KR101377419B1 - Novel derivatives inhibiting activity of 11beta-HSD1 (11β-Hydroxysteroid dehydrogenase type 1) enzyme, preparation method thereof and pharmaceutical composition containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel derivative having an inhibitory activity of 11-beta-HSD1 enzyme, a preparation method thereof, and a pharmaceutical composition containing the same as an active ingredient, wherein the compound according to the present invention is 11-beta-hydroxysteroid dehydrogena. Selective inhibition of azeotype 1 (11β-HSD1) causes diseases caused by the overactivity of 11β-HSD1, such as insulin-independent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome, and excessive glucos It can be usefully used as a therapeutic agent for treating diseases and conditions mediated by corticosteroid action.

Description

Novel derivatives inhibiting activity of 11beta-HSD1 (11β-Hydroxysteroid dehydrogenase type 1) enzyme, preparation method according to pharmaceutical and pharmaceutical composition containing the same derivative having inhibitory activity of 11beta-HSD1 enzyme composition containing the same as an active ingredient}

The present invention relates to a novel derivative having an inhibitory activity of 11beta-HSD1 enzyme, a preparation method thereof, and a pharmaceutical composition containing the same as an active ingredient.

Glucocorticoids (cortisol in humans, corticosterone in mice and rats) that bind to the glucocorticoid receptor are steroid hormones present in almost all vertebrates (Dallman MF, Strack AM, Akana SF et al. 1993; Front Neuroendocrinol 14, 303-347. It regulates the expression of liver enzymes involved in gluconeogenesis to increase stromal supply by releasing glycerol from fat cells and releasing amino acids from muscle. It has also been reported that glucocorticoids play an important role in the differentiation of adipocyte precursors into mature adipocytes capable of storing triglycerides (Bujalska IJ et al. 1999; Endocrinology 140, 3188-3196), Induced glucocorticoids themselves play an important role in disease states associated with abdominal obesity, a risk factor for type 2 diabetes, hypertension and coronary artery disease (Bjorntorp P & Rosmond R 2000; Int. J. Obesity 24, S80-S85).

The glucocorticoid activity is determined by secretion of cortisol, as well as by active cortisol and inactive cortisol by 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and 11beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2). It has been experimentally demonstrated that it is also controlled at the tissue level by intracellular interconversion of (Sandeep TC & Walker BR 2001 Trends in Endocrinol & Metab. 12, 446-453). At this time, the 11β-HSD1 converts the inactive glucocorticoid to the activity, thereby playing an important role in the regulation of the concentration of cellular agents and the activation of corticosteroid receptors in the target tissue.

This mechanism has been shown to play a very beneficial role in the treatment of diabetes and obesity. Specifically, it has been demonstrated using treatment with carbenoxolone, an anti-ulcer drug that inhibits both 11β-HSD1 and 11β-HSD2, which increases insulin sensitivity, whereby inhibition of 11β-HSD1 decreases the cell's cortisol concentration. By controlling the effects of insulin (Walker BR et al. 1995; J. Clin. Endocrinol. Metab. 80, 3155-3159). In addition, inhibition of 11β-HSD1 in the 11β-HSD1 gene depletion mouse test attenuated glucocorticoid-induced activation of glucose angiogenesis enzymes and decreased plasma glucose concentrations in response to stress or obesity (Kotelevtsev Y. et al., Proc Natl Acad Sci USA.1997 Dec 23; 94 (26): 14924-14929), has shown that inhibition of 11β-HSD1 is useful for lowering plasma glucose and hepatic glucose levels in type 2 diabetes. Not only does it reduce typical diabetes-related syndromes, it also has the advantage of not having significant side effects.

However, studies with the nonspecific inhibitor carbenoxolone showed an adverse side effect of elevating blood pressure when inhibiting the 11 [beta] -HSD2 enzyme. Therefore, it is necessary to develop an inhibitor having selectivity for ll [beta] -HSDl.

Therefore, the present inventors have studied to prepare a substance that selectively inhibits 11β-HSD1, and thus synthesize new derivatives, and these derivatives exhibit excellent inhibitory activity against 11β-HSD1. The present invention has been completed with the understanding that it is possible to treat diseases and conditions mediated by resistance, obesity, lipid disorders, metabolic syndrome and excessive glucocorticoid action.

An object of the present invention is to provide a substance that selectively inhibits 11β-HSD1.

Another object of the present invention to provide a method for producing a substance that selectively inhibits the 11β-HSD1.

Another object of the present invention to provide a pharmaceutical composition containing a substance that selectively inhibits the 11β-HSD1 as an active ingredient.

In order to achieve the above object, the present invention provides a derivative represented by the following formula (1).

[Formula 1]

(In the formula 1,

R ¹ , R ² , R ³ , R ⁴ , R ⁵ And X is as defined herein.)

The present invention also provides a process for preparing the compound of formula (1).

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating a disease caused by the overactivity of 11β-HSD1 containing the compound of Formula 1 as an active ingredient.

The compounds according to the invention selectively inhibit 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1), thereby causing diseases caused by overactivity of 11β-HSD1, for example insulin independent type 2 It can be usefully used as a therapeutic agent for treating diseases and conditions mediated by diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome, and excessive glucocorticoid action.

Hereinafter, the present invention will be described in detail.

The present invention provides a compound having a inhibitory activity of the 11β-HSD1 enzyme represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

(In the formula 1,

X is carbonyl or sulfonyl;

R ¹ represents C ₁ to C ₄ straight or branched chain alkyl, C ₃ to C ₈ cycloalkyl, C ₅ to C ₁₂ aryl, C ₁₀ to C ₁₂ biaryl, N or O hetero atoms in the ring 5-8 membered heterocycloalkyl, 5-8 membered heteroaryl containing one or more heteroatoms of N or O in the ring, C ₅ -C ₁₂ aryl C ₁ -C ₃ linear or branched alkyl Or C ₃ -C ₆ cycloalkyl C ₁ -C ₃ straight or branched alkyl;

In this case, the aryl is unsubstituted or substituted by one or more halogens, unsubstituted or straight or branched chain of a C ₁ substituted with one or more halogen ~ C ₄ alkyl, straight or branched chain of a C ₁ ~ C ₄ substituted with an unsubstituted or at least one halogen Alkoxy, nitro, amino, cyano, formamide, unsubstituted or one or more cyano, halogen, C ₅ to C ₁₂ aryl substituted with C ₁ to C ₄ straight or branched alkyl, and C ₃ to C ₈ cycloalkyl Substituted with a substituent selected from the group consisting of;

The cycloalkyl, heterocycloalkyl or heteroaryl is unsubstituted or substituted with C ₁ to C ₄ straight or branched alkyl or C ₅ to C ₁₂ aryl;

R ² And R ³ are each independently one hydrogen, C ₁ -C ₄ straight or branched alkyl, the other is C ₁ -C ₄ straight or branched alkyl, C ₃ -C ₈ cycloalkyl, C ₅ -C _12-aryl, N or O, the 5 to 8-membered heteroaryl, C ₅ ~ C ₁₂ aryl C ₁ ~ C ₄ straight chain containing at least 1 or branched alkyl, C ₅ ~ C ₈ cycloalkyl C ₁ ~ C ₃ Linear or branched alkyl, norbornyl or adamantyl of or together with the nitrogen to which they are attached may form a 5-8 membered heterocycloalkyl,

In this case, the aryl is unsubstituted or substituted with halogen, C ₁ ~ C ₃ straight or branched alkoxy,

The heterocycloalkyl is unsubstituted or substituted with C ₁ -C ₃ straight or branched alkyl,

The adamantyl is unsubstituted or hydroxy, methylsulfonyl, C ₁ to C ₄ straight or branched chain alkylsulfanyl, formamide, methylformamide, dimethylformamide, pyrrolidinecarbonyl, ethanethioate and carboxyl. Substituted with a substituent selected from the group consisting of carboxyl;

R ⁴ and R ⁵ are each independently hydrogen, C ₁ -C ₄ straight or branched chain alkyl, 5-8 membered heteroaryl C ₁ -C ₃ including S, straight or branched chain alkyl or a carbon atom to which they are attached Or a C ₃ to C ₆ cycloalkyl, dihydroindenyl or indolyl together with the adjacent nitrogen atom.

