KR101657678B1 - Novel compound, method for preparation thereof, and antifungal composition comprising the same - Google Patents

Abstract

상기 식에서, A, R₁, R₂, R₃, R₄, R₅ 및 R₆는 명세서에 정의된 바와 같다.The present invention provides a compound represented by the following formula (1) having excellent antifungal activity, an antifungal agent composition containing the same, and a use thereof for the treatment and prevention of fungal infectious diseases.
[Chemical Formula 1]

Wherein A, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are as defined in the specification.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel compound, a process for producing the same, and an antifungal compound composition containing the compound,

The present invention relates to a novel compound having excellent antifungal activity, an antifungal agent composition containing the same, and a use thereof for the treatment and prevention of fungal infectious diseases.

Recently, serious fungal infections are becoming more prominent in immunocompromised patients such as cancer, organ transplantation, and AIDS receiving chemotherapy. Many of these infections is Candida (Candida spp.), Aspergillus (Aspergillus spp . ) And opportunistic pathogens such as Cryptococcus neoformans . Therefore, in an aging society that will surely come close in the near future, measures for new infectious diseases including the problem of resistant bacteria are expected to be an important task.

To date, available antifungal agents are far less than the number of antibiotics used for bacterial infection. Among the antifungal agents developed so far, there are polyenic amphotericin B and azole fluconazole, itraconazole, voriconazole, posaconazole and the like in the treatment of systemic mycoses, but the emergence of azole-resistant bacteria has been a problem. Recently, cyclic hexapeptide-type echinocandins (carpofungin, mikaphengin, and anidulafungin) derived from natural products have been developed as 1,3-beta-glucan synthase inhibitors of the novel mechanism.

Antifungal agents can be classified as fungicides and fungicides according to their action effects. In general, fungicides are known to be rapid, powerful, and clinically valuable. Amphotericin B and echinocandins are the treatment of systemic mycosis. However, all of these fungicides can only be used as injections, limiting their use to various patients.

Accordingly, the inventors of the present invention have completed the present invention by studying a compound that can be used as an antifungal agent, confirming that the compound represented by Chemical Formula 1 described in the present invention has excellent antifungal activity.

The present invention provides a novel compound having excellent antifungal activity, or a pharmaceutically acceptable salt thereof.

The present invention also provides an antifungal agent composition comprising the compound as an active ingredient.

In order to solve the above-mentioned problems, the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

In this formula,

A is a 5- to 11-membered heteroaryl having 1 to 3 heteroatoms each selected from the group consisting of N, O and S,

R < ₁ > is hydrogen or halogen,

R ₂ is halogen or C _{1 -4} alkoxy,

R ₃ is hydrogen, 3-methylthien-2-ylcarbonyl or t-butoxycarbonyl,

R ₄ is hydrogen, R ₅ is hydrogen, C _{1 -4} alkyl, C _{1 -4} haloalkyl, halogen or benzyl; Or R ₄ and R ₅ are bonded together to form C _{2 -4} alkylene,

R ₆ is hydrogen, C _{1 -4} alkyl, C _{1 -4} alkoxy, C _{1 -4} haloalkyl, C ₃ to _-6 cyclo-alkyl, halogen, nitro, amino, NH (t- butoxycarbonyl), NH ( C _{1 -4} alkyl), phenyl, pyridinyl, pyrrolyl or a blood Im ah pyridazinyl,

Wherein said phenyl, pyridinyl, pyrrolyl or thiazolyl Im Ah 1 is unsubstituted or C _{1 -4} alkyl, each selected from the group consisting of C _{1 -4} haloalkyl, halogen, cyano and phenyl or 2 ≪ / RTI >

Wherein R ₅ and R ₆ represent a substituent substituted on A.

Preferably, A is benzo [b] thienyl, benzofura [3,2-b] pyrrolyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl , Thienyl or triazolyl. More preferably, A is selected from the group consisting of benzo [b] thien-3-yl, benzofura [3,2-b] pyrrol- Yl, isoxazol-5-yl, pyrrol-2-yl, thiazol-2-yl Thiazol-3-yl, thiazol-5-yl, thien-2-yl, Lt; / RTI >

Preferably, R < ₁ > is hydrogen and R < ₂ > is fluoro; Or R < ₁ > is fluoro and R < ₂ > is methoxy.

Preferably, R ₅ is hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, chloro or benzyl.

Preferably, R ₆ is hydrogen, methyl, methoxy, difluoromethyl, cyclopropyl, fluoro, chloro, nitro, amino, NH (t- Pyrrolyl or thiazolyl,

Wherein said phenyl, pyridinyl, pyrrolyl or thiazolyl is unsubstituted or substituted by one or more substituents each independently selected from the group consisting of methyl, t-butyl, trifluoromethyl, fluoro, chloro, cyano, Substituted with two substituents.

Preferably, R ₆ is unsubstituted or substituted by C _{1 -4} alkyl, C _{1 -4} haloalkyl, halogen, cyano and phenyl which is substituted by one or two substituents each selected from the group consisting of phenyl; Unsubstituted pyridinyl; C _{1 -4} alkyl substituted with a blood pyrrolyl; Or C _{1 -4} is an Im ah pyridazinyl substituted with alkyl.

Preferably,

A is indolyl,

R ₅ is hydrogen or C _{1 -4} alkyl,

R ₆ is hydrogen, C _{1 -4} alkyl, C _{1 -4} alkoxy or halogen.

Preferably,

A is isoxazolyl,

R < ₅ > is hydrogen,

And R ₆ is C _{1 -4} alkyl or phenyl,

Wherein said phenyl is unsubstituted or substituted with halogen.

Preferably,

A is oxazolyl,

R ₅ is hydrogen or C _{1 -4} alkyl,

And R ₆ is C _{1 -4} alkyl or phenyl,

Wherein said phenyl is substituted by one or two substituents each selected from the group consisting of unsubstituted or C _{1 -4} haloalkyl, halogen, and phenyl beach.

Preferably,

A is pyrazolyl,

R ₄ is hydrogen, R ₅ is hydrogen, C _{1 -4} alkyl, C _{1 -4} haloalkyl or benzyl; Or R ₄ and R ₅ are bonded together to form C _{2 -4} alkylene,

R ₆ is C _{1 -4} alkyl, C _{3 -6} cyclo-alkyl, nitro, phenyl, pyridinyl or pyrrolyl,

Wherein said phenyl, pyridinyl, or pyrrolyl substituted with a substituent which is selected from unsubstituted or substituted C _{1 -4} alkyl, C _{1 -4} haloalkyl, halogen and cyano group consisting furnace.

Preferably,

A is thiazolyl,

R ₅ is hydrogen, C _{1 -4} alkyl or C _{1 -4} haloalkyl,

R ₆ is hydrogen, C _{1 -4} alkyl, C _{1 -4} alkoxy, C _{1 -4} haloalkyl, C _{3 -6} cyclo-alkyl, halogen, amino, NH (t- butoxycarbonyl), NH (C _{1 - 4} < / RTI > alkyl) or phenyl,

Wherein said phenyl is substituted by one or two substituents each selected from the group that is unsubstituted or substituted by C _{1 -4} haloalkyl, halogen and cyano configuration.

Preferably,

A is thienyl,

R < ₅ > is hydrogen or halogen,

R ₆ is hydrogen, C _{1 -4} alkyl, halogen or phenyl,

Wherein said phenyl is optionally substituted with substituents selected from unsubstituted or substituted C _{1 -4} alkyl, C _{1 -4} haloalkyl, halogen and cyano group consisting furnace.

Preferably,

A is triazolyl,

And R ₅ is C _{1 -4} alkyl,

R ₆ is phenyl.

Representative examples of the compound represented by the above formula (1) are as follows:

1) N '- (6-fluoropyridin-3-yl) -4- (2- methylthiazol-

2) N '-( 6-fluoropyridin-3-yl) thiophene-2-carbohydrazide,

3) N '-( 6-fluoropyridin-3-yl) -3-methylthiophene-2-carbohydrazide,

4) N '- (6-Fluoropyridin-3-yl) -4-methylthiophene-2-carbohydrazide,

5) N '-( 3-methylthien-2-ylcarbonyl) -N '-( 6-fluoropyridin- 3- yl) -3-methylthiophene-2-carbohydrazide,

6) 2,5-Dichloro-N '- (6-fluoropyridin-3-yl) thiophene-3-carbohydrazide,

7) 2,5-Dichloro-N '- (5-fluoro-6-methoxypyridin-3- yl) thiophene-3-carbohydrazide,

8) N '- (6-Fluoropyridin-3-yl) -5-phenylthiophene-2-carbohydrazide,

9) N '-( 5-fluoro-6-methoxypyridin-3-yl) -5- phenylthiophene-2-carbohydrazide,

10) 5- (4-Fluorophenyl) -N'- (6-fluoropyridin-3-yl) thiophene-2-carbohydrazide,

11) N '- (5-fluoro-6-methoxypyridin-3- yl) -5- (4- fluorophenyl) thiophene-

12) 5- (4-Chlorophenyl) -N '- (5-fluoro-6-methoxypyridin-3- yl) thiophene-

13) 5- (4-Cyanophenyl) -N '- (5-fluoro-6-methoxypyridin-3- yl) thiophene-

14) N '- (5-Fluoro-6-methoxypyridin-3- yl) -5- (4- (trifluoromethyl) phenyl) thiophene-

15) 5- (4- (t-Butyl) phenyl) -N '- (5-fluoro-6-methoxypyridin- 3- yl) thiophene-

16) N '-( 6-Fluoropyridin-3-yl) -5- nitro- lH- pyrazole- 3-carbohydrazide,

17) 3-Cyclopropyl-N '- (5-fluoro-6-methoxypyridin-3- yl) -lH- pyrazole-5-carbohydrazide,

18) N '-( 6-Fluoropyridin-3-yl) -3-phenyl-lH- pyrazole-5-carbohydrazide,

19) 3- (4-Fluorophenyl) -N '- (6-fluoropyridin-3-yl) -1H- pyrazole-5-carbohydrazide,

20) 3- (4-Chlorophenyl) -N '-( 6-fluoropyridin-3-yl) -lH- pyrazole-5-carbohydrazide,

21) N '-( 6-Fluoropyridin-3-yl) -3- (4- (trifluoromethyl) phenyl) -lH- pyrazole-5-carbohydrazide,

22) Synthesis of 3- (4-cyanophenyl) -N '- (6-fluoropyridin-3-yl) -1H-pyrazole-5-carbohydrazide,

23) N '-( 6-fluoropyridin-3-yl) -3- (1 -methyl-lH- pyrrol- 2-yl) -lH- pyrazole-5-carbohydrazide,

24) N '-( 6-Fluoropyridin-3-yl) -3- (pyridin- 2-yl) -lH- pyrazole-5-carbohydrazide,

25) A mixture of t-butyl 1- (5-fluoro-6-methoxypyridin-3-yl) -2-

26) N '-( 5-fluoro-6-methoxypyridin-3-yl) -3-phenyl- lH- pyrazole-5-carbohydrazide,

27) N '-( 5-fluoro-6-methoxypyridin-3-yl) -3- (4- fluorophenyl) -lH- pyrazole-5-carbohydrazide,

28) 3- (4-Chlorophenyl) -N '- (5-fluoro-6-methoxypyridin-3- yl) -1H- pyrazole-5-carbohydrazide,

29) N '-( 5-fluoro-6-methoxypyridin-3-yl) -3- (4- (trifluoromethyl) phenyl) -lH-pyrazole-

30) A mixture of 3- (4-cyanophenyl) -N '- (5-fluoro-6-methoxypyridin-

31) N '-( 6-Fluoropyridin-3-yl) -l-methyl-5-phenyl-lH- pyrazole-3-carbohydrazide,

32) 5- (4-Fluorophenyl) -N '- (6-fluoropyridin-3- yl) -l -methyl- lH- pyrazole-3-carbohydrazide,

33) N '-( 6-Fluoropyridin-3-yl) -l-methyl-3-phenyl-lH- pyrazole-5-carbohydrazide,

34) N '- (5-Fluoro-6-methoxypyridin-3-yl)

35) N '- (5-fluoro-6-methoxypyridin-3-yl) -3- (4- fluorophenyl)

36) 1-Ethyl-N '- (5-fluoro-6-methoxypyridin-3- yl) -3- (4- fluorophenyl)

37) 1-Ethyl-N '-( 6-fluoropyridin-3-yl) -3-phenyl- lH- pyrazole-5-carbohydrazide,

38) 3- (4-Fluorophenyl) -N'- (6-fluoropyridin-3-yl) -l-methyl- lH- pyrazole-5-carbohydrazide,

39) A mixture of 1-ethyl-3- (4-fluorophenyl) -N '- (6-fluoropyridin-

40) To a solution of 3- (4-fluorophenyl) -N '- (6-fluoropyridin-3-

41) A mixture of 3- (4-fluorophenyl) -N '- (6-fluoropyridin-3-

42) Synthesis of l-benzyl-3- (4-fluorophenyl) -N '- (6-fluoropyridin-

43) N '-( 6-fluoropyridin-3-yl) -3-methyl-l- phenyl- lH- pyrazole-

44) Synthesis of l-benzyl-N '- (6-fluoropyridin-3-yl) -3-phenyl-lH- pyrazole-5-carbohydrazide,

45) A mixture of 3- (4-chlorophenyl) -N '- (5-fluoro-6-methoxypyridin-

46) 3- (4-Chlorophenyl) -1-ethyl-N '-( 5-fluoro-6- methoxypyridin-

47) N '-( 5-fluoro-6-methoxypyridin-3-yl) -1- methyl-3- (4- (trifluoromethyl) phenyl) -lH-pyrazole- Zaid,

48) A mixture of 1-ethyl-N '- (5-fluoro-6-methoxypyridin-3- yl) -3- (4- (trifluoromethyl) phenyl) -1H- pyrazole- Zaid,

49) 3- (4-Cyanophenyl) -N '- (5-fluoro-6-methoxypyridin-

50) A mixture of 3- (4-cyanophenyl) -N '- (5-fluoro-6-methoxypyridin-

51) 3- (4-Chlorophenyl) -N '- (6-fluoropyridin-3-yl)

52) N '- (6-Fluoropyridin-3-yl) -1-methyl-3- (4- (trifluoromethyl) phenyl) -1 H- pyrazole-

53) 3- (4-Cyanophenyl) -N'- (6-fluoropyridin-3-yl) -1-methyl-lH- pyrazole-5-carbohydrazide,

54) A mixture of 3- (4-chlorophenyl) -l-ethyl-N '- (6-fluoropyridin-

55) 1-Ethyl-N '- (6-fluoropyridin-3-yl) -3- (4- (trifluoromethyl) phenyl) -1 H- pyrazole-

56) A mixture of 3- (4-cyanophenyl) -1-ethyl-N '- (6-fluoropyridin-

57) 3- (4-Cyanophenyl) -1-ethyl-N '-( 5-fluoro-6- methoxypyridin-

58) 1-Ethyl-N '- (5-fluoro-6-methoxypyridin-3- yl) -3-phenyl-lH- pyrazole-5-carbohydrazide,

59) A mixture of 1-benzyl-N '- (5-fluoro-6-methoxypyridin-

60) 3- (4-Fluorophenyl) -N'- (6-fluoropyridin-3-yl) Hydrazide,

61) N '- (5-fluoro-6-methoxypyridin-3-yl) -3- (4- fluorophenyl) -1- (2,2,2-trifluoroethyl) Sol-5-carbohydrazide,

62) N '-( 6-fluoropyridin-3-yl) -5-methylisoxazole-3-carbohydrazide,

63) N '-( 5-fluoro-6-methoxypyridin-3- yl) -5- (4- fluorophenyl) isoxazole-3-carbohydrazide,

64) 5- (4-Chlorophenyl) -N '- (5-fluoro-6-methoxypyridin- 3- yl) isoxazole-

65) N '- (5-fluoro-6-methoxypyridin-3- yl) -3- (4- fluorophenyl) isoxazole-

66) N '-( 6-Fluoropyridin-3-yl) -3,5-dimethyl- lH- pyrazole-4-carbohydrazide,

67) N '-( 6-Fluoropyridin-3-yl) -1H-imidazole-2-carbohydrazide,

68) N '- (5-fluoro-6-methoxypyridin-3-yl) -5-

69) N '-( 6-Fluoropyridin-3-yl) thiazole-2-carbohydrazide,

70) N '-( 5-fluoro-6-methoxypyridin-3-yl) -4-phenylthiazole-2-carbohydrazide,

71) N '-( 6-Fluoropyridin-3-yl) thiazole-4-carbohydrazide,

72) N '-( 5-fluoro-6-methoxypyridin-3-yl) -2-phenylthiazole-

73) N '-( 6-Fluoropyridin-3-yl) -4-methyloxazole-5-carbohydrazide,

74) N '-( 6-Fluoropyridin-3-yl) -2-phenyloxazole-5-carbohydrazide,

75) N '- (5-fluoro-6-methoxypyridin-3-yl) -2-phenyloxazole-

76) 2- (4-Fluorophenyl) -N'- (6-fluoropyridin-3-yl) oxazole-

77) 2- (3,4-Difluorophenyl) -N '- (6-fluoropyridin-3-yl) oxazole-

78) 2- (3,4-Difluorophenyl) -N '- (5-fluoro-6-methoxypyridin-3-yl) oxazole-

79) N '- (6-fluoropyridin-3-yl) -2- (4- (trifluoromethyl) phenyl) oxazole-

80) N '- (5-fluoro-6-methoxypyridin-3-yl) -2- (4- (trifluoromethyl) phenyl) oxazole-

81) N '- (6-Fluoropyridin-3-yl) -4-methyl-2-phenyloxazole-

82) N '- (5-fluoro-6-methoxypyridin-3-yl) -4-methyl-

Biphenyl-3-yl) -N '- (6-fluoropyridin-3-yl) oxazole-5-carbohydrazide,

84) 2 - ([1,1'-biphenyl] -3- yl) -N '- (5-fluoro-6- methoxypyridin- 3- yl) oxazole-

