-bromopyrimidine to obtain 65mg (39% yield) of the title compound.

Step 4-2: preparation of (4- (5-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (5-methylpyrimidin-2-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 35mg (50% yield) of the title compound.

Example 5: preparation of 4- (5-ethylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 5)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 2-chloro-5-ethylpyrimidine (1.10mmol) was used instead of 2-bromopyrimidine to give 169mg (93% yield) of the title compound.

Step 5-2: preparation of 4- (5-ethylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (5-ethylpyrimidin-2-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 35mg (25% yield) of the title compound.

Example 6: preparation of (4- (4-ethylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 6)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 2-chloro-4-ethylpyrimidine (1.10mmol) was used instead of 2-bromopyrimidine to give 169mg (93% yield) of the title compound.

Step 6-2: preparation of (4- (4-ethylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (4-ethylpyrimidin-2-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 80mg (66% yield) of the title compound.

Example 7: preparation of (4- (5-Chloropyrimidin-2-yl) carbohydrazone acyldinitrile (Compound 7)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 2-chloro-5-chloropyrimidine (1.10mmol) was used in place of 2-bromopyrimidine to obtain 67mg (36% yield) of the title compound.

Step 7-2: preparation of (4- (5-chloropyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (5-chloropyrimidin-2-yl) aniline was used in place of 4- (pyrimidin-2-yl) aniline, to obtain 30mg (16% yield) of the title compound.

Example 8: preparation of (4- (5-methoxypyrimidin-2-yl) -phenyl) carbohydrazone acyldinitrile (Compound 8)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 2-chloro-5-methoxypyrimidine (1.10mmol) was used instead of 2-bromopyrimidine to obtain 67mg (36% yield) of the title compound.

Step 8-2: preparation of (4- (5-methoxypyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (5-methoxypyrimidin-2-yl) aniline was used in place of 4- (pyrimidin-2-yl) aniline, to obtain 26mg (30% yield) of the title compound.

Example 9: preparation of (4- (2,4-dimethylthiazol-5-yl) phenyl) carbohydrazone acyldinitrile (Compound 9)

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

The reaction was carried out in the same manner as in step 1-1 of example 1, except that 5-bromo-2, 4-dimethylthiazole (1.10mmol) was used instead of 2-bromopyrimidine, to obtain 48mg (26% yield) of the title compound.

Step 9-2: preparation of (4- (2,4-dimethylthiazol-5-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (2,4-dimethylthiazol-5-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 55mg (93% yield) of the title compound.

Example 10: preparation of (4- (pyridin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 10)

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

The reaction was carried out in the same manner as in step 1-1 of example 1, except that 2-bromopyridine (1.10mmol) was used instead of 2-bromopyrimidine, to give 101mg (65% yield) of the title compound.

Step 10-2: preparation of (4- (pyridin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (pyridin-2-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 18mg (25% yield) of the title compound.

Example 11: preparation of (4- (2-methylthiazol-5-yl) phenyl) carbohydrazone acyldinitrile (Compound 11)

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

The reaction was carried out in the same manner as in step 1-1 of example 1, except that 5-bromo-2-methylthiazole (1.10mmol) was used instead of 2-bromopyrimidine, to obtain 112mg (57% yield) of the title compound.

Step 11-2: preparation of (4- (2-methylthiazol-5-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (2-methylthiazol-5-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 11mg (16% yield) of the title compound.

Example 12: preparation of (4- (4-methylthiazol-5-yl) phenyl) carbohydrazone acyldinitrile (Compound 12)

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

The reaction was carried out in the same manner as in step 1-1 of example 1, except that 5-bromo-4-methylthiazole (1.10mmol) was used instead of 2-bromopyrimidine, to give 133mg (76% yield) of the title compound.

Step 12-2: preparation of (4- (4-methylthiazol-5-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (4-methylthiazol-5-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 62mg (89% yield) of the title compound.

Example 13: preparation of biphenyl-4-ylcarbonhydrazone acyldinitrile (Compound 13)

Step 13-1: preparation of biphenyl-4-amines

The reaction was carried out in the same manner as in step 1-1 of example 1 except that bromobenzene (1.10mmol) was used instead of 2-bromopyrimidine to obtain 109mg (70% yield) of the title compound.

Step 13-2: preparation of biphenyl-4-yl carbohydrazone acyldinitriles

The reaction was carried out in the same manner as in step 1-2 of example 1, except that biphenyl-4-amine was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 29mg (38% yield) of the title compound.

Example 14: preparation of (4' -methylbiphenyl-4-yl) carbohydrazone acyldinitrile (Compound 14)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 1-bromo-4-methylbenzene (1.10mmol) was used in place of 2-bromopyrimidine to obtain the title compound.

Step 14-2: preparation of (4' -methylbiphenyl-4-yl) carbohydrazone acyldinitriles

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4' -methylbiphenyl-4-amine was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 48mg (23% yield) of the title compound.

Example 15: preparation of (4- (pyridin-3-yl) phenyl) carbohydrazone acyldinitrile (Compound 15)

Step 15-1: preparation of 4- (pyridin-3-yl) aniline

The reaction was carried out in the same manner as in step 1-1 of example 1, except that 3-bromopyridine (10.95mmol) was used instead of 2-bromopyrimidine, to obtain 367mg (23% yield) of the title compound.

Step 15-2: preparation of (4- (pyridin-3-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (pyridin-3-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 533mg (100% yield) of the title compound.

Example 16: preparation of (4- (pyridin-4-yl) phenyl) carbohydrazone acyldinitrile (Compound 16)

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

The reaction was carried out in the same manner as in step 1-1 of example 1, except that 4-bromopyridine hydrochloride (1.53mmol) was used instead of 2-bromopyrimidine, to give 70mg (32% yield) of the title compound.

Step 16-2: preparation of (4- (pyridin-4-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (pyridin-4-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 9mg (9% yield) of the title compound.

Example 17: preparation of (4- (pyridazin-3-yl) phenyl) carbohydrazone acyldinitrile (Compound 17)

Step 17-1: preparation of 4- (pyridazin-3-yl) anilines

The reaction was carried out in the same manner as in step 1-1 of example 1, except that 3-bromopyridazine (0.64mmol) was used instead of 2-bromopyrimidine, to give 76mg (84% yield) of the title compound.

Step 17-2: preparation of (4- (pyridazin-3-yl) phenyl) carbohydrazone acyldinitriles

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (pyridazin-3-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 42mg (38% yield) of the title compound.

Example 18: preparation of (4- (5-methylthiazol-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 18)

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

The reaction was carried out in the same manner as in step 1-1 of example 1, except that 2-bromo-5-methylthiazole (0.69mmol) was used instead of 2-bromopyrimidine, to obtain 88mg (68% yield) of the title compound.

Step 18-2: preparation of (4- (5-methylthiazol-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (5-methylthiazol-2-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 30mg (42% yield) of the title compound.

Example 19: preparation of ethyl2- (4- (2- (dicyanomethylene) hydrazino) phenyl) thiazole-5-carboxylate (Compound 19)

Step 19-1: preparation of ethyl2- (4-aminophenyl) thiazole-5-carboxylate

The reaction was carried out in the same manner as in step 1-1 of example 1, except that ethyl 2-bromothiazole-5-carboxylate (1.61mmol) was used instead of 2-bromopyrimidine, to obtain 12mg (3% yield) of the title compound.

Step 19-2: preparation of ethyl2- (4- (2- (dicyanomethylene) hydrazino) phenyl) thiazole-5-carboxylate

The reaction was carried out in the same manner as in step 1-2 of example 1, except that ethyl2- (4-aminophenyl) thiazole-5-carboxylate was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 12mg (75% yield) of the title compound.

Example 20: preparation of (4- (thiazol-5-yl) phenyl) carbohydrazone acyldinitrile (Compound 20)

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

The reaction was carried out in the same manner as in step 1-1 of example 1, except that 5-bromothiazole (0.91mmol) was used instead of 2-bromopyrimidine, to give 137mg (85% yield) of the title compound.

Step 20-2: preparation of (4- (thiazol-5-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (thiazol-5-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 60mg (83% yield) of the title compound.

Example 21: preparation of (3 '-fluoro-4' -nitrobiphenyl-4-yl) carbohydrazone acyldinitrile (Compound 21)

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 3 '-fluoro-4' -nitrobiphenyl-4-amine was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 6mg (7% yield) of the title compound.

Example 22: preparation of (4- (6-fluoropyridin-3-yl) phenyl) carbohydrazone acyldinitrile (Compound 22)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 3-bromo-6-fluoropyridine (0.55mmol) was used instead of 2-bromopyrimidine to obtain 38mg (45% yield) of the title compound.

Step 22-2: preparation of (4- (6-fluoropyridin-3-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (6-fluoropyridin-3-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 23mg (53% yield) of the title compound.

Example 23: preparation of (2',4' -dimethylbiphenyl-4-yl) carbohydrazone acyldinitrile (Compound 23)

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 2',4' -dimethylbiphenyl-4-amine was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 8mg (6% yield) of the title compound.

Example 24: preparation of methyl 4' - (2- (dicyanomethylene) hydrazino) -2-fluorobiphenyl-4-carboxylate (Compound 24)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that methyl 4-bromo-3-fluorobenzoate (0.69mmol) was used instead of 2-bromopyrimidine to obtain 93mg (60% yield) of the title compound.

Step 24-2: preparation of methyl 4' - (2- (dicyanomethylene) hydrazino) -2-fluorobiphenyl-4-carboxylate

The reaction was carried out in the same manner as in step 1-2 of example 1 except that 4' -amino-2-fluorobiphenyl-4-carboxylic acid ester was used in place of 4- (pyrimidin-2-yl) aniline to obtain 16mg (16% yield) of the title compound.

Example 25: preparation of (2 '-methyl-4' -nitrobiphenyl-4-yl) carbohydrazone acyldinitrile (Compound 25)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 1-bromo-2-methyl-4-nitrobenzene (0.69mmol) was used instead of 2-bromopyrimidine to give 98mg (63% yield) of the title compound.

Step 25-2: preparation of (2 '-methyl-4' -nitrobiphenyl-4-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 2 '-methyl-4' -nitrobiphenyl-4-amine was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 38mg (27% yield) of the title compound.

Example 26: preparation of (2',4' -dichlorobiphenyl-4-yl) carbohydrazone acyldinitrile (Compound 26)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 1-bromo-2, 4-dichlorobenzene (0.91mmol) was used in place of 2-bromopyrimidine to obtain 182mg (84% yield) of the title compound.

Step 26-2: preparation of (2',4' -dichlorobiphenyl-4-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 2',4' -dichlorobiphenyl-4-amine was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 47mg (20% yield) of the title compound.

Example 27: preparation of (2 '-methoxy-4' -methylbiphenyl-4-yl) carbohydrazone acyldinitrile (Compound 27)

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

The reaction was carried out in the same manner as in step 1-1 of example 1, except that 1-bromo-2-methoxy-4-methylbenzene (0.69mmol) was used instead of 2-bromopyrimidine to give 36mg (24% yield) of the title compound.

Step 27-2: preparation of (2 '-methoxy-4' -methylbiphenyl-4-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 2 '-methoxy-4' -methylbiphenyl-4-amine was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 3mg (6% yield) of the title compound.

Example 28: preparation of (4- (pyrazin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 28)

Step 28-1: preparation of 4- (pyrazin-2-yl) anilines

The reaction was carried out in the same manner as in step 1-1 of example 1, except that 2-bromopyrazine (1.26mmol) was used instead of 2-bromopyrimidine, to give 72mg (33% yield) of the title compound.

Step 28-2: preparation of (4- (pyrazin-2-yl) phenyl) carbohydrazone acyldinitriles

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (pyrazin-2-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 12mg (12% yield) of the title compound.

Example 29: preparation of (4- (5- (trifluoromethyl) pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 29)

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

The reaction was carried out in the same manner as in step 1-1 of example 1, except that 2-chloro-5- (trifluoromethyl) pyrimidine (0.83mmol) was used instead of 2-bromopyrimidine, to give 127mg (78% yield) of the title compound.

Step 29-2: preparation of (4- (5- (trifluoromethyl) pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (5- (trifluoromethyl) pyrimidin-2-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 47mg (31% yield) of the title compound.

Example 30: preparation of (4- (4,6-dimethylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 30)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 2-chloro-4, 6-dimethylpyrimidine (1.05mmol) was used instead of 2-bromopyrimidine to obtain 118mg (67% yield) of the title compound.

Step 30-2: preparation of (4- (4,6-dimethylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (4,6-dimethylpyrimidin-2-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 110mg (77% yield) of the title compound.

Example 31: preparation of (4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 31)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 2-bromo-4-methylpyrimidine (0.87mmol) was used instead of 2-bromopyrimidine to obtain 77mg (57% yield) of the title compound.

Step 31-2: preparation of (4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (4-methylpyrimidin-2-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 66mg (61% yield) of the title compound.

Example 32: preparation of (4- (pyrimidin-5-yl) phenyl) carbohydrazone acyldinitrile (Compound 32)

Step 32-1: preparation of 4- (pyrimidin-5-yl) anilines

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 5-bromopyrimidine (0.87mmol) was used in place of 2-bromopyrimidine to give 502mg (64% yield) of the title compound.

Step 32-2: preparation of (4- (pyrimidin-5-yl) phenyl) carbohydrazone acyldinitriles

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (pyrimidin-5-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 100mg (69% yield) of the title compound.

Example 33: preparation of (4- (1-methyl-1H-1,2,4-triazol-5-yl) phenyl) carbohydrazone acyldinitrile (Compound 33)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 5-bromo-1-methyl-1H-1, 2, 4-triazole (0.96mmol) was used in place of 2-bromopyrimidine to give 40mg (20% yield) of the title compound.

Step 33-2: preparation of (4- (1-methyl-1H-1,2,4-triazol-5-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1 except that 4- (1-methyl-1H-1,2,4-triazol-5-yl) aniline was used in place of 4- (pyrimidin-2-yl) aniline to obtain 18mg (25% yield) of the title compound.

Example 34: preparation of (4- (1-methyl-1H-1,2,4-triazol-3-yl) phenyl) carbohydrazone acyldinitrile (Compound 34)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 3-bromo-1-methyl-1H-1, 2, 4-triazole (0.96mmol) was used in place of 2-bromopyrimidine to give 100mg (50% yield) of the title compound.

Step 34-2: preparation of (4- (1-methyl-1H-1,2,4-triazol-3-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (1-methyl-1H-1,2,4-triazol-3-yl) aniline was used in place of 4- (pyrimidin-2-yl) aniline, to obtain 29mg (40% yield) of the title compound.

Example 35: preparation of (4- (1H-pyrazol-1-yl) phenyl) carbohydrazone acyldinitrile (Compound 35)

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (1H-pyrazol-1-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 163mg (55% yield) of the title compound.

Example 36: preparation of (4- (4-methyl-1H-pyrazol-1-yl) phenyl) carbohydrazone acyldinitrile (Compound 36)

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

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

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

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

Step 36-3: preparation of (4- (4-methyl-1H-pyrazol-1-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1 except that 4- (4-methyl-1H-pyrazol-1-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 50mg (69% yield) of the title compound.

Example 37: preparation of (2-fluoro-4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 37)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except for using 4-amino-3-fluorophenylboronic acid pinacol ester (2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline) (0.84mmol) in place of 4-aminophenylboronic acid pinacol ester and using 2-bromo-4-methylpyrimidine (1.01mmol) in place of 2-bromopyrimidine to obtain 100mg (50% yield) of the title compound.

Step 37-2: preparation of (2-fluoro-4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1 except that 2-fluoro-4- (4-methylpyrimidin-2-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline to obtain 46mg (67% yield) of the title compound.

Example 38: preparation of (2-fluoro-4- (pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 38)

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

The reaction was carried out in the same manner as in step 37-1 of example 37, except that 2-bromopyrimidine (1.26mmol) was used in place of 2-bromo-4-methylpyrimidine, to give 41mg (17% yield) of the title compound.