Preferably,

X is carbonyl or sulfonyl;

R ¹ is methyl, ethyl, propyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthalenyl, a 5-6 membered heterocycloalkyl containing at least one hetero atom of N or O in the ring, ring 5-6 membered heteroaryl containing at least one hetero atom of N or O, phenylmethyl, phenylethyl, phenylcyclopropyl, phenylcyclobutyl or C ₃ -C ₅ cycloalkyl C ₁ -C ₂ alkyl ,

Wherein the phenyl is unsubstituted or one or more of F, Cl, methyl, ethyl, propyl, n-butyl, t-butyl, trifluoromethyl, trichloromethyl, methoxy, alkoxy, trifluoromethoxy, trichloromethoxy, Substituted with a substituent selected from the group consisting of nitro, amino, cyano, formamide, cyanophenyl, fluorophenyl, difluorophenyl, methylphenyl and cyclohexyl,

The heterocycloalkyl or heteroaryl is unsubstituted or substituted with methyl, ethyl, propyl or phenyl;

R ² And each R ³ is independently one hydrogen, methyl, ethyl, propyl, the other methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, N or O 5- to 6-membered heteroaryl containing 1 or more, phenylmethyl, phenylethyl, phenylpropyl, cycloheptyl methyl, cycloheptyl ethyl, norbornyl or adamantyl, or methylpiperazinyl together with the nitrogen atom to which they are attached Form azocanyl,

In this case, the adamantyl is composed of unsubstituted or hydroxy, methylsulfonyl, methylsulfanyl, ethylsulfanyl, formamide, methylformamide, dimethylformamide, pyrrolidinecarbonyl, ethylthioate and carboxyl. Substituted with a substituent selected from the group;

R ⁴ and R ⁵ are each independently hydrogen, methyl, ethyl, propyl or together with the carbon atoms to which they are attached form cyclopropyl, cyclobutyl, dihydroindenyl, thiophenylethyl, or carbon atoms to which they are attached and adjacent nitrogen Together with the atom to form indolyl.

More preferably,

X is carbonyl or sulfonyl;

R ¹ is isobutyl, cyclopropyl, phenyl, morpholinyl, pyridinyl, isooxazolyl substituted with isopropyl, phenylmethyl, phenylcyclopropyl, cyclopropyl methyl, naphthalenyl;

Wherein the phenyl is unsubstituted or one or more of F, Cl, methyl, t-butyl, methoxy, nitro, amino, cyano, trifluoromethyl, trifluoromethoxy, formamide, cyanophenyl, fluorophenyl, di Substituted with a substituent selected from the group consisting of fluorophenyl, methylphenyl and cyclohexyl;

R ² And R ³ are each independently one hydrogen, methyl or isopropyl, the other methyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, fluorophenyl, pyridinyl, phenyl ethyl substituted with methoxy, methoxy Substituted phenyl methyl, cycloheptyl methyl, norbornyl or adamantyl, or together with the nitrogen atom to which they are attached form methyl piperazinyl or azocanyl,

Wherein the adamantyl is unsubstituted or selected from the group consisting of hydroxy, methylsulfonyl, methylsulfanyl, formamide, methylformamide, dimethylformamide, pyrrolidinecarbonyl, ethylthioate and carboxyl Substituted with a substituent;

R ⁴ and R ⁵ are each independently hydrogen or methyl, or they form cyclopropyl, dihydroindenyl, thiophenylethyl together with the carbon atoms to which they are attached, or indolyl together with the adjacent carbon atoms and carbon atoms to which they are attached; do.

Specific compounds represented by the formula (1) are as follows.

1) 3- (3-chloro-2-methylphenylsulfonamido) -N-cyclohexyl-N-isopropyl-3- methylbutanamide;

2) 3- (3-chloro-2-methylphenylsulfonamido) -N-cycloheptyl-3-methylbutanamide;

3) 3- (3-chloro-2-methylphenylsulfonamido) -N-cyclohexyl-3-methylbutanamide;

4) 3-chloro-2-methyl-N- (2-methyl-4- (4-methyl-1,4-diazepan-1-yl) -4-oxobutan-2-yl) benzenesulfonamide;

5) N- (4- (azonocan-1-yl) -2-methyl-4-oxobutan-2-yl) -3-chloro-2-methylbenzene sulfonamide;

6) 3- (3-chloro-2-methylphenylsulfonamido) -3-methyl-N- (pyridin-2-yl) butanamide;

7) 3- (3-chloro-2-methylphenylsulfonamido) -N- (4-fluorophenyl) -3-methylbutanamide;

8) N- (bicyclo [2.2.1] heptan-2-yl) -3- (3-chloro-2-methylphenylsulfonamido) -3-methylbutanamide;

9) 3- (3-chloro-2-methylphenylsulfonamido) -N- (4-methoxybenzyl) -3-methylbutanamide;

10) 3- (3-chloro-2-methylphenylsulfonamido) -N-cyclooctyl-3-methylbutanamide;

11) 3- (3-chloro-2-methylphenylsulfonamido) -N-isopropyl-3-methylbutanamide;

12) (S) -3- (3-chloro-2-methylphenylsulfonamido) -N- (1- (4-methoxyphenyl) ethyl) -3-methylbutanamide;

13) (R) -3- (3-chloro-2-methylphenylsulfonamido) -N- (1- (4-methoxyphenyl) ethyl) -3-methylbutanamide;

14) 3- (3-chloro-2-methylphenylsulfonamido) -N- (cycloheptylmethyl) -3-methylbutanamide;

15) N-adamantan-1-yl-3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-butyrylamide;

16) 3- (3-chloro-2-methyl-benzenesulfonylamino) -N- (3-hydroxy-adamantan-1-yl) -3-methyl-butyramide;

17) N-adamantan-1-yl-3- (4-t-butyl-benzenesulfonylamino) -3-methyl-butyramide;

18) N-adamantan-1-yl-3-methyl-3- (naphthalene-2-sulfonylamino) -butyramide;

19) N-adamantan-1-yl-3- (4-methoxy-benzenesulfonylamino) -3-methyl-butyramide;

20) N-adamantan-1-yl-3-methyl-3- (toluene-4-sulfonylamino) -butyramide;

21) N-adamantan-1-yl-3-methyl-3- (4-nitro-benzenesulfonylamino) -butyramide;

22) N-adamantan-1-yl-3-methyl-3-phenylmethanesulfonylamino-butyramide;

23) N-adamantan-1-yl-3- (3-chloro-benzenesulfonylamino) -3-methyl-butyramide;

24) N-adamantan-1-yl-3- (3-fluoro-benzenesulfonylamino) -3-methyl-butyramide;

25) N-adamantan-1-yl-3-methyl-3- (4-trifluoromethoxy-benzenesulfonylamino) -butyramide;

26) N-adamantan-1-yl-3-methyl-3- (3-trifluoromethyl-benzenesulfonylamino) -butyramide;

27) N-adamantan-1-yl-3-methyl-3- (3-nitro-benzenesulfonylamino) -butyramide;

28) N-adamantan-1-yl-3- (2-chloro-4-cyano-benzenesulfonylamino) -3-methyl-butyrylamide;

29) N-adamantan-1-yl-3-benzenesulfonylamino-3-methyl-butyrylamide;

30) cyclopropanecarboxylic acid [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethyl] -amide;

31) N-adamantan-1-yl-3-methyl-3- (3-methyl-aminobutyric acid) -butyramide;

32) N-adamantan-1-yl-3- (4-amino-benzenesulfonylamino) -3-methyl-butyrylamide;