85) N '-( 6-fluoropyridin-3-yl) -4-methylthiazole-5-carbohydrazide,

86) N '-( 6-fluoropyridin-3-yl) -2,4- dimethylthiazole- 5- carbohydrazide,

87) 2- (4-Chlorophenyl) -N '- (6-fluoropyridin-3- yl) -4-methylthiazole-

88) 2-Chloro-N '- (6-fluoropyridin-3-yl) thiazole- 5-carbohydrazide,

89) t-butyl (5- (2- (6-fluoropyridin-3-yl) hydrazine-1-carbonyl) thiazol-

90) 2-Amino-N '- (6-fluoropyridin-3-yl) thiazole-

91) 4- (Difluoromethyl) -N '- (6-fluoropyridin-3-yl) -2-methylthiazole-

92) 2- (Ethylamino) -N'- (6-fluoropyridin-3-yl) -4-methylthiazole-5-carbohydrazide,

93) 2-Chloro-N '- (6-fluoropyridin-3-yl) -4-methylthiazole-

94) 2-Chloro-N '- (5-fluoro-6-methoxypyridin-3- yl) thiazole-

95) N '-( 6-fluoropyridin-3-yl) -2-methoxy-4- methylthiazole-

96) 2-Cyclopropyl-N '- (5-fluoro-6-methoxypyridin-3- yl) thiazole-

97) N '-( 6-Fluoropyridin-3-yl) -2-phenylthiazole-5-carbohydrazide,

98) N '- (5-fluoro-6-methoxypyridin-3- yl) -2- (4- fluorophenyl) thiazole-

99) 2- (4-Chlorophenyl) -N '- (5-fluoro-6-methoxypyridin-3- yl) thiazole-

100) N '- (6-Fluoropyridin-3-yl) -2- (4- (trifluoromethyl) phenyl) thiazole-

101) N '- (5-fluoro-6-methoxypyridin-3-yl) -2-phenylthiazole-

102) N '- (5-Fluoro-6-methoxypyridin-3- yl) -2- (4- (trifluoromethyl) phenyl) thiazole-

103) N '- (5-fluoro-6-methoxypyridin-3-yl) -2- (3- fluorophenyl) thiazole-

104) 2- (2,4-Difluorophenyl) -N '- (5-fluoro-6-methoxypyridin-3- yl) thiazole-

105) 2- (3,4-Difluorophenyl) -N '- (5-fluoro-6-methoxypyridin-3- yl) thiazole-

106) 2- (4-Fluorophenyl) -N '- (6-fluoropyridin-3- yl) -4-methylthiazole-

107) 2- (4-Chlorophenyl) -N '- (6-fluoropyridin-3- yl) -4- (trifluoromethyl) thiazole-

108) 2- (4-Chlorophenyl) -N '-( 5-fluoro-6-methoxypyridin- 3- yl) -4-methylthiazole-

109) 2- (4-Cyanophenyl) -N '- (6-fluoropyridin-3- yl) -4-methylthiazole-

110) N '- (6-Fluoropyridin-3-yl) -4-methyl-2- (4- (trifluoromethyl) phenyl) thiazole-

111) 4-Ethyl-N'- (6-fluoropyridin-3-yl) -2-phenylthiazole-

112) N '- (6-Fluoropyridin-3-yl) -2-phenyl-4- (trifluoromethyl) thiazole-

113) 2- (4-Fluorophenyl) -N'- (6-fluoropyridin-3-yl) -4- (trifluoromethyl) thiazole-

114) 2- (4-Chlorophenyl) -N '- (5-fluoro-6-methoxypyridin-3- yl) -4- (trifluoromethyl) thiazole-

4- (trifluoromethyl) -2- (4- (trifluoromethyl) phenyl) thiazole-5-carbo Hydrazide,

116) N '- (5-fluoro-6-methoxypyridin-3-yl) -5-

117) N '-( 6-fluoropyridin-3-yl) -1-methyl-3-phenyl-1H-1,2,4- triazole-

118) N '- (5-fluoro-6-methoxypyridin-3-yl)

119) N '-( 5-fluoro-6-methoxypyridin-3- yl) -l-methyl- lH- indole- 3-carbohydrazide,

120) N '-( 6-fluoropyridin-3-yl) -lH-indole-2-carbohydrazide,

121) 6-Fluoro-N '-( 6-fluoropyridin-3-yl) -lH- indole-2-carbohydrazide,

122) 7-Chloro-N '-( 6-fluoropyridin-3- yl) -lH- indole- 2-carbohydrazide,

123) 6-Chloro-N '-( 6-fluoropyridin-3-yl) -lH- indole- 2-carbohydrazide,

124) 4-Chloro-N '-( 6-fluoropyridin-3-yl) -lH- indole-2-carbohydrazide,

125) 3-Chloro-N '-( 6-fluoropyridin-3-yl) -lH- indole-2-carbohydrazide,

126) N '-( 6-fluoropyridin-3-yl) -l-methyl- lH-indole-

127) 5-Fluoro-N '- (6-fluoropyridin-3-yl)

128) N '-( 5-fluoro-6-methoxypyridin-3- yl) -lH- indole- 2-carbohydrazide,

129) 6-Fluoro-N '- (5-fluoro-6-methoxypyridin- 3- yl) -lH- indole- 2-carbohydrazide,

130) N '-( 5-fluoro-6-methoxypyridin-3- yl) -l-methyl- lH- indole- 2-carbohydrazide,

131) 3-Chloro-N '- (5-fluoro-6-methoxypyridin-3- yl) -lH- indole-

132) 4-Chloro-N '-( 5-fluoro-6-methoxypyridin- 3- yl) -lH- indole- 2-carbohydrazide,

133) 6-Chloro-N '-( 5-fluoro-6-methoxypyridin- 3- yl) -lH- indole- 2-carbohydrazide,

134) 7-Chloro-N '-( 5-fluoro-6-methoxypyridin- 3- yl) -lH- indole- 2-carbohydrazide,

135) 5-Fluoro-N '- (5-fluoro-6-methoxypyridin-3- yl) -lH- indole- 2-carbohydrazide,

136) 5-Chloro-N '-( 5-fluoro-6-methoxypyridin- 3- yl) -lH- indole- 2-carbohydrazide,

137) N '-( 5-fluoro-6-methoxypyridin-3-yl) -5- methoxy- lH- indole- 2-carbohydrazide,

138) A mixture of 5-fluoro-N '- (5-fluoro-6-methoxypyridin-

139) N '-( 6-fluoropyridin-3-yl) -l-methyl- lH-benzofuro [3,2- b] pyrrole- 2-carbohydrazide,

140) N '-( 6-Fluoropyridin-3-yl) benzo [b] thiophene-3-carbohydrazide,

L, 5-a] pyrazin-4 (5H) - (5-fluoro-6-methoxypyridin- On,

2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] pyrimidin- [1,4] diazepin-4-one, and

A) < RTI ID = 0.0 > [1, < / RTI & 4] diazocin-4 (5H) -one.

The present invention also provides a process for producing the compound represented by the above formula (1). For example, the compound represented by the formula (1) can be prepared by the following reaction scheme (1).

[Reaction Scheme 1]

In the above scheme, A, R _1, R _2, R ₃ and R ₆ are the same as defined above, R ₅ is hydrogen, C _{1 -4} alkyl, C _{1 -4} haloalkyl, halogen, or benzyl.

The above reaction can be carried out under the reaction conditions for forming an amide bond by reacting an amine group of the compound represented by the formula (2) with a carboxyl group of the compound represented by the formula (3) to form an amide bond. In addition, the carboxylic acid of formula (2) can be converted into methyl or ethyl carboxylate or chloroacyl group by a conventional method. At this time, the reaction temperature is preferably 0 ° C to 50 ° C, more preferably 50 ° C to room temperature, and preferably 30 minutes to 24 hours.

The compound represented by the formula (1) can also be prepared by the following reaction scheme (2).

[Reaction Scheme 2]

In the above reaction formula, A, R ₁ , R ₂ and R ₆ are the same as defined above, and n is an integer of 1 to 3.

The above step 1 is a reaction for forming an amide bond by reacting an amine group of the compound represented by the general formula (4) with a carboxyl group of the compound represented by the general formula (5) as in the reaction scheme 1, . The carboxylic acid of formula (5) may be converted into methyl or ethyl carboxylate or chloroacyl group by a conventional method. At this time, the reaction temperature is preferably from 0 ° C to 50 ° C, more preferably from room temperature to 50 ° C, and preferably from 30 minutes to 24 hours.

Step 2 is a step of reacting a compound represented by formula (6) with a compound represented by formula (7) to produce a structure in which R ₄ and R ₅ are bonded together to form C _{2 -4} alkylene. The reaction is preferably carried out under basic conditions. Examples of the base used in the present invention include inorganic bases such as sodium hydroxide (NaOH), potassium hydroxide (KOH), potassium carbonate (K ₂ CO ₃ ), sodium hydride (NaH) And the like can be used. The reaction solvent used here is preferably a polar organic solvent, more preferably a polar solvent such as dimethylformamide.

Step 3 is a reaction for eliminating the protecting group of the compound represented by the formula (8), whereby the compound represented by the formula (1) can be prepared. The acid halide may be used to remove the protecting group, for example, a hydrochloric acid solution may be used.

The compound represented by Formula 1 of the present invention may be provided in the form of a pharmaceutically acceptable salt derived from an inorganic acid or an organic acid. As the salts usable in the present invention, there can be used salts which are known and can be used in the field of antifungal drugs including inorganic acids or organic acid salts, which can be prepared by known methods. Specific examples include inorganic acids such as hydrochloric acid and nitric acid; Sulfonic acids such as methanesulfonic acid; Or an organic acid such as oxalic acid or the like.

The compounds of formula (I) according to the present invention also include hydrates and solvates which may be prepared therefrom.

The present invention also provides an antifungal agent composition comprising the compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

Since the compounds of formula (1), pharmaceutically acceptable salts, isomers, hydrates and solvates thereof have fungicidal activity with excellent antifungal activity, Candida spp . ), Aspergillus spp . ), Cryptosporidium caucus's only neo-Fort (Cryptococcus neoformans and Trichophyton spp . ) And the like can be effectively used for the treatment and prevention of various fungal infections. Accordingly, the present invention provides an antifungal drug composition comprising, as an active ingredient, a compound selected from the group consisting of the compound of formula (I), a pharmaceutically acceptable salt thereof, an isomer, a hydrate and a solvate thereof. The antifungal agent composition may include a pharmaceutically acceptable carrier or vehicle.

The antifungal agent compositions can be formulated into various formulations using conventional techniques in the art by mixing the compounds according to the invention with pharmaceutically acceptable inert carriers or vehicles suitable for oral, parenteral or topical administration . The antifungal agent composition of the present invention is particularly fungicidal and has the characteristic of being orally administered.

Examples of formulations for oral administration include tablets and capsules. These formulations may contain, in addition to the active ingredient, a diluent (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose or glycine) Such as, for example, silica, talc, stearic acid and its magnesium or calcium salt, or polyethylene glycol, or a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose or Polyvinyl pyrrolidine, etc.), and may further contain a disintegrating agent such as starch, agar, alginic acid or a sodium salt thereof, a boiling mixture, an absorbent, a colorant, a flavoring agent and a sweetening agent.

The dose of the active ingredient such as the compound according to the present invention may vary depending on various factors such as the subject to be treated, the severity of the disease, the mode of administration, the sex, the prescription of the physician, The effective amount thereof can be easily determined. Preferably, the compounds of the present invention are administered at a dose of 0.05 mg / kg / day to 200 mg / kg / day, more preferably from 0.05 mg / kg / day to 100 mg / kg / day for the treatment of mammals, including humans infected with fungi, day may be administered orally or in the form of an injection.

The novel antifungal oxo-dihydropyridin-carbonyl hydrazide derivatives according to the present invention because they have excellent fungicidal activity and with antifungal, Candida (Candida spp.), Aspergillus (Aspergillus spp . ), Cryptococcus neoformans and Trichophyton spp . ) And the like can be effectively used for the treatment and prevention of various fungal infections. In addition, there is an advantage that it can be administered orally in a fungicidal preparation.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided to further understand the present invention, and the present invention is not limited by the examples.

Example  One: N ' - (6- Fluoropyridine Yl) -4- (2- Methylthiazole -4-yl) -1H-pyrrole-2-carbohydrazide

4-yl) -1H-pyrrole-2-carboxylic acid (16.7 mg, 0.08 mmol) was added to a solution of 4- (2-methylthiazol- And dissolved in 1 mL of N, N-dimethylformamide. N, N, N ', N'-tetramethyluronium hexafluorophosphate (45.4 mg, 0.12 mmol), diisopropylethylamine (34.8 uL, 0.2 mmol) were added and the reaction was stirred at room temperature for 6 hours. When the reaction was complete, the solvent was removed, diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected by dry filtration with magnesium sulfate and concentrated under reduced pressure to give the title compound (14.2 mg, yield 56%) by column chromatography (developing solvent, ethyl acetate: hexane = 1: 1).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.69 (s, 1H), 7.42-7.38 (m, 2H), 7.25 (s, 1H), 7.18 (s, 1H), 6.91 (dd, 1H), 2.71 (s, 3 H)

Example  2: N ' - (6- Fluoropyridine -3 days) Thiophene -2- Carbohydrazide  Produce

The procedure of Example 1 was repeated except that thiophene-2-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H- pyrrole- To obtain the title compound (9.7 mg, yield 51%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.79 (d, 1H), 7.73 (d, 1H), 7.71 (s, 1H), 7.43-7.40 (m, 1H), 7.18 (t, 1H), 6.92 (dd, 1 H)

Example  3: N ' - (6- Fluoropyridine Yl) -3- Methyl thiophene -2- Carbohydrazide  Produce

Example 1 was repeated except that 3-methylthiophene-2-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H- To give the title compound (11.5 mg, yield 57%).

¹ H NMR (CH ₃ OH-d ₄ ):? 8.17 (s, IH), 7.95-7.94 (m, IH), 7.45 (d, 2.32 (s, 3 H)

Example  4: N ' - (6- Fluoropyridine Yl) -4- Methyl thiophene -2- Carbohydrazide  Produce

Example 1 was repeated except that 4-methylthiophene-2-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H- , The title compound (11.1 mg, yield 55%) was obtained.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.70 (s, 1H), 7.60 (s, 1H), 7.43-7.39 (m, 1H), 7.32 (s, 1H), 6.92 (dd, 1H), 2.30 (s, 3 H)

Example  5: N ' - (3- Methylcyene -2- Ylcarbonyl ) -N ' - (6- Fluoropyridine Yl) -3- Methyl thiophene -2- Carbohydrazide  Produce

Example 1 was repeated except that 3-methylthiophene-2-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H- , The title compound (17.7 mg, yield 59%) was obtained.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.17 (s, 1H), 7.95-7.94 (m, 1H), 7.45 (d, 2H), 7.04 (dd, 1H), 6.83 (d, 2H), 2.32 (s, 6H)

Example  6: 2,5- Dichloro - N ' - (6- Fluoropyridine -3 days) Thiophene -3- Carbohydrazide  Produce

Except that 2,5-dichlorothiophene-3-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H-pyrrole-2-carboxylic acid in Example 1 The title compound (10.3 mg, yield 42%) was obtained by carrying out the same processes as in Example 1.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.76 (s, 1H), 7.48-7.45 (m, 1H), 7.24 (s, 1H), 6.95 (dd, 1H)

Example  7: 2,5- Dichloro - N ' - (5- Fluoro -6- Methoxypyridine -3 days) Thiophene -3-carbohydrazide < / RTI >

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (13.4 mg, yield 50%) was prepared following the same procedure as in Example 1, except that 2,5-dichlorothiophene-3-carboxylic acid was used instead of 1H-pyrrole- ≪ / RTI >

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.57 (s, 1H), 7.19 (s, 1H), 7.10 (d, 2H), 3.90 (s, 3H)

Example  8: N ' - (6- Fluoropyridine Yl) -5- Phenyl thiophene -2- Carbohydrazide  Produce

Example 1 was repeated except that 5-phenylthiophene-2-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H- , The title compound (14.0 mg, yield 56%) was obtained.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.76 (d, 1H), 7.72-7.69 (m, 3H), 7.46-7.41 (m, 4H), 7.37-7.36 (m, 1H), 6.93 (dd , 1H)

Example  9: N ' - (5- Fluoro -6- Methoxypyridine Yl) -5- Phenyl thiophene -2- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (14.0 mg, yield 51%) was obtained by carrying out the same procedure as in Example 1, except that 5-phenylthiophene-2-carboxylic acid was used instead of 1H-pyrrole-2-carboxylic acid.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.75 (d, 1H), 7.71 (d, 2H), 7.69 (s, 1H), 7.56-7.41 (m, 3H), 7.38-7.34 (m, 1H ), 7.10 (d, 1 H), 3.91 (s, 3 H)

Example  10: 5- (4- Fluorophenyl ) - N ' - (6- Fluoropyridine -3 days) Thiophene -2- Carbohydrazide  Produce

Except that 5- (4-fluorophenyl) thiophene-2-carboxylic acid was used in place of 4- (2-methylthiazol-4-yl) -1H- pyrrole-2-carboxylic acid in Example 1 , And the same processes as in Example 1 were carried out to obtain the title compound (15.1 mg, yield 57%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.75-7.72 (m, 3H), 7.55 (d, 1H), 7.40 (d, 1H), 7.19-7.15 (m, 2H), 7.11-7.08 (m , ≪ / RTI > 1H), 3.90 (s, 3H)

Example  11: N ' - (5- Fluoro -6- Methoxypyridine Yl) -5- (4- Fluorophenyl ) Thiophene -2- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (15.9 mg, yield) was obtained in the same manner as in Example 1, except that 5- (4-fluorophenyl) thiophene-2-carboxylic acid was used instead of 1H- 55%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.85 (d, 2H), 7.78 (d, 1H), 7.60-7.55 (m, 2H), 7.33 (d, 2H), 7.09 (dd, 1H), 3.89 (s, 3H)

Example  12: 5- (4- Chlorophenyl ) - N ' - (5- Fluoro -6- Methoxypyridine -3 days) Thiophene -2-car Bohidrazade Manufacturing

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (16.6 mg, yield 55%) was prepared following the same procedure as in Example 1, except using 5- (4-chlorophenyl) thiophene-2-carboxylic acid in place of 1H-pyrrole- %).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.81 (d, 2H), 7.78 (d, 1H), 7.62 (d, 2H), 7.60-7.55 (m, 2H), 7.09 (dd, 1H), 3.89 (s, 3H)

Example  13: 5- (4- Cyanophenyl ) - N ' - (5- Fluoro -6- Methoxypyridine -3 days) Thiophene -2-car Bohidrazade Manufacturing