Step 38-2: preparation of (2-fluoro-4- (pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 2-fluoro-4- (pyrimidin-2-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 11mg (19% yield) of the title compound.

Example 39: preparation of (3-fluoro-4- (pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 39)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except for using 4-amino-2-fluorophenylboronic acid pinacol ester (1.38mmol) in place of 4-aminophenylboronic acid pinacol ester to obtain 156mg (66% yield) of the title compound.

Step 39-2: preparation of (3-fluoro-4- (pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 3-fluoro-4- (pyrimidin-2-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 80mg (81% yield) of the title compound.

Example 40: preparation of (3-fluoro-4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 40)

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

The reaction was carried out in the same manner as in step 39-1 of example 39, except that 2-bromo-4-methylpyrimidine (1.16mmol) was used instead of 2-bromopyrimidine, to obtain 82mg (35% yield) of the title compound.

Step 40-2: preparation of (3-fluoro-4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1 except that 3-fluoro-4- (4-methylpyrimidin-2-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 56mg (92% yield) of the title compound.

Example 41: preparation of (2-methoxy-4- (5-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 41)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except for using 4-amino-3-methoxyphenylboronic acid pinacol ester (0.99mmol) in place of 4-aminophenylboronic acid pinacol ester and using 2-chloro-5-methylpyrimidine (1.19mmol) in place of 2-bromopyrimidine, to obtain 99mg (47% yield) of the title compound.

Step 41-2: preparation of (2-methoxy-4- (5-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 2-methoxy-4- (5-methylpyrimidin-2-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 25mg (61% yield) of the title compound.

Example 42: preparation of (2-methoxy-4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 42)

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

The reaction was carried out in the same manner as in step 41-1 of example 41 except that 2-bromo-4-methylpyrimidine (1.12mmol) was used instead of 2-chloro-5-methylpyrimidine, to give 80mg (42% yield) of the title compound.

Step 42-2: preparation of (2-methoxy-4- (4-methylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 2-methoxy-4- (4-methylpyrimidin-2-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 10mg (58% yield) of the title compound.

Example 43: preparation of (2-methoxy-4- (pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 43)

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

The reaction was carried out in the same manner as in step 41-1 of example 41 except that 2-bromopyrimidine (0.96mmol) was used in place of 2-chloro-5-methylpyrimidine to obtain 29mg (18% yield) of the title compound.

Step 43-2: preparation of (2-methoxy-4- (pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 2-methoxy-4- (pyrimidin-2-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 26mg (65% yield) of the title compound.

Example 44: preparation of (4- (5-fluoropyrimidin-2-yl) -2-morpholinophenyl) carbohydrazone acyldinitrile (Compound 44)

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

4-bromo-2-fluoro-1-nitrobenzene (2g, 7.88mmol) and bis (pinacolato) diboron (4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolan), 2.1g, 9.45mmol) were dissolved in 60mL of 1, 4-dioxane solution in the presence of nitrogen, and Pd (dppf) was added₂Cl₂(1.3g, 1.58mmol) and potassium acetate (3.1g, 31.5mmol) to give a reaction mixture. The reaction mixture was stirred at 80 ℃ 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 1.6 g.

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

2- (3-fluoro-4-nitrophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan prepared according to step 44-1 and morpholine (0.68mL, 7.79mmol) were dissolved in acetonitrile (20mL) in the presence of nitrogen to give a reaction mixture, which was then stirred at 80 ℃ 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give 700g of the title compound.

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except for using 4- (2-nitro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) morpholine prepared according to step 44-2 instead of 4-aminophenylboronic acid pinacol ester and 2-chloro-5-fluoropyrimidine (2.51mmol) instead of 2-bromopyrimidine to obtain 164mg (26% yield) of the title compound.

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

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

Step 44-5: preparation of (4- (5-fluoropyrimidin-2-yl) -2-morpholinophenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (5-fluoropyrimidin-2-yl) -2-morpholinoaniline prepared according to step 44-4 was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 70mg (65% yield) of the title compound.

Example 45: preparation of methyl (4- (pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 45)

(4- (pyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (50mg, 0.20mmol) prepared according to example 1 was dissolved in 1.5mL of tetrahydrofuran, followed by addition of potassium tert-butoxide (29mg, 0.26mmol) at room temperature, and iodomethane (25. mu.L, 0.40mmol) to give a reaction mixture. The reaction mixture was stirred at 60 ℃ for 4 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by recrystallization from an ethanol solvent to obtain the title compound 3mg (yield 6%).

Example 46: preparation of (3- (5-fluoropyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 46)

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

The reaction was carried out in the same manner as in step 1-1 of example 41 except for using 3-aminophenylboronic acid pinacol ester (1.37mmol) in place of 4-aminophenylboronic acid pinacol ester and using 2-chloro-5-fluoropyrimidine (1.64mmol) in place of 2-bromopyrimidine to obtain 180mg of the title compound.

Step 46-2: preparation of (3- (5-fluoropyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1 except that 3- (5-fluoropyrimidin-2-yl) aniline was used in place of 4- (pyrimidin-2-yl) aniline to obtain 70.5mg of the title compound.

Example 47: preparation of (5- (5-fluoropyrimidin-2-yl) -2-morpholinophenyl) carbohydrazone acyldinitrile (Compound 47)

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

The reaction was carried out in the same manner as in step 44-2 of example 44 except for using 2- (4-chloro-3-nitrophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan instead of 2- (3-fluoro-4-nitrophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan to obtain 480mg (41% yield) of the title compound.

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except for using 4- (2-nitro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) morpholine prepared according to step 47-1 in place of 4-aminophenylboronic acid pinacol ester and using 2-chloro-5-fluoropyrimidine in place of 2-bromopyrimidine to obtain 300mg (70% yield) of the title compound.

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

4- (5- (5-Fluoropyrimidin-2-yl) -2-nitrophenyl) morpholine prepared according to step 44-3 was dissolved in dichloromethane and reduced in the same manner as in step 36-2 of example 36 to give 86mg (48% yield) of the title compound.

Step 47-4: preparation of (5- (5-fluoropyrimidin-2-yl) -2-morpholinophenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 5- (5-fluoropyrimidin-2-yl) -2-morpholinoaniline prepared according to step 47-3 was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 84mg (77% yield) of the title compound.

Example 48: preparation of (4- (benzo [ d ] thiazol-6-yl) phenyl) carbohydrazone acyldinitrile (Compound 48)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 6-bromobenzo [ d ] thiazole (0.55mmol) was used instead of 2-bromopyrimidine to obtain 58mg (68% yield) of the title compound.

Step 48-2: preparation of (4- (benzo [ d ] thiazol-6-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (benzo [ d ] thiazol-6-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 10mg (13% yield) of the title compound.

Example 49: preparation of (4- (naphthalen-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 49)

Step 49-1: preparation of 4- (naphthalen-2-yl) anilines

The reaction was carried out in the same manner as in step 1-1 of example 1, except that 2-bromonaphthalene (0.46mmol) was used in place of 2-bromopyrimidine to obtain 40mg (21% yield) of the title compound.

Step 49-2: preparation of (4- (naphthalen-2-yl) phenyl) carbohydrazone acyldinitriles

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (naphthalen-2-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 5mg (9% yield) of the title compound.

Example 50: preparation of (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) carbohydrazone acyldinitrile (Compound 50)

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

The reaction was carried out in the same manner as in step 1-1 of example 1, except that 6-bromopyrazolo [1,5-a ] pyrimidine (1.65mmol) was used instead of 2-bromopyrimidine, to obtain 180mg (62% yield) of the title compound.

Step 50-2: preparation of (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (pyrazolo [1,5-a ] pyrimidin-6-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 79mg (32% yield) of the title compound.

Example 51: preparation of (4- (imidazo [1,2-a ] pyrimidin-6-yl) phenyl) carbohydrazone acyldinitrile (Compound 51)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 6-bromoimidazo [1,2-a ] pyrimidine (2.53mmol) was used in place of 2-bromopyrimidine to give 76mg (17% yield) of the title compound.

Step 51-2: preparation of (4- (imidazo [1,2-a ] pyrimidin-6-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (imidazo [1,2-a ] pyrimidin-6-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 40mg (38% yield) of the title compound.

Example 52: preparation of (4- (quinoxalin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 52)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 2-chloroquinoxaline (1.64mmol) was used in place of 2-bromopyrimidine to obtain 100mg (33% yield) of the title compound.

Step 52-2: preparation of (4- (quinoxalin-2-yl) phenyl) carbohydrazone acyldinitriles

The reaction was carried out in the same manner as in step 1-2 of example 1 except that 4- (quinoxalin-2-yl) aniline was used in place of 4- (pyrimidin-2-yl) aniline to obtain 30mg (44% yield) of the title compound.

Example 53: preparation of (4- (imidazo [1,2-a ] pyridin-6-yl) phenyl) carbohydrazone acyldinitrile (Compound 53)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 6-bromoimidazo [1,2-a ] pyridine (1.64mmol) was used instead of 2-bromopyrimidine to give 100mg (33% yield) of the title compound.

Step 53-2: preparation of (4- (imidazo [1,2-a ] pyridin-6-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (imidazo [1,2-a ] pyridin-6-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 22mg (32% yield) of the title compound.

Example 54: preparation of (4- (isoquinolin-3-yl) phenyl) carbohydrazone acyldinitrile (Compound 54)

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

The reaction was carried out in the same manner as in step 1-1 of example 1 except that 3-chloroisoquinoline (2.80mmol) was used in place of 2-bromopyrimidine to give 80mg (16% yield) of the title compound.

Step 54-2: preparation of (4- (isoquinolin-3-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (isoquinolin-3-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 23mg (42% yield) of the title compound.

Example 55: preparation of (4- (2-methyl-2H-indazol-4-yl) phenyl) carbohydrazone acyldinitrile (Compound 55)

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

The reaction was carried out in the same manner as in step 1-1 of example 1, except that 4-bromo-2-methyl-2H-indazole (2.20mmol) was used instead of 2-bromopyrimidine, to give 331mg (80% yield) of the title compound.

Step 55-2: preparation of (4- (2-methyl-2H-indazol-4-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (2-methyl-2H-indazol-4-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 100mg (24% yield) of the title compound.

Example 56: preparation of (4- (2-methyl-2H-indazol-5-yl) phenyl) carbohydrazone acyldinitrile (Compound 56)

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

The reaction was carried out in the same manner as in step 1-1 of example 1, except that 5-bromo-2-methyl-2H-indazole (2.20mmol) was used instead of 2-bromopyrimidine, to give 100mg (38% yield) of the title compound.

Step 56-2: preparation of (4- (2-methyl-2H-indazol-5-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (2-methyl-2H-indazol-5-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 26mg (65% yield) of the title compound.

Example 57: preparation of (4- (2-methyl-2H-indazol-7-yl) phenyl) carbohydrazone acyldinitrile (Compound 57)

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

The reaction was carried out in the same manner as in step 1-1 of example 1, except that 7-bromo-2-methyl-2H-indazole (2.20mmol) was used instead of 2-bromopyrimidine, to give 550mg (86% yield) of the title compound.

Step 57-2: preparation of (4- (2-methyl-2H-indazol-7-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4- (2-methyl-2H-indazol-7-yl) aniline was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 345mg (47% yield) of the title compound.

Example 58: preparation of (4- (1H-indol-5-yl) phenyl) carbohydrazone acyldinitrile (Compound 58)

Step 58-1: preparation of 5- (4-aminophenyl) -1H-indole-1-carboxylic acid tert-butyl ester

The reaction was carried out in the same manner as in step 1-1 of example 1 except that tert-butyl 5-bromo-1H-indole-1-carboxylate (3.38mmol) was used instead of 2-bromopyrimidine to obtain 596mg (6% yield) of the title compound.

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

The reaction was carried out in the same manner as in step 1-2 of example 1 except that tert-butyl 5- (4-aminophenyl) -1H-indole-1-carboxylate was used instead of 4- (pyrimidin-2-yl) aniline to obtain 107mg (14% yield) of the title compound.

Step 58-3: preparation of (4- (1H-indol-5-yl) phenyl) carbohydrazone acyldinitrile

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

Example 59: preparation of (4-methoxybenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile (Compound 59)

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 4-methoxybenzo [ d ] thiazol-2-amine was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 141mg (51% yield) of the title compound.

Example 60: preparation of benzo [ d ] thiazol-6-yl-carbohydrazone acyldinitrile (Compound 60)

The reaction was carried out in the same manner as in step 1-2 of example 1, except that benzo [ d ] thiazol-6-amine was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 290mg (48% yield) of the title compound.

Example 61: preparation of benzo [ d ] thiazol-5-yl-carbohydrazone acyldinitrile (Compound 61)

The reaction was carried out in the same manner as in step 1-2 of example 1, except that benzo [ d ] thiazol-5-amine was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 180mg (40% yield) of the title compound.

Example 62: preparation of (9-ethyl-9H-carbazol-3-yl) carbohydrazone acyldinitrile (Compound 62)

The reaction was carried out in the same manner as in step 1-2 of example 1 except that 9-ethyl-9H-carbazol-3-amine was used instead of 4- (pyrimidin-2-yl) aniline to obtain 77mg (11% yield) of the title compound.

Example 63: preparation of (1-methyl-1H-indazol-6-yl) carbohydrazone acyldinitrile (Compound 63)

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 1-methyl-1H-indazol-6-amine was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 246mg (54% yield) of the title compound.

Example 64: preparation of quinolin-3-yl carbohydrazone acyldinitrile (Compound 64)

The reaction was carried out in the same manner as in step 1-2 of example 1, except that quinolin-3-amine was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 163mg (27% yield) of the title compound.

Example 65: preparation of (2-methyl-2H-indazol-6-yl) carbohydrazone acyldinitrile (Compound 65)

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 2-methyl-2H-indazol-6-amine was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 23mg (3% yield) of the title compound.

Example 66: preparation of (1-methyl-1H-indazol-5-yl) carbohydrazone acyldinitrile (Compound 66)

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 1-methyl-1H-indazol-5-amine was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 128mg (17% yield) of the title compound.

Example 67: preparation of quinolin-6-yl carbohydrazone acyldinitrile (Compound 67)

The reaction was carried out in the same manner as in step 1-2 of example 1 except that quinolin-6-amine was used instead of 4- (pyrimidin-2-yl) aniline to obtain 56mg (9% yield) of the title compound.

Example 68: preparation of (1-methyl-1H-indol-5-yl) carbohydrazone acyldinitrile (Compound 68)

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 1-methyl-1H-indol-5-amine was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 69mg (11% yield) of the title compound.

Example 69: preparation of (1H-indazol-5-yl) carbohydrazone acyldinitrile (Compound 69)

The reaction was carried out in the same manner as in step 1-2 of example 1, except that tert-butyl 5-amino-1H-indazole-1-carboxylate was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 70mg (19% yield) of the title compound.

Example 70: preparation of (1H-indazol-6-yl) carbohydrazone acyldinitrile (Compound 70)

The reaction was carried out in the same manner as in step 1-2 of example 1, except that tert-butyl 6-amino-1H-indazole-1-carboxylate was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 62mg (12% yield) of the title compound.

Example 71: preparation of (1H-indol-5-yl) carbohydrazone acyldinitrile (Compound 71)

Step 71-1: preparation of 5- (2- (dicyanomethylene) hydrazino) -1H-indole-1-carboxylic acid tert-butyl ester

The reaction was carried out in the same manner as in step 1-2 of example 1 except for using tert-butyl 5-amino-1H-indole-1-carboxylate instead of 4- (pyrimidin-2-yl) aniline to obtain 25mg (6% yield) of the title compound.

Step 71-2: preparation of (1H-indol-5-yl) carbohydrazone acyldinitriles

The reaction was carried out in the same manner as in step 58-3 of example 58 except for using tert-butyl 5- (2- (dicyanomethylene) hydrazino) -1H-indole-1-carboxylate instead of tert-butyl 5- (4- (2- (dicyanomethylene) hydrazino) phenyl) -1H-indol-1-ylcarboxylate to obtain 15mg (88% yield) of the title compound.