33) N-adamantan-1-yl-3- (3-amino-benzenesulfonylamino) -3-methyl-butyrylamide

34) 4- [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethylsulfamoyl] -3-chloro-benzamide;

35) N- [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethyl] -5-fluoro-2-methyl-benzamide;

36) N- [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethyl] -4-methyl-benzamide;

37) 5-isopropyl-isoxazole-3-carboxylic acid [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethyl] -amide;

38) N- [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethyl] -3-chloro-2-methyl-benzamide;

39) N-adamantan-1-yl-3- (2-cyclopropyl-acetylamino) -3-methyl-butyramide;

40) N-adamantan-1-yl-3- [2- (2-methoxy-phenyl) -acetylamino] -3-methyl-butyramide;

41) N-adamantan-2-yl-3- (2,6-dichloro-benzenesulfonylamino) -3-methyl-butyrylamide;

42) N-adamantan-2-yl-3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-butyramide;

43) N-adamantan-2-yl-3- (4-fluoro-2-trifluoromethyl-benzenesulfonylamino) -3-methyl-butyramide;

44) N-adamantan-2-yl-3- (2-fluoro-benzenesulfonylamino) -3-methyl-butyramide;

45) N-adamantan-2-yl-3- (4′-cyano-biphenyl-4-sulfonylamino) -3-methyl-butyramide;

46) N-adamantan-2-yl-3-methyl-3- (toluene-2-sulfonylamino) -butyramide;

47) N-adamantan-2-yl-3- (4-fluoro-2-methyl-benzenesulfonylamino) -3-methyl-butyramide;

48) N-adamantan-2-yl-3- (2,4-difluoro-benzenesulfonylamino) -3-methyl-butyrylamide;

49) N-adamantan-2-yl-3- (2-chloro-4-fluoro-benzenesulfonylamino) -3-methyl-butyramide;

50) N-adamantan-2-yl-3- (4-chloro-2-fluoro-benzenesulfonylamino) -3-methyl-butyrylamide;

51) N-adamantan-2-yl-3-methyl-3- (2,4,6-trifluoro-benzenesulfonylamino) -butyramide;

52) N-adamantan-2-yl-3-benzenesulfonylamino-3-methyl-butyrylamide;

53) N-adamantan-2-yl-3- (2,6-difluoro-benzenesulfonylamino) -3-methyl-butyrylamide;

54) N-adamantan-2-yl-3- (2-chloro-6-methyl-benzenesulfonylamino) -3-methyl-butyramide;

55) N-adamantan-2-yl-3-methyl-3- (2-trifluoromethyl-benzenesulfonylamino) -butyramide;

56) N-adamantan-2-yl-3- (3-chloro-2-methyl-benzenesulfonylamino) -butyramide;

57) N-adamantan-2-yl-3- (3-chloro-2-methyl-benzenesulfonylamino) -butyramide;

58) N-adamantan-2-yl-3- (naphthalene-2-sulfonylamino) -butyramide;

59) N-adamantan-2-yl-3- (naphthalene-2-sulfonylamino) -butyramide;

60) N-adamantan-2-yl-2- [1- (3-chloro-2-methyl-benzenesulfonylamino) -cyclopropyl] -acetamide;

61) N- [2- (adamantane-2-ylcarbamoyl) -1,1-dimethyl-ethyl] -3-chloro-2-methyl-benzamide;

62) N-adamantan-2-yl-3- [2- (2-methoxy-phenyl) -acetylamino] -3-methyl-butyramide;

63) 1-phenyl-cyclopropanecarboxylic acid [2- (adamantane-2-ylcarbamoyl) -1,1-dimethyl-ethyl] -amide;

64) N- [2- (adamantane-2-ylcarbamoyl) -1,1-dimethyl-ethyl] -3,4-dichloro-benzamide;

65) 3- (3-chloro-2-methyl-benzenesulfonylamino) -N- (5-hydrocy-adamantan-2-yl) -3-methyl-butyrylamide;

66) 3- (3-chloro-2-methyl-benzenesulfonylamino) -N- (5-hydrocy-adamantan-2-yl) -3-methyl-butyramide;

67) 3- (3-chloro-6-methyl-benzenesulfonylamino) -N- (5-hydrocy-adamantan-2-yl) -3-methyl-butyramide;

68) 3- (2-chloro-4-fluoro-benzenesulfonylamino) -N- (5-hydrocy-adamantan-2-yl) -3-methyl-butyramide;

69) 3- (3-chloro-benzenesulfonylamino) -N- (5-hydrocy-adamantan-2-yl) -3-methyl-butyramide;

70) 3- (3-chloro-2-fluoro-benzenesulfonylamino) -N- (5-hydrocy-adamantan-2-yl) -3-methyl-butyramide;

71) methanesulfonic acid 4- [3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantan-1-yl ester;

72) methanesulfonic acid 4- [3- (2-chloro-6-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantan-1-yl ester;

73) 3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-N- (5-methylsulfanyl-adamantan-2-yl) -butyramide;

74) 3- (2-chloro-6-methyl-benzenesulfonylamino) -3-methyl-N- (5-methylsulfanyl-adamantan-2-yl) -butyramide;

75) 4- [3- (3-Chloro-2-methyl-benzene-sulfonylamino) -3-methyl-butyrylamino] adamantan-1-yl-ethanechiate;

76) 3- (3-chloro-2-methyl-benzene-sulfonylamino) -3-methyl-N- (5-methylsulfonyl-adamantan-2-yl) butanamide;

77) 3- (3-chloro-2-fluoro-benzene-sulfonylamino) -3-methyl-N- (5-methylsulfonyl-adamantan-2-yl) butanamide;

78) 3- (3-chloro-2-methyl-benzene-sulfonylamino) -3-methyl-N- (5-methylsulfonyl-adamantan-2-yl) butanamide;

79) 4- [3- (3-chloro-2-methyl-benzenesulfonylamino) -3-butyrylamino] -adamantane-1-carboxylic acid;

80) 4- [3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

81) 4- [3- (2-chloro-6-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

82) 4- [3- (2-chloro-4-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

83) 4- [3- (4-chloro-2-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

84) 4- [3- (2-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

85) 4- [3- (2-trifluoromethyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

86) 4- [3- (2-chloro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

87) 4- [3- (2-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

88) 4- [3- (3-chloro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

89) 4- [3- (3-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

90) 4- [3- (3-trifluoromethyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

91) 4- [3- (3-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

92) 4- [3- (4-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

93) 4- [3- (4-trifluoromethyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

94) 4- [3- (pyridine-3-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

95) 4- [3- (6-trifluoromethyl-pyridine-3-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

96) 4- [3- (2-chloro-4-cyano-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

97) 4- [3- (4-carbamoyl-2-chloro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

98) 4- [3- (2,3-dichloro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

99) 4- [3- (3,5-Dichloro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

100) 4- [3- (3-chloro-4-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

101) 4- [3- (3-chloro-4-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

102) 4- [3- (3-chloro-2-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

103) 4- [3- (5-chloro-2-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

104) 4- [3- (2-fluoro-3-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

105) 4- [3- (2-Fluoro-4-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

106) 4- [3- (2-Fluoro-5-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

107) 4- [3- (2-Fluoro-5-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

108) 4- [3- (3-fluoro-4-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

109) 4- [3- (3,4-difluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

110) 4- [3- (2,3-difluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

111) 4- [3- (2,4-Difluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

112) 4- [3- (2,5-difluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

113) 4- [3- (2,6-difluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

114) 4- [3- (3,5-difluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

115) 4- [3- (4-Fluoro-2- (trifluoromethyl) -benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

116) 4- [3- (2-Fluoro-5- (trifluoromethyl) -benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

117) 4- [3- (2-Chloro-4- (trifluoromethyl) -benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

118) 4- [3- (2,4,6-trifluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

119) 4- [3- (2,3,4,5,6-pentafluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