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (4-cyanophenyl) thiophene-2-carboxylic acid in place of 1H-pyrrole-2-carboxylic acid, the title compound (17.4 mg, yield 59%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.80 (d, 2H), 7.78 (d, 1H), 7.75 (d, 2H), 7.60-7.55 (m, 2H), 7.09 (dd, 1H), 3.89 (s, 3H)

Example  14: N ' - (5- Fluoro -6- Methoxypyridine Yl) -5- (4- ( Trifluoromethyl ) Phenyl) Thiophene -2- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- Carboxyric acid instead of 5- (4- (trifluoromethyl) phenyl) thiophene-2-carboxylic acid in place of 1H-pyrrole-2-carboxylic acid 16.8 mg, yield 51%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.87 (d, 2H), 7.78 (d, 1H), 7.71 (d, 2H), 7.60-7.55 (m, 2H), 7.09 (dd, 1H), 3.89 (s, 3H)

Example  15: 5- (4- (t-Butyl) Phenyl ) - N ' - (5- Fluoro -6- Methoxypyridine -3 days) Thiophene -2- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (18.9 mg, 86%) was obtained as white crystals by the same procedure as in Example 1, except that 5- (4- (t-butyl) phenyl) thiophene-2-carboxylic acid was used instead of 1H- mg, yield: 59%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.78 (d, 1H), 7.69 (d, 2H), 7.60-7.55 (m, 2H), 7.38 (d, 2H), 7.09 (dd, 1H), 3.89 (s, 3H), 1.35 (s, 9H)

Example  16: N ' - (6- Fluoropyridine Yl) -5-nitro-1H- Pyrazole -3- Carbohydrazide  Produce

Pyrazole-3-carboxylic acid in place of 4- (2-methylthiazol-4-yl) -1H-pyrrole-2-carboxylic acid in Example 1, The title compound (10.4 mg, yield 49%) was obtained by carrying out the same processes as in the above Example 1.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.71 (s, 1H), 7.47 (s, 1H), 7.44-7.41 (m, 1H), 6.92 (dd, 1H)

Example  17: 3- Cyclopropyl - N ' - (5- Fluoro -6- Methoxypyridine 3-yl) -1H- Fira Sol-5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (11.0 mg, yield 47%) was obtained by following the same procedure as in Example 1, except that 3-cyclopropyl-1H-pyrazole-5-carboxylic acid was used instead of 1H-pyrrole- ).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.53 (d, 1H), 7.08 (dd, 1H), 6.40 (s, 1H), 3.90 (s, 3H), 1.98-1.90 (m, 1H), 1.02-1.01 (m, 2H), 0.76-0.73 (m, 2H)

Example  18: N ' - (6- Fluoropyridine Yl) -3- Phenyl -1H- Pyrazole -5- Carbohydrazide  Produce

Except that 3-phenyl-1H-pyrazole-5-carboxylic acid was used in place of 4- (2-methylthiazol-4-yl) -1H- The title compound (13.3 mg, yield 56%) was obtained by the same procedure as in Example 1.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.74-7.71 (m, 3H), 7.45-7.42 (m, 3H), 7.38 (d, 1H), 7.08 (s, 1H), 6.91 (dd, 1H )

Example  19: 3- (4- Fluorophenyl ) - N ' - (6- Fluoropyridine 3-yl) -1H- Pyrazole -5-carbohydrazide < / RTI >

(4-fluorophenyl) -1H-pyrazole-5-carboxylic acid instead of 4- (2-methylthiazol-4-yl) (12.9 mg, yield 51%) was obtained by carrying out the same processes as in Example 1,

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.74 (m, 3H), 7.45 (m, 1H), 7.22 (m, 2H), 7.05 (s, 1H), 6.93 (dd, 1H)

Example  20: 3- (4- Chlorophenyl ) - N ' - (6- Fluoropyridine 3-yl) -1H- Pyrazole -5- Car Manufacture of borides

(4-chlorophenyl) -1H-pyrazole-5-carboxylic acid instead of 4- (2-methylthiazol-4-yl) , The title compound (15.1 mg, yield 57%) was obtained by carrying out the same processes as in the above Example 1.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.74 (m, 3H), 7.43-7.48 (m, 3H), 7.10 (m, 1H), 6.93 (dd, 1H)

Example  21: N ' - (6- Fluoropyridine Yl) -3- (4- ( Trifluoromethyl ) Phenyl ) -1H-pyrazole-5- Carbohydrazide  Produce

(Trifluoromethyl) phenyl) -1H-pyrazole-5-carboxylic acid in place of 4- (2-methylthiazol-4-yl) (16.1 mg, yield 55%) was obtained by carrying out the same processes as in the above Example 1, except that the carboxylic acid was used instead of the carboxylic acid.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.95 (m, 3H), 7.75 (m, 3H), 7.45 (m, 1H), 7.24 (s, 1H), 6.93 (dd, 1H)

Example  22: 3- (4- Cyanophenyl ) - N ' - (6- Fluoropyridine 3-yl) -1H- Pyrazole -5- Carbohydrazide  Produce

(4-cyanophenyl) -1H-pyrazole-5-carboxylic acid in place of 4- (2-methylthiazol-4-yl) (16.2 mg, yield: 63%) was obtained by carrying out the same processes as in Example 1,

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.03 (s, 1H), 7.92 (s, 1H), 7.83 (m, 2H), 7.74 (s, 1H), 7.45 (m, 1H), 7.25 ( s, 1 H), 6.93 (dd, 1 H)

Example  23: N ' - (6- Fluoropyridine Yl) -3- (1- methyl -1H-pyrrol-2-yl) -1H- Pyrazole -5- Carbohydrazide  Produce

Methyl-1H-pyrrole-2-yl) -1H-pyrazole-2-carboxylic acid in place of 4- (2-methylthiazol- (12.3 mg, yield 51%) was obtained by carrying out the same processes as in the above Example 1, except that 5-carboxylate acid was used.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.74 (s, 1H), 7.47-7.43 (m, 1H), 6.93 (dd, 1H), 6.87 (m, 1H), 6.81 (m, 1H), 6.44 (m, 1 H), 6.12 (s, 1 H), 3.76 (s, 3 H)

Example  24: N ' - (6- Fluoropyridine Yl) -3- (pyridin-2-yl) -1H- Pyrazole -5- Cabo Manufacture of Hydrazide

(Pyridin-2-yl) -1H-pyrazole-5-carboxylic acid in place of 4- (2-methylthiazol-4-yl) (14.6 mg, yield: 61%) was obtained by carrying out the same processes as in Example 1,

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.61 (s, 1H), 7.89-7.80 (m, 2H), 7.74 (s, 1H), 7.46-7.42 (m, 2H), 7.29 (m, 1H ), 6.92 (d, 1 H)

Example  25: t-Butyl 1- (5- Fluoro -6- Methoxypyridine Yl) -2- (3- Phenyl -1H- Pyrazole -5- Carbonyl ) Hydrazine -One- Carboxylate  Produce

Step 1) Preparation of t-butyl (5-fluoro-6-methoxypyridin-3-yl) carbamate

Tert-Butyl dicarbonate (42 mL, 182.8 mmol) was dissolved in t-butanol (7.04 mL, 10 M) And the mixture was stirred at 40-50 DEG C for 15 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and purified by column chromatography (developing solvent, ethyl acetate: hexane = 1: 4) to obtain the title compound (16 g, yield 94%).

Step 2) Preparation of t-butyl 1- (5-fluoro-6-methoxypyridin-3-yl) hydrazine-1-carboxylate

N, N-dimethylformamide (21 mL, 1.0 M) was added to 60% sodium hydride (1.8 g, 51.6 mmol) and the nitrogen atmosphere was maintained. The t-butyl (5-fluoro-methoxypyridin-3-yl) carbamate (5 g, 20.6 mmol) obtained in the above step 1 was dissolved in N, N- dimethylformamide (3 mL, And the mixture was stirred. After 30 minutes, P, P-diphenylphosphinic amide (8.7 g, 37.1 mmol) was added in one portion, and N, N-dimethylformamide (21 mL) was added to dissolve the mixed solution. After stirring for 1 hour, the reaction was terminated with water. The reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, concentrated under reduced pressure and purified by column chromatography (developing solvent, ethyl acetate: hexane = 1: 4) Yield: 68%).

Step 3) Preparation of t-butyl 1- (5-fluoro-6-methoxypyridin-3- yl) -2- (3-phenyl-1H-pyrazole-5-carbonyl) hydrazine-

Butyl 1- (5-fluoro-6-methoxypyridin-3-yl) hydrazine-1-carboxylate prepared in the above Step 2 instead of 2-fluoro-5-hydrazinylpyridine in Example 1 Phenyl-1H-pyrazole-5-carboxylic acid was used in place of 4- (2-methylthiazol-4-yl) , The title compound (19.1 mg, yield 56%) was obtained.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.09 (s, 1H), 7.72 (d, 2H), 7.46 (t, 2H), 7.39 (m, 2H), 7.10 (s, 1H), 4.00 ( s, 3H), 1.48 (s, 9H)

Example  26: N ' - (5- Fluoro -6- Methoxypyridine Yl) -3- Phenyl -1H- Pyrazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (13.4 mg, yield 51%) was obtained by following the same procedure as in Example 1, except that 3-phenyl-1H-pyrazole-5-carboxylic acid was used instead of 1H-pyrrole- ≪ / RTI >

¹ H NMR (CH ₃ OH-d ₄ ):? 7.70 (m, 2H), 7.55 (d, 1H), 7.45-7.43 (m, 2H), 7.39-7.37 ), 7.09-7.07 (m, 1 H), 3.89 (s, 3H)

Example  27: N ' - (5- Fluoro -6- Methoxypyridine Yl) -3- (4- Fluorophenyl ) -1H- Pyrazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- Pyrrole-5-carboxylic acid was used instead of 3- (4-fluorophenyl) -1H-pyrazole-5-carboxylic acid in place of 1H-pyrrole- mg, yield: 57%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.75 (t, 2H), 7.57 (d, 1H), 7.22 (t, 2H), 7.12 (dd, 1H), 7.05 (s, 1H)

Example  28: 3- (4- Chlorophenyl ) - N ' - (5- Fluoro -6- Methoxypyridine 3-yl) -1H- Pyrazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- Following the same procedure as in Example 1, except using 3- (4-chlorophenyl) -1H-pyrazole-5-carboxylic acid in place of 1H-pyrrole-2-carboxylic acid, the title compound (15.9 mg , Yield: 55%).

_{^{1 H NMR (DMSO-d 6}} ): δ 13.85 (s, 1H), 10.35 (s, 1H), 8.02 (s, 1H), 7.81 (d, 2H), 7.53-7.46 (m, 3H), 7.23- 7.09 (m, 2 H), 3.82 (s, 3 H)

Example  29: N ' - (5- Fluoro -6- Methoxypyridine Yl) -3- (4- ( Trifluoromethyl ) Phenyl) -lH- Pyrazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The same procedure as in Example 1 was performed except that 3- (4- (trifluoromethyl) phenyl) -1H-pyrazole-5-carboxylic acid was used instead of 1H-pyrrole-2-carboxylic acid The title compound (14.9 mg, yield 47%) was obtained.

_{^{1 H NMR (DMSO-d 6}} ): δ 14.01 (s, 1H), 10.42 (s, 1H), 8.05-8.00 (m, 3H), 7.82 (d, 2H), 7.52 (d, 1H), 7.37 ( s, 1 H), 7.12 (d, 1 H), 3.82 (s, 3 H)

Example  30: 3- (4- Cyanophenyl ) - N ' - (5- Fluoro -6- Methoxypyridine 3-yl) -1H- Pyrazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (4-cyanophenyl) -1H-pyrazole-5-carboxylic acid was used in place of 1H-pyrrole-2-carboxylic acid to give the title compound mg, yield: 42%).

_{^{1 H NMR (DMSO-d 6}} ): δ 14.06 (s, 1H), 10.42 (s, 1H), 8.05 (s, 1H), 7.98 (d, 2H), 7.92 (d, 2H), 7.51 (d, 1H), 7.40 (s, IH), 7.12 (d, IH), 3.82 (s, 3H)

Example  31: N ' - (6- Fluoropyridine Yl) -1- methyl -5- Phenyl -1H- Pyrazole -3- Carbohydrazide  Produce

Step 1) Preparation of ethyl 1-methyl-5-phenyl-1H-pyrazole-3-carboxylate

(130 mg, 0.6 mmol) and potassium carbonate (165 mg, 1.2 mmol) were dissolved in N, N-dimethylformamide, and then iodomethane 55.9 uL, 0.9 mmol) was added slowly. The reaction solution was stirred at 35 DEG C for 2 hours. After the reaction was completed, the reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (developing solvent, ethyl acetate: hexane = 1: 4) to obtain the title compound (102 mg, yield 74%).

Step 2) Preparation of 1-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid

Methyl-5-phenyl-1H-pyrazole-3-carboxylate (102 mg, 0.44 mmol) obtained in the above step 1 was dissolved in a mixed solvent of tetrahydrofuran / methanol (2 mL / Hydroxide (1.3 mL, 6.0 eq.) Was added and stirred at ambient temperature for 2 hours. After the reaction was completed, the reaction mixture was acidified with 1N hydrochloric acid and then diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (80.8 mg, yield 90%).

Step 3) Preparation of N '- (6-fluoropyridin-3-yl) -1-methyl-5-phenyl-1H-pyrazole-3-carbohydrazide

Methyl-5-phenyl-1H-pyrazole-3-carboxylic acid (16.2 mg, 0.08 mmol) prepared in the above step 2 was dissolved in tetrahydrofuran Is dissolved in 1 mL of N, N-dimethylformamide. N, N, N ', N'-tetramethyluronium hexafluorophosphate (45.4 mg, 0.12 mmol), diisopropylethylamine (34.8 uL, 0.2 mmol) were added and the reaction was stirred at room temperature for 6 hours. When the reaction was complete, the solvent was removed, diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected by dry filtration with magnesium sulfate and concentrated under reduced pressure to give the title compound (12.5 mg, yield 50%) as a colorless solid (developing solvent, ethyl acetate: hexane = 1: 1).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.73 (s, 1H), 7.53 (d, 4H), 7.42-7.51 (m, 2H), 6.93 (dd, 1H), 6.83 (s, 1H), 3.96 (s 3H)

Example  32: 5- (4- Fluorophenyl ) - N ' - (6- Fluoropyridine Yl) -1- methyl -1H- Pyrazole -3- Carbohydrazide  Produce

Pyrazole-3-carboxylate was used in place of 5-phenyl-1H-pyrazole-3-carboxylate in Step 1 of Example 31, 31, the title compound (13.7 mg, yield 52%) was obtained.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.72 (s, 1H), 7.56 (m, 2H), 7.44 (m, 1H), 7.27 (t, 2H), 6.93 (dd, 1H), 6.83 ( s, 1 H), 3.95 (s, 3 H)

Example  33: N ' - (6- Fluoropyridine Yl) -1- methyl -3- Phenyl -1H- Pyrazole -5- Carbohydrazide  Produce

The same procedure as in Example 31 was performed except that 3-phenyl-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate in the step 1 of Example 31 To obtain the title compound (11.7 mg, yield 47%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.80 (d, 2H), 7.75 (s, 1H), 7.46 (m, 1H), 7.41 (t, 2H), 7.33 (t, 1H), 7.23 ( s, 1 H), 6.94 (dd, 1 H), 4.16 (s, 3 H)

Example  34: N ' - (5- Fluoro -6- Methoxypyridine Yl) -1- methyl -3- Phenyl -1H- Pyrazole -5-car Bohidrazade Manufacturing

3-phenyl-lH-pyrazole-5-carboxylate was used in place of 5-phenyl-lH-pyrazole-3-carboxylate in step 1 of Example 31 above using 2-fluoro-5-hydrazinyl (11.5 mg, yield 42%) was obtained by following the same procedure as in Example 31, except that 5-fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was used instead of pyridine.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.79 (d, 1H), 7.57 (d, 1H), 7.41-7.38 (m, 2H), 7.33- 7.31 (m, 1H), 7.20 (s, 1H ), 7.12 (dd, 1 H), 4.14 (s, 3 H), 3.90 (s, 3 H)

Example  35: N ' - (5- Fluoro -6- Methoxypyridine Yl) -3- (4- Fluorophenyl )-One- methyl -1H- Pyrazole -5- Carbohydrazide  Produce

(4-fluorophenyl) -lH-pyrazole-5-carboxylate instead of 5-phenyl-lH-pyrazole-3-carboxylate in step 1 of Example 31, (16.1 mg, yield 56%) was obtained by following the same procedure as in Example 31, but using 5-fluoro-6-methoxy-pyridin- ).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.85-7.83 (m, 2H), 7.53 (s, 1H), 7.17-7.10 (m, 4H), 3.96 (s, 3H), 3.90 (s, 3H )

Example  36: 1-Ethyl- N ' - (5- Fluoro -6- Methoxypyridine Yl) -3- (4- Fluorophenyl ) -1H- Pyrazole -5- Carbohydrazide  Produce

(4-fluorophenyl) -1H-pyrazole-5-carboxylate in place of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31, Was used in the same manner as in Example 31, except that 5-fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine in Step 3 To obtain the title compound (15.2 mg, yield 51%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.84-7.81 (m, 2H), 7.55 (s, 1H), 7.16-7.10 (m, 4H), 4.56 (m, 2H), 3.90 (s, 3H ), 1.42 (t, 3H)

Example  37: 1-Ethyl- N ' - (6- Fluoropyridine Yl) -3- Phenyl -1H- Pyrazole -5- Carbohydrazide  Produce

Except that 3-phenyl-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate in the step 1 of Example 31 and ethyl iodide was used instead of iodomethane , The same procedure as in Example 31 was conducted to give the title compound (14.8 mg, yield 57%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.82 (d, 2H), 7.75 (s, 1H), 7.48-7.73 (m, 4H), 7.23 (s, 1H), 6.95 (dd, 1H), 4.59 (m, 2 H), 1.44 (t, 3 H)

Example  38: 3- (4- Fluorophenyl ) - N ' - (6- Fluoropyridine Yl) -1- methyl -1H- Pyrazole -5- Carbohydrazide  Produce