Example 72: preparation of (1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile (Compound 72)

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

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

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

Tert-butyl 5-nitro-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate (600mg, 2.28mmol) prepared according to step 72-1 was dissolved in 5mL of acetic acid solution in the presence of nitrogen, followed by addition of iron (1.2g, 22.80mmol) to give a reaction mixture. The reaction mixture was stirred at room temperature 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 261mg (yield 48%).

Step 72-3: preparation of (1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitriles

The reaction was carried out in the same manner as in step 1-2 of example 1, except that tert-butyl 5-amino-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 128mg (54% yield) of the title compound.

Example 73: preparation of (3-methyl-1H-indazol-6-yl) carbohydrazone acyldinitrile (Compound 73)

Step 73-1: preparation of 3-methyl-6-nitro-1H-indazole-1-carboxylic acid tert-butyl ester

The reaction was carried out in the same manner as in step 72-1 of example 72 except for using 3-methyl-6-nitro-1H-indazole instead of 5-nitro-1H-pyrrolo [2,3-b ] pyridine to obtain 1.43g (92% yield) of the title compound.

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

Tert-butyl 3-methyl-6-nitro-1H-indazole-1-carboxylate prepared according to step 73-1 was dissolved in ethyl acetate and reduced in the same manner as in step 36-2 of example 36 to give 500mg (80% yield) of the title compound.

Step 73-3: preparation of (3-methyl-1H-indazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that tert-butyl 6-amino-3-methyl-1H-indazole-1-carboxylate was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 40mg (10% yield) of the title compound.

Example 74: preparation of (3-methyl-1H-indazol-5-yl) carbohydrazone acyldinitrile (Compound 74)

Step 74-1: preparation of 3-methyl-5-nitro-1H-indazole-1-carboxylic acid tert-butyl ester

The reaction was carried out in the same manner as in step 72-1 of example 72 except for using 3-methyl-5-nitro-1H-indazole (1.29mmol) instead of 5-nitro-1H-pyrrolo [2,3-b ] pyridine to obtain 2.83g (90% yield) of the title compound.

Step 74-2: preparation of 5-amino-3-methyl-1H-indazole-1-carboxylic acid tert-butyl ester

Tert-butyl 3-methyl-5-nitro-1H-indazole-1-carboxylate prepared according to step 74-1 was dissolved in ethyl acetate and reduced in the same manner as in step 36-2 of example 36 to give 761mg (85% yield) of the title compound.

Step 74-3: preparation of (3-methyl-1H-indazol-5-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that tert-butyl 5-amino-3-methyl-1H-indazole-1-carboxylate was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 100mg (15% yield) of the title compound.

Example 75: preparation of (1H-indol-4-yl) carbohydrazone acyldinitrile (Compound 75)

Step 75-1: preparation of 4-amino-1H-indole-1-carboxylic acid tert-butyl ester

Tert-butyl 4-nitro-1H-indole-1-carboxylate was dissolved in acetonitrile (MeCN) and reduced in the same manner as in step 36-2 of example 36 to give 198mg (75% yield) of the title compound.

Step 75-2: preparation of (1H-indol-4-yl) carbohydrazone acyldinitriles

The reaction was carried out in the same manner as in step 1-2 of example 1 except for using tert-butyl 4-amino-1H-indole-1-carboxylate instead of 4- (pyrimidin-2-yl) aniline to obtain 40mg (10% yield) of the title compound.

Example 76: preparation of (1-methyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile (Compound 76)

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

5-Nitro-1H-pyrrolo [2,3-b ] pyridine (600mg, 3.72mmol) was dissolved in DMF (6mL) in the presence of nitrogen, followed by addition of sodium hydride (60%, 300mg, 7.44mmol) followed by addition of methyl iodide (0.93mL, 14.88mmol) to give a reaction mixture. The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 380mg (yield 57%).

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

The reaction was carried out in the same manner as in step 72-2 of example 72 except for using 1-methyl-5-nitro-1H-pyrrolo [2,3-b ] pyridine obtained in step 76-1 in place of tert-butyl 5-nitro-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate to obtain 69mg (55% yield) of the title compound.

Step 76-3: preparation of (1-methyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile

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

Example 77: preparation of (1-propyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile (Compound 77)

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

Reacting 5-nitro-1H-pyrrolo [2,3-b ]]Pyridine (600mg, 3.72mmol), cesium carbonate (CsCO)₃2.4g, 7.44mmol) and 1-iodopropane (1.10mL, 11.01mmol) were dissolved in DMF to give a reaction mixture, which was then stirred at 60 ℃ for 17 hours to give 523mg of the title compound (yield 70%).

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

The reaction was carried out in the same manner as in step 72-2 of example 72 except for using 5-nitro-1-propyl-1H-pyrrolo [2,3-b ] pyridine obtained in step 77-1 in place of tert-butyl 5-nitro-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate, to obtain 297mg (67% yield) of the title compound.

Step 77-3: preparation of (1-propyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1 except that 1-propyl-1H-pyrrolo [2,3-b ] pyridin-5-amine was used instead of 4- (pyrimidin-2-yl) aniline to obtain 98mg (23% yield) of the title compound.

Example 78: preparation of (1-isopropyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile (Compound 78)

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

The reaction was carried out in the same manner as in step 77-1 of example 77 except that 2-iodopropane (1.10mL, 11.01mmol) was used instead of 1-iodopropane to obtain 591mg (78% yield) of the title compound.

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

The reaction was carried out in the same manner as in step 72-2 of example 72 except for using 5-nitro-1-isopropyl-1H-pyrrolo [2,3-b ] pyridine obtained in step 78-1 in place of tert-butyl 5-nitro-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate, to obtain 270mg (54% yield) of the title compound.

Step 78-3: preparation of (1-isopropyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 1-isopropyl-1H-pyrrolo [2,3-b ] pyridin-5-amine was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 81mg (21% yield) of the title compound.

Example 79: preparation of (1-ethyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile (Compound 79)

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

The reaction was carried out in the same manner as in step 77-1 of example 77 except that iodoethane (0.83mL, 10.14mmol) was used instead of 1-iodopropane to obtain 363mg (52% yield) of the title compound.

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

The reaction was carried out in the same manner as in step 72-2 of example 72 except for using 1-ethyl-5-nitro-1H-pyrrolo [2,3-b ] pyridine obtained in step 79-1 in place of tert-butyl 5-nitro-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate, to obtain 184mg (61% yield) of the title compound.

Step 79-3: preparation of (1-ethyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1 except that 1-ethyl-1H-pyrrolo [2,3-b ] pyridin-5-amine was used instead of 4- (pyrimidin-2-yl) aniline to obtain 187mg (69% yield) of the title compound.

Example 80: preparation of (1- (2,2,2-trifluoroethyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile (Compound 80)

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

The reaction was carried out in the same manner as in step 77-1 of example 77 except for using 1,1, 1-trifluoro-2-iodoethane (1.80mL, 18.39mmol) instead of 1-iodopropane to obtain 784mg (52% yield) of the title compound.

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

The reaction was carried out in the same manner as in step 72-2 of example 72 except for using 5-nitro-1- (2,2,2-trifluoroethyl) -1H-pyrrolo [2,3-b ] pyridine obtained in step 80-1 in place of tert-butyl 5-nitro-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate to obtain 235mg (53% yield) of the title compound.

Step 80-3: preparation of (1- (2,2,2-trifluoroethyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1, except that 1- (2,2,2-trifluoroethyl) -1H-pyrrolo [2,3-b ] pyridin-5-amine was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 150mg (55% yield) of the title compound.

Example 81: preparation of (2-methyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile (Compound 81)

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

The reaction was carried out in the same manner as in step 72-1 of example 72 except for using 2-methyl-1H-pyrrolo [2,3-b ] pyridine instead of 5-nitro-1H-pyrrolo [2,3-b ] pyridine to obtain 1.83g (98% yield) of the title compound.

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

Tert-butyl 2-methyl-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate and tetrabutylammonium nitrate were dissolved in dichloromethane in the presence of nitrogen and then stirred at 0 ℃ for 10 minutes. Thereafter, trifluoroacetic anhydride (TFAA, 1.43mL, 0.125mmol) was added, stirred at 0 ℃ for 5 minutes, and then further stirred at room temperature 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 1.34g (yield 61%).

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

The reaction was carried out in the same manner as in step 72-2 of example 72 except for using tert-butyl 2-methyl-5-nitro-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate obtained in step 81-2 instead of tert-butyl 5-nitro-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate, to obtain 311mg (58% yield) of the title compound.

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

The reaction was carried out in the same manner as in step 1-2 of example 1 except for using tert-butyl 5-amino-2-methyl-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate instead of 4- (pyrimidin-2-yl) aniline to obtain 160mg (68% yield) of the title compound.

Step 81-5: preparation of (2-methyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 58-3 of example 58 except for using tert-butyl 5- (2- (dicyanomethylene) hydrazino) -2-methyl-1H-pyrrolo [2,3-b ] pyridin-1-ylcarboxylate instead of tert-butyl 5- (4- (2- (dicyanomethylene) hydrazino) phenyl) -1H-indol-1-ylcarboxylate to obtain 29mg (71% yield) of the title compound.

Example 82: preparation of (3-methyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile (Compound 82)

Step 82-1: preparation of 3-methyl-1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

The reaction was carried out in the same manner as in step 72-1 of example 72 except for using 3-methyl-1H-pyrrolo [2,3-b ] pyridine instead of 5-nitro-1H-pyrrolo [2,3-b ] pyridine to obtain 3.4g (97% yield) of the title compound.

Step 82-2: preparation of 3-methyl-5-nitro-1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

The reaction was carried out in the same manner as in step 81-2 of example 81 except for using tert-butyl 3-methyl-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate instead of tert-butyl 2-methyl-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate to obtain 800mg (42% yield) of the title compound.

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

Tert-butyl 3-methyl-5-nitro-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate is dissolved in ethyl acetate and reduced in the same manner as in step 36-2 of example 36 to give 367mg (82% yield) of the title compound.

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

The reaction was carried out in the same manner as in step 1-2 of example 1, except that tert-butyl 5-amino-3-methyl-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate was used instead of 4- (pyrimidin-2-yl) aniline, to obtain 106mg (40% yield) of the title compound.

Step 82-5: preparation of (3-methyl-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile

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

Example 83: preparation of (3-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile (Compound 83)

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

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

Step 83-2: preparation of 3-chloro-5-nitro-1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

The reaction was carried out in the same manner as in step 72-1 of example 72 except for using 3-chloro-5-nitro-1H-pyrrolo [2,3-b ] pyridine in place of 5-nitro-1H-pyrrolo [2,3-b ] pyridine to obtain 419g (70% yield) of the title compound.

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

Tert-butyl 3-chloro-5-nitro-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate is dissolved in ethyl acetate and reduced in the same manner as in step 36-2 of example 36 to give 118mg (60% yield) of the title compound.

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

The reaction was carried out in the same manner as in step 1-2 of example 1 except for using tert-butyl 5-amino-3-chloro-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate instead of 4- (pyrimidin-2-yl) aniline to obtain 35mg (23% yield) of the title compound.

Step 83-5: preparation of (3-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile

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

Example 84: preparation of (4-methoxy-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile (Compound 84)

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

The reaction was carried out in the same manner as in step 81-2 of example 81 except for using 4-chloro-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridine in place of tert-butyl 2-methyl-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate to obtain 2.0mg (60% yield) of the title compound.

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

4-chloro-5-nitro-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridine and solid potassium carbonate were dissolved in methanol in the presence of nitrogen: water 3: 1, and refluxing for 7 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 235mg (yield 68%).

Step 84-3: preparation of 4-methoxy-5-nitro-1H-pyrrolo [2,3-b ] pyridine-1-carboxylic acid tert-butyl ester

The reaction was carried out in the same manner as in step 72-1 of example 72 except for using 4-methoxy-5-nitro-1H-pyrrolo [2,3-b ] pyridine in place of 5-nitro-1H-pyrrolo [2,3-b ] pyridine to obtain 234mg (77% yield) of the title compound.

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

Tert-butyl 4-methoxy-5-nitro-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate is dissolved in ethyl acetate and reduced in the same manner as in step 36-2 of example 36 to give 107mg (99% yield) of the title compound.

Step 84-5: preparation of (4-methoxy-1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 1-2 of example 1 except for using tert-butyl 5-amino-4-methoxy-1H-pyrrolo [2,3-b ] pyridine-1-carboxylate instead of 4- (pyrimidin-2-yl) aniline to obtain 22mg (17% yield) of the title compound.

Example 85: preparation of (2- (dimethylcarbamoyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitrile (Compound 85)

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

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

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

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

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

N, N-dimethyl-5-nitro-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridine-2-carboxamide (0.95mmol) and solid potassium tert-butoxide (0.95mmol) were dissolved in dioxane (15mL) in the presence of nitrogen and stirred at 80 ℃ 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 71mg (yield 48%).

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

The reaction was carried out in the same manner as in step 72-1 of example 72 except for using N, N-dimethyl-5-nitro-1H-pyrrolo [2,3-b ] pyridine-2-carboxamide instead of 5-nitro-1H-pyrrolo [2,3-b ] pyridine-2-carboxamide, to obtain 100mg (99% yield) of the title compound.

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

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

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

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

Step 85-7: preparation of (2- (dimethylcarbamoyl) -1H-pyrrolo [2,3-b ] pyridin-5-yl) carbohydrazone acyldinitriles

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

Example 86: preparation of (2- (4-methoxybenzamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 86)

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

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

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

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

Step 86-3: preparation of (2- (4-methoxybenzamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

Except that N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide was used instead of 4- (pyrimidin-2-yl) aniline, 10: a reaction was carried out in the same manner as in step 1-2 of example 1 except that a mixed solution of ethanol and water of 3 was used as a solvent and a 35% aqueous HCl solution was used as an acidic solution, to obtain 78mg (69% yield) of the title compound.

Example 87: preparation of (2- (2-hydroxybenzamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 87)

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

The reaction was carried out in the same manner as in step 86-1 of example 86, except that 2-hydroxybenzoic acid (3.62mmol) was used instead of 4-methoxybenzoic acid, to give 611mg (65% yield) of the title compound.

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

The reaction was carried out in the same manner as in step 86-2 of example 86, except that 2-hydroxy-N- (6-nitrobenzo [ d ] thiazol-2-yl) benzamide prepared according to step 87-1 was used instead of 4-methoxy-N- (6-nitrobenzo [ d ] thiazol-2-yl) benzamide to obtain 48mg (53% yield) of the title compound.

Step 87-3: preparation of (2- (2-hydroxybenzamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

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

Example 88: preparation of (2-acetamidobenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 88)

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

6-Nitrobenzo [ d ] thiazol-2-amine was dissolved in MeCN in the presence of nitrogen, followed by the addition of DIPEA and acetic anhydride to give a reaction mixture, and the reaction mixture was stirred at 60 ℃ for 14 hours. After the reaction was complete, the reaction product was filtered using MeCN to give 200mg (75% yield) of the title compound as a solid filtrate.

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

The reaction was carried out in the same manner as in step 86-2 of example 86, except that N- (6-nitrobenzo [ d ] thiazol-2-yl) acetamide was used instead of 4-methoxy-N- (6-nitrobenzo [ d ] thiazol-2-yl) benzamide, to obtain 66mg (83% yield) of the title compound.

Step 88-3: preparation of (2-acetamidobenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that N- (6-aminobenzo [ d ] thiazol-2-yl) acetamide was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 28mg (42% yield) of the title compound.

Example 89: preparation of (2- (3-cyanobenzoylamino) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 89)

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

The reaction was carried out in the same manner as in step 86-1 of example 86, except that 3-cyanobenzoic acid (3.62mmol) was used instead of 4-methoxybenzoic acid, to give 718mg (65% yield) of the title compound.