120) 4- [3-naphthalene-sulfonylamino-3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

121) 4- [3- (4'-cyano- [1,1'-biphenyl] -4-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

122) 4- [3- (4'-Fluoro- [1,1'-biphenyl] -4-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

123) 4- [3- (2 ', 4'-difluoro- [1,1'-biphenyl] -4-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amides;

124) 4- [3- (2 ', 3,4'-trifluoro- [1,1'-biphenyl] -4-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1 Carboxylic acid amides;

125) 4- [3- (4'-methyl- [1,1'-biphenyl] -4-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

126) 4- [3- (4-cyclohexylphenyl-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

127) 4- [3- (6-morpholinopyridine-3-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;

128) 4- [3- (3-chloro-2-methyl-benzene-sulfonylamino) -3-methyl-butyrylamino] -N-methyl-adamantane-1-carboxylic acid amide;

129) 4- [3- (3-chloro-2-methyl-benzene-sulfonylamino) -3-methyl-butyrylamino] -N, N-dimethyl-adamantane-1-carboxylic acid amide; And

130) 3- (2-chloro-2-methyl-benzene-sulfonylamino) -3-methyl-N- (5- (pyrrolidine-1-carbonyl) adamantan-2-yl) butanamide.

The compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The term pharmaceutically acceptable salt means a concentration that is relatively non-toxic to a patient and has a beneficial effect that is harmless to the patient, such that the side effects caused by the salt are any organic or inorganic salt of the base compound of Formula 1 that does not impair the beneficial effects of the base compound of Formula An inorganic addition salt. Examples of the inorganic acid include hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid and phosphoric acid. Examples of the organic acid include citric acid, acetic acid, lactic acid, maleic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, maleic acid, succinic acid, tartaric acid, galacturonic acid, embic acid, glutamic acid, aspartic acid, oxalic acid, P-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid or malonic acid. These salts also include alkali metal salts (sodium salts, potassium salts, etc.) and alkaline earth metal salts (calcium salts, magnesium salts, etc.). For example, the acid addition salt may be selected from the group consisting of acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camylate, citrate, eddylate, Hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, malate, glucoside, gluconate, gluconate, glucuronate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / , Maleate, maleate, methylsulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, , Stearate, succinate, tartrate, tosylate, trifluoroacetate Diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, zinc salts, and the like. Hydrochloride or trifluoroacetate is preferred.

In addition, the compound represented by Formula 1 of the present invention includes not only pharmaceutically acceptable salts, but also all salts, isomers, hydrates and solvates which can be prepared by conventional methods.

The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Chemical Formula 1 in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile, etc., Followed by precipitation or crystallization. Subsequently, in this mixture, a solvent or an excess acid is evaporated and dried to obtain an additional salt, or the precipitated salt may be produced by suction filtration.

Some compounds of formula I include chiral centers or geometric centers (E and Z isomers), and the present invention is understood to encompass all such optical isomers, diastereomers and geometric isomers with < RTI ID = 0.0 & have.

It is understood that the present invention relates to any and all arc variants of the compounds of formula (I) having a llbeta-HSDl inhibitory activity and that certain compounds of formula (I) may exist in solvated and unsolvated forms, . The present invention can be understood to encompass all such solvated forms with < RTI ID = 0.0 > llbeta-HSDl < / RTI > inhibitory activity.

The present invention also provides a process for preparing the compound of formula (1).

The compound of Chemical Formula 1 according to the present invention reacts the substituted sulfonyl or acetyl halide of Chemical Formula 3 with the amine derivative of Chemical Formula 2, as represented by Schemes 1 and 2 below, or the carboxylic acid of Chemical Formula 5 and Chemical Formula It can be prepared by reacting an amine derivative of 4.

[Reaction Scheme 1]

[Reaction Scheme 2]

(In Schemes 1 and 2, R ¹ To R ⁵ , and X are as defined in Formula 1).

In the preparation method according to the present invention, the sulfonyl or acetyl halide compound of Formula 3 may be used by purchasing a commercially available material, and the compounds of Formulas 2, 5 and 6 are commercially available depending on the substituent group Or a person having ordinary skill in the art can easily prepare and use.

Specifically, the compound of Chemical Formula 1 according to the present invention is added to the amine derivative compound of Chemical Formula 2 by adding sulfonyl or acetyl halide of Chemical Formula 3 and an appropriate amount of diisopropylethylamine in a general organic solvent such as dichloromethane. It can be manufactured easily by making it react. At this time, the reaction temperature and reaction time is preferably performed for 1 hour to 24 hours in the room temperature range according to the chemical reactivity of the sulfonyl or acetyl halide of the formula (3).

In addition, the compound of Formula 1 according to the present invention is a cycloalkyl, bicycloalkyl, aryl, heteroaryl or 1-adamantyl of Formula 4 in a carboxylic acid of Formula 5 in a general organic solvent such as dichloromethane, It can be easily prepared by adding 2-adamantyl or benzyl amine, an appropriate amount of diisopropylethylamine, and bis (2-oxo-3-oxazolidinyl) phosphonic chloride to react. At this time, the reaction temperature and the reaction time is from 1 hour to room temperature depending on the chemical reactivity of the cycloalkyl, bicycloalkyl, aryl, heteroaryl or 1-adamantyl, 2-adamantyl or benzyl amine of the formula (4) Preference is given to performing for 24 hours.

After the preparation, the compound of Chemical Formula 1 is prepared by infrared spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy, liquid chromatography, X-ray structure determination, photoluminescence measurement, and elemental analysis calculations and actual measurements of representative compounds. The molecular structure can be confirmed by comparison.

Furthermore, the present invention provides a pharmaceutical composition containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound of Formula 1 showed an excellent inhibitory effect of 11β-HSD1 activity by showing an activity inhibition rate of 1104-HSD1 as 0.0004 to 5.8 μM in the evaluation of 11β-HSD1 enzyme inhibitory activity (see Table 12).

Therefore, the compound of formula 1 according to the present invention is excellent in 11β-HSD1 inhibitory activity, and diseases caused by abnormally activated 11β-HSD1, for example, insulin independent type 2 diabetes, insulin resistance, obesity, lipid disorders , Metabolic syndrome and diseases mediated by excessive glucocorticoid action can be usefully used.

When the composition of the present invention is used as a medicine, the pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be used in various oral or non-oral dosage forms as described below. It may be formulated and administered, but is not limited thereto.

Examples of the formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules and elixirs. These formulations may contain, in addition to the active ingredient, a diluent (e.g., lactose, dextrose, (For example, silica, talc, stearic acid and magnesium or calcium salts thereof and / or polyethylene glycol), and the like. The tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain additives such as starch, agar, alginic acid or its sodium salt A disintegrating or boiling mixture and / or an absorbent, a colorant, a flavoring agent, and a sweetening agent.

The dose of the compound of the present invention to the human body may vary depending on the patient's age, body weight, sex, dosage form, health condition, and disease severity. When the patient is 70 kg in body weight, 0.1 to 1,000 mg / day, preferably 1 to 500 mg / day, and may be administered once to several times a day at predetermined intervals according to the judgment of a doctor or pharmacist.

Hereinafter, the present invention will be described in detail by production examples and examples.

However, the following Preparation Examples and Examples are merely to illustrate the present invention is not limited by the following Examples.

< Manufacturing example  1> methyl  3-amino-3- Methylbutanoate  Preparation of hydrochloride

50 mg (0.43 mmol) of 3-chloro-3-methylbutyric acid were dissolved in methanol and 0.06 mL (0.85 mmol) of thionyl chloride was added. The mixture was refluxed and stirred for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and distilled under reduced pressure to obtain 64 mg (90%) of methyl 3-amino-3-methylbutanoate hydrochloride.