Pyrazole-5-carboxylate was used in place of 5-phenyl-1H-pyrazole-3-carboxylate in the step 1 of Example 31, 31, the title compound (14.5 mg, yield 55%) was obtained.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.84 (m, 2H), 7.75 (s, 1H), 7.46 (m, 1H), 7.20 (s, 1H), 7.16 (t, 2H), 6.95 ( dd, 1 H), 4.16 (s, 3 H)

Example  39: 1-Ethyl-3- (4- Fluorophenyl ) - N ' - (6- Fluoropyridine 3-yl) -1H- Pyrazole -5- Carbohydrazide  Produce

(4-fluorophenyl) -1H-pyrazole-5-carboxylate in place of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31, (16.2 mg, yield 59%) was obtained by carrying out the same processes as in Example 31. The physical properties of the compound are as follows.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.84 (m, 2H), 7.75 (s, 1H), 7.46 (m, 1H), 7.14-7.19 (m, 3H), 6.95 (dd, 1H), 4.58 (m, 2 H), 1.44 (t, 3 H)

Example  40: 3- (4- Fluorophenyl ) - N ' - (6- Fluoropyridine Yl) -l-propyl-lH-pyrazol-5- Carbohydrazide  Produce

3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of the above Example 31 instead of iodomethane , The title compound (14.6 mg, yield 51%) was obtained by carrying out the same processes as in Example 31.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.84 (m, 2H), 7.74 (s, 1H), 7.45 (m, 1H), 7.15 (m, 3H), 6.95 (dd, 1H), 4.52 ( t, 2H), 1.87 (m, 2H), 0.91 (t, 3H)

Example  41: 3- (4- Fluorophenyl ) - N ' - (6- Fluoropyridine Yl) -1- Isopropyl -1H- Pyrazole -5- Carbohydrazide  Produce

(4-fluorophenyl) -1H-pyrazole-5-carboxylate in place of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31, (14.0 mg, yield 49%) was obtained by carrying out the same processes as in Example 31,

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.85 (m, 1H), 7.75 (s, 1H), 7.46 (m, 1H), 7.15 (m, 3H), 6.95 (dd, 1H), 5.42 ( m, 1 H), 1.51 (d, 6 H)

Example  42: 1-Benzyl-3- (4- Fluorophenyl ) - N ' - (6- Fluoropyridine 3-yl) -1H- Pyrazole -5- Carbohydrazide  Produce

(4-fluorophenyl) -1H-pyrazole-5-carboxylate in place of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31 and benzyl bromide instead of iodomethane (15.2 mg, yield 47%) was obtained by carrying out the same procedure as in Example 31,

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.87 (m, 2H), 7.63 (s, 1H), 7.15-7.31 (m, 9H), 6.86 (dd, 1H), 5.77 (s, 2H)

Example  43: N ' - (6- Fluoropyridine Yl) -3- methyl -One- Phenyl -1H- Pyrazole -5- Carbohydrazide  Produce

Except that 3-methyl-1H-pyrazole-5-carboxylate was used instead of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31 and bromobenzene was used instead of iodomethane. The title compound (13.9 mg, yield 56%) was obtained by the same procedure as in Example 31.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.72 (s, 1H), 7.57-7.55 (m, 4H), 7.51 (m, 1H), 7.43 (m, 1H), 6.92 (dd, 1H), 6.74 (s, 1 H), 2.38 (s, 3 H)

Example  44: 1-Benzyl- N ' - (6- Fluoropyridine Yl) -3- Phenyl -1H- Pyrazole -5- Carbohydrazide  Produce

Pyrazole-5-carboxylate instead of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of the above Example 31, except that benzyl bromide was used in place of iodomethane. The title compound (15.8 mg, yield 51%) was obtained by following the same procedure as in Example 31.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.86 (m, 2H), 7.64 (s, 1H), 7.43 (t, 2H), 7.20-7.36 (m, 8H), 6.86 (dd, 1H), 5.79 (s, 2 H)

Example  45: 3- (4- Chlorophenyl ) - N ' - (5- Fluoro -6- Methoxypyridine Yl) -1- methyl -LH-pyrazole-5- Carbohydrazide  Produce

3- (4-Chlorophenyl) -1H-pyrazole-5-carboxylate was used in place of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31 above, (17.1 mg, yield 57%) was obtained by following the same procedure as in Example 31, but using 5-fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride instead of 5-hydrazinylpyridine. ≪ / RTI >

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.80 (d, 2H), 7.57 (d, 1H), 7.42 (d, 2H), 7.21 (s, 1H), 7.12 (dd, 1H), 4.16 ( s, 3H), 3.91 (s, 3H)

Example  46: 3- (4- Chlorophenyl ) -1-ethyl- N ' - (5- Fluoro -6- Methoxypyridine 3-yl) -1H- Pyrazole -5- Carbohydrazide  Produce

(4-chlorophenyl) -1H-pyrazole-5-carboxylate in place of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31 was used instead of ethyl iodide Was used in the same manner as in Example 31, except that 5-fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine in Step 3 The title compound (17.2 mg, yield 55%) was obtained.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.81 (d, 2H), 7.57 (d, 1H), 7.42 (d, 2H), 7.22 (s, 1H), 7.12 (dd, 1H), 4.58 ( s, 3H), 3.91 (s, 3H), 1.45 (t, 3H)

Example  47: N ' - (5- Fluoro -6- Methoxypyridine Yl) -1- methyl -3- (4- ( Trifluoromethyl ) Phenyl ) -1H- Pyrazole -5- Carbohydrazide  Produce

(Trifluoromethyl) phenyl) -1H-pyrazole-5-carboxylate in place of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31, Fluoro-5-hydrazinylpyridine was used in place of 5-fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride, the title compound (18.7 mg, , Yield: 57%).

¹ H NMR (CH ₃ OH-d ₄ ):? 8.01 (d, 2H), 7.72 (d, 2H), 7.58 s, 3H), 3.92 (s, 3H)

Example  48: 1-Ethyl- N ' - (5- Fluoro -6- Methoxypyridine Yl) -3- (4- ( Trifluoromethyl ) Phenyl ) -1H- Pyrazole -5- Carbohydrazide  Produce

(Trifluoromethyl) phenyl) -1H-pyrazole-5-carboxylate in place of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31 above was treated with iodomethane The procedure of Example 31 was repeated except that ethyl iodide was used instead of 5-fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride instead of 2-fluoro-5-hydrazinylpyridine in step 3 The same procedure was followed to give the title compound (18.6 mg, 55% yield).

¹ H NMR (CH ₃ OH-d ₄ ):? 8.02 (d, 2H), 7.72 (d, 2H), 7.58 s, 3H), 3.92 (s, 3H), 1.45 (t, 3H)

Example  49: 3- (4- Cyanophenyl ) - N ' - (5- Fluoro -6- Methoxypyridine Yl) -1- methyl -LH-pyrazole-5- Carbohydrazide  Produce

3- (4-cyanophenyl) -1H-pyrazole-5-carboxylate was used in place of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31, (17.3 mg, yield 59%) was obtained by following the same procedure as in Example 31, but using 5-fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride instead of 5- ).

¹ H NMR (CH ₃ OH-d ₄ ):? 8.01 (d, 2H), 7.79 (d, 2H), 7.58 s, 3H), 3.92 (s, 3H)

Example 50: Synthesis of 3- (4-cyanophenyl) -N '- (5-fluoro-6-methoxypyridin- Produce

(4-cyanophenyl) -1H-pyrazole-5-carboxylate in place of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31, Was used in the same manner as in Example 31, except that 5-fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine in Step 3 To obtain the title compound (16.1 mg, yield 50%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.00 (d, 2H), 7.78 (d, 2H), 7.58 (d, 1H), 7.33 (s, 1H), 7.14 (dd, 1H), 4.58 ( m, 2 H), 4.19 (s, 3 H), 1.42 (t, 3 H)

Example  51: 3- (4- Chlorophenyl ) - N ' - (6- Fluoropyridine Yl) -1- methyl -1H- Pyrazole -5- Carbohydrazide  Produce

Pyrazole-5-carboxylate was used in place of 5-phenyl-1H-pyrazole-3-carboxylate in the step 1 of Example 31, , The title compound (15.5 mg, yield 56%) was obtained.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.80 (d, 2H), 7.75 (s, 1H), 7.42-7.48 (m, 3H), 7.23 (s, 1H), 6.94 (dd, 1H), 4.16 (s, 3 H)

Example  52: N ' - (6- Fluoropyridine Yl) -1- methyl -3- (4- ( Trifluoromethyl ) Phenyl ) -1H- Pyrazole -5- Carbohydrazide  Produce

Except that 3- (4- (trifluoromethyl) phenyl) -1H-pyrazole-5-carboxylate was used in place of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31. , The same procedure as in Example 31 was conducted to give the title compound (15.5 mg, yield 51%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.80 (d, 2H), 7.66 (s, 1H), 7.40 (m, 2H), 6.99 (s, 1H), 6.86 (dd, 1H), 4.20 ( s, 3H)

Example  53: 3- (4- Cyanophenyl ) - N ' - (6- Fluoropyridine Yl) -1- methyl -1H- Pyrazole -5- Carbohydrazide  Produce

Pyrazole-5-carboxylate was used in place of 5-phenyl-1H-pyrazole-3-carboxylate in the step 1 of Example 31, 31, the title compound (15.3 mg, yield 57%) was obtained.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.02 (d, 2H), 7.79 (d, 2H), 7.76 (s, 1H), 7.47 (m, 2H), 7.36 (s, 1H), 6.94 ( dd, 1 H), 4.17 (s, 3 H)

Example  54: 3- (4- Chlorophenyl ) -1-ethyl- N ' - (6- Fluoropyridine 3-yl) -1H- Pyrazole -5- Carbohydrazide  Produce

(4-chlorophenyl) -1H-pyrazole-5-carboxylate in place of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31 was used instead of ethyl iodide , The title compound (15.8 mg, yield 55%) was obtained by carrying out the same processes as in Example 31.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.81 (d, 2H), 7.75 (s, 1H), 7.42-7.48 (m, 3H), 7.22 (s, 1H), 6.95 (dd, 1H), 4.58 (m, 2 H), 1.42 (t, 3 H)

Example  55: 1-Ethyl- N ' - (6- Fluoropyridine Yl) -3- (4- ( Trifluoromethyl ) Phenyl ) -1H- Pyrazole -5- Carbohydrazide  Produce

(Trifluoromethyl) phenyl) -1H-pyrazole-5-carboxylate in place of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31 above was treated with iodomethane The procedure of Example 31 was repeated to obtain the title compound (18.6 mg, yield 59%), except that ethyl iodide was used in place of ethyl iodide.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.02 (d, 2H), 7.75 (s, 1H), 7.73 (d, 2H), 7.47 (m, 2H), 7.33 (s, 1H), 6.95 ( dd, 1 H), 4.61 (m, 2 H), 1.45 (t, 3 H)

Example  56: 3- (4- Cyanophenyl ) -1-ethyl- N ' - (6- Fluoropyridine 3-yl) -1H- Pyrazole -5- Carbohydrazide  Produce

(4-cyanophenyl) -1H-pyrazole-5-carboxylate in place of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31, (14.3 mg, yield 51%) was obtained by carrying out the same processes as in Example 31.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.02 (d, 2H), 7.79 (d, 2H), 7.75 (m, 1H), 7.46 (m, 1H), 7.34 (s, 1H), 4.60 ( m, 2 H), 1.44 (t, 3 H)

Example  57: 3- (4- Cyanophenyl ) -1-ethyl- N ' - (5- Fluoro -6- Methoxypyridine 3-yl) -1H- Pyrazole -5- Carbohydrazide  Produce

(4-cyanophenyl) -1H-pyrazole-5-carboxylate in place of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31, Was used in the same manner as in Example 31, except that 5-fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine in Step 3 To obtain the title compound (14.9 mg, yield 49%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.07 (d, 2H), 7.78 (d, 2H), 7.58 (d, 1H), 7.31 (s, 1H), 7.13 (dd, 1H), 4.62 ( s, 2H), 3.92 (s, 3H), 1.46 (t, 3H)

Example  58: 1-Ethyl- N ' - (5- Fluoro -6- Methoxypyridine Yl) -3- Phenyl -1H- Pyrazole -5-car Bohidrazade Manufacturing

Phenyl-1H-pyrazole-5-carboxylate in place of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31, ethyl iodide in place of iodomethane, Fluoro-5-hydrazinylpyridine was used instead of 5-fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride to give the title compound (13.4 mg , Yield: 47%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.82 (d, 2H), 7.57 (d, 1H), 7.42 (t, 2H), 7.34 (t, 1H), 7.21 (s, 1H), 7.13 ( (s, 3H), 1.46 (t, 3H)

Example  59: 1-Benzyl- N ' - (5- Fluoro -6- Methoxypyridine Yl) -3- Phenyl -1H- Pyrazole -5-car Bohidrazade Manufacturing

3-phenyl-1H-pyrazole-5-carboxylate instead of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31, benzyl bromide instead of iodomethane, 2- Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride instead of 5-fluoro-5-hydrazinylpyridine, the title compound (14.0 mg, yield 42%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.84 (d, 2H), 7.48 (d, 1H), 7.43 (t, 2H), 7.34 (t, 1H), 7.20-7.30 (m, 6H), 6.94 (dd, 1 H), 5.78 (s, 2 H), 3.92 (s, 3 H)

Example  60: 3- (4- Fluorophenyl ) - N ' - (6- Fluoropyridine Yl) -1- (2,2,2- Trifluoroethyl ) -1H- Pyrazole -5- Carbohydrazide  Produce

(4-fluorophenyl) -1H-pyrazole-5-carboxylate instead of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31, (15.9 mg, yield 50%) was obtained by following the same procedure as in Example 31, except that 2,2-trifluoroethyl iodide was used.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.90 (m, 2H), 7.73 (s, 1H), 7.44 (m, 1H), 7.33 (s, 1H), 7.19 (t, 2H), 6.94 ( dd, 1 H), 5.42 (m, 2 H)

Example  61: N ' - (5- Fluoro -6- Methoxypyridine Yl) -3- (4- Fluorophenyl ) -1- (2,2,2-tri Reflux Chloro-ethyl) -lH- Pyrazole -5- Carbohydrazide  Produce

(4-fluorophenyl) -1H-pyrazole-5-carboxylate instead of 5-phenyl-1H-pyrazole-3-carboxylate in step 1 of Example 31, 2,2-trifluoroethyl) iodide was prepared in analogy to the procedure described in Example 1, except that 5-fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was used instead of 2-fluoro-5-hydrazinylpyridine in step 3 , And the procedure of Example 31 was followed to obtain the title compound (17.8 mg, yield 52%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.88 (m, 2H), 7.56 (d, 1H), 7.31 (s, 1H), 7.18 (t, 2H), 7.10 (dd, 1H), 5.42 ( m, 2 H), 3.92 (s, 3 H)

Example  62: N ' - (6- Fluoropyridine Yl) -5- Methyl isoxazole -3- Carbohydrazide  Produce

Except that 5-methylisoxazole-3-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H-pyrrole-2-carboxylic acid in Example 1, 1, the title compound (11.5 mg, yield 61%) was obtained.

¹ H NMR (CH ₃ OH-d ₄ ):? 7.71 (s, IH), 7.44-7.40 (m, IH), 6.92 (dd,

Example  63: N ' - (5- Fluoro -6- Methoxypyridine Yl) -5- (4- Fluorophenyl ) Isoxazol -3- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (4-fluorophenyl) isoxazole-3-carboxylic acid was used in place of 1H-pyrrole-2-carboxylic acid, the title compound (17.5 mg, yield 63%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.99-7.96 (m, 2H), 7.60 (s, 1H), 7.33-7.29 (m, 2H), 7.16-7.14 (m, 2H), 3.94 (s , 3H)

Example  64: 5- (4- Chlorophenyl ) - N ' - (5- Fluoro -6- Methoxypyridine -3 days) Isoxazol -3- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (16.3 mg, yield 56%) was prepared following the same procedure as in Example 1, except that 5- (4-chlorophenyl) isoxazole-3-carboxylic acid was used instead of 1H-pyrrole- %).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.74 (m, 2H), 7.59 (s, 1H), 7.50 (m, 2H), 7.15-7.12 (m, 2H), 3.93 (s, 3H)

Example  65: N ' - (5- Fluoro -6- Methoxypyridine Yl) -3- (4- Fluorophenyl ) Isoxazol -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (4-fluorophenyl) isoxazole-5-carboxylic acid was used in place of 1H-pyrrole-2-carboxylic acid, the title compound (14.1 mg, yield 51%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.97-7.94 (m, 2H), 7.58 (s, 1H), 7.47 (s, 1H), 7.26 (t, 2H), 7.12 (d, 1H), 3.92 (s, 3 H)

Example  66: N ' - (6- Fluoropyridine Yl) -3,5- Dimethyl -1H- Pyrazole -4- Carbohydrazide  Produce

Except that 3,5-dimethyl-1H-pyrazole-4-carboxylic acid was used in place of 4- (2-methylthiazol-4-yl) -1H- pyrrole-2-carboxylic acid in Example 1 , And the same processes as in Example 1 were carried out to obtain the title compound (11.4 mg, yield 57%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.17 (s, 1H), 7.45 (d, 1H), 7.04 (dd, 1H), 2.47 (s, 6H)

Example  67: N ' - (6- Fluoropyridine 3-yl) -1H- Imidazole -2- Cabo Hydrazide Manufacturing

Example 1 was repeated except that 1H-imidazole-2-carboxylic acid was used in place of 4- (2-methylthiazol-4-yl) -1H- pyrrole- The same procedure was followed to give the title compound (9.7 mg, 55% yield).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.75 (s, 1H), 7.48-7.44 (m, 1H), 7.25 (m, 2H), 6.94 (dd, 1H)

Example  68: N ' - (5- Fluoro -6- Methoxypyridine Yl) -5- methyl -2- Phenyloxazole -4-carbohydrazide < / RTI >

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (14.2 mg, yield 52%) was prepared following the same procedure as in Example 1, except that 5-methyl-2-phenyloxazole-4-carboxylic acid was used instead of 1H- ).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.08-8.06 (m, 2H), 7.56 (s, 1H), 7.51-7.50 (m, 3H), 7.10 (dd, 1H), 3.89 (s, 3H ), 2.68 (s, 3H)

Example  69: N ' - (6- Fluoropyridine -3 days) Thiazole -2- Carbohydrazide  Produce

The procedure of Example 1 was repeated except that thiazole-2-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H-pyrrole- To give the title compound (12.0 mg, yield 63%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.02 (d, 1H), 7.92 (d, 1H), 7.73 (s, 1H), 7.46-7.42 (m, 1H), 6.93 (dd, 1H)

Example  70: N ' - (5- Fluoro -6- Methoxypyridine Yl) -4- Phenylthiazole -2- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (13.5 mg, yield 49%) was obtained by following the same procedure as in Example 1, except that 4-phenylthiazole-2-carboxylic acid was used instead of 1H-pyrrole-2-carboxylic acid.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.15 (s, 1H), 8.05 (d, 2H), 7.58 (d, 1H), 7.46-7.42 (m, 2H), 7.37-7.36 (m, 1H ), 7.12 (dd, 1 H), 3.90 (s, 3 H)

Example  71: N ' - (6- Fluoropyridine -3 days) Thiazole -4- Carbohydrazide  Produce

In the same manner as in Example 1 except that thiazole-4-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H- pyrrole- To obtain the title compound (9.0 mg, yield 47%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 9.05 (s, 1H), 8.35 (s, 1H), 7.72 (s, 1H), 7.44-7.41 (m, 1H), 6.91 (d, 1H)

Example  72: N ' - (5- Fluoro -6- Methoxypyridine Yl) -2- Phenylthiazole -4- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (11.6 mg, yield 42%) was obtained by carrying out the same processes as in the above Example 1, except that 2-phenylthiazole-4-carboxylic acid was used instead of 1H-pyrrole-2-carboxylic acid.