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

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

Step 89-3: preparation of (2- (3-cyanobenzamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that N- (6-aminobenzo [ d ] thiazol-2-yl) -3-cyanobenzamide was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 33mg (52% yield) of the title compound.

Example 90: preparation of (2- (5-methylnicotinamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 90)

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

The reaction was carried out in the same manner as in step 86-1 of example 86, except that 5-methylnicotinic acid (3.65mmol) was used instead of 4-methoxybenzoic acid, to give 1.02g (88% yield) of the title compound.

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

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

Step 90-3: preparation of (2- (5-methylnicotinamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

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

Example 91: preparation of (2- (3-hydroxypicolinamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 91)

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

The reaction was carried out in the same manner as in step 86-1 of example 86, except that 3-hydroxypicolinic acid (1.44mmol) was used instead of 4-methoxybenzoic acid, to give 327mg (72% yield) of the title compound.

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

The reaction was carried out in the same manner as in step 86-2 of example 86, except that 3-hydroxy-N- (6-nitrobenzo [ d ] thiazol-2-yl) pyridinecarboxamide was used instead of 4-methoxy-N- (6-nitrobenzo [ d ] thiazol-2-yl) benzamide to obtain 46mg (51% yield) of the title compound.

Step 91-3: preparation of (2- (3-hydroxypicolinamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

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

Example 92: preparation of (2- (pyrazine-2-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 92)

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

The reaction was carried out in the same manner as in step 86-1 of example 86, except that pyrazine-2-carboxylic acid (3.65mmol) was used instead of 4-methoxybenzoic acid, to give 870mg (71% yield) of the title compound.

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

The reaction was carried out in the same manner as in step 86-2 of example 86, except that N- (6-nitrobenzo [ d ] thiazol-2-yl) pyrazine-2-carboxamide was used instead of 4-methoxy-N- (6-nitrobenzo [ d ] thiazol-2-yl) benzamide to obtain 155mg (87% yield) of the title compound.

Step 92-3: preparation of (2- (pyrazine-2-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that N- (6-aminobenzo [ d ] thiazol-2-yl) pyrazine-2-carboxamide was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 55mg (43% yield) of the title compound.

Example 93: preparation of (2- (5-methylpyrazine-2-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 93)

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

The reaction was carried out in the same manner as in step 86-1 of example 86, except that 5-methylpyrazine-2-carboxylic acid (3.65mmol) was used instead of 4-methoxybenzoic acid, to obtain 766mg (67% yield) of the title compound.

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

The reaction was carried out in the same manner as in step 86-2 of example 86, except that 5-methyl-N- (6-nitrobenzo [ d ] thiazol-2-yl) pyrazine-2-carboxamide was used instead of 4-methoxy-N- (6-nitrobenzo [ d ] thiazol-2-yl) benzamide to obtain 165mg (92% yield) of the title compound.

Step 93-3: preparation of (2- (5-methylpyrazine-2-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

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

Example 94: preparation of (2- (pyrimidine-5-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 94)

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

The reaction was carried out in the same manner as in step 86-1 of example 86, except that pyrimidine-5-carboxylic acid (3.65mmol) was used instead of 4-methoxybenzoic acid, to give 510mg (70% yield) of the title compound.

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

The reaction was carried out in the same manner as in step 86-2 of example 86, except that N- (6-nitrobenzo [ d ] thiazol-2-yl) pyrimidine-5-carboxamide was used instead of 4-methoxy-N- (6-nitrobenzo [ d ] thiazol-2-yl) benzamide to obtain 113mg (83% yield) of the title compound.

Step 94-3: preparation of (2- (pyrimidine-5-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that N- (6-aminobenzo [ d ] thiazol-2-yl) pyrimidine-5-carboxamide was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 15mg (24% yield) of the title compound.

Example 95: preparation of (2- (2-methylpyrimidine-5-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 95)

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

The reaction was carried out in the same manner as in step 86-1 of example 86, except that 2-methylpyrimidine-5-carboxylic acid (3.65mmol) was used instead of 4-methoxybenzoic acid, to obtain 414mg (61% yield) of the title compound.

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

The reaction was carried out in the same manner as in step 86-2 of example 86, except that 2-methyl-N- (6-nitrobenzo [ d ] thiazol-2-yl) pyrimidine-5-carboxamide was used instead of 4-methoxy-N- (6-nitrobenzo [ d ] thiazol-2-yl) benzamide to obtain 119mg (88% yield) of the title compound.

Step 95-3: preparation of (2- (2-methylpyrimidine-5-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

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

Example 96: preparation of (2- (4-methylpyrimidine-5-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 96)

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

The reaction was carried out in the same manner as in step 86-1 of example 86, except that 4-methylpyrimidine-5-carboxylic acid (3.65mmol) was used instead of 4-methoxybenzoic acid, to obtain 327mg (72% yield) of the title compound.

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

The reaction was carried out in the same manner as in step 86-2 of example 86, except that 4-methyl-N- (6-nitrobenzo [ d ] thiazol-2-yl) pyrimidine-5-carboxamide was used instead of 4-methoxy-N- (6-nitrobenzo [ d ] thiazol-2-yl) benzamide to obtain 131mg (96% yield) of the title compound.

Step 96-3: preparation of (2- (4-methylpyrimidine-5-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

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

Example 97: preparation of (2- (3-methylpyrazine-2-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 97)

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

The reaction was carried out in the same manner as in step 86-1 of example 86, except that 3-methylpyrazine-2-carboxylic acid (3.65mmol) was used instead of 4-methoxybenzoic acid, to obtain 542mg (79% yield) of the title compound.

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

The reaction was carried out in the same manner as in step 86-2 of example 86, except that 3-methyl-N- (6-nitrobenzo [ d ] thiazol-2-yl) pyrazine-2-carboxamide was used instead of 4-methoxy-N- (6-nitrobenzo [ d ] thiazol-2-yl) benzamide to obtain 158mg (88% yield) of the title compound.

Step 97-3: preparation of (2- (3-methylpyrazine-2-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that N- (6-aminobenzo [ d ] thiazol-2-yl) -3-methylpyrazine-2-carboxamide was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 86mg (68% yield) of the title compound.

Example 98: preparation of (2- (6-methylpyrazine-2-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 98)

Step 98-1: preparation of 6-methyl-N- (6-nitrobenzo [ d ] thiazol-2-yl) pyrazine-2-carboxamide

The reaction was carried out in the same manner as in step 86-1 of example 86, except that 6-methylpyrazine-2-carboxylic acid (3.65mmol) was used instead of 4-methoxybenzoic acid, to obtain 542mg (79% yield) of the title compound.

Step 98-2: preparation of N- (6-aminobenzo [ d ] thiazol-2-yl) -6-methylpyrazine-2-carboxamide

The reaction was carried out in the same manner as in step 86-2 of example 86, except that 6-methyl-N- (6-nitrobenzo [ d ] thiazol-2-yl) pyrazine-2-carboxamide was used instead of 4-methoxy-N- (6-nitrobenzo [ d ] thiazol-2-yl) benzamide to obtain 105mg (58% yield) of the title compound.

Step 98-3: preparation of (2- (6-methylpyrazine-2-carboxamido) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that N- (6-aminobenzo [ d ] thiazol-2-yl) -6-methylpyrazine-2-carboxamide was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 54mg (53% yield) of the title compound.

Example 99: preparation of (2- (pyrazine-2-carboxamido) benzo [ d ] thiazol-5-yl) carbohydrazone acyldinitrile (Compound 99)

Step 99-1: preparation of N- (5-nitrobenzo [ d ] thiazol-2-yl) pyrazine-2-carboxamide

The reaction was carried out in the same manner as in step 86-1 of example 86, except that pyrazine-2-carboxylic acid (3.65mmol) was used instead of 4-methoxybenzoic acid and 5-nitrobenzo [ d ] thiazol-2-amine was used instead of 6-nitrobenzo [ d ] thiazol-2-amine, to obtain 486mg (67% yield) of the title compound.

Step 99-2: preparation of N- (5-aminobenzo [ d ] thiazol-2-yl) pyrazine-2-carboxamide

The reaction was carried out in the same manner as in step 86-2 of example 86, except that N- (5-nitrobenzo [ d ] thiazol-2-yl) pyrazine-2-carboxamide was used instead of 4-methoxy-N- (6-nitrobenzo [ d ] thiazol-2-yl) benzamide to obtain 110mg (81% yield) of the title compound.

Step 99-3: preparation of (2- (pyrazine-2-carboxamido) benzo [ d ] thiazol-5-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that N- (5-aminobenzo [ d ] thiazol-2-yl) pyrazine-2-carboxamide was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 22mg (21% yield) of the title compound.

Example 100: preparation of (2- (5-methylpyrazine-2-carboxamido) benzo [ d ] thiazol-5-yl) carbohydrazone acyldinitrile (Compound 100)

Step 100-1: preparation of 5-methyl-N- (5-nitrobenzo [ d ] thiazol-2-yl) pyrazine-2-carboxamide

The reaction was carried out in the same manner as in step 86-1 of example 86, except that 5-methylpyrazine-2-carboxylic acid (3.65mmol) was used instead of 4-methoxybenzoic acid and 5-nitrobenzo [ d ] thiazol-2-amine was used instead of 6-nitrobenzo [ d ] thiazol-2-amine, to obtain 512mg (75% yield) of the title compound.

Step 100-2: preparation of N- (5-aminobenzo [ d ] thiazol-2-yl) -5-methylpyrazine-2-carboxamide

The reaction was carried out in the same manner as in step 86-2 of example 86, except that 5-methyl-N- (5-nitrobenzo [ d ] thiazol-2-yl) pyrazine-2-carboxamide was used instead of 4-methoxy-N- (6-nitrobenzo [ d ] thiazol-2-yl) benzamide to obtain 83mg (65% yield) of the title compound.

Step 100-3: preparation of (2- (5-methylpyrazine-2-carboxamido) benzo [ d ] thiazol-5-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that N- (5-aminobenzo [ d ] thiazol-2-yl) -5-methylpyrazine-2-carboxamide was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 102mg (80% yield) of the title compound.

Example 101: preparation of (2-phenylbenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 101)

Step 101-1: preparation of 2-bromo-6-nitrobenzo [ d ] thiazole

6-Nitrobenzo [ d ] thiazol-2-amine (500mg, 2.56mmol) was dissolved in water, and CuBr (55mg, 0.38mmol) and 48% HBr (5mL) were added to give a reaction mixture. Then, sodium nitrite (1.41g, 20.48mmol) was added to the reaction mixture at 0 ℃ and the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction product was extracted twice with a saturated aqueous NaCl solution and ethyl acetate, and the water was dried with anhydrous magnesium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with methanol and filtered to give 564mg (85% yield) of the title compound as a solid.

Step 101-2: preparation of 2-bromobenzo [ d ] thiazol-6-amine

2-bromo-6-nitrobenzo [ d ] thiazole and Fe (539mg, 9.65mmol) obtained in step 101-1 were dissolved in acetic acid to give a reaction mixture, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction product was extracted twice with a saturated aqueous NaCl solution and ethyl acetate, and the water was dried with anhydrous magnesium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 342mg (yield 69%).

Step 101-3: preparation of 2-phenylbenzo [ d ] thiazol-6-amine

The reaction was carried out in the same manner as in step 1-1 of example 1 except for using 2-bromobenzo [ d ] thiazol-6-amine instead of 2-bromopyrimidine, using phenyl boronic acid pinacol ester instead of 4-aminophenylboronic acid pinacol ester, and using aqueous potassium carbonate solution instead of aqueous sodium carbonate solution, to obtain 56mg (48% yield) of the title compound.

Step 101-4: preparation of (2-phenylbenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitriles

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 2-phenylbenzo [ d ] thiazol-6-amine was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 46mg (76% yield) of the title compound.

Example 102: preparation of (2- (4-fluorophenyl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 102)

Step 102-1: preparation of 2- (4-fluorophenyl) benzo [ d ] thiazol-6-amine

The reaction was carried out in the same manner as in step 101-3 of example 101 except for using 4-fluorophenylboronic acid pinacol ester in place of phenylboronic acid pinacol ester to obtain 30mg (28% yield) of the title compound.

Step 102-2: preparation of (2- (4-fluorophenyl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 2- (4-fluorophenyl) benzo [ d ] thiazol-6-amine was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 31mg (79% yield) of the title compound.

Example 103: preparation of (2- (4- (dimethylamino) phenyl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 103)

Step 103-1: preparation of 2- (4- (dimethylamino) phenyl) benzo [ d ] thiazol-6-amine

The reaction was carried out in the same manner as in step 101-3 of example 101 except that 4- (dimethylamino) phenylboronic acid pinacol ester was used instead of the phenylboronic acid pinacol ester to obtain 43mg (37% yield) of the title compound.

Step 103-2: preparation of (2- (4- (dimethylamino) phenyl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 2- (4- (dimethylamino) phenyl) benzo [ d ] thiazol-6-amine was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 31mg (79% yield) of the title compound.

Example 104: preparation of (2- (pyridin-3-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 104)

Step 104-1: preparation of 2- (pyridin-3-yl) benzo [ d ] thiazol-6-amine hydrochloride

A reaction was carried out in the same manner as in step 101-3 of example 101, except that pyridin-3-ylboronic acid pinacol ester was used in place of phenylboronic acid pinacol ester. 48mg (41% yield) of the title compound are obtained as the hydrochloride salt by dissolving in dioxane as 4M HCl solution.

Step 104-2: preparation of (2- (pyridin-3-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 2- (pyridin-3-yl) benzo [ d ] thiazol-6-amine hydrochloride was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 15mg (26% yield) of the title compound.

Example 105: preparation of (2- (6-methylpyridin-3-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 105)

Step 105-1: preparation of 2- (6-methylpyridin-3-yl) benzo [ d ] thiazol-6-amine

The reaction was carried out in the same manner as in step 101-3 of example 101 except for using 6-methylpyridin-3-ylboronic acid pinacol ester in place of phenylboronic acid pinacol ester to obtain 68mg (52% yield) of the title compound.

Step 105-2: preparation of (2- (6-methylpyridin-3-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 2- (6-methylpyridin-3-yl) benzo [ d ] thiazol-6-amine was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 6mg (9% yield) of the title compound.

Example 106: preparation of (2- (6-fluoropyridin-3-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 106)

Step 106-1: preparation of 2- (6-fluoropyridin-3-yl) benzo [ d ] thiazol-6-amine

The reaction was carried out in the same manner as in step 101-3 of example 101 except for using 6-fluoropyridin-3-ylboronic acid pinacol ester in place of phenylboronic acid pinacol ester to obtain 25mg (23% yield) of the title compound.

Step 106-2: preparation of (2- (6-fluoropyridin-3-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 2- (6-fluoropyridin-3-yl) benzo [ d ] thiazol-6-amine was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 22mg (63% yield) of the title compound.

Example 107: preparation of (2- (furan-2-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 107)

Step 107-1: preparation of 2- (furan-2-yl) benzo [ d ] thiazol-6-amine hydrochloride

A reaction was carried out in the same manner as in step 101-3 of example 101, except that the pinacol ester of furan-2-ylboronic acid was used in place of the pinacol ester of phenylboronic acid. 68mg (61% yield) of the title compound are obtained as the hydrochloride salt by dissolving in dioxane as 4M HCl solution.

Step 107-2: preparation of (2- (furan-2-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 2- (furan-2-yl) benzo [ d ] thiazol-6-amine hydrochloride was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 53mg (48% yield) of the title compound.

Example 108: preparation of (2- (thien-2-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 108)

Step 108-1: preparation of 2- (thien-2-yl) benzo [ d ] thiazol-6-amine hydrochloride

A reaction was carried out in the same manner as in step 101-3 of example 101, except that thiophen-2-ylboronic acid pinacol ester was used in place of phenylboronic acid pinacol ester. 32mg (27% yield) of the title compound are obtained as the hydrochloride salt by dissolving in dioxane as 4M HCl solution.