¹ H NMR (400 MHz, MeOD) δ 3.76 (s, 3H), 2.74 (s, 2H), 1.44 (s, 6H)

< Manufacturing example  2> methyl  3- (3- Chloro -2- Methylphenylsulfonamido ) -3- Of methylbutanoate  Produce

59 mg (0.35 mmol) of methyl 3-amino-3-methylbutanoate hydrochloride and 81.7 mg (0.35 mmol) of 3-chloro-2-methylbenzenesulfonyl chloride prepared in Preparation Example 1 were dissolved in 1.2 ml of methylene chloride. I was. 0.10 mL (0.70 mmol) of TEA was added and stirred at room temperature for 2 hours, and then the methylene chloride was removed by evaporation under reduced pressure. After completion of the reaction, the solution was dissolved in 10 ml of water and extracted with 3 × 10 ml of ethyl acetate. Thereafter, the mixture was dried over anhydrous magnesium sulfate, distilled under reduced pressure, and separated by column chromatography to obtain 90 mg (80%) of methyl 3- (3-chloro-2-methylphenylsulfonamido) -3-methylbutanoate.

¹ H NMR (400 MHz, CDCl ₃ ) d 7.98 (dd, J = 8.0, 1.2 Hz, 1H), 7.56 (dd, J = 8.0, 1.2 Hz, 1H), 7.22-7.26 (m, 1H), 5.86 ( s, 1H), 3.70 (s, 3H), 2.72 (s, 3H), 2.55 (s, 2H), 1.27 (s, 6H)

< Manufacturing example  3> methyl  3- (3- Chloro -2- Methylphenylsulfonamido ) -3- Methylbutanoic  Produce

43.5 mg (0.14 mmol) of methyl 3- (3-chloro-2-methylphenylsulfonamido) -3-methylbutanoate prepared in Preparation Example 2 was dissolved in 1.4 mL of methanol, and 0.68 mL (0.68 mmol) of 1N NaOH solution. ) Was added. The mixture was stirred at 60 ° C. for 2 hours and then evaporated to remove methanol. The residue was dissolved in 5 mL of water, acidified to pH 4 with 1N HCl and extracted with 3 × 10 mL of ethyl acetate. Thereafter, the mixture was dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to obtain 39 mg (94%) of methyl 3- (3-chloro-2-methylphenylsulfonamido) -3-methylbutanoic acid.

¹ H NMR (400 MHz, MeOD) δ 7.97 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 2.69 (s, 3H), 2.55 (s, 2H), 1.26 (s, 6H)

< Manufacturing example  4> [2- ( Adamantan -One- Il carbamoyl ) -1,1- Dimethyl -ethyl]- Carbamic acid  Preparation of t-butyl ester

467 mg (2.15 mmol) of 3- (t-butoxycarbonylamino) -3-methylbutanoic acid were dissolved in 7.2 mL of methylene chloride, and 348.5 mg (2.58 mmol) of HOBt and 494.5 mg (2.58 mmol) of EDCI were added. After stirring for 10 minutes at room temperature, 503 mg (3.22 mmol) of 1-adamantaneamine were added thereto. The mixture was stirred at room temperature for 12 hours. After completion of the reaction methylene chloride was removed by evaporation under reduced pressure. The residue was dissolved in 30 mL of water and extracted with 3 × 30 mL of ethyl acetate. The extract was then dried over anhydrous magnesium sulfate, distilled under reduced pressure and separated by column chromatography to obtain [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethyl] -carbamic acid t-butyl ester 567 mg (75%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.46 (s, 1H), 5.05 (s, 1H), 2.42 (s, 2H), 2.06 (brs, 3H), 1.98 (d, J = 3.2 Hz, 6H) , 1.66 (t, J = 3.2 Hz, 6H), 1.45 (s, 9H), 1.37 (s, 6H).

< Manufacturing example  5> N- Adamantan -1-yl-3-amino-3- methyl - Butyramide  Preparation of hydrochloride

250 mg (0.71 mmol) of [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethyl] -carbamic acid t-butyl ester prepared in Preparation Example 4 was prepared using 4M HCl 1,4 Dissolve in 2 ml of dioxane solution and stir at room temperature for 2 hours. After completion of the reaction, distillation under reduced pressure yielded 200 mg (98%) of N-adamantan-1-yl-3-amino-3-methyl-butyamide hydrochloride.

¹ H NMR (400 MHz, MeOD) δ 2.38 (s, 2H), 2.04 (s, 9H), 1.72 (s, 6H), 1.35 (s, 6H)

< Manufacturing example  6> 3- (t- Butoxycarbonylamino ) -3- Methylbutanoic  Produce

300 mg (2.56 mmol) of 3-chloro-3-methylbutyric acid were dissolved in 5.6 mL of 0.5N NaOH solution and 2.8 mL of 1,4-dioxane, and 670.7 mg (3.07 mmol) of Boc ₂ O was added thereto. After stirring for 24 hours at room temperature, 1,4-dioxane was removed by evaporation under reduced pressure. The residue was acidified to pH 3 with 1N HCl and extracted with 3 × 20 mL of ethyl acetate. The extract was then dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain 329 mg (59%) of 3- (t-butoxycarbonylamino) -3-methylbutanoic acid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.72 (s, 2H), 1.45 (s, 9H), 1.40 (s, 6H)

< Manufacturing example  7> [2- ( Adamantan -2- Il carbamoyl ) -1,1- Dimethyl -ethyl]- Carbamic acid  Preparation of t-butyl ester

510 mg (2.35 mmol) of 3- (t-butoxycarbonylamino) -3-methylbutanoic acid prepared in Preparation Example 6 was dissolved in methylene chloride 7.8 and 739 mg (2.82 mmol) of BOP-Cl, 2-a Only 540 mg (2.82 mmol) of tanamine hydrochloride and 0.65 mL (4.69 mmol) of TEA were added. The mixture was stirred at room temperature for 12 hours. After completion of the reaction methylene chloride was removed by evaporation under reduced pressure. The residue was dissolved in 30 mL of water and extracted with 3 × 10 mL of ethyl acetate. The extract was then dried over anhydrous magnesium sulfate, distilled under reduced pressure and separated by column chromatography to obtain [2- (adamantane-2-ylcarbamoyl) -1,1-dimethyl-ethyl] -carbamic acid t-butyl ester 353 mg (43%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) d 6.14 (d, J = 8.0 Hz, 1H), 5.04 (s, 1H), 4.03 (d, J = 8.0 Hz, 1H), 2.58 (s, 2H), 1.73 -1.89 (m, 12H), 1.59-1.63 (m, 2H), 1.43 (s, 9H), 1.38 (s, 6H)

< Manufacturing example  8> N - Adamantan -2-yl-3-amino-3- methyl - Butyramide  Preparation of hydrochloride

353 mg (1.01 mmol) of [2- (adamantane-2-ylcarbamoyl) -1,1-dimethyl-ethyl] -carbamic acid t-butyl ester prepared in Preparation Example 7 was prepared using 4M HCl 1,4 Dissolve in 3.5 ml of dioxane solution and stir at room temperature for 2 hours. After completion of the reaction, distillation under reduced pressure afforded 280 mg (97%) of N-adamantan-2-yl-3-amino-3-methyl-butyamide hydrochloride.

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.02 (s, 1H), 2.56 (s, 2H), 1.79-2.00 (m, 12H), 1.63-1.66 (m, 2H), 1.37 (s, 6H)

< Manufacturing example  9> ethyl 1- ( Benzyloxycarbonylamino ) Of cyclopropanecarboxylate  Produce

888 mg (5.361 mmol) of 1-aminocyclopropane-1-carboxylic acid ethyl ester hydrochloride were cooled to 0 ° C., and 21 mL (21.4 mmol) of 1M Na ₂ CO ₃ aqueous solution was added thereto. 0.95 mL (6.433 mmol) of benzene chloroformate was added and stirred at room temperature overnight. Extraction with methylene chloride, washing with brine, drying with Na ₂ SO ₄ , and separation by column chromatography yielded 1.3 g (92%) of ethyl 1- (benzyloxycarbonylamino) cyclopropanecarboxylate.