¹ H NMR (CH ₃ OH-d ₄ ):? 8.28 (s, 1H), 8.08-8.06 (m, 2H), 7.57 (s, ), 3.90 (s, 3 H)

Example  73: N ' - (6- Fluoropyridine Yl) -4- Methyloxazole -5- Carbohydrazide  Produce

Example 1 was repeated except that 4-methyloxazole-5-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H- pyrrole- , The title compound (9.4 mg, yield 50%) was obtained.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.23 (s, 1H), 7.70 (s, 1H), 7.41 (m, 1H), 6.91 (d, 1H), 2.45 (s, 3H)

Example  74: N ' - (6- Fluoropyridine Yl) -2- Phenyloxazole -5- Carbohydrazide  Produce

Example 1 was repeated except that 2-phenyloxazole-5-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H- pyrrole- , The title compound (13.4 mg, yield 56%) was obtained.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.19 (dd, 2H), 7.91 (s, 1H), 7.76 (dd, 1H), 7.60-7.54 (m, 3H), 7.48-7.45 (m, 1H ), 6.95 (dd, 1 H)

Example  75: N ' - (5- Fluoro -6- Methoxypyridine Yl) -2- Phenyloxazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (13.4 mg, yield 51%) was obtained by following the same procedure as in Example 1, except that 2-phenyloxazole-5-carboxylic acid was used instead of 1H-pyrrole-2-carboxylic acid.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.19 (dd, 2H), 7.90 (s, 1H), 7.60-7.53 (m, 4H), 7.15 (dd, 1H), 3.91 (s, 3H)

Example  76: 2- (4- Fluorophenyl ) - N ' - (6- Fluoropyridine -3 days) Oxazole -5- Carbohydrazide  Produce

Except that 2- (4-fluorophenyl) oxazole-5-carboxylic acid was used in place of 4- (2-methylthiazol-4-yl) -1H- pyrrole-2-carboxylic acid in Example 1 , And the same processes as in Example 1 were carried out to obtain the title compound (14.4 mg, yield 57%).

¹ H NMR (CH ₃ OH-d ₄ ):? 8.24-8.21 (m, 2H), 7.90 ), 6.95 (dd, 1 H)

Example  77: 2- (3,4- Difluorophenyl ) - N ' - (6- Fluoropyridine -3 days) Oxazole -5-car Bohidrazade Manufacturing

(3,4-difluorophenyl) oxazole-5-carboxylic acid in place of 4- (2-methylthiazol-4-yl) (14.7 mg, yield 55%) was obtained by carrying out the same processes as in the above Example 1,

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.12-8.08 (m, 1H), 8.04-8.01 (m, 1H), 7.91 (s, 1H), 7.59 (dd, 1H), 7.53-7.44 (m , ≪ / RTI > 2H), 6.95 (dd, 1H)

Example  78: 2- (3,4- Difluorophenyl ) - N ' - (5- Fluoro -6- Methoxypyridine -3 days) Oxazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- Carboxylic acid instead of 2- (3,4-difluorophenyl) oxazole-5-carboxylic acid in place of 1H-pyrrole-2-carboxylic acid, the title compound (16.6 mg, yield: 57%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.12-8.08 (m, 1H), 8.03-8.00 (m, 1H), 7.90 (s, 1H), 7.58 (d, 1H), 7.51-7.46 (m , 7.15 (dd, 1 H), 3.91 (s, 3 H)

Example  79: N ' - (6- Fluoropyridine Yl) -2- (4- ( Trifluoromethyl ) Phenyl ) Oxazole -5- Carbohydrazide  Produce

(4- (trifluoromethyl) phenyl) oxazole-5-carboxylic acid in place of 4- (2-methylthiazol-4-yl) , The title compound (16.1 mg, yield: 55%) was obtained by carrying out the same processes as in the above Example 1.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.37 (d, 2H), 7.96 (s, 1H), 7.88 (d, 2H), 7.76 (dd, 1H), 7.46-7.45 (m, 1H), 6.95 (dd, 1 H)

Example  80: N ' - (5- Fluoro -6- Methoxypyridine Yl) -2- (4- ( Trifluoromethyl ) Phenyl) Oxazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (Trifluoromethyl) phenyl) oxazole-5-carboxylic acid in place of 1H-pyrrole-2-carboxylic acid, the title compound ( 18.7 mg, yield 59%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.37 (d, 2H), 7.95 (s, 1H), 7.88 (d, 2H), 7.59 (d, 1H), 7.16 (dd, 1H), 3.91 ( s, 3H)

Example  81: N ' - (6- Fluoropyridine Yl) -4- methyl -2- Phenyloxazole -5- Carbohydrazide  Produce

Except that 4-methyl-2-phenyloxazole-5-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H- pyrrole-2-carboxylic acid in Example 1, The title compound (15.7 mg, yield 63%) was obtained by the same procedure as in Example 1.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.19 (dd, 2H), 7.76 (dd, 1H), 7.60-7.53 (m, 3H), 7.48-7.44 (m, 1H), 6.95 (dd, 1H ), 2.52 (s, 3H)

Example  82: N ' - (5- Fluoro -6- Methoxypyridine Yl) -4- methyl -2- Phenyloxazole -5-carbohydrazide < / RTI >

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (13.4 mg, yield 49%) was obtained by following the same procedure as in Example 1, except that 4-methyl-2-phenyloxazole-5-carboxylic acid was used instead of 1H-pyrrole- ).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.18 (dd, 2H), 7.59-7.53 (m, 4H), 7.15 (dd, 1H), 3.91 (s, 3H), 2.52 (s, 3H)

Example  83: 2 - ([1,1'- Biphenyl ]-3 days)- N ' - (6- Fluoropyridine -3 days) Oxazole -5-car Bohidrazade Manufacturing

([L, l ' -biphenyl] -3-yl) oxazole-5-carboxylic acid in place of 4- (2- methylthiazol- -Carboxylic acid as a starting material, the title compound (14.1 mg, yield 47%) was obtained.

¹ H NMR (CH ₃ OH-d ₄ ):? 8.48 (d, IH), 8.17 (d, IH), 7.94 (d, 2H), 7.64 (t, 1H), 7.50-7.46 (m, 3H), 7.40

Example  84: 2 - ([1,1'- Biphenyl ]-3 days)- N ' - (5- Fluoro -6- Methoxypyridine -3 days) Oxazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The same procedure as in Example 1 was carried out except that 2 - ([1,1'-biphenyl] -3-yl) oxazole-5-carboxylic acid was used in place of 1H-pyrrole-2-carboxylic acid To obtain the title compound (13.6 mg, yield 42%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.48 (t, 1H), 8.17 (d, 1H), 7.93 (s, 1H), 7.86 (d, 1H), 7.74 (d, 2H), 7.64 ( 2H), 7.40 (d, 1H), 7.60 (d, 1H)

Example  85: N ' - (6- Fluoropyridine Yl) -4- Methylthiazole -5- Carbohydrazide  Produce

Example 1 was repeated except that 4-methylthiazole-5-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H- pyrrole- The title compound (10.1 mg, yield 50%) was obtained.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 9.01 (s, 1H), 7.70 (s, 1H), 7.43-7.39 (m, 1H), 6.91 (d, 1H), 2.67 (s, 3H)

Example  86: N ' - (6- Fluoropyridine Yl) -2,4- Dimethylthiazole -5- Carbohydrazide  Produce

Except that 2,4-dimethylthiazole-5-carboxylic acid was used in place of 4- (2-methylthiazol-4-yl) -1H-pyrrole- The title compound (11.1 mg, yield 52%) was obtained by carrying out the same processes as in Example 1.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.70 (s, 1H), 7.43-7.39 (m, 1H), 6.93 (d, 1H), 2.70 (s, 3H), 2.61 (s, 3H)

Example  87: 2- (4- Chlorophenyl ) - N ' - (6- Fluoropyridine Yl) -4- Methylthiazole -5-car Bohidrazade Manufacturing

2- (4-chlorophenyl) -4-methylthiazole-5-carboxylic acid in place of 4- (2-methylthiazol-4-yl) (16.3 mg, yield 56%) was obtained by carrying out the same processes as in Example 1,

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.93 (d, 2H), 7.70 (s, 1H), 7.48 (d, 2H), 7.42-7.39 (m, 1H), 6.91 (d, 1H), 2.68 (s, 3 H)

Example  88: 2- Chloro - N ' - (6- Fluoropyridine -3 days) Thiazole -5- Carbohydrazide  Produce

Example 1 was repeated except that 2-chlorothiazole-5-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H- pyrrole- , The title compound (11.1 mg, yield 51%) was obtained.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.18 (s, 1H), 7.71 (s, 1H), 7.44-7.41 (m, 1H), 6.93 (dd, 1H)

Example  89: t-Butyl (5- (2- (6- Fluoropyridine -3 days) Hydrazine -One- Carbonyl ) Thiazole -2 days) Carbamate  Produce

2 - ((t-butoxycarbonyl) amino) thiazole-5-carboxylic acid instead of 4- (2-methylthiazol- , The title compound (16.1 mg, yield 57%) was obtained by carrying out the same processes as in the above Example 1.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.19 (s, 1H), 7.70 (s, 1H), 7.42-7.39 (m, 1H), 6.92 (d, 1H), 1.54 (s, 9H)

Example  90: 2-Amino- N ' - (6- Fluoropyridine -3 days) Thiazole -5- Carbohydrazide  Produce

Example 1 was repeated except that 2-aminothiazole-5-carboxylic acid was used in place of 4- (2-methylthiazol-4-yl) -1H- pyrrole- , The title compound (11.1 mg, yield 55%) was obtained.

¹ H NMR (CH ₃ OH-d ₄ ):? 7.69-7.68 (m, 2H), 7.39 (s,

Example  91: 4- ( Difluoromethyl ) - N ' - (6- Fluoropyridine Yl) -2- Methylthiazole -5- Carbohydrazide  Produce

4- (difluoromethyl) -2-methylthiazole-5-carboxylic acid in place of 4- (2-methylthiazol-4-yl) (14.3 mg, yield 59%) was obtained by carrying out the same processes as in Example 1,

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.71 (s, 1H), 7.51-7.41 (m, 2H), 6.94 (dd, 1H), 2.78 (s, 3H)

Example  92: 2- ( Ethylamino ) - N ' - (6- Fluoropyridine Yl) -4- Methylthiazole -5-carbohydrazide < / RTI >

(Ethylamino) -4-methylthiazole-5-carboxylic acid in place of 4- (2-methylthiazol-4-yl) -1H-pyrrole-2-carboxylic acid in Example 1 , The title compound (9.9 mg, yield 42%) was obtained by carrying out the same processes as in the above Example 1.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.06 (d, 1H), 7.65 (s, 1H), 7.53 (m, 1H), 3.45 (m, 2H), 2.59 (s, 3H), 1.32 ( t, 3H)

Example  93: 2- Chloro - N ' - (6- Fluoropyridine Yl) -4- Methylthiazole -5- Carbohydrazide  Produce

Except that 2-chloro-4-methylthiazole-5-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H- pyrrole-2-carboxylic acid in Example 1, The title compound (11.5 mg, yield 50%) was obtained by the same procedure as in Example 1.

¹ H NMR (CH ₃ OH-d ₄ ):? 8.08 (d, IH), 7.67 (s, IH), 7.57-7.55

Example  94: 2- Chloro - N ' - (5- Fluoro -6- Methoxypyridine -3 days) Thiazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (12.6 mg, yield 52%) was obtained by carrying out the same procedure as in Example 1, except that 2-chlorothiazole-5-carboxylic acid was used instead of 1H-pyrrole-2-carboxylic acid.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.23 (s, 1H), 8.12 (s, 1H), 7.71 (dd, 1H), 4.03 (s, 3H)

Example  95: N ' - (6- Fluoropyridine Yl) -2- Methoxy -4- Methylthiazole -5- Carbohydrazide  Produce

Except that 2-methoxy-4-methylthiazole-5-carboxylic acid was used in place of 4- (2-methylthiazol-4-yl) -1H- pyrrole-2-carboxylic acid in Example 1 , The same procedure as in Example 1 was conducted to obtain the title compound (11.5 mg, yield 51%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.06 (d, 1H), 7.65 (s, 1H), 7.53 (m, 1H), 3.85 (s, 3H), 2.50 (s, 3H)

Example  96: 2- Cyclopropyl - N ' - (5- Fluoro -6- Methoxypyridine -3 days) Thia Sol-5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (14.1 mg, yield 57%) was obtained by following the procedure of Example 1 while using 2-cyclopropylthiazole-5-carboxylic acid instead of 1H-pyrrole-2-carboxylic acid .

¹ H NMR (CH ₃ OH-d ₄ ):? 8.16 (s, IH), 7.52 (d, IH), 7.08 (dd, 1.27-1.20 (m, 2H), 1.15-1. 12 (m, 2H)

Example  97: N ' - (6- Fluoropyridine Yl) -2- Phenylthiazole -5- CabohydrAza Manufacture of Id

Example 1 was repeated except that 2-phenylthiazole-5-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H- To give the title compound (13.8 mg, yield 55%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.66 (s, 1H), 8.22 (d, 2H), 7.83 (d, 2H), 7.76 (s, 1H), 7.48-7.44 (m, 1H), 6.95 (dd, 1 H)

Example  98: N ' - (5- Fluoro -6- Methoxypyridine Yl) -2- (4- Fluorophenyl ) Thiazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (16.2 mg, yield) was obtained in the same manner as in Example 1, except that 2- (4-fluorophenyl) thiazole-5-carboxylic acid was used instead of 1H- 56%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.48 (s, 1H), 7.79 (d, 2H), 7.55 (s, 1H), 7.37 (d, 2H), 7.10 (d, 1H), 3.89 ( s, 3H)

Example  99: 2- (4- Chlorophenyl ) - N ' - (5- Fluoro -6- Methoxypyridine -3 days) Thiazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (15.5 mg, yield 51%) was prepared following the same procedure as in Example 1, except that 2- (4-chlorophenyl) thiazole-5-carboxylic acid was used instead of 1H-pyrrole- %).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.46 (s, 1H), 8.25 (d, 2H), 7.81 (d, 2H), 7.55 (s, 1H), 7.10 (d, 1H), 3.89 ( s, 3H)

Example  100: N ' - (6- Fluoropyridine Yl) -2- (4- ( Trifluoromethyl ) Phenyl ) Thiazole -5- Carbohydrazide  Produce

(4- (trifluoromethyl) phenyl) thiazole-5-carboxylic acid in place of 4- (2-methylthiazol-4-yl) , The title compound (17.4 mg, yield 57%) was obtained by carrying out the same processes as in the above Example 1.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.68 (s, 1H), 8.10 (d, 2H), 7.57-7.53 (m, 3H), 7.76 (s, 1H), 7.48-7.44 (m, 1H ), 6.95 (dd, 1 H)

Example  101: N ' - (5- Fluoro -6- Methoxypyridine Yl) -2- Phenylthiazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (15.2 mg, yield 55%) was obtained by following the same procedure as in Example 1, except that 2-phenylthiazole-5-carboxylic acid was used instead of 1H-pyrrole-2-carboxylic acid.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.62 (s, 1H), 8.01 (d, 2H), 7.57 (d, 1H), 7.52-7.46 (m, 3H), 7.12 (dd, 1H), 3.91 (s, 3 H)

Example  102: N ' - (5- Fluoro -6- Methoxypyridine Yl) -2- (4- ( Trifluoromethyl ) Phenyl ) Thiazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (Trifluoromethyl) phenyl) thiazole-5-carboxylic acid in place of 1H-pyrrole-2-carboxylic acid, the title compound ( 19.5 mg, yield 59%).

¹ H NMR (CH ₃ OH-d ₄ ): δ 8.46 (s, 1H), 8.19 (d, 2H), 7.79 (d, 2H), 7.55 s, 3H)

Example  103: N ' - (5- Fluoro -6- Methoxypyridine Yl) -2- (3- Fluorophenyl ) Thiazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (14.2 mg, yield) was obtained in the same manner as in Example 1, except that 2- (3-fluorophenyl) thiazole-5-carboxylic acid was used instead of 1H- 49%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.44 (s, 1H), 7.83 (d, 1H), 7.78 (d, 1H), 7.57-7.53 (m, 2H), 7.30-7.26 (m, 1H ), 7.17 (dd, 1 H), 3.91 (s, 3 H)

Example  104: 2- (2,4- Difluorophenyl ) - N ' - (5- Fluoro -6- Methoxypyridine -3 days) Thiazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (14.3 mg) was obtained by following the same procedure as in Example 1, except using 2- (2,4-difluorophenyl) thiazole-5-carboxylic acid in place of 1H-pyrrole- mg, yield: 47%).