Step 108-2: preparation of (2- (thien-2-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitriles

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 2- (thiophen-2-yl) benzo [ d ] thiazol-6-amine hydrochloride was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 13mg (27% yield) of the title compound.

Example 109: preparation of (2- (5-fluoropyridin-3-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 109)

Step 109-1: preparation of 2- (5-fluoropyridin-3-yl) benzo [ d ] thiazol-6-amine hydrochloride

A reaction was carried out in the same manner as in step 101-3 of example 101, except that pinacol ester of phenyl boronic acid was replaced with pinacol ester of 5-fluoropyridin-3-yl boronic acid. 56mg (45% yield) of the title compound are obtained as the hydrochloride salt by dissolving in dioxane as 4M HCl solution.

Step 109-2: preparation of (2- (5-fluoropyridin-3-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 2- (5-fluoropyridin-3-yl) benzo [ d ] thiazol-6-amine hydrochloride was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 42mg (57% yield) of the title compound.

Example 110: preparation of (2- (5-methylpyridin-3-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 110)

Step 110-1: preparation of 2- (5-methylpyridin-3-yl) benzo [ d ] thiazol-6-amine hydrochloride

A reaction was carried out in the same manner as in step 101-3 of example 101, except that pinacol ester of phenyl boronic acid was replaced with pinacol ester of 5-methylpyridin-3-ylboronic acid. 56mg (45% yield) of the title compound are obtained as the hydrochloride salt by dissolving in dioxane as 4M HCl solution.

Step 110-2: preparation of (2- (5-methylpyridin-3-yl) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 2- (5-methylpyridin-3-yl) benzo [ d ] thiazol-6-amine hydrochloride was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 9mg (36% yield) of the title compound.

Example 111: preparation of (2- (pyridin-3-yl) benzo [ d ] thiazol-5-yl) carbohydrazone acyldinitrile (Compound 111)

Step 111-1: preparation of 2-bromo-5-nitrobenzo [ d ] thiazoles

The reaction was carried out in the same manner as in step 101-1 of example 101 except that 5-nitrobenzo [ d ] thiazol-2-amine was used instead of 6-nitrobenzo [ d ] thiazol-2-amine to obtain 780mg (59% yield) of the title compound.

Step 111-2: preparation of 2-bromobenzo [ d ] thiazol-5-amine

The reaction was carried out in the same manner as in step 101-2 of example 101 except for using 2-bromo-5-nitrobenzo [ d ] thiazole instead of 2-bromo-6-nitrobenzo [ d ] thiazole to obtain 153mg (58% yield) of the title compound.

Step 111-3: preparation of 2- (pyridin-3-yl) benzo [ d ] thiazol-5-amine

The reaction was carried out in the same manner as in step 101-3 of example 101 except for using 2-bromobenzo [ d ] thiazol-5-amine instead of 2-bromobenzo [ d ] thiazol-6-amine and using pyridin-3-ylboronic acid pinacol ester instead of phenylboronic acid pinacol ester to obtain 48mg (48% yield) of the title compound.

Step 111-4: preparation of (2- (pyridin-3-yl) benzo [ d ] thiazol-5-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 2- (pyridin-3-yl) benzo [ d ] thiazol-5-amine was used instead of 2N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 18mg (23% yield) of the title compound.

Example 112: preparation of (2- (5-methylpyridin-3-yl) benzo [ d ] thiazol-5-yl) carbohydrazone acyldinitrile (Compound 112)

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 2- (5-methylpyridin-3-yl) benzo [ d ] thiazol-5-amine was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 26mg (39% yield) of the title compound.

Example 113: preparation of benzo [ d ] thiazol-2-yl-carbohydrazone acyldinitrile (Compound 113)

The reaction was carried out in the same manner as in step 86-3 of example 86, except that benzo [ d ] thiazol-2-yl) -4-methoxybenzamide was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, and water was used as a solvent, to obtain 29mg (19% yield) of the title compound.

Example 114: preparation of (6-fluorobenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile (Compound 114)

The reaction was carried out in the same manner as in example 113, except that 6-fluorobenzo [ d ] thiazol-2-amine was used instead of benzo [ d ] thiazol-2-amine, to obtain 29mg (19% yield) of the title compound.

Example 115: preparation of (6-chlorobenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile (Compound 115)

The reaction was carried out in the same manner as in example 113, except that 6-chlorobenzo [ d ] thiazol-2-amine was used instead of benzo [ d ] thiazol-2-amine, to obtain 29mg (21% yield) of the title compound.

Example 116: preparation of (6-bromobenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile (Compound 116)

The reaction was carried out in the same manner as in example 113, except that 6-bromobenzo [ d ] thiazol-2-amine was used instead of benzo [ d ] thiazol-2-amine, to obtain 23mg (17% yield) of the title compound.

Example 117: preparation of (6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile (Compound 117)

The reaction was carried out in the same manner as in example 113, except that 6- (trifluoromethyl) benzo [ d ] thiazol-2-amine was used instead of benzo [ d ] thiazol-2-amine, to obtain 27mg (20% yield) of the title compound.

Example 118: preparation of (4-chlorobenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile (Compound 118)

The reaction was carried out in the same manner as in example 113, except that 4-chlorobenzo [ d ] thiazol-2-amine was used instead of benzo [ d ] thiazol-2-amine, to obtain 20mg (15% yield) of the title compound.

Example 119: preparation of (5-chlorobenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile (Compound 119)

The reaction was carried out in the same manner as in example 113, except that 5-chlorobenzo [ d ] thiazol-2-amine was used instead of benzo [ d ] thiazol-2-amine, to obtain 11mg (8% yield) of the title compound.

Example 120: preparation of (5-bromobenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile (Compound 120)

The reaction was carried out in the same manner as in example 113, except that 5-bromobenzo [ d ] thiazol-2-amine was used instead of benzo [ d ] thiazol-2-amine, to obtain 18mg (7% yield) of the title compound.

Example 121: preparation of (6-methoxybenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile (Compound 121)

The reaction was carried out in the same manner as in example 113, except that 6-methoxybenzo [ d ] thiazol-2-amine was used instead of benzo [ d ] thiazol-2-amine, to obtain 26mg (18% yield) of the title compound.

Example 122: preparation of (6-ethoxybenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile (Compound 122)

The reaction was carried out in the same manner as in example 113, except that 6-ethoxybenzo [ d ] thiazol-2-amine was used instead of benzo [ d ] thiazol-2-amine, to obtain 40mg (29% yield) of the title compound.

Example 123: preparation of (6- (trifluoromethoxy) benzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile (Compound 123)

The reaction was carried out in the same manner as in example 113, except that 6- (trifluoromethoxy) benzo [ d ] thiazol-2-amine was used instead of benzo [ d ] thiazol-2-amine, to obtain 15mg (10% yield) of the title compound.

Example 124: preparation of (6-methylbenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile (Compound 124)

The reaction was carried out in the same manner as in example 113, except that 6-methylbenzo [ d ] thiazol-2-amine was used instead of benzo [ d ] thiazol-2-amine, to obtain 36mg (24% yield) of the title compound.

Example 125: preparation of (4-methylbenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile (Compound 125)

The reaction was carried out in the same manner as in example 113, except that 4-methylbenzo [ d ] thiazol-2-amine was used instead of benzo [ d ] thiazol-2-amine, to obtain 68mg (46% yield) of the title compound.

Example 126: preparation of (4,6-dimethylbenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile (Compound 126)

The reaction was carried out in the same manner as in example 113, except that 4,6-dimethylbenzo [ d ] thiazol-2-amine was used instead of benzo [ d ] thiazol-2-amine, to obtain 41mg (29% yield) of the title compound.

Example 127: preparation of (5,6-dimethylbenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile (Compound 127)

The reaction was carried out in the same manner as in example 113, except that 5,6-dimethylbenzo [ d ] thiazol-2-amine was used instead of benzo [ d ] thiazol-2-amine, to obtain 32mg (22% yield) of the title compound.

Example 128: preparation of (6-phenoxybenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile (Compound 128)

The reaction was carried out in the same manner as in example 113, except that 6-phenoxybenzo [ d ] thiazol-2-amine was used instead of benzo [ d ] thiazol-2-amine, to obtain 6mg (4% yield) of the title compound.

Example 129: preparation of (6-phenylbenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile (Compound 129)

Step 129-1: preparation of 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] thiazol-2-amine

Reacting 6-bromobenzo [ d ] in the presence of nitrogen]Thiazol-2-amine (50mg, 0.22mmol) was dissolved in dioxane and Pd (dppf) Cl was added₂-DCM (36mg, 0.04mmol), bis (pinacolato) diboron (84mg, 0.33mmol), and potassium acetate (65mg, 0.66mmol) to give a reaction mixture. The reaction mixture was stirred at 90 ℃ 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 38mg (yield 62%).

Step 129-2: preparation of 6-phenylbenzo [ d ] thiazol-2-amine

The reaction was carried out in the same manner as in step 101-3 of example 101 except for using bromobenzene in place of 2-bromobenzo [ d ] thiazol-6-ylamine and using 2-aminobenzo [ d ] thiazol-6-ylboronic acid pinacol ester in place of phenylboronic acid pinacol ester to obtain 81mg (50% yield) of the title compound.

Step 129-3: preparation of (6-phenylbenzo [ d ] thiazol-2-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in example 113, except that 6-phenylbenzo [ d ] thiazol-2-amine was used instead of benzo [ d ] thiazol-2-amine, to obtain 6mg (5% yield) of the title compound.

Example 130: preparation of (3- (pyrazine-2-carboxamido) benzo [ d ] isoxazol-5-yl) carbohydrazone acyldinitrile (Compound 130)

Step 130-1: preparation of 5- (tert-butoxycarbonyl) amino-2-fluorobenzonitrile and 5-di (tert-butoxycarbonyl) amino-2-fluorobenzonitrile

5-amino-2-fluorobenzonitrile (1g, 7.35mmol) and DMAP (4-dimethylaminopyridine, 90mg, 0.74mmol) were dissolved in DCM in the presence of nitrogen and di-tert-butyl dicarbonate ((Boc) was added₂O, 2.4g, 11.02mmol) to give a reaction mixture. The reaction mixture was refluxed 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give 1.8g of the title compounds (5- (tert-butoxycarbonyl) amino-2-fluorobenzonitrile and 5-bis (tert-butoxycarbonyl) amino-2-fluorobenzonitrile).

Step 130-2: preparation of 3-aminobenzo [ d ] isoxazol-5-ylcarbamic acid tert-butyl ester

Potassium carbonate (8.34g, 60.36mmol) and acetohydroxamic acid (2.27g, 30.18mmol) were dissolved in DCM/H in the presence of nitrogen₂To O, a mixture (1.44g) of 5- (tert-butoxycarbonyl) amino-2-fluorobenzonitrile and 5-bis (tert-butoxycarbonyl) amino-2-fluorobenzonitrile prepared according to step 130-1 was then added to obtain a reaction mixture. The reaction mixture was stirred 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with diethyl ether and then filtered to obtain 743mg of the title compound.

Step 130-3: preparation of 3- (pyrazine-2-carboxamido) benzo [ d ] isoxazol-5-ylcarbamic acid tert-butyl ester

Pyrazine-2-carboxylic acid (200mg, 1.61mmol) was dissolved in DCM in the presence of nitrogen, then oxalyl chloride (0.25mL, 2.93mmol) and a drop of DMF were added to give a reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. Then, 3-aminobenzo [ d ] isoxazol-5-ylcarbamic acid tert-butyl ester (365mg, 1.47mmol) prepared according to step 130-2 and pyridine were added, and the reaction mixture was stirred 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with methanol and then filtered to obtain 225mg (yield 43%) of the title compound.

Step 130-4: preparation of 3- (pyrazine-2-carboxamido) benzo [ d ] isoxazole-5-ammonium 2,2, 2-trifluoroacetate

Tert-butyl 3- (pyrazine-2-carboxamido) benzo [ d ] isoxazol-5-ylcarbamate (100mg, 0.28mmol) prepared according to step 130-3 was dissolved in DCM in the presence of nitrogen, and trifluoroacetic acid (0.43mL, 5.63mmol) was then added to give a reaction mixture. The reaction mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction product was concentrated under reduced pressure and then dried for 4 hours. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with methanol and then filtered to obtain 225mg (yield 43%) of the title compound. Then, the concentrate was solidified with ethyl acetate, and then filtered to obtain 97mg (yield 93%) of the title compound.

Step 130-5: preparation of (3- (pyrazine-2-carboxamido) benzo [ d ] isoxazol-5-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 3- (pyrazine-2-carboxamido) benzo [ d ] isoxazol-5-ammonium 2,2, 2-trifluoroacetate was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 29mg (63% yield) of the title compound.

Example 131: preparation of (3- (5-methylpyrazine-2-carboxamido) benzo [ d ] isoxazol-5-yl) carbohydrazone acyldinitrile (Compound 131)

Step 131-1: preparation of tert-butyl 3- (5-methylpyrazine-2-carboxamido) benzo [ d ] isoxazol-5-ylcarbamate

The reaction was carried out in the same manner as in step 130-3 of example 130, except that 5-methylpyrazine-2-carboxylic acid was used instead of pyrazine-2-carboxylic acid, to obtain 209mg (43% yield) of the title compound.

Step 131-2: preparation of 3- (5-methylpyrazine-2-carboxamido) benzo [ d ] isoxazole-5-ammonium 2,2, 2-trifluoroacetate

The reaction was carried out in the same manner as in step 130-4 of example 130 except for using tert-butyl 3- (5-methylpyrazine-2-carboxamido) benzo [ d ] isoxazol-5-ylcarbamate in place of tert-butyl 3- (pyrazine-2-carboxamido) benzo [ d ] isoxazol-5-ylcarbamate to obtain 84mg (81% yield) of the title compound.

Step 131-3: preparation of (3- (5-methylpyrazine-2-carboxamido) benzo [ d ] isoxazol-5-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 3- (5-methylpyrazine-2-carboxamido) benzo [ d ] isoxazol-5-ammonium 2,2, 2-trifluoroacetate was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to give 34mg (75% yield) of the title compound.

Example 132: preparation of (3- (3-cyanobenzoylamino) benzo [ d ] isoxazol-5-yl) carbohydrazone acyldinitrile (Compound 132)

Step 132-1: preparation of tert-butyl 3- (3-cyanobenzoylamino) benzo [ d ] isoxazol-5-ylcarbamate

The reaction was carried out in the same manner as in step 130-3 of example 130, except that 3-cyanobenzoic acid was used instead of pyrazine-2-carboxylic acid, to give 203mg (43% yield) of the title compound.

Step 132-2: preparation of N- (5-aminobenzo [ d ] isoxazol-3-yl) -3-cyanobenzamide

Tert-butyl 3- (3-cyanobenzoylamino) benzo [ d ] isoxazol-5-ylcarbamate prepared according to step 132-1 was dissolved in DCM in the presence of nitrogen, and trifluoroacetic acid was then added to give a reaction mixture. The reaction mixture was stirred at room temperature for 6 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 then filtered. The filtrate was concentrated under reduced pressure and dried for 4 hours. Then, the concentrate was solidified with ethyl acetate, and then filtered to obtain 71mg (yield 96%) of the title compound.

Step 132-3: preparation of (3- (3-cyanobenzamido) benzo [ d ] isoxazol-5-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that N- (5-aminobenzo [ d ] isoxazol-3-yl) -3-cyanobenzamide was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 42mg (65% yield) of the title compound.

Example 133: preparation of (3- (4-methoxybenzamido) benzo [ d ] isoxazol-5-yl) carbohydrazone acyldinitrile (Compound 133)

Step 133-1: preparation of tert-butyl 3- (4-methoxybenzamido) benzo [ d ] isoxazol-5-ylcarbamate

The reaction was carried out in the same manner as in step 130-3 of example 130, except that 4-methoxybenzoic acid was used instead of pyrazine-2-carboxylic acid, to give 312mg (68% yield) of the title compound.