< Manufacturing example  10> benzyl 1- ( Hydroxymethyl ) Of cyclopropyl carbamate  Produce

To 11 g (4.93 mmol) of ethyl 1- (benzyloxycarbonylamino) cyclopropanecarboxylate prepared in Preparation Example 9 was slowly added 11 ml (11 mmol) of 1M LiBH ₄ dissolved in tetrahydrofuran at room temperature. Stir for 21 hours. After cooling to 0 ° C., it was left to 50% AcOH and diluted with water and ether. The organic layer was washed with NaHCO ₃ aqueous solution and brine, dried over Na ₂ SO _4, and the solvent was distilled under reduced pressure to obtain 0.92 g (84%) of benzyl 1- (hydroxymethyl) cyclopropylcarbamate.

< Manufacturing example  11> benzyl 1- ( Bromomethyl ) Of cyclopropyl carbamate  Produce

920 mg (4.158 mmol) of benzyl 1- (hydroxymethyl) cyclopropylcarbamate and 1.69 g (5.114 mmol) prepared in Preparation Example 10 were dissolved in 25 ml of methylene chloride, and cooled to 0 ° C. 1.66 g (6.32 mmol) of triphenylphosphine were added in portions. After stirring overnight at room temperature, extracted with methylene chloride, washed with water and brine, dried over Na ₂ SO ₄ and separated by column chromatography to obtain 708 mg (60%) of benzyl 1- (bromomethyl) cyclopropyl carbamate. .

< Manufacturing example  12> benzyl 1- ( Cyanomethyl ) Of cyclopropyl carbamate  Produce

600 mg (2.12 mmol) of benzyl 1- (bromomethyl) cyclopropylcarbamate prepared in Preparation Example 11 was dissolved in 5 ml of DMSO, and 2.95 g (60.21 mmol) of NaCN and 3.23 g (19.54 mmol) of KI were added thereto. After stirring at room temperature for 3 days. Extraction with methylene chloride, washing with water, drying with Na ₂ SO ₄ , and separation by column chromatography yielded 237 mg (48%) of benzyl 1- (cyanomethyl) cyclopropylcarbamate.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (m, 5H), 5.12 (s, 2H), 2.77 (s, 2H), 0.96 (m, 4H)

< Manufacturing example  13> 2- (1- ( Benzyloxycarbonylamino ) Cyclopropyl ) Preparation of acetic acid

45 mg (0.195 mmol) of benzyl 1- (cyanomethyl) cyclopropylcarbamate prepared in Preparation Example 12 was dissolved in 1.4 ml of ethanol and cooled to 0 ° C. After adding 0.34 mL (0.34 mmol) of 1N NaOH aqueous solution and 1.1 mL of 30% H ₂ O ₂ , the mixture was further stirred at 0 ° C. for 1 hour, followed by stirring at room temperature overnight. Acidified with 1N HCl, extracted with methylene chloride, washed with NaHCO ₃ aqueous solution and brine, dried over Na ₂ SO ₄ to obtain 48 mg (98%) of 2- (1- (benzyloxycarbonylamino) cyclopropyl) acetic acid. .

< Manufacturing example  14> [1- ( Adamantan -2- Ilcarbamoylmethyl ) - Cyclopropyl ] - Carbamic acid  Preparation of Benzyl Esters

48 mg (0.192 mmol) of 2- (1- (benzyloxycarbonylamino) cyclopropyl) acetic acid and 40 mg (0.212 mmol) of 2-aminoadamantane hydrochloride prepared in Preparation Example 13 were mixed with 1 ml of methylene chloride and THF. Dissolved in 1ml, 59 mg (0.231 mmol) of BOP-Cl and 0.134 mL (0.77 mmol) of DIPEA were added thereto, and the resultant was stirred at 50 ° C for 4 hours. Then, washed with NaHCO ₃ aqueous solution and brine, dried over Na ₂ SO ₄ and separated by column chromatography [1- (adamantane-2-ylcarbamoylmethyl) -cyclopropyl] -carbamic acid benzyl ester 15 mg (20.5%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32 (m, 5H), 5.50 (br, 1H), 5.32 (s, 2H), 4.07 (m, 1H), 2.54 (s, 2H), 1.62-1.91 ( m, 14H), 0.96 (m, 2H), 0.84 (m, 2H)

< Manufacturing example  15> N- Adamantan -2-yl-2- (1-amino- Cyclopropyl ) - Acetamide  Produce

15 mg (0.039 mmol) of [1- (adamantane-2-ylcarbamoylmethyl) -cyclopropyl] -carbamic acid benzyl ester prepared in Preparation Example 14 was dissolved in 0.5 ml of methanol, and 2 mg of Pd / C was dissolved. After the addition, the mixture was stirred for 2 hours under hydrogen stream. Pd / C was removed by filtration, and the solvent was distilled under reduced pressure to obtain 6.5 mg (67%) of N-adamantan-2-yl-2- (1-amino-cyclopropyl) -acetamide.

< Manufacturing example  16> 4-oxo- Adamantan -One- Carboxylic acid methyl  Manufacture of Esters

The 30% fuming sulfuric acid solution was warmed to 60 ° C. and 1 g (6.02 mmol) of 5-hydroxy-2-adamantanone dissolved in 6 ml of 99% formic acid was slowly added over 1 hour. 6 ml of 99% formic acid was slowly added over 1 hour and then stirred at 60 ° C. for 1 hour. The reaction solution was slowly added to 50 ml of methanol cooled to 0 ° C., and the reaction solution was distilled under reduced pressure after stirring at room temperature for 2 hours. 15 g of ice and 50 ml of methylene chloride were added thereto, and the mixture was further extracted twice with methylene chloride. The mixture was washed with brine, dried over Na ₂ SO _4, and the solvent was distilled under reduced pressure to obtain 1.09 g (87%) of 4-oxo-adamantane-1-carboxylic acid methyl ester.

^{1 H NMR (400 MHz, CDCl} 3) δ 3.69 (s, 3H), 2.19 (m, 2H), 1.98-2.24 (m, 11H)

< Manufacturing example  17> 4-amino- Adamantan -One- Carboxylic acid methyl  Manufacture of Esters

1.09 g (5.234 mmol) of 4-oxo-adamantane-1-carboxylic acid methyl ester and 0.5 g of 4 ′ molecular sieves prepared in Preparation Example 16 were dissolved in 9.3 ml of 7N methanolic ammonia. After stirring overnight at room temperature, the mixture was cooled to 0 ° C, NaBH ₄ was added slowly, and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered off and the solvent was removed by distillation under reduced pressure. It was dissolved in 100 ml of methylene chloride, acidified with 10% citric acid, neutralized with aqueous NaHCO ₃ solution, and washed with brine. Extraction with methylene chloride twice more, followed by drying with Na ₂ SO ₄ and distillation of the solvent under reduced pressure yielded 800 mg (73%) of 4-amino-adamantane-1-carboxylic acid methyl ester.

¹ H NMR (400 MHz, CDCl ₃ )? 3.67 (s, 3H), 3.03 (m,

< Manufacturing example  18> 4- [3- (3- Chloro -2- methyl - Benzenesulfonylamino ) -3- methyl - Butyrylamino ] - Adamantan -One- Carboxylic acid methyl  Manufacture of Esters

100 mg (0.328 mmol) of methyl 3- (3-chloro-2-methylphenylsulfonamido) -3-methylbutanoic acid prepared in Preparation Example 3 was dissolved in 5.2 ml of methylene chloride and 160 mg (0.63 mmol) of BOP-Cl ), 69 mg (0.328 mmol) of 4-amino-adamantane-1-carboxylic acid methyl ester and 0.15 mL (1.05 mmol) of TEA were added. The mixture was stirred at room temperature for 12 hours. After completion of the reaction methylene chloride was removed by evaporation under reduced pressure. The residue was dissolved in 15 mL of water and extracted with 3 × 15 mL of ethyl acetate. The extract was then dried over anhydrous magnesium sulfate, distilled under reduced pressure, separated by column chromatography, and then extracted with 4- [3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane. 50.7 mg (31%) of -1-carboxylic acid methyl ester were obtained.