¹ H NMR (CH ₃ OH-d ₄ ):? 8.49 (d, IH), 8.40-8.35 (m, IH), 7.57 (s, IH), 7.26-7.11 )

Example  105: 2- (3,4- Difluorophenyl ) - N ' - (5- Fluoro -6- Methoxypyridine -3 days) Thiazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (12.8 mg, 86%) was obtained as a white solid by following the procedure of Example 1 while using 2- (3,4-difluorophenyl) thiazole-5-carboxylic acid instead of lH-pyrrole- mg, yield: 42%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.43 (s, 1H), 8.00-7.96 (m, 1H), 7.86-7.84 (m, 1H), 7.56 (d, 1H), 7.46-7.36 (m , 7.13 (dd, 1 H), 3.91 (s, 3 H)

Example  106: 2- (4- Fluorophenyl ) - N ' - (6- Fluoropyridine Yl) -4- Methylthiazole -5- Carbohydrazide  Produce

(4-fluorophenyl) -4-methylthiazole-5-carboxylic acid in place of 4- (2-methylthiazol-4-yl) , The title compound (13.9 mg, yield 50%) was obtained by carrying out the same processes as in the above Example 1.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.05-8.03 (m, 2H), 7.73 (s, 1H), 7.45-7.43 (m, 1H), 7.26-7.23 (m, 2H), 6.95-6.93 (m, 1 H), 2.70 (s, 3 H)

Example  107: 2- (4- Chlorophenyl ) - N ' - (6- Fluoropyridine Yl) -4- ( Trifluoromethyl ) Thiazole -5- Carbohydrazide  Produce

(4-chlorophenyl) -4- (trifluoromethyl) thiazole-5-carboxylic acid in place of 4- (2-methylthiazol- -Carboxylic acid as a starting material, the title compound (17.3 mg, yield 52%) was obtained.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.89 (d, 2H), 7.74 (s, 1H), 7.54 (d, 2H), 7.47-7.45 (m, 1H), 6.94 (d, 1H)

Example  108: 2- (4- Chlorophenyl ) - N ' - (5- Fluoro -6- Methoxypyridine Yl) -4- Methylthiazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (4-chlorophenyl) -4-methylthiazole-5-carboxylic acid in place of 1H-pyrrole-2-carboxylic acid, the title compound (16.0 mg, yield: 51%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.97 (d, 2H), 7.56 (d, 1H), 7.51 (d, 2H), 7.10 (d, 1H), 3.91 (s, 3H), 2.70 ( s, 3H)

Example  109: 2- (4- Cyanophenyl ) - N ' - (6- Fluoropyridine Yl) -4- Methylthiazole -5-car Bohidrazade Manufacturing

(4-cyanophenyl) -4-methylthiazole-5-carboxylic acid in place of 4- (2-methylthiazol-4-yl) , The title compound (16.1 mg, yield 57%) was obtained by carrying out the same processes as in the above Example 1.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.95 (d, 2H), 7.82 (d, 2H), 7.73 (s, 1H), 7.45-7.43 (m, 1H), 6.95-6.93 (m, 1H ), 2.70 (s, 3H)

Example  110: N ' - (6- Fluoropyridine Yl) -4- methyl -2- (4- ( Trifluoromethyl ) Phenyl) Thiazole -5- Carbohydrazide  Produce

Methyl-2- (4- (trifluoromethyl) phenyl) thiazole-5-carboxylic acid in place of 4- (2-methylthiazol- -Carboxylic acid as a starting material, the title compound (17.4 mg, yield 55%) was obtained.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.00-7.90 (m, 2H), 7.73 (s, 1H), 7.68-7.65 (m, 2H), 7.45-7.43 (m, 1H), 6.95-6.93 (m, 1 H), 2.70 (s, 3 H)

Example  111: 4-Ethyl- N ' - (6- Fluoropyridine Yl) -2- Phenylthiazole -5- Carbohydrazide  Produce

Except that 4-ethyl-2-phenylthiazole-5-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) The title compound (16.2 mg, yield 59%) was obtained by carrying out the same processes as in the above Example 1.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.01-8.00 (m, 2H), 7.73 (s, 1H), 7.51-7.50 (m, 3H), 7.45-7.42 (m, 1H), 6.95 (d , ≪ / RTI > 1H), 3.12 (q, 2H), 1.33 (t,

Example  112: N ' - (6- Fluoropyridine Yl) -2- Phenyl -4-( Trifluoromethyl ) Thiazole -5- Carbohydrazide  Produce

Phenyl-4- (trifluoromethyl) thiazole-5-carboxylic acid instead of 4- (2-methylthiazol-4-yl) -1H- pyrrole- (17.1 mg, yield 56%) was obtained by carrying out the same processes as in Example 1,

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.03 (d, 2H), 7.74 (s, 1H), 7.57-7.52 (m, 3H), 7.46-7.43 (m, 1H), 6.96 (d, 1H )

Example  113: 2- (4- Fluorophenyl ) - N ' - (6- Fluoropyridine Yl) -4- ( Triple O-methyl) Thiazole -5- Carbohydrazide  Produce

2- (4-fluorophenyl) -4- (trifluoromethyl) thiazole-2-carboxylic acid in place of 4- (2-methylthiazol- (16.3 mg, yield 51%) was obtained by carrying out the same processes as in the above Example 1, except that 5-carboxylate acid was used.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.09-8.06 (m, 2H), 7.72 (s, 1H), 7.44-7.40 (m, 1H), 7.29-7.26 (m, 2H), 6.95 (d , 1H)

Example  114: 2- (4- Chlorophenyl ) - N ' - (5- Fluoro -6- Methoxypyridine Yl) -4- ( Trifluoromethyl ) Thiazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The same procedure as in Example 1 was carried out except that 2- (4-chlorophenyl) -4- (trifluoromethyl) thiazole-5-carboxylic acid was used in place of 1H-pyrrole-2-carboxylic acid To give the title compound (20.4 mg, yield 57%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.88 (d, 2H), 7.55 (d, 1H), 7.52 (d, 2H), 7.10 (dd, 1H), 3.90 (s, 3H)

Example  115: N ' - (5- Fluoro -6- Methoxypyridine Yl) -4- ( Trifluoromethyl ) -2- (4- Reflux Lt; / RTI > Phenyl ) Thiazole -5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- Was obtained in the same manner as in Example 1 (1), except that 4- (trifluoromethyl) -2- (4- (trifluoromethyl) phenyl) thiazole-5-carboxylic acid was used in place of 1H- , The title compound (21.1 mg, yield 55%) was obtained.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.26 (d, 2H), 7.85 (d, 2H), 7.57 (s, 1H), 7.11 (d, 1H), 3.90 (s, 3H)

Example  116: N ' - (5- Fluoro -6- Methoxypyridine Yl) -5- methyl -2- Phenyl -2H-1,2,3-triazol-4- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- Methyl-2-phenyl-2H-1,2,3-triazole-4-carboxylic acid was used in place of 1H-pyrrole-2-carboxylic acid in the same manner as in Example 1 To obtain the title compound (14.2 mg, yield 52%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.12 (d, 2H), 7.58 (s, 1H), 7.56-7.52 (m, 2H), 7.44-7.41 (m, 1H), 7.12 (dd, 1H ), 3.90 (s, 3 H), 2.58 (s, 3 H)

Example  117: N ' - (6- Fluoropyridine Yl) -1- methyl -3- Phenyl -1H-1,2,4- Triazole -5-car Bohidrazade Manufacturing

Methyl-3-phenyl-1H-1,2,4-triazole-5-carboxylic acid in place of 4- (2-methylthiazol- The title compound (12.2 mg, yield 49%) was obtained by carrying out the same processes as in the above Example 1, except that the carboxylic acid was used.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 8.13 (t, 2H), 7.78 (s, 1H), 7.51-7.41 (m, 4H), 6.95 (dd, 1H), 4.25 (s, 3H)

Example  118: N ' - (5- Fluoro -6- Methoxypyridine Yl) -1- methyl -3- Phenyl -1H-l, 2,4-triazol-5- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- Methyl-3-phenyl-1H-1,2,4-triazole-5-carboxylic acid was used in place of 1H-pyrrole-2-carboxylic acid To obtain the title compound (12.9 mg, yield 47%).

¹ H NMR (CH ₃ OH-d ₄ ):? 8.13 (t, 2H), 7.61 (d, IH), 7.60-7.43 (m, 3H), 7.18 3.91 (s, 3 H)

Example 119: Preparation of N '- (5-fluoro-6-methoxypyridin-3-yl) -1-methyl-1H-indole-3-carbohydrazide

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (11.8 mg, yield 42%) was obtained by following the same procedure as in Example 1, except that 1-methyl-1H-indole-3-carboxylic acid was used instead of 1H-pyrrole- .

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.30 (d, 1H), 7.12 (s, 1H), 6.78 (d, 1H), 6.67 (d, 1H), 6.47 (t, 1H), 6.42- 6.38 (m, 2 H), 3.14 (s, 3 H), 3.08 (s, 3 H)

Example  120: N ' - (6- Fluoropyridine Yl) -lH-indol-2- Carbohydrazide  Produce

The procedure of Example 1 was repeated except that 1H-indole-2-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H- pyrrole- To obtain the title compound (10.8 mg, yield 50%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.75 (s, 1H), 7.63 (d, 1H), 7.44 (d, 2H), 7.24 (t, 1H), 7.19 (s, 1H), 7.08 ( t, 1 H), 6.93 (dd, 1 H)

Example  121: 6- Fluoro - N ' - (6- Fluoropyridine Yl) -lH-indol-2- Carbohydrazide  Produce

Fluoro-1H-indole-2-carboxylic acid was used in place of 4- (2-methylthiazol-4-yl) -1H- pyrrole-2-carboxylic acid in Example 1, The title compound (11.8 mg, yield 51%) was obtained by carrying out the same processes as in Example 1.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.74 (s, 1H), 7.62 (m, 1H), 7.44 (s, 1H), 7.19 (s, 1H), 7.14 (dd, 1H), 6.87- 6.95 (m, 2H)

Example  122: 7- Chloro - N ' - (6- Fluoropyridine Yl) -lH-indol-2- Carbohydrazide  Produce

Except that 7-chloro- lH-indole-2-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -lH- pyrrole-2-carboxylic acid in Example 1 The title compound (13.9 mg, yield 57%) was obtained by carrying out the same procedure as in Example 1.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.76 (m, 1H), 7.61 (d, 1H), 7.47 (m, 1H), 7.29 (m, 1H), 7.27 (s, 1H), 7.09 ( t, 1 H), 6.94 (dd, 1 H)

Example  123: 6- Chloro - N ' - (6- Fluoropyridine Yl) -lH-indol-2- Carbohydrazide  Produce

Except that 6-chloro-1 H-indole-2-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H-pyrrole-2-carboxylic acid in Example 1 The title compound (13.7 mg, yield 56%) was obtained by carrying out the same procedure as in Example 1.

¹ H NMR (CH ₃ OH-d ₄ ):? 7.74 (s, IH), 7.61 (d, IH), 7.43-7.29 6.94 (dd, 1 H)

Example  124: 4- Chloro - N ' - (6- Fluoropyridine Yl) -lH-indol-2- Carbohydrazide  Produce

Except that 4-chloro- lH-indole-2-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H-pyrrole-2-carboxylic acid in Example 1 The title compound (12.4 mg, yield 51%) was obtained by carrying out the same processes as in Example 1.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.75 (s, 1H), 7.45 (m, 1H), 7.41 (d, 1H), 7.30 (s, 1H), 7.21 (t, 1H), 7.12 ( t, 1 H), 6.94 (dd, 1 H)

Example  125: 3- Chloro - N ' - (6- Fluoropyridine Yl) -lH-indol-2- Carbohydrazide  Produce

Except that 3-chloro-1 H-indole-2-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H- pyrrole-2-carboxylic acid in Example 1 The title compound (13.9 mg, yield 57%) was obtained by carrying out the same procedure as in Example 1.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.81 (m, 1H), 7.64 (d, 1H), 7.50 (m, 1H), 7.46 (d, 1H), 7.34 (m, 1H), 7.20 ( t, 1 H), 6.95 (dd, 1 H)

Example  126: N ' - (6- Fluoropyridine Yl) -1- methyl -1H-indole-2- CabohydrAza Manufacture of Id

Except that 1-methyl-1H-indole-2-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H-pyrrole-2-carboxylic acid in Example 1 The procedure of Example 1 was repeated to obtain the title compound (12.5 mg, yield 55%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.77 (s, 1H), 7.64 (d, 1H), 7.47 (m, 2H), 7.32 (t, 1H), 7.19 (s, 1H), 7.13 ( t, 1 H), 6.93 (dd, 1 H), 4.00 (s, 3 H)

Example  127: 5- Fluoro - N ' - (6- Fluoropyridine Yl) -1- methyl -1H-indole-2- Carbohydrazide  Produce

Fluoro-1-methyl-1H-indole-2-carboxylic acid was used instead of 4- (2-methylthiazol-4-yl) -1H- pyrrole-2-carboxylic acid in Example 1 , The title compound (11.8 mg, yield 49%) was obtained by carrying out the same processes as in the above Example 1.

¹ H NMR (CH ₃ OH-d ₄ ):? 7.76 (m, 1H), 7.45-7.50 (m, 2H), 7.32 6.94 (dd, 1 H), 4.00 (s, 3 H)

Example  128: N ' - (5- Fluoro -6- Methoxypyridine Yl) -lH-indol-2- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (11.3 mg, yield 47%) was obtained by carrying out the same processes as in the above Example 1, except that 1H-indole-2-carboxylic acid was used instead of 1H-pyrrole-2-carboxylic acid.

¹ H NMR (CH ₃ OH-d ₄ ):? 7.63 (d, IH), 7.57 (d, IH), 7.45 7.13 (m, 2 H), 3.91 (s, 3 H)

Example  129: 6- Fluoro - N ' - (5- Fluoro -6- Methoxypyridine 3-yl) -1H-indole-2-carbohydrazide

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (10.7 mg, yield 42%) was obtained by following the same procedure as in Example 1, except that 6-fluoro-1H-indole-2-carboxylic acid was used instead of 1H- ≪ / RTI >

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.62 (m, 1H), 7.57 (d, 1H), 7.09-7.18 (m, 3H), 6.89 (m, 3H), 6.89 (m, 1H), 3.91 (s, 3 H)

Example  130: N ' - (5- Fluoro -6- Methoxypyridine Yl) -1- methyl -1H-indole-2- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (12.8 mg, yield 51%) was obtained by following the same procedure as in Example 1, except that 1-methyl-1H-indole-2-carboxylic acid was used instead of 1H-pyrrole- .

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.64 (d, 1H), 7.60 (d, 1H), 7.45 (d, 1H), 7.31 (m, 1H), 7.11-7.17 (m, 3H), 4.00 (s, 3 H), 3.91 (s, 3 H)

Example  131: 3- Chloro - N ' - (5- Fluoro -6- Methoxypyridine Yl) -lH-indol-2- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (15.3 mg, yield 57%) was obtained by following the same procedure as in Example 1, except that 3-chloro-lH-indole-2-carboxylic acid was used instead of lH-pyrrole- .

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.64 (m, 2H), 7.46 (d, 1H), 7.34 (t, 1H), 7.17-7.21 (m, 2H), 3.92 (s, 3H)

Example  132: 4- Chloro - N ' - (5- Fluoro -6- Methoxypyridine Yl) -lH-indol-2- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (14.7 mg, yield 55%) was obtained by following the same procedure as in Example 1, except that 4-chloro-1H-indole-2-carboxylic acid was used instead of 1H-pyrrole- .

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.57 (d, 1H), 7.41 (d, 1H), 7.29 (s, 1H), 7.20 (t, 1H), 7.10-7.13 (m, 2H), 3.91 (s, 3 H)

Example  133: 6- Chloro - N ' - (5- Fluoro -6- Methoxypyridine Yl) -lH-indol-2- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (15.8 mg, yield 59%) was prepared following the same procedure as in Example 1, except that 6-chloro-lH-indole-2-carboxylic acid was used instead of lH-pyrrole- .

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.61 (d, 1H), 7.57 (d, 1H), 7.47 (s, 1H), 7.17 (s, 1H), 7.11 (dd, 1H), 7.07 ( dd, 1 H), 3.91 (s, 3 H)

Example  134: 7- Chloro - N ' - (5- Fluoro -6- Methoxypyridine Yl) -lH-indol-2- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- The title compound (15.0 mg, yield 56%) was prepared by the same procedure as in Example 1, except that 7-chloro-1H-indole-2-carboxylic acid was used instead of 1H-pyrrole- .

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.58-7.63 (m, 2H), 7.29 (m, 1H), 7.26 (s, 1H), 7.13 (dd, 1H), 7.07 (m, 1H), 3.91 (s, 3 H)

Example  135: 5- Fluoro - N ' - (5- Fluoro -6- Methoxypyridine 3-yl) -1H-indole-2-carbohydrazide

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (13.0 mg, yield 51%) was obtained by following the same procedure as in Example 1, except that 5-fluoro-1H-indole-2-carboxylic acid was used instead of 1H- ≪ / RTI >

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.58-7.63 (m, 2H), 7.29 (m, 1H), 7.26 (s, 1H), 7.13 (dd, 1H), 7.07 (m, 1H), 3.91 (s, 3 H)

Example  136: 5- Chloro - N ' - (5- Fluoro -6- Methoxypyridine Yl) -lH-indol-2- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (15.3 mg, yield 57%) was obtained by following the same procedure as in Example 1, except that 5-chloro- lH-indole-2-carboxylic acid was used instead of 1H-pyrrole- .