Step 133-2: preparation of N- (5-aminobenzo [ d ] isoxazol-3-yl) -4-methoxybenzamide

The reaction was carried out in the same manner as in step 132-3 of example 132 except for using tert-butyl 3- (4-methoxybenzamido) benzo [ d ] isoxazol-5-ylcarbamate in place of tert-butyl 3- (3-cyanobenzoamido) benzo [ d ] isoxazol-5-ylcarbamate to obtain 116mg (78% yield) of the title compound.

Step 133-3: preparation of (3- (4-methoxybenzamido) benzo [ d ] isoxazol-5-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that N- (5-aminobenzo [ d ] isoxazol-3-yl) -4-methoxybenzamide was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 38mg (58% yield) of the title compound.

Example 134: preparation of (2-oxo-2,3-dihydrobenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 134)

Step 134-1: preparation of 6-aminobenzo [ d ] thiazol-2 (3H) -one

6-Nitrobenzo [ d ] thiazol-2 (3H) -one (200mg, 1.02mmol) was dissolved in ethanol/water in the presence of nitrogen, then Fe (228mg, 4.08mmol) and ammonium chloride (545mg, 10.19mmol) were added to give a reaction mixture. The reaction mixture was stirred at 80 ℃ 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 83mg (yield 49%).

Step 134-2: preparation of (2-oxo-2,3-dihydrobenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitriles

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 6-aminobenzo [ d ] thiazol-2 (3H) -one was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 34mg (47% yield) of the title compound.

Example 135: preparation of (3-methyl-2-oxo-2,3-dihydrobenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 135)

Step 135-1: preparation of 3-methyl-6-nitrobenzo [ d ] thiazol-2 (3H) -one

6-Nitrobenzo [ d ] thiazol-2 (3H) -one (100mg, 0.48mmol) and 10% Pd/C (101mg, 0.10mmol) were dissolved in methanol in the presence of nitrogen, followed by the addition of methyl iodide (0.05mL, 0.76mmol) and DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene, 0.11mL, 0.76mmol) to give a reaction mixture. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with methanol to give 68mg (64% yield) of the title compound.

Step 135-2: preparation of 6-amino-3-methylbenzo [ d ] thiazol-2 (3H) -one

3-methyl-6-nitrobenzo [ d ] thiazol-2 (3H) -one (100mg, 0.48mmol) and 10% Pd/C (101mg, 0.10mmol) were dissolved in methanol in the presence of nitrogen to give a reaction mixture. The reaction mixture was stirred at room temperature for 1 hour in the presence of hydrogen. After completion of the reaction, the reaction product was filtered, and then the filtrate was concentrated under reduced pressure to obtain 79mg (91% yield) of the title compound.

Step 135-3: preparation of (3-methyl-2-oxo-2,3-dihydrobenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 6-amino-3-methylbenzo [ d ] thiazol-2 (3H) -one was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 94mg (83% yield) of the title compound.

Example 136: preparation of (2-methoxybenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 136)

Step 136-1: preparation of 2-methoxy-6-nitrobenzo [ d ] thiazole

60% sodium hydride (45mg, 1.12mmol) and methanol (0.05mL, 1.12mmol) were dissolved in THF at 0 ℃ in the presence of nitrogen, and 2-chloro-6-nitrobenzo [ d ] thiazole (200mg, 0.93mmol) was then added to give a reaction mixture. The reaction mixture was stirred at room temperature 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 95mg (yield 49%).

Step 136-2: preparation of 2-methoxybenzo [ d ] thiazol-6-amine

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 2-methoxy-6-nitrobenzo [ d ] thiazole was used instead of 3-methyl-6-nitrobenzo [ d ] thiazol-2 (3H) -one, to obtain 69mg (90% yield) of the title compound.

Step 136-3: preparation of (2-methoxybenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 135-2 of example 135 except for using 2-methoxybenzo [ d ] thiazol-6-amine instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide to obtain 60mg (61% yield) of the title compound.

Example 137: preparation of (2-oxo-2,3-dihydrobenzo [ d ] oxazol-6-yl) carbohydrazone acyldinitrile (Compound 137)

Step 137-1: preparation of 6-aminobenzo [ d ] oxazol-2 (3H) -one

The reaction was carried out in the same manner as in step 135-2 of example 135 except for using 6-nitrobenz [ d ] oxazol-2 (3H) -one instead of 3-methyl-6-nitrobenz [ d ] thiazol-2 (3H) -one to obtain 131mg (78% yield) of the title compound.

Step 137-2: preparation of (2-oxo-2,3-dihydrobenzo [ d ] oxazol-6-yl) carbohydrazone acyldinitriles

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 6-aminobenzo [ d ] oxazol-2 (3H) -one was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 115mg (76% yield) of the title compound.

Example 138: preparation of (3-methyl-2-oxo-2,3-dihydrobenzo [ d ] oxazol-6-yl) carbohydrazone acyldinitrile (Compound 138)

Step 138-1: preparation of 3-methyl-6-nitrobenzo [ d ] oxazol-2 (3H) -one

The reaction was carried out in the same manner as in step 135-1 of example 135 except for using 6-nitrobenzo [ d ] oxazol-2 (3H) -one instead of 6-nitrobenzo [ d ] thiazol-2 (3H) -one to obtain 111mg (88% yield) of the title compound.

Step 138-2: preparation of 6-amino-3-methylbenzo [ d ] oxazol-2 (3H) -one

The reaction was carried out in the same manner as in step 135-2 of example 135 except for using 3-methyl-6-nitrobenz [ d ] oxazol-2 (3H) -one instead of 3-methyl-6-nitrobenz [ d ] thiazol-2 (3H) -one to obtain 282mg (87% yield) of the title compound.

Step 138-3: preparation of (3-methyl-2-oxo-2,3-dihydrobenzo [ d ] oxazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 6-amino-3-methylbenzo [ d ] oxazol-2 (3H) -one was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 107mg (73% yield) of the title compound.

Example 139: preparation of (2-oxo-2,3-dihydro-1H-benzo [ d ] imidazol-5-yl) carbohydrazone acyldinitrile (Compound 139)

Step 139-1: preparation of 5-amino-1H-benzo [ d ] imidazol-2 (3H) -one

The reaction was carried out in the same manner as in step 135-2 of example 135, except that 5-nitro-1H-benzo [ d ] imidazol-2 (3H) -one was used instead of 3-methyl-6-nitrobenz [ d ] thiazol-2 (3H) -one, to obtain 122mg (73% yield) of the title compound.

Step 139-2: preparation of (2-oxo-2,3-dihydro-1H-benzo [ d ] imidazol-5-yl) carbohydrazone acyldinitriles

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 5-amino-1H-benzo [ d ] imidazol-2 (3H) -one was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 15mg (10% yield) of the title compound.

Example 140: preparation of diethyl2- (2- (4- (4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) hydrazone) malonate (compound 140)

6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one (50mg, 0.25mmol) and sodium nitrite (40mg, 0.29mmol) were dissolved in ethanol in the presence of nitrogen, followed by addition of 1.0M aqueous hydrochloric acid (0.74mL, 0.74mmol) to give a reaction mixture. The reaction mixture was stirred at 0 ℃ for 10 minutes to form the diazonium salt. After the diazonium salt was formed, diethyl malonate (80 μ L, 0.50mmol) was added, followed by stirring at room temperature for 10 minutes. Then, the pH of the reaction mixture was adjusted using an aqueous solution of sodium acetate, and then the reaction mixture was further stirred at room temperature for 1 hour. 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 17mg (yield 18%).

Example 141: preparation of 2-imino-N' - (4- (4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) -2- (piperazin-1-yl) acetylhydrazone acylnitrile (Compound 141)

(4- (4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile (50mg, 0.18mmol) and piperazine (23mg, 0.27mmol) were dissolved in ethanol and then stirred at 80 ℃ for 17.5 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with ethanol to give 50mg (76% yield) of the title compound.

Example 142: preparation of 2-imino-N' - (4- (4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) -2-morpholinoacetyl hydrazone acylnitrile (Compound 142)

The reaction was carried out in the same manner as in example 141, except that morpholine was used instead of piperazine, to obtain 61mg (93% yield) of the title compound.

Example 143: preparation of methyl2- (2- (4- (4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) hydrazone) propionate (Compound 143)

6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one (200mg, 0.98mmol), sodium nitrite (81.4mg, 1.18mmol), and 1.0M aqueous hydrochloric acid (2.9mL, 2.95mmol) were mixed to give a reaction mixture, and the reaction mixture was stirred at 0 ℃ for 10 minutes. Then, tin (II) chloride hydrate (666mg, 2.95mmol) and 1.0M aqueous hydrochloric acid (0.68mL) were added, followed by stirring at 0 ℃ for 10 minutes; methyl pyruvate (0.18mL, 1.97mmol) was then added, followed by stirring at room temperature for 30 minutes. 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with ethanol to give 177mg (60% yield) of the title compound.

Example 144: preparation of methyl 2-cyano-2- (2- (4- (pyrimidin-2-yl) phenyl) hydrazone) acetate (compound 144)

4- (pyrimidin-2-yl) aniline (50mg, 0.29mmol) and sodium nitrite (24mg, 0.35mmol) were dissolved in ethanol in the presence of nitrogen, and then 1.0M aqueous hydrochloric acid (0.88mL, 0.88mmol) was added to give a reaction mixture, and the reaction mixture was stirred at 0 ℃ for 10 minutes. After the diazonium salt was formed, diethyl malonate (80 μ L, 0.50mmol) was added, followed by stirring at room temperature for 10 minutes. Methyl 2-cyanoacetate (31. mu.L, 0.35mmol) was added, followed by stirring at room temperature for 10 minutes. The pH of the reaction mixture was adjusted to 6.0 using aqueous sodium hydroxide solution, and then the reaction mixture was further stirred at room temperature 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 25mg (yield 64%).

Example 145: preparation of 2-amino-2-oxo-N' - (4- (pyrimidin-2-yl) phenyl) acetyl hydrazone acylnitrile (Compound 145)

The reaction was carried out in the same manner as in example 144 except for using 2-cyanoacetamide instead of methyl 2-cyanoacetate to obtain 14mg (18% yield) of the title compound.

Example 146: preparation of ethyl 2-cyano-2- (2- (4- (pyrimidin-2-yl) phenyl) hydrazone) acetate (compound 146)

The reaction was carried out in the same manner as in example 144 except for using 2-cyanoacetamide instead of methyl 2-cyanoacetate to obtain 24mg (30% yield) of the title compound.

Example 147: preparation of 2-amino-N' - (4- (pyrimidin-2-yl) phenyl) -2-thioacetohydrazone carbonitrile (compound 147)

The reaction was carried out in the same manner as in example 144 except for using 2-cyanothioacetamide instead of methyl 2-cyanoacetate to obtain 35mg (43% yield) of the title compound.

Example 148: preparation of 4-methyl-N' - (4- (pyrimidin-2-yl) phenyl) thiazole-2-carbohydrazone acylnitrile (compound 148)

Step 148-1: preparation of 2- (4-methylthiazol-2-yl) acetonitrile

2-Cyanothioacetamide (500mg, 4.99mmol), chloroacetone (0.45mL, 5.49mmol), and triethylamine (0.70mL, 4.99mmol) were dissolved in dimethylformamide to give a reaction mixture, and the reaction mixture was stirred at 40 ℃ for 1.5 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 163mg (yield 24%).

Step 148-2: preparation of 4-methyl-N' - (4- (pyrimidin-2-yl) phenyl) thiazole-2-carbohydrazone acylnitrile

The reaction was carried out in the same manner as in example 144 except for using 2- (4-methylthiazol-2-yl) acetonitrile prepared according to step 148-1 instead of 2-cyanothioacetamide to obtain 18mg (19% yield) of the title compound.

Example 149: preparation of (4- (5-ethynylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile (Compound 149)

Step 149-1: preparation of 4- (5-bromopyrimidin-2-yl) aniline

2, 5-dibromopyrimidine (2g, 8.41mmol) and 4-aminophenylboronic acid pinacol ester (2.3g, 10.51mmol) were dissolved in a1, 4-dioxane solution, and Pd (PPh) was added₃)₄(484mg, 0.42mmol) and 2.0M aqueous potassium phosphate solution (12.6mL, 25.2mmol) to give a reaction mixture. The reaction mixture was stirred at 90 ℃ for 2.5 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 1.8g (yield 68%).

Step 149-2: preparation of 4- (5- ((trimethylsilyl) ethynyl) pyrimidin-2-yl) aniline

4- (5-Bromopyrimidin-2-yl) aniline prepared according to step 149-1 (220mg, 0.88mmol) and ethynyltrimethylsilane (1.32mmol) were dissolved in dimethylformamide, followed by addition of Pd (PPh)₃)₂Cl₂(31mg, 0.04mmol), copper iodide (CuI, 13mg, 0.07mmol), and triethylamine (0.3mL, 2.2mmol) to give a reaction mixture. The reaction mixture was stirred at 100 ℃ 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 148mg (yield 63%)。

Step 149-3: preparation of (4- (5-ethynylpyrimidin-2-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in example 144 except for using malononitrile instead of methyl 2-cyanoacetate and using 4- (5- ((trimethylsilyl) ethynyl) pyrimidin-2-yl) aniline prepared according to step 149-2 instead of 4- (pyrimidin-2-yl) aniline to obtain 92mg (22% yield) of the title compound.

Example 150: preparation of (4' - (dimethylamino) -3-fluorobiphenyl-4-yl) carbohydrazone acyldinitrile (Compound 150)

Step 150-1: preparation of 3 '-fluoro-N, N-dimethyl-4' -nitrobiphenyl-4-amine

The reaction was carried out in the same manner as in step 149-1 of example 149 except for using 4-bromo-2-fluoro-1-nitrobenzene instead of 2, 5-dibromopyrimidine and 4-dimethylaminophenylboronic acid pinacol ester instead of 4-aminophenylboronic acid pinacol ester, to obtain 134mg (54% yield) of the title compound.

Step 150-2: 3-fluoro-N^4',N^4'Preparation of (E) -dimethylbiphenyl-4, 4' -diamine

The reaction was carried out in the same manner as in step 135-2 of example 135 except for using 3 '-fluoro-N, N-dimethyl-4' -nitrobiphenyl-4-amine instead of 3-methyl-6-nitrobenzo [ d ] thiazol-2 (3H) -one to obtain 51mg (48% yield) of the title compound.

Step 150-3: preparation of (4' - (dimethylamino) -3-fluorobiphenyl-4-yl) carbohydrazone acyldinitrile

Except using 3-fluoro-N^4',N^4'A reaction was carried out in the same manner as in step 149-3 of example 149 except for substituting 4- (5- ((trimethylsilyl) ethynyl) pyrimidin-2-yl) aniline with dimethylbiphenyl-4, 4' -diamine to obtain 11mg (14% yield) of the title compound.

Example 151: preparation of (4' - (dimethylamino) biphenyl-4-yl) carbohydrazone acyldinitrile (Compound 151)

Step 151-1: preparation of N, N-dimethyl-4' -nitrobiphenyl-4-amine

The reaction was carried out in the same manner as in step 149-1 of example 149 except for using 4-bromo-1-nitrobenzene instead of 2, 5-dibromopyrimidine and using 4-dimethylaminophenylboronic acid pinacol ester instead of 4-aminophenylboronic acid pinacol ester, to obtain 182mg (93% yield) of the title compound.

Step 151-2: n is a radical of^4',N^4'Preparation of (E) -dimethylbiphenyl-4, 4' -diamine

The reaction was carried out in the same manner as in step 135-2 of example 135 except for using N, N-dimethyl-4' -nitrobiphenyl-4-amine instead of 3-methyl-6-nitrobenzo [ d ] thiazol-2 (3H) -one to obtain 51mg (48% yield) of the title compound.