< Example  1> 3- (3- Chloro -2- Methylphenylsulfonamido ) -N- Cyclohexyl -N- Isopropyl -3- Methylbutanamide  Produce

26 mg (0.09 mmol) of methyl 3- (3-chloro-2-methylphenylsulfonamido) -3-methylbutanoic acid prepared in Preparation Example 3 was dissolved in 1 ml of methylene chloride and 32.5 mg (0.13 mmol of BOP-Cl). ), 24 mg (0.17 mmol) of N-isopropylcyclohexylamine and 0.02 mL (0.17 mmol) of TEA were added. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, methylene chloride was concentrated under reduced pressure. The residue was dissolved in 5 mL of water and extracted with 3 × 10 mL of ethyl acetate. The extract was then dried over anhydrous magnesium sulfate, distilled under reduced pressure, separated by column chromatography, and 3- (3-chloro-2-methylphenylsulfonamido) -N-cyclohexyl-N-isopropyl-3-methylbutanamide 16 mg (Yield 44%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, J = 8.0 Hz, 1H), 7.55 (m, 1H), 7.52 (dd, J = 8.0, 0.8 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 2.75 (s, 3H), 2.36 (d, J = 8.0 Hz, 2H), 1.82 (t, J = 10.4 Hz, 2H), 1.44-1.71 (m, 6H), 1.37 (d, J = 6.8 Hz, 3H), 1.20-1.31 (m, 10H), 1.17 (d, J = 6.8 Hz, 3H)

< Example   2> 3- (3- Chloro -2- Methylphenylsulfonamido ) -N- Cycloheptyl -3- Methylbutanamide  Produce

20 mg (0.07 mmol) of methyl 3- (3-chloro-2-methylphenylsulfonamido) -3-methylbutanoic acid prepared in Preparation Example 3 was dissolved in 1 ml of methylene chloride, and HOBt 10.6 mg (0.08 mmol), 15 mg (0.08 mmol) of EDCI were added. After stirring for 10 minutes at room temperature, 14.8 mg (0.13 mmol) of icloheptylamine were added thereto. The mixture was stirred at room temperature for 2 hours. After completion of the reaction methylene chloride was removed by evaporation under reduced pressure. The residue was dissolved in 5 ml of water and extracted with 3 x 5 ml of ethyl acetate. The extract was then dried over anhydrous magnesium sulfate, distilled under reduced pressure, separated by column chromatography, and 19 mg of 3- (3-chloro-2-methylphenylsulfonamido) -N-cycloheptyl-3-methylbutanamide (yield: 73% )

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (dd, J = 8.0, 0.8 Hz, 1H), 7.54 (dd, J = 8.0, 1.2 Hz, 1H), 7.20-7.24 (m, 1H), 6.66 ( s, 1H), 5.63 (d, J = 8.0 Hz, 1H), 3.92-3.98 (m, 1H), 2.73 (s, 3H), 2.27 (s, 2H), 1.88-1.98 (m, 2H), 1.57 -1.69 (m, 4H), 1.37-1.57 (m, 6H), 1.23 (s, 6H)

Through the same synthesis method as in Example 2, the compounds of Examples 3 to 16 were prepared, and the results and chemical structures thereof are shown in Table 1 below.

Example Name of compound rescue NMR data 3 3- (3-chloro-2-methylphenylsulfonamido) -N -cyclohexyl-3-methylbutanamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.98 (dd, J = 8.0, 1.2 Hz, 1H), 7.56 (dd, J = 8.0, 1.2 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H) , 6.74 (s, 1H), 5.65 (d, J = 7.6 Hz, 1H), 3.77-3.81 (m, 1H), 2.75 (s, 3H), 2.30 (s, 2H), 1.91-1.95 (m, 2H ), 1.70-1.76 (m, 2H), 1.61-1.68 (m, 1H), 1.33-1.44 (m, 2H), 1.24 (s, 6H), 1.10-1.22 (m, 3H) 4 3-chloro-2-methyl- N- (2-methyl-4- (4-methyl-1,4-diazepan-1-yl) -4-oxobutan-2-yl) benzenesulfonamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.98 (dd, J = 8.0, 0.8 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.25 (s, 1H), 7.23 (t, J = 8.0 Hz, 1H), 3.66-3.68 (m, 1H), 3.63 (t, J = 6.2 Hz, 1H), 3.42-3.47 (m, 2H), 2.74 (s, 3H), 2.58-2.62 (m, 2H ), 2.54-2.58 (m, 2H), 2.43 (s, 2H), 2.37 (s, 3H), 1.85-1.94 (m, 2H), 1.27 (s, 6H) 5 N- (4- (azonocan-1-yl) -2-methyl-4-oxobutan-2-yl) -3-chloro-2-methylbenzenesulfonamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.98 (dd, J = 8.0, 1.2 Hz, 1H), 7.53 (dd, J = 8.0, 1.2 Hz, 1H), 7.51 (s, 1H), 7.22 (t, J = 8.0 Hz, 1H), 3.48 (t, J = 6.0 Hz, 2H), 3.34 (t, J = 6.0 Hz, 2H), 2.75 (s, 3H), 2.43 (s, 2H), 1.63-1.78 ( m, 4H), 1.49-1.62 (m, 6H), 1.28 (s, 6H) 6 3- (3-chloro-2-methylphenylsulfonamido) -3-methyl- N- (pyridin-2-yl) butanamide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.28 (dd, J = 5.0, 1.0 Hz, 1H), 8.17 (d, J = 8.4 Hz, 2H), 8.00 (dd, J = 7.8, 1.0 Hz, 1H) , 7.70-7.75 (m, 1H), 7.54 (dd, J = 8.0, 1.2 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.05-7.09 (m, 1H), 6.36 (s, 1H ), 2.74 (s, 3H), 2.60 (s, 2H), 1.31 (s, 6H) 7 3- (3-chloro-2-sulfonamido-phenyl) - N - (4- fluorophenyl) -3-methylbutane amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.99 (dd, J = 8.0, 1.2 Hz, 1H), 7.78 (s, 1H), 7.57 (dd, J = 8.0, 0.8 Hz, 1H), 7.50 (m, 2H), 7.26 (t, J = 8.0 Hz, 1H), 7.00-7.05 (m, 2H), 5.78 (s, 1H), 2.71 (s, 3H), 2.61 (s, 2H), 1.27 (s, 6H ) 8 N- (bicyclo [2.2.1] heptan-2-yl) -3- (3-chloro-2-methylphenylsulfonamido) -3-methylbutanamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.96 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 6.60 (s , 1H), 5.63 (s, 1H), 3.70-3.75 (m, 1H), 2.73 (s, 3H), 2.28 (s, 3H), 2.20 (d, J = 3.6 Hz, 1H), 1.78-1.84 ( m, 1H), 1.42-1.58 (m, 2H), 1.09-1.33 (m, 12H) 9 3- (3-chloro-2-sulfonamido-phenyl) - N - (4- methoxybenzyl) -3-methylbutane amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.96 (dd, J = 8.0, 0.8 Hz, 1H), 7.55 (dd, J = 8.0, 1.2 Hz, 1H), 7.18-7.25 (m, 4H), 6.85- 6.89 (m, 2H), 6.66 (s, 1H), 5.93 (s, 1H), 4.38 (d, J = 5.6 Hz, 2H), 3.80 (s, 3H), 2.74 (s, 3H), 2.34 (s , 2H), 1.24 (s, 6H) 10 3- (3-chloro-2-methylphenylsulfonamido) -N -cyclooctyl-3-methylbutanamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.97 (dd, J = 8.0, 1.2 Hz, 1H), 7.54 (dd, J = 8.0, 0.8 Hz, 1H), 7.20-7.24 (m, 1H), 6.72 ( s, 1H), 5.67 (d, J = 7.6 Hz, 1H), 3.99-4.02 (m, 1H), 2.73 (s, 3H), 2.27 (s, 2H), 1.78-1.85 (m, 2H), 1.51 -1.65 (m, 12H), 1.26 (s, 6H) 11 3- (3-chloro-2-methylphenylsulfonamido) -N -isopropyl-3-methylbutanamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.97 (dd, J = 7.8, 1.0 Hz, 1H), 7.54 (dd, J = 8.0, 1.2 Hz, 1H), 7.21-7.25 (m, 1H), 6.74 ( s, 1H), 5.58 (d, J = 6.4 Hz, 1H), 4.04-4.13 (m, 1H), 2.73 (s, 3H), 2.27 (s, 2H), 1.65 (s, 1H), 1.23 (s , 6H), 1.17 (d, J = 6.4 Hz, 6H) 12 (S) -3- (3- chloro-2-sulfonamido-phenyl) - N - (1- (4- methoxyphenyl) ethyl) -3-methylbutane amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.96 (dd, J = 7.8, 1.0 Hz, 1H), 7.54 (dd, J = 8.2, 1.0 Hz, 1H), 7.20-7.26 (m, 3H), 6.85- 6.89 (m, 2H), 6.58 (s, 1H), 5.88 (d, J = 7.6 Hz, 1H), 5.05-5.12 (m, 1H), 3.80 (s, 3H), 2.72 (s, 3H), 2.30 (q, J = 30.0, 14.4 Hz, 2H), 1.49 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 5.2 Hz, 6H) 13 (R) -3- (3- chloro-2-sulfonamido-phenyl) - N - (1- (4- methoxyphenyl) ethyl) -3-methylbutane amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.95 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.19-7.26 (m, 3H), 6.86 (d, J = 8.8 Hz, 2H), 6.67 (s, 1H), 5.98 (d, J = 7.6 Hz, 1H), 5.04-5.11 (m, 1H), 3.80 (s, 3H), 2.71 (s, 3H), 2.29 ( q, J = 29.6, 14.4 Hz, 2H), 1.48 (d, J = 7.2 Hz, 3H), 1.20 (d, J = 8.0 Hz, 6H) 14 3- (3-chloro-2-sulfonamido-phenyl) - N - (cycloheptyl) -3-methylbutane amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.97 (dd, J = 8.0, 1.2 Hz, 1H), 7.54 (dd, J = 8.0, 1.2 Hz, 1H), 7.20-7.24 (m, 1H), 6.78 ( s, 1H), 5.79 (brs, 1H), 3.11 (t, J = 6.4 Hz, 2H), 2.73 (s, 3H), 2.31 (s, 2H), 1.62-1.72 (m, 5H), 1.39-1.52 (m, 4H), 1.23 (s, 6H), 1.16-1.22 (m, 2H) 15 N -adamantan-1-yl-3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-butyrylamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.96 (dd, J = 8.0, 1.2 Hz, 1H), 7.53 (dd, J = 8.0, 0.8 Hz, 1H), 7.19-7.24 (m, 1H), 6.80 ( s, 1H), 5.38 (s, 1H), 2.73 (s, 3H), 2.20 (s, 2H), 2.08 (s, 3H), 2.00 (d, J = 2.8 Hz, 6H), 1.68 (t, J = 2.8 Hz, 6H), 1.23 (s, 6H) 16 3- (3-chloro-benzenesulfonylamino) - N - (3-hydroxy-adamantan-1-yl) -3-methyl-butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.96 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.48 (s , 1H), 5.51 (s, 1H), 2.73 (s, 3H), 2.29 (brs, 2H), 2.25 (s, 2H), 2.01 (s, 2H), 1.93 (s, 4H), 1.51-1.70 ( m, 6H), 1.22 (s, 6H)