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.64 (d, 1H), 7.57 (d, 1H), 7.43 (d, 1H), 7.21 (dd, 1H), 7.11 (m, 2H), 3.91 ( s, 3H)

Example  137: N ' - (5- Fluoro -6- Methoxypyridine Yl) -5- Methoxy -1H-indole-2- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- (14.5 mg, yield 55%) was obtained by following the same procedure as in Example 1, except that 5-methoxy-1H-indole-2-carboxylic acid was used instead of 1H- ≪ / RTI >

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.59 (d, 1H), 7.36 (d, 1H), 7.12 (m, 2H), 6.93 (s, 1H), 3.93 (s, 3H), 3.84 ( s, 3H)

Example  138: 5- Fluoro - N ' - (5- Fluoro -6- Methoxypyridine Yl) -1- methyl -1H-indole-2- Carbohydrazide  Produce

5-Fluoro-6-methoxy-pyridin-3-yl hydrazine hydrochloride was prepared in analogy to example 1, using 4- (2-methylthiazol- Pyrrole-2-carboxylic acid was used instead of 5-fluoro-1-methyl-1H-indole-2-carboxylic acid, the title compound (12.5 mg, Yield: 47%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.59 (d, 1H), 7.45 (m, 1H), 7.32 (dd, 1H), 7.07-7.15 (m, 3H), 4.00 (s, 3H), 3.89 (s, 3H)

Example  139: N ' - (6- Fluoropyridine Yl) -1- methyl -1H- Benzofuro [3,2-b] pyrrole -2-car Bohidrazade Manufacturing

Methyl-1H-benzofuro [3,2-b] pyrrole-2-carboxylate in place of 4- (2-methylthiazol- The title compound (14.5 mg, yield 56%) was obtained by carrying out the same procedure as in Example 1, except that acetic acid was used.

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.82-7.81 (m, 1H), 7.72 (s, 1H), 7.50-7.48 (m, 1H), 7.75-7.42 (m, 1H), 7.31-7.26 (m, 2 H), 6.92 (dd, 1 H), 6.89 (s, 1 H)

Example  140: N ' - (6- Fluoropyridine -3 days) Benzo [b] Thiophene -3- Carbohydrazide  Produce

Except that benzo [b] thiophene-3-carboxylic acid was used in place of 4- (2-methylthiazol-4-yl) -1H- pyrrole-2-carboxylic acid in Example 1, 1, the title compound (11.7 mg, yield 51%) was obtained.

¹ H NMR (CH ₃ OH-d ₄ ):? 8.36 (d, IH), 8.33 (s, IH), 7.95 7.46-7.42 (m, 2H), 6.94 (dd, 1H)

Example  141: 5 - ((5- Fluoro -6- Methoxypyridine Yl) amino) -2- Phenyl -6,7- Dihydropyrazolo [1,5-a] pyrazine -4 (5H) -one

Step 1) Preparation of t-butyl 1- (5-fluoro-6-methoxypyridin-3-yl) -2- (3-phenyl-1H-pyrazole-5-carbonyl) hydrazine-

1-carboxylate (20.6 mg, 0.08 mmol), 3-phenyl-1H-pyrazole-5-carboxylic acid ( 15.1 mg, 0.08 mmol) was dissolved in 1 mL of N, N-dimethylformamide. N, N, N ', N'-tetramethyluronium hexafluorophosphate (45.4 mg, 0.12 mmol), diisopropylethylamine (34.8 uL, 0.2 mmol) were added and the reaction was stirred at room temperature for 6 hours. When the reaction was complete, the solvent was removed, diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected by dry filtration with magnesium sulfate and concentrated under reduced pressure to give the title compound (21.2 mg, yield 62%) as a colorless oil (developing solvent, ethyl acetate: hexane = 1: 1).

Step 2) A mixture of t-butyl (5-fluoro-6-methoxypyridin-3-yl) (4-oxo-2-phenyl-6,7-dihydropyrazolo [ 4H) -yl) carbamate < / RTI >

(5-fluoro-6-methoxypyridin-3-yl) -2- (3-phenyl-1H-pyrazole-5-carbonyl) hydrazine-1-carboxylate Dibromoethane (43.1 uL, 0.5 mmol), tetrabutylammonium bromide (16.0 mg, 0.05 mmol) and 40% sodium hydroxide (14.9 mg, 0.15 mmol) After heating to 35 [deg.] C, the mixture was stirred for 15 hours. When the reaction was complete, it was diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (11.8 mg, yield 52%) as a colorless oil (developing solvent, ethyl acetate: hexane = 1: 1).

4,5-a] pyrazin-4 (5H) -one [0253] < EMI ID = - Manufacture of onions

(5-fluoro-6-methoxypyridin-3-yl) (4-oxo-2-phenyl-6,7- dihydropyrazolo [1,5- a] pyrazine- 5 (4H) -yl) carbamate (11.8 mg, 0.03 mmol) was completely dissolved in 4 N hydrochloric acid, and then methanol (4 N hydrochloric acid capacity x 0.3) was slowly added dropwise. When crystals were formed, the mixture was stirred for 1 hour, filtered and washed with tetrahydrofuran (4 mL) to obtain the title compound (8.0 mg, yield 75%).

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.83 (d, 2H), 7.61 (d, 1H), 7.41 (t, 2H), 7.34 (t, 1H), 7.24 (m, 2H), 4.67 ( t, 2H), 4.12 (t, 2H), 3.94 (s, 3H)

Example  142: 5 - ((5- Fluoro -6- Methoxypyridine Yl) amino) -2- Phenyl -5,6,7,8-tetrahydro-4H- Pyrazolo [1,5-a] [1,4] diazepine -4-one

The title compound (16.2 mg, yield 55%) was prepared by the same procedure as in Example 141, except for using 1,3-dibromopropane instead of 1,2-dibromoethane in Step 2 of Example 141. .

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.82 (d, 2H), 7.56 (d, 1H), 7.41 (t, 2H), 7.33 (t, 1H), 7.21 (s, 1H), 7.14 ( 2H), 2.48 (m, 2H), 3.40 (s, 3H)

Example  143: 5 - ((5- Fluoro -6- Methoxypyridine Yl) amino) -2- Phenyl -6,7,8,9-tetrahydropyrazolo [ 1,5-a] [1,4] diazo -4 (5H) -one

The title compound (18.0 mg, yield 59%) was prepared by the same procedure as in Example 141, except for using 1,4-dibromobutane instead of 1,2-dibromoethane in step 2 of Example 141. .

_{^{1 H NMR (CH 3 OH-}} d 4): δ 7.82 (d, 2H), 7.52 (d, 1H), 7.41 (t, 2H), 7.33 (t, 1H), 7.11 (dd, 1H), 7.00 ( 2H), 3.45 (s, 3H), 2.45 (m, 2H)

Experimental Example  One: In vitro  Antifungal activity test ( MIC )

Candida albicans was used as a yeast fungus, and Aspergillus fumigatus as a fungus was used to evaluate the antifungal activity of the compound according to the present invention. All of the above strains were purchased from American Type Culture Collection (ATCC).

The strains used in the experiments were inoculated into Sabouraud dextrose agar and incubated at 35 ° C for 24 hours for Candida albicans and for about 7 days for Aspergillus fumigatus. Candida albicans was thoroughly suspended in 1 mL of 0.85% sterile physiological saline prepared from about 5 to 7 cultured single colonies, and then the absorbance was corrected to 0.095 to 0.107 at 530 nm. The prepared bacterial dilution was diluted 1:10 with RPMI (Roswell park memorial institute) 1640 medium, and the diluted solution was further diluted 1: 100 to give a bacterial count of 1.0 × 10 ³ to 5.0 × 10 ³ CFU / mL, Prepared. Aspergillus fumigatus was prepared by adding 1 mL of 0.2% Tween 20 diluted in 0.85% sterile physiological saline to the cultured Sabouraud dextrose agar, and shaking the plate to allow the conidium to fall off. The solution recovered from the plate surface was transferred to a sterilized tube, and the tube was allowed to stand at room temperature for 5 minutes to immerse a heavy substance such as a medium. After transferring the supernatant to a sterilized tube, the supernatant was sufficiently suspended for about 15 seconds, and a bacterial dilution of 0.4 × 10 ⁶ to 5.0 × 10 ⁶ CFU / mL was prepared using a hemocytometer. The prepared bacterial dilution was diluted 1: 100 with RPMI 1640 medium to prepare inoculum. Candida albicans was cultured for 24 hours, Aspergillus fumigatus for 48 hours at 35 ° C, and the concentration of 80% or 50% inhibition of growth was determined using the Alarama blue coloring reagent compared to the negative control. All tests were repeated twice for each test concentration group. The results of the antifungal activity (MIC ₈₀ , MIC ₅₀ / / mL) are shown in Tables 1 to 4 below (in the following Tables 1 to 4, "-" means not measured)

Example
number Candida albicans
MIC ₈₀ Aspergillus fumigatus
MIC ₅₀ Example
number Candida albicans
MIC ₈₀ Aspergillus fumigatus
MIC ₅₀ One 0.2 - 21 0.14 - 2 0.1 - 22 0.13 - 3 0.2 - 23 0.12 - 4 0.1 - 24 0.12 - 5 1.2 - 25 0.14 - 6 0.1 0.5 26 <0.01 - 7 0.1 - 27 0.03 - 8 0.1 0.5 28 0.02 0.3 9 0.01 - 29 0.02 0.6 10 0.1 - 30 0.03 - 11 0.02 - 31 0.1 - 12 0.02 1.2 32 0.1 1.0 13 0.01 0.6 33 0.1 0.5 14 0.04 1.3 34 0.07 - 15 0.16 1.2 35 0.04 1.1 16 0.1 - 36 0.02 0.6 17 0.03 - 37 0.1 - 18 0.1 - 38 0.1 - 19 0.06 - 39 0.1 0.5 20 0.13 - 40 0.1 0.6

Example
number Candida albicans
MIC ₈₀ Aspergillus fumigatus
MIC ₅₀ Example
number Candida albicans
MIC ₈₀ Aspergillus fumigatus
MIC ₅₀ 41 0.1 0.6 61 <0.01 0.3 42 0.04 1.3 62 0.1 - 43 0.1 - 63 0.07 - 44 0.1 1.2 64 0.14 - 45 0.04 0.6 65 0.14 - 46 <0.01 0.6 66 0.8 - 47 0.04 - 67 0.2 - 48 0.02 0.3 68 0.1 - 49 0.04 0.6 69 0.1 - 50 <0.01 - 70 0.02 0.3 51 0.07 - 71 0.1 - 52 0.07 - 72 0.03 - 53 0.26 - 73 0.1 - 54 0.07 - 74 0.1 - 55 0.01 - 75 0.03 0.5 56 0.07 - 76 0.1 - 57 0.07 - 77 0.13 - 58 0.03 - 78 0.04 - 59 <0.01 - 79 0.14 1.1 60 0.08 0.6 80 0.04 -

Example
number Candida albicans
MIC ₈₀ Aspergillus fumigatus
MIC ₅₀ Example
number Candida albicans
MIC ₈₀ Aspergillus fumigatus
MIC ₅₀ 81 0.1 - 101 0.03 0.5 82 0.03 0.5 102 <0.01 0.6 83 0.01 0.3 103 0.07 - 84 <0.01 0.6 104 0.04 - 85 0.1 - 105 0.04 - 86 0.1 - 106 0.1 0.5 87 0.1 0.6 107 0.1 0.7 88 0.1 0.9 108 <0.01 - 89 0.6 - 109 0.1 0.6 90 0.4 - 110 0.1 0.6 91 0.12 - 111 0.1 1.1 92 0.46 - 112 0.3 - 93 0.11 - 113 0.2 - 94 0.9 - 114 0.04 - 95 0.06 - 115 <0.01 - 96 0.03 - 116 0.1 1.1 97 0.1 0.5 117 0.1 - 98 0.1 - 118 0.03 - 99 <0.01 - 119 0.27 1.1 100 0.1 - 120 0.05 0.4

Example
number Candida albicans
MIC ₈₀ Aspergillus fumigatus
MIC ₅₀ Example
number Candida albicans
MIC ₈₀ Aspergillus fumigatus
MIC ₅₀ 121 0.11 - 134 0.03 0.5 122 0.06 0.5 135 0.03 0.5 123 0.12 - 136 0.03 - 124 0.12 - 137 0.03 - 125 0.12 - 138 0.03 0.3 126 0.06 0.4 139 1.0 - 127 0.06 - 140 0.1 - 128 0.03 0.2 141 0.6 - 129 0.06 0.5 142 2.3 - 130 0.06 0.2 143 > 9.5 - 131 0.03 0.3 132 0.03 0.5 Caspofungin 0.25 0.3 133 0.03 0.5 Fluconazole 0.25 > 32

As shown in Tables 1 to 4, the compounds according to the present invention exhibited remarkably excellent antifungal effects compared to the antifungal agents caspofungin and fluconazole.

Experimental Example  2: In vitro Fungus  Activity test ( MFC , Minimum Fungicidal Concentration )

Fungicide samples were diluted 10 times by adding RPMI 1640 medium to 10 mM stock solution, and then diluted 5 times in succession to use the highest concentration of antifungal activity (MIC). The highest concentration of the sample was diluted to two times with 11 concentrations in the dilution medium, and the final concentration was determined by mixing 1: 1 with the bacteria. At this time, the concentration of dimethyl sulfoxide used as an excipient was finally adjusted to 1% (v / v). The fungicidal activity of Candida albicans was evaluated as a sample of the test plate on which the antifungal activity evaluation was completed and was evaluated from the highest concentration of the sample to the next one determined by MIC. The test solution at each concentration was pipetted 5 times, and all (about 225 L) was taken and added to 12-well Sabouraud dextrose agar. The test plate was cultured at 35 DEG C for 48 hours, and the minimum concentration at which no growth of fungi was observed was visually observed. The fungicidal activity results (MFC / / mL) are shown in Table 5 below.

Example
number Candida albicans
MFC Example
number Candida albicans
MFC Example
number Candida albicans
MFC 6 1.9 60 0.3 126 0.1 8 0.5 61 0.2 128 0.1 12 0.1 75 0.5 129 0.1 13 0.6 79 0.3 130 0.1 14 0.2 82 0.1 131 0.1 15 0.6 83 0.1 132 0.1 28 0.1 84 0.2 133 0.1 29 0.2 87 0.6 134 0.1 33 3.9 88 0.2 135 0.1 36 0.1 102 0.2 136 0.1 44 0.6 108 2.5 137 0.1 45 0.3 111 0.3 46 0.1 119 2.2 48 0.1 120 0.1 Caspofungin 4 49 0.1 122 0.1 Fluconazole > 32

As shown in Table 5 above, the compounds according to the present invention showed remarkably excellent fungicidal effect compared to the conventional fungicides, caspofungin and fluconazole.

Formulation example : refine

The compound (50 mg) prepared in Example 1 and magnesium stearate (20 mg) were granulated with soluble starch (35 mg), dried and treated with lactose (65 mg) and corn starch (30 mg) And mixed using a mechanical shaker and a mixer. The resulting mixture was pressed into a tablet shape.

Claims (15)