Step 151-3: preparation of (4' - (dimethylamino) biphenyl-4-yl) carbohydrazone acyldinitrile

Except using N^4',N^4'A reaction was carried out in the same manner as in step 149-3 of example 149 except for substituting 4- (5- ((trimethylsilyl) ethynyl) pyrimidin-2-yl) aniline with dimethylbiphenyl-4, 4' -diamine to obtain 10mg (6% yield) of the title compound.

Example 152: preparation of (4- (6- (dimethylamino) pyridin-3-yl) phenyl) carbohydrazone acyldinitrile (Compound 152)

Step 152-1: preparation of 5- (4-aminophenyl) -N, N-dimethylpyridin-2-amine

The reaction was carried out in the same manner as in step 149-1 of example 149 except for using 5-bromo-N, N-dimethylpyridin-2-amine instead of 2, 5-dibromopyrimidine to obtain 127mg (60% yield) of the title compound.

Step 152-2: preparation of (4- (6- (dimethylamino) pyridin-3-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 149-3 of example 149 except for using 5- (4-aminophenyl) -N, N-dimethylpyridin-2-amine instead of 4- (5- ((trimethylsilyl) ethynyl) pyrimidin-2-yl) aniline to obtain 16mg (38% yield) of the title compound.

Example 153: preparation of (4- (6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile (Compound 153)

Step 153-1: preparation of 6-chloropyridazin-3 (2H) -one

3, 6-dichloropyridazine (1g, 6.71mmol) was dissolved in acetic acid (26mL) to give a reaction mixture, and the reaction mixture was stirred at 110 ℃ for 12 hours. After completion of the reaction, the reaction product was concentrated, and an aqueous sodium hydrogencarbonate solution was added, and then the reaction product was stirred at room temperature to solidify and concentrated under reduced pressure to obtain the title compound 420mg (yield 48%).

Step 153-2: preparation of 6- (4-aminophenyl) pyridazin-3 (2H) -one

6-Chloropyridazin-3 (2H) -one (100mg, 0.77mmol) and 4-aminophenylboronic acid pinacol ester (168mg, 0.77mmol) were dissolved in a1, 4-dioxane solution, and Pd (PPh) was added₃)₄(89mg, 0.08mmol) and an aqueous potassium carbonate solution (423mg, 3.06mmol) to give a reaction mixture. The reaction mixture was stirred in a microwave at 160 ℃ for 1.5 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 36mg (yield 25%).

Step 153-3: preparation of (4- (6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 149-3 of example 149 except for using 6- (4-aminophenyl) pyridazin-3 (2H) -one instead of 4- (5- ((trimethylsilyl) ethynyl) pyrimidin-2-yl) aniline to obtain 96mg (68% yield) of the title compound.

Example 154: preparation of (4- (4-methyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile (Compound 154)

Step 154-1: preparation of 6-chloro-5-methylpyridazin-3 (2H) -one and 6-chloro-4-methylpyridazin-3 (2H) -one

3, 6-dichloro-4-methylpyridazine (500mg, 3.07mmol) was dissolved in acetic acid (13mL) to give a reaction mixture, and the reaction mixture was stirred at 110 ℃ for 12 hours. After completion of the reaction, the reaction product was concentrated, and an aqueous sodium hydrogencarbonate solution was added, and the reaction product was stirred at room temperature. Then, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compounds 184mg (yield 41%) of 6-chloro-5-methylpyridazin-3 (2H) -one and 31mg (yield 7%) of 6-chloro-4-methylpyridazin-3 (2H) -one.

Step 154-2: preparation of 6- (4-aminophenyl) -5-methylpyridazin-3 (2H) -one

The reaction was carried out in the same manner as in step 153-2 of example 153 except for using a mixture of 6-chloro-5-methylpyridazin-3 (2H) -one and 6-chloro-4-methylpyridazin-3 (2H) -one in place of 6-chloropyridazin-3 (2H) -one to obtain 122mg (44% yield) of the title compound.

Step 154-3: preparation of (4- (4-methyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 149-3 of example 149 except for using 6- (4-aminophenyl) -5-methylpyridazin-3 (2H) -one instead of 4- (5- ((trimethylsilyl) ethynyl) pyrimidin-2-yl) aniline to obtain 96mg (70% yield) of the title compound.

Example 155: preparation of (4- (5-methyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile (Compound 155)

Step 155-1: preparation of 6- (4-aminophenyl) -4-methylpyridazin-3 (2H) -one

Step 155-2: preparation of (4- (5-methyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 149-3 of example 149 except for using 6- (4-aminophenyl) -4-methylpyridazin-3 (2H) -one instead of 4- (5- ((trimethylsilyl) ethynyl) pyrimidin-2-yl) aniline to obtain 60mg (87% yield) of the title compound.

Example 156: preparation of (4- (1-methyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile (Compound 156)

Step 156-1: preparation of 6-chloro-2-methylpyridazin-3 (2H) -one

6-chloropyridazin-3 (2H) -one (100mg, 0.77mmol), iodomethane (95. mu.L, 1.53mmol), and potassium carbonate (212mg, 1.53mmol) were dissolved in dimethylformamide to give a reaction mixture, which was then stirred at room temperature for 4 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 82mg (yield 74%).

Step 156-2: preparation of 6- (4-aminophenyl) -2-methylpyridazin-3 (2H) -one

The reaction was carried out in the same manner as in step 153-2 of example 153, except that 6-chloro-2-methylpyridazin-3 (2H) -one was used instead of 6-chloropyridazin-3 (2H) -one, to give 86mg (95% yield) of the title compound.

Step 156-3: preparation of (4- (1-methyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 149-3 of example 149 except for using 6- (4-aminophenyl) -2-methylpyridazin-3 (2H) -one instead of 4- (5- ((trimethylsilyl) ethynyl) pyrimidin-2-yl) aniline, to obtain 41mg (59% yield) of the title compound.

Example 157: preparation of (4- (1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile (Compound 157)

Step 157-1: preparation of 6-chloro-2, 5-dimethylpyridazin-3 (2H) -one

The reaction was carried out in the same manner as in step 156-1 of example 156 except for using 6-chloro-5-methylpyridazin-3 (2H) -one instead of 6-chloropyridazin-3 (2H) -one to obtain 53mg (49% yield) of the title compound.

Step 157-2: preparation of 6- (4-aminophenyl) -2, 5-dimethylpyridazin-3 (2H) -one

The reaction was carried out in the same manner as in step 153-2 of example 153, except that 6-chloro-2, 5-dimethylpyridazin-3 (2H) -one was used instead of 6-chloropyridazin-3 (2H) -one, to give 51mg (76% yield) of the title compound.

Step 157-3: preparation of (4- (1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 149-3 of example 149 except for using 6- (4-aminophenyl) -2, 5-dimethylpyridazin-3 (2H) -one instead of 4- (5- ((trimethylsilyl) ethynyl) pyrimidin-2-yl) aniline to obtain 37mg (77% yield) of the title compound.

Example 158: preparation of (4- (1,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile (Compound 158)

Step 158-1: preparation of 6-chloro-2, 4-dimethylpyridazin-3 (2H) -one

The reaction was carried out in the same manner as in step 156-1 of example 156 except for using 6-chloro-4-methylpyridazin-3 (2H) -one instead of 6-chloropyridazin-3 (2H) -one to obtain 50mg (65% yield) of the title compound.

Step 158-2: preparation of 6- (4-aminophenyl) -2, 4-dimethylpyridazin-3 (2H) -one

The reaction was carried out in the same manner as in step 153-2 of example 153, except that 6-chloro-2, 4-dimethylpyridazin-3 (2H) -one was used instead of 6-chloropyridazin-3 (2H) -one, to give 47mg (70% yield) of the title compound.

Step 158-3: preparation of (4- (1,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 149-3 of example 149 except for using 6- (4-aminophenyl) -2, 4-dimethylpyridazin-3 (2H) -one instead of 4- (5- ((trimethylsilyl) ethynyl) pyrimidin-2-yl) aniline to obtain 11mg (22% yield) of the title compound.

Example 159: preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 159)

Step 159-1: preparation of 3-isopropyl-6-nitrobenzo [ d ] thiazol-2 (3H) -one

The reaction was carried out in the same manner as in step 135-1 of example 135, except that 2-iodopropane was used instead of iodomethane, to give 162mg (44% yield) of the title compound.

Step 159-2: preparation of 6-amino-3-isopropylbenzo [ d ] thiazol-2 (3H) -one

The reaction was carried out in the same manner as in step 135-2 of example 135, except that 3-isopropyl-6-nitrobenzo [ d ] thiazol-2 (3H) -one was used instead of 3-methyl-6-nitrobenzo [ d ] thiazol-2 (3H) -one, to obtain 112mg (85% yield) of the title compound.

Step 159-3: preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 6-amino-3-isopropylbenzo [ d ] thiazol-2 (3H) -one was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 109mg (80% yield) of the title compound.

Example 160: preparation of (3- (difluoromethyl) -2-oxo-2,3-dihydrobenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 160)

Step 160-1: preparation of 3- (difluoromethyl) -6-nitrobenzo [ d ] thiazol-2 (3H) -one

6-Nitrobenzo [ d ] thiazol-2 (3H) -one (300mg, 1.53mmol) was dissolved in DMF under nitrogen, followed by addition of sodium 2-chloro-2, 2-difluoroacetate (467mg, 3.06mmol) and DBU (0.46mL, 3.06mmol) to give a reaction mixture, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with methanol to give 176mg (47% yield) of the title compound.

Step 160-2: preparation of 6-amino-3- (difluoromethyl) benzo [ d ] thiazol-2 (3H) -one

The reaction was carried out in the same manner as in step 135-2 of example 135, except that 3- (difluoromethyl) -6-nitrobenzo [ d ] thiazol-2 (3H) -one was used instead of 3-methyl-6-nitrobenzo [ d ] thiazol-2 (3H) -one, to obtain 125mg (95% yield) of the title compound.

Step 160-3: preparation of (3- (difluoromethyl) -2-oxo-2,3-dihydrobenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 6-amino-3- (difluoromethyl) benzo [ d ] thiazol-2 (3H) -one was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 85mg (63% yield) of the title compound.

Example 161: preparation of (2-Isopropoxybenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 161)

Step 161-1: preparation of 2-isopropoxy-6-nitrobenzo [ d ] thiazole

60% sodium hydride (84mg, 2.10mmol) and isopropanol (0.16mL, 2.10mmol) were dissolved in THF at 0 ℃ in the presence of nitrogen, then 2-chloro-6-nitrobenzo [ d ] thiazole (300mg, 1.40mmol) was added to give a reaction mixture, and the reaction mixture was stirred at room temperature 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 184mg (yield 55%).

Step 161-2: preparation of 2-isopropoxybenzo [ d ] thiazol-6-amine

The reaction was carried out in the same manner as in step 135-2 of example 135, except that 2-isopropoxy-6-nitrobenzo [ d ] thiazole was used instead of 3-methyl-6-nitrobenzo [ d ] thiazol-2 (3H) -one, to obtain 126mg (96% yield) of the title compound.

Step 161-3: preparation of (2-isopropoxybenzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 2-isopropoxybenzo [ d ] thiazol-6-amine was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 30mg (22% yield) of the title compound.

Example 162: preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo [ d ] oxazol-6-yl) carbohydrazone acyldinitrile (Compound 162)

Step 162-1: preparation of 3-isopropyl-6-nitrobenzo [ d ] oxazol-2 (3H) -one

Step 162-2: preparation of 6-amino-3-isopropylbenzo [ d ] oxazol-2 (3H) -one

Step 162-3: preparation of (3-isopropyl-2-oxo-2,3-dihydrobenzo [ d ] oxazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 6-amino-3-isopropylbenzo [ d ] oxazol-2 (3H) -one was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 99mg (59% yield) of the title compound.

Example 163: preparation of (3- (difluoromethyl) -2-oxo-2,3-dihydrobenzo [ d ] oxazol-6-yl) carbohydrazone acyldinitrile (Compound 163)

Step 163-1: preparation of 3- (difluoromethyl) -6-nitrobenzo [ d ] oxazol-2 (3H) -one

The reaction was carried out in the same manner as in step 160-1 of example 160 except for using 6-nitrobenzo [ d ] oxazol-2 (3H) -one instead of 6-nitrobenzo [ d ] thiazol-2 (3H) -one to obtain 144mg (38% yield) of the title compound.

Step 163-2: preparation of 6-amino-3- (difluoromethyl) benzo [ d ] oxazol-2 (3H) -one

The reaction was carried out in the same manner as in step 135-2 of example 135 except for using 3- (difluoromethyl) -6-nitrobenz [ d ] oxazol-2 (3H) -one instead of 3-methyl-6-nitrobenz [ d ] thiazol-2 (3H) -one to obtain 110mg (98% yield) of the title compound.

Step 163-3: preparation of (3- (difluoromethyl) -2-oxo-2,3-dihydrobenzo [ d ] oxazol-6-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 6-amino-3- (difluoromethyl) benzo [ d ] oxazol-2 (3H) -one was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 85mg (63% yield) of the title compound.

Example 164: preparation of (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo [ d ] imidazol-5-yl) carbohydrazone acyldinitrile (Compound 164)

Step 164-1: preparation of 1, 3-dimethyl-5-nitro-1H-benzo [ d ] imidazol-2 (3H) -one

The reaction was carried out in the same manner as in step 135-1 of example 135 except for using 5-nitro-1H-benzo [ d ] imidazol-2 (3H) -one instead of 6-nitrobenz [ d ] thiazol-2 (3H) -one to obtain 207mg (64% yield) of the title compound.

Step 164-2: preparation of 5-amino-1, 3-dimethyl-1H-benzo [ d ] imidazol-2 (3H) -one

The reaction was carried out in the same manner as in step 135-2 of example 135 except that 1, 3-dimethyl-5-nitro-1H-benzo [ d ] imidazol-2 (3H) -one was used instead of 3-methyl-6-nitrobenz [ d ] thiazol-2 (3H) -one, to obtain 105mg (82% yield) of the title compound.

Step 164-3: preparation of (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo [ d ] imidazol-5-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 5-amino-1, 3-dimethyl-1H-benzo [ d ] imidazol-2 (3H) -one was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 11mg (8% yield) of the title compound.

Example 165: preparation of (1,3-diisopropyl-2-oxo-2,3-dihydro-1H-benzo [ d ] imidazol-5-yl) carbohydrazone acyldinitrile (Compound 165)

Step 165-1: preparation of 1, 3-diisopropyl-5-nitro-1H-benzo [ d ] imidazol-2 (3H) -one

Step 165-2: preparation of 5-amino-1, 3-diisopropyl-1H-benzo [ d ] imidazol-2 (3H) -one

The reaction was carried out in the same manner as in step 135-2 of example 135 except that 1, 3-diisopropyl-5-nitro-1H-benzo [ d ] imidazol-2 (3H) -one was used instead of 3-methyl-6-nitrobenz [ d ] thiazol-2 (3H) -one to obtain 118mg (89% yield) of the title compound.

Step 165-3: preparation of (1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo [ d ] imidazol-5-yl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 5-amino-1, 3-diisopropyl-1H-benzo [ d ] imidazol-2 (3H) -one was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 12mg (10% yield) of the title compound.

Example 166: preparation of (1,3-bis (difluoromethyl) -2-oxo-2,3-dihydro-1H-benzo [ d ] imidazol-5-yl) carbohydrazone acyldinitrile (Compound 166)

Step 166-1: preparation of 1,3-bis (difluoromethyl) -5-nitro-1H-benzo [ d ] imidazol-2 (3H) -one

The reaction was carried out in the same manner as in step 160-1 of example 160 except for using 5-nitro-1H-benzo [ d ] imidazol-2 (3H) -one instead of 6-nitrobenz [ d ] thiazol-2 (3H) -one, to obtain 179mg (38% yield) of the title compound.