1. A compound represented by the following formula (1): &lt; EMI ID =
[Chemical Formula 1]

In this formula,
A is selected from the group consisting of benzo [b] thienyl, benzofura [3,2-b] pyrrolyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, Enyl or triazolyl,
R &lt; ₁ &gt; is hydrogen or halogen,
R ₂ is halogen or C _1-4 alkoxy,
R ₃ is hydrogen, 3-methylthien-2-ylcarbonyl or t-butoxycarbonyl,
R ₄ is hydrogen, R ₅ is hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, halogen or benzyl; Or R ₄ and R ₅ are bonded together to form C _2-4 alkylene,
R ₆ is hydrogen, C _1-4 alkoxy, C _3-6 cyclo alkyl, halogen, nitro, amino, NH (t- butoxycarbonyl), NH (C _1-4 alkyl), phenyl, pyridinyl, P Lt; / RTI &gt; is hydrogen,
Wherein the phenyl, pyridinyl, pyrrolyl, or thiazolyl is unsubstituted or substituted with one or two groups independently selected from the group consisting of C _1-4 alkyl, C _1-4 haloalkyl, halogen, cyano, and phenyl &Lt; / RTI &gt;
delete The method according to claim 1,
R &lt; ₁ &gt; is hydrogen and R &lt; ₂ &gt; is fluoro; or
R &lt; ₁ &gt; is fluoro and R &lt; ₂ &gt; is methoxy.
The method according to claim 1,
R ₅ is A compound or a pharmaceutically acceptable salt thereof, characterized in that hydrogen, methyl, ethyl, propyl, isopropyl, a methyl, 2,2,2-trifluoro-trifluoroethyl, chloro, or benzyl.
The method according to claim 1,
R ₆ is hydrogen, methoxy, cyclopropyl, fluoro, chloro, nitro, amino, NH (t-butoxycarbonyl), ethylamino, phenyl, pyridinyl, pyrrolyl or thiazolyl,
Wherein said phenyl, pyridinyl, pyrrolyl or thiazolyl is unsubstituted or substituted by one or more substituents each independently selected from the group consisting of methyl, t-butyl, trifluoromethyl, fluoro, chloro, cyano, &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof, wherein said compound is substituted with two substituents.
The method according to claim 1,
R ₆ is unsubstituted or substituted by C _{1 -4} alkyl, C _{1 -4} haloalkyl, halogen, cyano and phenyl which is substituted by one or two substituents each selected from the group consisting of phenyl; Unsubstituted pyridinyl; C _{1 -4} alkyl substituted with a blood pyrrolyl; Or a C _{1 -4} Im ah pyridazinyl The compound or a pharmaceutically acceptable salt thereof, characterized in that substituted with alkyl.
The method according to claim 1,
A is indolyl,
R ₅ is hydrogen or C _1-4 alkyl,
Wherein R &lt; ₆ &gt; is hydrogen, Ci- ₄ alkoxy or halogen; or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
A is isoxazolyl,
R &lt; ₅ &gt; is hydrogen,
R &lt; ₆ &gt; is phenyl,
Wherein said phenyl is unsubstituted or substituted by halogen.
The method according to claim 1,
A is oxazolyl,
R ₅ is hydrogen or C _1-4 alkyl,
R &lt; ₆ &gt; is phenyl,
Wherein said phenyl is unsubstituted or substituted with one or two substituents each independently selected from the group consisting of C _1-4 haloalkyl, halogen and phenyl, or a pharmaceutically acceptable salt thereof. .
The method according to claim 1,
A is pyrazolyl,
R ₄ is hydrogen, R ₅ is hydrogen, C _1-4 alkyl, C _1-4 haloalkyl or benzyl; Or R ₄ and R ₅ are bonded together to form C _2-4 alkylene,
R ₆ is C _3-6 cycloalkyl, nitro, phenyl, pyridinyl or pyrrolyl,
Wherein said phenyl, pyridinyl or pyrrolyl is unsubstituted or substituted with a substituent selected from the group consisting of C _1-4 alkyl, C _1-4 haloalkyl, halogen and cyano. A pharmaceutically acceptable salt.
The method according to claim 1,
A is thiazolyl,
R ₅ is hydrogen, C _1-4 alkyl or C _1-4 haloalkyl,
R ₆ is hydrogen, C _1-4 alkoxy, C _3-6 cycloalkyl, halogen, amino, NH (t-butoxycarbonyl), NH (C _1-4 alkyl)
Wherein said phenyl is unsubstituted or substituted with one or two substituents each independently selected from the group consisting of C _1-4 haloalkyl, halogen and cyano.
The method according to claim 1,
A is thienyl,
R &lt; ₅ &gt; is hydrogen or halogen,
R &lt; ₆ &gt; is hydrogen, halogen or phenyl,
Wherein said phenyl is unsubstituted or substituted with a substituent selected from the group consisting of C _1-4 alkyl, C _1-4 haloalkyl, halogen and cyano.
The method according to claim 1,
A is triazolyl,
And R ₅ is C _{1 -4} alkyl,
And R &lt; ₆ &gt; is phenyl.
The compound according to claim 1, wherein the compound is
1) N '- (6-fluoropyridin-3-yl) -4- (2- methylthiazol-
2) N &apos;-( 6-fluoropyridin-3-yl) thiophene-2-carbohydrazide,
3) N &apos;-( 6-fluoropyridin-3-yl) -3-methylthiophene-2-carbohydrazide,
4) N '- (6-Fluoropyridin-3-yl) -4-methylthiophene-2-carbohydrazide,
5) N &apos;-( 3-methylthien-2-ylcarbonyl) -N &apos;-( 6-fluoropyridin- 3- yl) -3-methylthiophene-2-carbohydrazide,
6) 2,5-Dichloro-N '- (6-fluoropyridin-3-yl) thiophene-3-carbohydrazide,
7) 2,5-Dichloro-N '- (5-fluoro-6-methoxypyridin-3- yl) thiophene-3-carbohydrazide,
8) N '- (6-Fluoropyridin-3-yl) -5-phenylthiophene-2-carbohydrazide,
9) N &apos;-( 5-fluoro-6-methoxypyridin-3-yl) -5- phenylthiophene-2-carbohydrazide,
10) 5- (4-Fluorophenyl) -N'- (6-fluoropyridin-3-yl) thiophene-2-carbohydrazide,
11) N '- (5-fluoro-6-methoxypyridin-3- yl) -5- (4- fluorophenyl) thiophene-
12) 5- (4-Chlorophenyl) -N '- (5-fluoro-6-methoxypyridin-3- yl) thiophene-
13) 5- (4-Cyanophenyl) -N '- (5-fluoro-6-methoxypyridin-3- yl) thiophene-
14) N '- (5-Fluoro-6-methoxypyridin-3- yl) -5- (4- (trifluoromethyl) phenyl) thiophene-
15) 5- (4- (t-Butyl) phenyl) -N '- (5-fluoro-6-methoxypyridin- 3- yl) thiophene-
16) N &apos;-( 6-Fluoropyridin-3-yl) -5- nitro- lH- pyrazole- 3-carbohydrazide,
17) 3-Cyclopropyl-N '- (5-fluoro-6-methoxypyridin-3- yl) -lH- pyrazole-5-carbohydrazide,
18) N &apos;-( 6-Fluoropyridin-3-yl) -3-phenyl-lH- pyrazole-5-carbohydrazide,
19) 3- (4-Fluorophenyl) -N '- (6-fluoropyridin-3-yl) -1H- pyrazole-5-carbohydrazide,
20) 3- (4-Chlorophenyl) -N &apos;-( 6-fluoropyridin-3-yl) -lH- pyrazole-5-carbohydrazide,
21) N &apos;-( 6-Fluoropyridin-3-yl) -3- (4- (trifluoromethyl) phenyl) -lH- pyrazole-5-carbohydrazide,
22) Synthesis of 3- (4-cyanophenyl) -N '- (6-fluoropyridin-3-yl) -1H-pyrazole-5-carbohydrazide,
23) N &apos;-( 6-fluoropyridin-3-yl) -3- (1 -methyl-lH- pyrrol- 2-yl) -lH- pyrazole-5-carbohydrazide,
24) N &apos;-( 6-Fluoropyridin-3-yl) -3- (pyridin- 2-yl) -lH- pyrazole-5-carbohydrazide,
25) A mixture of t-butyl 1- (5-fluoro-6-methoxypyridin-3-yl) -2-
26) N &apos;-( 5-fluoro-6-methoxypyridin-3-yl) -3-phenyl- lH- pyrazole-5-carbohydrazide,
27) N &apos;-( 5-fluoro-6-methoxypyridin-3-yl) -3- (4- fluorophenyl) -lH- pyrazole-5-carbohydrazide,
28) 3- (4-Chlorophenyl) -N '- (5-fluoro-6-methoxypyridin-3- yl) -1H- pyrazole-5-carbohydrazide,
29) N &apos;-( 5-fluoro-6-methoxypyridin-3-yl) -3- (4- (trifluoromethyl) phenyl) -lH-pyrazole-
30) A mixture of 3- (4-cyanophenyl) -N '- (5-fluoro-6-methoxypyridin-
31) N &apos;-( 6-Fluoropyridin-3-yl) -l-methyl-5-phenyl-lH- pyrazole-3-carbohydrazide,
32) 5- (4-Fluorophenyl) -N '- (6-fluoropyridin-3- yl) -l -methyl- lH- pyrazole-3-carbohydrazide,
33) N &apos;-( 6-Fluoropyridin-3-yl) -l-methyl-3-phenyl-lH- pyrazole-5-carbohydrazide,
34) N '- (5-Fluoro-6-methoxypyridin-3-yl)
35) N '- (5-fluoro-6-methoxypyridin-3-yl) -3- (4- fluorophenyl)
36) 1-Ethyl-N '- (5-fluoro-6-methoxypyridin-3- yl) -3- (4- fluorophenyl)
37) 1-Ethyl-N &apos;-( 6-fluoropyridin-3-yl) -3-phenyl- lH- pyrazole-5-carbohydrazide,
38) 3- (4-Fluorophenyl) -N'- (6-fluoropyridin-3-yl) -l-methyl- lH- pyrazole-5-carbohydrazide,
39) A mixture of 1-ethyl-3- (4-fluorophenyl) -N '- (6-fluoropyridin-
40) To a solution of 3- (4-fluorophenyl) -N '- (6-fluoropyridin-3-
41) A mixture of 3- (4-fluorophenyl) -N '- (6-fluoropyridin-3-
42) Synthesis of l-benzyl-3- (4-fluorophenyl) -N '- (6-fluoropyridin-
43) N &apos;-( 6-fluoropyridin-3-yl) -3-methyl-l- phenyl- lH- pyrazole-
44) Synthesis of l-benzyl-N '- (6-fluoropyridin-3-yl) -3-phenyl-lH- pyrazole-5-carbohydrazide,
45) A mixture of 3- (4-chlorophenyl) -N '- (5-fluoro-6-methoxypyridin-
46) 3- (4-Chlorophenyl) -1-ethyl-N &apos;-( 5-fluoro-6- methoxypyridin-
47) N &apos;-( 5-fluoro-6-methoxypyridin-3-yl) -1- methyl-3- (4- (trifluoromethyl) phenyl) -lH-pyrazole- Zaid,
48) A mixture of 1-ethyl-N '- (5-fluoro-6-methoxypyridin-3- yl) -3- (4- (trifluoromethyl) phenyl) -1H- pyrazole- Zaid,
49) 3- (4-Cyanophenyl) -N '- (5-fluoro-6-methoxypyridin-
50) A mixture of 3- (4-cyanophenyl) -N '- (5-fluoro-6-methoxypyridin-
51) 3- (4-Chlorophenyl) -N '- (6-fluoropyridin-3-yl)
52) N '- (6-Fluoropyridin-3-yl) -1-methyl-3- (4- (trifluoromethyl) phenyl) -1 H- pyrazole-
53) 3- (4-Cyanophenyl) -N'- (6-fluoropyridin-3-yl) -1-methyl-lH- pyrazole-5-carbohydrazide,
54) A mixture of 3- (4-chlorophenyl) -l-ethyl-N '- (6-fluoropyridin-
55) 1-Ethyl-N '- (6-fluoropyridin-3-yl) -3- (4- (trifluoromethyl) phenyl) -1 H- pyrazole-
56) A mixture of 3- (4-cyanophenyl) -1-ethyl-N '- (6-fluoropyridin-
57) 3- (4-Cyanophenyl) -1-ethyl-N &apos;-( 5-fluoro-6- methoxypyridin-
58) 1-Ethyl-N '- (5-fluoro-6-methoxypyridin-3- yl) -3-phenyl-lH- pyrazole-5-carbohydrazide,
59) A mixture of 1-benzyl-N '- (5-fluoro-6-methoxypyridin-
60) 3- (4-Fluorophenyl) -N'- (6-fluoropyridin-3-yl) Hydrazide,
61) N '- (5-fluoro-6-methoxypyridin-3-yl) -3- (4- fluorophenyl) -1- (2,2,2-trifluoroethyl) Sol-5-carbohydrazide,
62) N &apos;-( 6-fluoropyridin-3-yl) -5-methylisoxazole-3-carbohydrazide,
63) N &apos;-( 5-fluoro-6-methoxypyridin-3- yl) -5- (4- fluorophenyl) isoxazole-3-carbohydrazide,
64) 5- (4-Chlorophenyl) -N '- (5-fluoro-6-methoxypyridin- 3- yl) isoxazole-
65) N '- (5-fluoro-6-methoxypyridin-3- yl) -3- (4- fluorophenyl) isoxazole-
67) N &apos;-( 6-Fluoropyridin-3-yl) -1H-imidazole-2-carbohydrazide,
68) N '- (5-fluoro-6-methoxypyridin-3-yl) -5-
69) N &apos;-( 6-Fluoropyridin-3-yl) thiazole-2-carbohydrazide,
70) N &apos;-( 5-fluoro-6-methoxypyridin-3-yl) -4-phenylthiazole-2-carbohydrazide,
71) N &apos;-( 6-Fluoropyridin-3-yl) thiazole-4-carbohydrazide,
72) N &apos;-( 5-fluoro-6-methoxypyridin-3-yl) -2-phenylthiazole-
73) N &apos;-( 6-Fluoropyridin-3-yl) -4-methyloxazole-5-carbohydrazide,
74) N &apos;-( 6-Fluoropyridin-3-yl) -2-phenyloxazole-5-carbohydrazide,
75) N '- (5-fluoro-6-methoxypyridin-3-yl) -2-phenyloxazole-
76) 2- (4-Fluorophenyl) -N'- (6-fluoropyridin-3-yl) oxazole-
77) 2- (3,4-Difluorophenyl) -N '- (6-fluoropyridin-3-yl) oxazole-
78) 2- (3,4-Difluorophenyl) -N '- (5-fluoro-6-methoxypyridin-3-yl) oxazole-
79) N '- (6-fluoropyridin-3-yl) -2- (4- (trifluoromethyl) phenyl) oxazole-
80) N '- (5-fluoro-6-methoxypyridin-3-yl) -2- (4- (trifluoromethyl) phenyl) oxazole-
81) N '- (6-Fluoropyridin-3-yl) -4-methyl-2-phenyloxazole-
82) N '- (5-fluoro-6-methoxypyridin-3-yl) -4-methyl-
Biphenyl-3-yl) -N '- (6-fluoropyridin-3-yl) oxazole-5-carbohydrazide,
84) 2 - ([1,1'-biphenyl] -3- yl) -N '- (5-fluoro-6- methoxypyridin- 3- yl) oxazole-
85) N &apos;-( 6-fluoropyridin-3-yl) -4-methylthiazole-5-carbohydrazide,
87) 2- (4-Chlorophenyl) -N '- (6-fluoropyridin-3- yl) -4-methylthiazole-
88) 2-Chloro-N '- (6-fluoropyridin-3-yl) thiazole- 5-carbohydrazide,
89) t-butyl (5- (2- (6-fluoropyridin-3-yl) hydrazine-1-carbonyl) thiazol-
90) 2-Amino-N '- (6-fluoropyridin-3-yl) thiazole-
92) 2- (Ethylamino) -N'- (6-fluoropyridin-3-yl) -4-methylthiazole-5-carbohydrazide,
93) 2-Chloro-N '- (6-fluoropyridin-3-yl) -4-methylthiazole-
94) 2-Chloro-N '- (5-fluoro-6-methoxypyridin-3- yl) thiazole-
95) N &apos;-( 6-fluoropyridin-3-yl) -2-methoxy-4- methylthiazole-
96) 2-Cyclopropyl-N '- (5-fluoro-6-methoxypyridin-3- yl) thiazole-
97) N &apos;-( 6-Fluoropyridin-3-yl) -2-phenylthiazole-5-carbohydrazide,
98) N '- (5-fluoro-6-methoxypyridin-3- yl) -2- (4- fluorophenyl) thiazole-
99) 2- (4-Chlorophenyl) -N '- (5-fluoro-6-methoxypyridin-3- yl) thiazole-
100) N '- (6-Fluoropyridin-3-yl) -2- (4- (trifluoromethyl) phenyl) thiazole-
101) N '- (5-fluoro-6-methoxypyridin-3-yl) -2-phenylthiazole-
102) N '- (5-Fluoro-6-methoxypyridin-3- yl) -2- (4- (trifluoromethyl) phenyl) thiazole-
103) N '- (5-fluoro-6-methoxypyridin-3-yl) -2- (3- fluorophenyl) thiazole-
104) 2- (2,4-Difluorophenyl) -N '- (5-fluoro-6-methoxypyridin-3- yl) thiazole-
105) 2- (3,4-Difluorophenyl) -N '- (5-fluoro-6-methoxypyridin-3- yl) thiazole-
106) 2- (4-Fluorophenyl) -N '- (6-fluoropyridin-3- yl) -4-methylthiazole-
107) 2- (4-Chlorophenyl) -N '- (6-fluoropyridin-3- yl) -4- (trifluoromethyl) thiazole-
108) 2- (4-Chlorophenyl) -N &apos;-( 5-fluoro-6-methoxypyridin- 3- yl) -4-methylthiazole-
109) 2- (4-Cyanophenyl) -N '- (6-fluoropyridin-3- yl) -4-methylthiazole-
110) N '- (6-Fluoropyridin-3-yl) -4-methyl-2- (4- (trifluoromethyl) phenyl) thiazole-
111) 4-Ethyl-N'- (6-fluoropyridin-3-yl) -2-phenylthiazole-
112) N '- (6-Fluoropyridin-3-yl) -2-phenyl-4- (trifluoromethyl) thiazole-
113) 2- (4-Fluorophenyl) -N'- (6-fluoropyridin-3-yl) -4- (trifluoromethyl) thiazole-
114) 2- (4-Chlorophenyl) -N '- (5-fluoro-6-methoxypyridin-3- yl) -4- (trifluoromethyl) thiazole-
4- (trifluoromethyl) -2- (4- (trifluoromethyl) phenyl) thiazole-5-carbo Hydrazide,
116) N '- (5-fluoro-6-methoxypyridin-3-yl) -5-
117) N &apos;-( 6-fluoropyridin-3-yl) -1-methyl-3-phenyl-1H-1,2,4- triazole-
118) N '- (5-fluoro-6-methoxypyridin-3-yl)
119) N &apos;-( 5-fluoro-6-methoxypyridin-3- yl) -l-methyl- lH- indole- 3-carbohydrazide,
120) N &apos;-( 6-fluoropyridin-3-yl) -lH-indole-2-carbohydrazide,
121) 6-Fluoro-N &apos;-( 6-fluoropyridin-3-yl) -lH- indole-2-carbohydrazide,
122) 7-Chloro-N &apos;-( 6-fluoropyridin-3- yl) -lH- indole- 2-carbohydrazide,
123) 6-Chloro-N &apos;-( 6-fluoropyridin-3-yl) -lH- indole- 2-carbohydrazide,
124) 4-Chloro-N &apos;-( 6-fluoropyridin-3-yl) -lH- indole-2-carbohydrazide,
125) 3-Chloro-N &apos;-( 6-fluoropyridin-3-yl) -lH- indole-2-carbohydrazide,
126) N &apos;-( 6-fluoropyridin-3-yl) -l-methyl- lH-indole-
127) 5-Fluoro-N '- (6-fluoropyridin-3-yl)
128) N &apos;-( 5-fluoro-6-methoxypyridin-3- yl) -lH- indole- 2-carbohydrazide,
129) 6-Fluoro-N '- (5-fluoro-6-methoxypyridin- 3- yl) -lH- indole- 2-carbohydrazide,
130) N &apos;-( 5-fluoro-6-methoxypyridin-3- yl) -l-methyl- lH- indole- 2-carbohydrazide,
131) 3-Chloro-N '- (5-fluoro-6-methoxypyridin-3- yl) -lH- indole-
132) 4-Chloro-N &apos;-( 5-fluoro-6-methoxypyridin- 3- yl) -lH- indole- 2-carbohydrazide,
133) 6-Chloro-N &apos;-( 5-fluoro-6-methoxypyridin- 3- yl) -lH- indole- 2-carbohydrazide,
134) 7-Chloro-N &apos;-( 5-fluoro-6-methoxypyridin- 3- yl) -lH- indole- 2-carbohydrazide,
135) 5-Fluoro-N '- (5-fluoro-6-methoxypyridin-3- yl) -lH- indole- 2-carbohydrazide,
136) 5-Chloro-N &apos;-( 5-fluoro-6-methoxypyridin- 3- yl) -lH- indole- 2-carbohydrazide,
137) N &apos;-( 5-fluoro-6-methoxypyridin-3-yl) -5- methoxy- lH- indole- 2-carbohydrazide,
138) A mixture of 5-fluoro-N '- (5-fluoro-6-methoxypyridin-
139) N &apos;-( 6-fluoropyridin-3-yl) -l-methyl- lH-benzofuro [3,2- b] pyrrole- 2-carbohydrazide,
140) N &apos;-( 6-Fluoropyridin-3-yl) benzo [b] thiophene-3-carbohydrazide,
L, 5-a] pyrazin-4 (5H) - (5-fluoro-6-methoxypyridin- On,
2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] pyrimidin- [1,4] diazepin-4-one, and
A) &lt; RTI ID = 0.0 &gt; [1, &lt; / RTI & 4] diazosuchin-4 (5H) -one
&Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.
14. An antifungal agent composition comprising a compound of any one of claims 1, 3 to 14 or a pharmaceutically acceptable salt thereof.