Step 166-2: preparation of 5-amino-1, 3-bis (difluoromethyl) -1H-benzo [ d ] imidazol-2 (3H) -one

The reaction was carried out in the same manner as in step 135-2 of example 135 except for using 1,3-bis (difluoromethyl) -6-nitro-1H-benzo [ d ] imidazol-2 (3H) -one instead of 3-methyl-6-nitrobenz [ d ] thiazol-2 (3H) -one to obtain 69mg (96% yield) of the title compound.

Step 166-3: preparation of (1,3-bis (difluoromethyl) -2-oxo-2,3-dihydro-1H-benzo [ d ] imidazol-5-yl) carbohydrazone acyldinitriles

The reaction was carried out in the same manner as in step 86-3 of example 86, except that 5-amino-1, 3-bis (difluoromethyl) -1H-benzo [ d ] imidazol-2 (3H) -one was used instead of N- (6-aminobenzo [ d ] thiazol-2-yl) -4-methoxybenzamide, to obtain 45mg (58% yield) of the title compound.

Example 167: preparation of (2- (methylamino) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 167)

Step 167-1: preparation of N-methyl-6-nitrobenzo [ d ] thiazol-2-amine

2-chloro-6-nitrobenzo [ d ] thiazole (500mg, 2.33mmol) was dissolved in THF at room temperature in the presence of nitrogen, then 2.0M methylamine (2.56mL, 5.13mmol) dissolved in THF was added to give a reaction mixture, and the reaction mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction product was extracted with distilled water and ethyl acetate to obtain an organic layer, which was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was solidified with ethyl acetate to give 442mg (91% yield) of the title compound.

Step 167-2: n is a radical of²-methylbenzo [ d ]]Preparation of thiazole-2, 6-diamines

The reaction was carried out in the same manner as in step 135-2 of example 135 except that N-methyl-6-nitrobenzo [ d ] thiazol-2-amine was used instead of 3-methyl-6-nitrobenzo [ d ] thiazol-2 (3H) -one, to obtain 101mg (78% yield) of the title compound.

Step 167-3: preparation of (2- (methylamino) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

Except using N²-methylbenzo [ d ]]Thiazole-2, 6-diamine instead of benzo [ d]A reaction was carried out in the same manner as in example 113 except for thiazole-2-amine to obtain 5mg (4% yield) of the title compound.

Example 168: preparation of (2- (dimethylamino) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile (Compound 168)

Step 168-1: preparation of N, N-dimethyl-6-nitrobenzo [ d ] thiazol-2-amine

The reaction was carried out in the same manner as in step 167-1 of example 167 except that dimethylamine was used instead of methylamine to obtain 392mg (75% yield) of the title compound.

Step 168-2: n is a radical of²,N²-dimethylbenzo [ d]Preparation of thiazole-2, 6-diamines

The reaction was carried out in the same manner as in step 135-2 of example 135 except for using N, N-dimethyl-6-nitrobenzo [ d ] thiazol-2-amine instead of 3-methyl-6-nitrobenzo [ d ] thiazol-2 (3H) -one, to obtain 103mg (80% yield) of the title compound.

Step 168-3: preparation of (2- (dimethylamino) benzo [ d ] thiazol-6-yl) carbohydrazone acyldinitrile

Except using N²,N²-dimethylbenzo [ d]Thiazole-2, 6-diamine instead of benzo [ d]A reaction was carried out in the same manner as in example 113 except for thiazole-2-amine to obtain 11mg (10% yield) of the title compound.

Example 169: preparation of (4- (6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile (Compound 169)

Step 169-1: preparation of N- (4- (6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) acetamide

4- (4-Acylaminophenyl) -4-oxobutanoic acid (100mg, 0.42mmol) was dissolved in ethanol, followed by addition of hydrazine hydrate (25. mu.L, 0.51mmol) to give a reaction mixture, which was stirred at 90 ℃ for 3.5 hours. After completion of the reaction, the reaction product was filtered to obtain 47mg (48% yield) of the title compound.

Step 169-2: preparation of 6- (4-aminophenyl) -4, 5-dihydropyridazin-3 (2H) -one

1.0M aqueous hydrochloric acid (21.6mL, 21.6mmol) was added to N- (4- (6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) acetamide prepared according to step 169-1, and then reacted at 110 ℃ for 1.5 hours. The reaction product is then neutralized with aqueous ammonium hydroxide and filtered to yield 118mg (28% yield) of the title compound.

Step 169-3: preparation of (4- (6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 149-3 of example 149 except for using 6- (4-aminophenyl) -4, 5-dihydropyridazin-3 (2H) -one instead of 4- (5- ((trimethylsilyl) ethynyl) pyrimidin-2-yl) aniline to obtain 66mg (93% yield) of the title compound.

Example 170: preparation of (4- (1-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile (Compound 170)

Step 170-1: preparation of 6- (4-aminophenyl) -2-methyl-4, 5-dihydropyridazin-3 (2H) -one

6- (4-aminophenyl) -4, 5-dihydropyridazin-3 (2H) -one (105mg, 0.55mmol) and 60% sodium hydride (24mg, 0.61mmol) were dissolved in a mixed solvent of DMF and THF, followed by addition of iodomethane (34. mu.L, 0.55mmol) to give a reaction mixture, and the reaction mixture was stirred at 0 ℃ 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 then filtered. The filtrate was concentrated under reduced pressure, and the concentrated solution was purified by column chromatography to give the title compound 33mg (yield 29%).

Step 170-2: preparation of (4- (1-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 149-3 of example 149 except for using 6- (4-aminophenyl) -2-methyl-4, 5-dihydropyridazin-3 (2H) -one in place of 4- (5- ((trimethylsilyl) ethynyl) pyrimidin-2-yl) aniline to obtain 90mg (95% yield) of the title compound.

Example 171: preparation of (4- (1,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile (Compound 171)

Step 171-1: preparation of 6- (4-aminophenyl) -2, 5-dimethyl-4, 5-dihydropyridazin-3 (2H) -one

The reaction was carried out in the same manner as in step 170-1 of example 170, except that 6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one was used instead of 6- (4-aminophenyl) -4, 5-dihydropyridazin-3 (2H) -one, to give 131mg (61% yield) of the title compound.

Step 171-2: preparation of (4- (1,4-dimethyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) carbohydrazone acyldinitrile

The reaction was carried out in the same manner as in step 149-3 of example 149 except for using 6- (4-aminophenyl) -2, 5-dimethyl-4, 5-dihydropyridazin-3 (2H) -one instead of 4- (5- ((trimethylsilyl) ethynyl) pyrimidin-2-yl) aniline to obtain 82mg (76% yield) of the title compound.

Preparation example 1: preparation of tablets by direct compression

5.0mg of each active ingredient prepared in examples 1 to 171 was sieved, mixed with 14.1mg of lactose, 0.8mg of crospovidone USNF and 0.1mg of magnesium stearate, and then compressed to make tablets.

Preparation example 2: preparation of tablets by wet granulation

5.0mg of each active ingredient prepared in examples 1-171 was sieved and mixed with 16.0mg lactose and 4.0mg starch. 0.3mg of polysorbate 80 was dissolved in pure water, and this solution was added to the mixture in an appropriate amount, followed by atomization to give fine particles. After drying, the microparticles are sieved, mixed with 2.7mg of colloidal silicon dioxide and 2.0mg of magnesium stearate and compressed into tablets.

Preparation example 3: preparation of powder and capsule

5.0mg of each active ingredient prepared in examples 1-171 was sieved and then mixed with 14.8mg of lactose, 10.0mg of polyvinylpyrrolidone and 0.2mg of magnesium stearate. Capsules were prepared by filling the mixture into hard size 5 gelatin capsules using suitable equipment.

Preparation example 4: preparation of injectable pharmaceutical

Each of the active ingredients prepared in examples 1-171 was mixed 100mg with 180mg of mannitol, 26mg of Na₂HPO₄·12H₂O and 2974mg of distilled water were mixed to prepare an injection medicine.

Experimental example 1: selection of tau aggregation inhibiting substances using cell models

In order to select a novel tau protein aggregation inhibitory substance, a tau-BiFC cell model in which the formation of tau oligomers in living cells is readily observed was used. Tau-BiFC cells were dispensed into 384-well plates and on the next day, the compounds prepared according to examples 1-171 were treated at 1 μ M, 3 μ M and 10 μ M, respectively, with forskolin (treatment concentration 30 μ M), which stimulates Tau phosphorylation by activating PKA and induces Tau protein aggregation. After 48 hours, intracellular nuclei were stained with Hoechst (treatment concentration 2 μ g/mL) and BiFC fluorescence intensity was automatically quantified using Operetta (PerkinElmer) to count stained nuclei in each well from the total well plate. The group treated with forskolin only (inducing aggregation of tau protein) was set as a reference point for the 100% tau protein aggregation state, and the effect thereof was confirmed by the formula "BiFC fluorescence intensity of the compound synthesized according to the example of the present invention/(fluorescence intensity of the control group treated with forskolin only inducing aggregation of tau protein-fluorescence intensity of the untreated control group) × 100". In addition, the degree of cytotoxicity induced by the newly synthesized compound was also based on the 100% survival rate of the group treated with forskolin alone, and the cytotoxicity value of the compound was calculated by the formula "number of stained nuclei in the compound-treated group/number of stained nuclei in the forskolin-treated group × 100". According to the treatment results, substances inhibiting the aggregation of tau protein in cells were selected from a series of candidate groups based on the inhibition rate of tau protein aggregation of 70% or more and the survival rate of cells of 100% at the treatment concentration of 10. mu.M or more of the compound.

Experimental example 2: confirmation of concentration-dependent tau protein aggregation inhibitory Effect of novel Compound

To evaluate the dose-dependent tau aggregation inhibitory effect of the compound selected according to experimental example 1, the selected compound was treated in tau-BiFC cells at concentrations of 0.03 μ M, 0.01 μ M, 0.3 μ M, 1 μ M, 3 μ M, 10 μ M and 30 μ M, respectively, together with forskolin (treatment concentration 30 μ M) as a tau aggregation-inducing substance. After 48 hours, tau aggregation reaction and degree of cytotoxicity were analyzed by observing cell images. Analysis of IC of Compounds by non-Linear regression analysis of prism software (Graph Pad)₅₀And toxicity. The results of calculations for representative compounds are shown in table 1 below.

[ Table 1]

Experimental example 3: inhibitory effect of novel compounds on CYP coenzyme activity

The inhibitory effect of the compounds prepared according to examples 1-171 on CYP-coenzyme activity was confirmed. Specifically, human liver microsomes (0.25mg/mL), 0.1M phosphate buffer solution (pH 7.4), substrate drug mixtures of five drug metabolizing enzymes (finacetine 50 μ M, diclofenac 10 μ M, S-mefenton 100 μ M, dextromethorphan 5 μ M, and midazolam 2.5 μ M), and the compounds at concentrations of 0 μ M or 10 μ M were added, respectively. Then, the mixture was incubated at 37 ℃ for 5 minutes in advance, and then further incubated together at 37 ℃ for 15 minutes with addition of the NADPH-producing system solution. Then, the reaction was terminated by adding an acetonitrile solution containing an internal standard substance (terfenadine), centrifugation (14,000rpm, 4 ℃) was performed for 5 minutes, and then the supernatant was injected into an LC-MS/MS system. And simultaneously analyzing metabolites of the substrate drug to evaluate the drug metabolism inhibition capability.

Metabolites of each CYP-coenzyme indicator drug produced by the reaction were analyzed using the Shimadzu Nexera XR system and TSQ vantage (Thermo). Kinetex C18(2.1 mm. times.100 mm, 2.6 μm, particle size; Phenomenex, USA) was used in an HPLC column and the gradient program shown in Table 2 was employed with (A) distilled water containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid as mobile phases.

[ Table 2]

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

The resulting metabolites were quantified using MRM (multiple reaction monitoring) quantification mode and data analysis was performed using Xcalibur (version 1.6.1). Table 3 shows the inhibitory effect of the novel compounds prepared according to the examples of the present invention on CYP-coenzyme activity.

[ Table 3]

Experimental example 4: confirmation of hepatic microsome stability of novel Compounds

The stability of liver microsomes was confirmed according to the compounds prepared in examples 1-171. Specifically, 4 kinds of liver microsomes (human, dog, rat and mouse, each 0.25mg/mL), 0.1M phosphate buffer solution (pH 7.4), and a compound at a concentration of 1. mu.M were added, respectively. Then, the mixture was incubated at 37 ℃ for 5 minutes in advance, and then further incubated at 37 ℃ for 30 minutes together with the addition of the NADPH-producing system solution. Then, the reaction was terminated by adding an acetonitrile solution containing an internal standard substance (chlorpropamide), centrifugation (14,000rpm, 4 ℃) was performed for 5 minutes, and then the supernatant was injected into an LC-MS/MS system. The substrate drug was analyzed to assess the metabolic stability of 8 compounds.

The amount of substrate remaining from the reaction was analyzed using a Shimadzu Nexera XR system and TSQ vantage (Thermo). Kinetex XB-C18(2.1mm X100 mm, 2.6 μm, particle size; Phenomenex, USA) was used in an HPLC column with (A) distilled water containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid as mobile phases. Data analysis was performed using Analyst software (version 1.6.3) and Xcalibur (version 1.6.1). The results of the calculations are shown in table 4 below.

[ Table 4]

Compound #	Human (%)	Dog (%)	Rat (%)	Mouse (%)
					1	44.1	5.7	28.3	86.1
2	92.7	92.1	97.2	6.4
					4	70.1	75	4.5	35.6
8	80.9	96	40.7	83.7
					11	87.5	79.6	49.6	65.6
12	52.2	81.6	25.8	45.2
					35	82.2	24.2	56.4	10.7
36	65.9	60.6	20.1	37.9
					37	55.7	61	25.9	32.7
42	53.4	30.7	46.5	47.9
					50	81.1	88.9	85.7	89.5
55	70	85.6	60.8	71.2
					61	70.4	32.6	66.2	33.5
63	87.4	82.6	72.1	9.5
					69	97.6	71.9	64.4	34.2
70		64.2	98.3	55.8
					72	86.3	84.8	72.8	58.6
83	64.1	31.9	62.2	11
					87	82.1	80.6	73.9	83.1
92	74.6	74.7	72.7	51.9
					93	83.9	60.4	63.3	37.3
110	55	60.2	51.3	70.8
					134	>100	>100	>100	>100
151	94.4	83.6	85.2	94.6

Experimental example 5: pharmacokinetic study of novel Compounds

The pharmacokinetics of the compounds prepared according to examples 1-171 were studied using experimental animal models. Specifically, 7 to 8-week-old SD rats (Core Tech, Hana tracing Co., Ltd.) weighing about 250g to 300g were purchased and managed in a small animal simple rearing room set with a temperature of 22 ℃. + -. 2 ℃, a relative humidity of 50%. + -. 5%, a light time of 12 hours (8: 00 lights on in the morning and 8:00 lights off in the evening) and an illuminance of 150lux to 300 lux. Throughout the duration of the experiment, feed was provided freely, RO water was provided freely, and fasted for 16 hours prior to oral administration. After preparing the drugs under the conditions shown in the following table 5, the drugs were administered by intravenous Injection (IV) or oral administration (PO). 500 μ L of the infused blood was collected in a tube containing heparin sodium and centrifuged at 8,000rpm for 6 minutes at 2 ℃ to 8 ℃ to obtain plasma from the blood. The resulting plasma was added to 180. mu.L of acetonitrile containing an internal standard substance, vortexed, and then centrifuged at 15,000rpm for 5 minutes at 4 ℃ to obtain a supernatant. The resulting supernatant was analyzed by LC-MS/MS. HPLC and MS conditions for analysis are shown in tables 6 and 7 below.

[ Table 5]

[ Table 6]

[ Table 7]

Specific PK parameters were obtained using the Phoenix WinNonlin program version 6.4 (Pharsight, usa) and calculated using a non-compartmental analysis model. The results are summarized in table 8 below.

[ Table 8]

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