< Example  17> N- Adamantan -1-yl-3- (4-t-butyl- Benzenesulfonylamino ) -3- methyl - Butyramide  Produce

24.6 mg (0.086 mmol) of N-adamantan-1-yl-3-amino-3-methyl-butyamide hydrochloride prepared in Preparation Example 5 and 18.3 mg (0.077 mmol of 4-t-butylbenzenesulfonyl chloride) ) Was dissolved in 1 ml of methylene chloride. 0.024 mL (0.171 mmol) of TEA was added and stirred at room temperature for 2 hours and then the methylene chloride was removed by evaporation under reduced pressure. After completion of the reaction, the solution was dissolved in 5 ml of water and extracted with 3 × 5 ml of ethyl acetate. Then, dried over anhydrous magnesium sulfate, distillation under reduced pressure, separation by column chromatography, and 20 mg of N-adamantan-1-yl-3- (4-t-butyl-benzenesulfonylamino) -3-methyl-butyamide (Yield 52%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79-7.82 (m, 2H), 7.45-7.48 (m, 2H), 6.30 (s, 1H), 5.42 (s, 1H), 2.21 (s, 2H), 2.08 (brs, 3H), 2.00 (d, J = 3.2 Hz, 6H), 1.67-1.69 (m, 6H), 1.33 (s, 9H), 1.25 (s, 6H)

By the same synthesis method as in Example 17, to prepare a compound of Examples 18 to 31 shown in Table 2.

Example Name of compound rescue NMR data 18 N -adamantan-1-yl-3-methyl-3- (naphthalene-2-sulfonylamino) -butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.45 (d, J = 0.8 Hz, 1H), 7.87-7.96 (m, 4H), 7.56-7.64 (m, 2H), 6.68 (s, 1H), 5.37 ( s, 1H), 2.19 (s, 2H), 2.07 (brs, 3H), 1.98 (d, J = 2.8 Hz, 6H), 1.67 (t, J = 3.0 Hz, 6H), 1.25 (s, 6H) 19 N -adamantan-1-yl-3- (4-methoxy-benzenesulfonylamino) -3-methyl-butyrylamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.81-7.84 (m, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.26 (s, 1H), 5.41 (s, 1H), 3.86 (s, 3H), 2.21 (s, 2H), 2.08 (brs, 3H), 2.00 (d, J = 2.8 Hz, 6H), 1.68 (s, 6H), 1.24 (s, 6H) 20 N-adamantan-1-yl-3-methyl-3- (toluene-4-sulfonylamino) -butyrylamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.78 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.31 (s, 1H), 5.40 (s, 1H), 2.41 (s, 3H), 2.21 (s, 2H), 2.08 (brs, 3H), 2.00 (d, J = 2.8 Hz, 6H), 1.68 (s, 6H), 1.24 (s, 6H) 21 N-adamantan-1-yl-3-methyl-3- (4-nitro-benzenesulfonylamino) -butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.30-8.34 (m, 2H), 8.08-8.12 (m, 2H), 7.33 (s, 1H), 5.25 (s, 1H), 2.15 (s, 2H), 2.10 (brs, 3H), 1.98 (d, J = 2.8 Hz, 6H), 1.69 (d, J = 2.8 Hz, 6H), 1.27 (s, 6H) 22 N-adamantan-1-yl-3-methyl-3-phenylmethanesulfonylamino-butyrylamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.36-7.40 (m, 5H), 5.46 (s, 1H), 5.43 (s, 1H), 4.26 (s, 2H), 2.29 (s, 2H), 2.05 ( brs, 3H), 1.99 (d, J = 2.8 Hz, 6H), 1.66 (s, 6H), 1.40 (s, 6H) 23 N-adamantan-1-yl-3- (3-chloro-benzenesulfonylamino) -3-methyl-butyrylamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.90 (t, J = 1.6 Hz, 1H), 7.78-7.81 (m, 1H), 7.48-7.50 (m, 1H), 7.41 (t, J = 7.8 Hz, 1H), 6.89 (s, 1H), 5.29 (s, 1H), 2.17 (s, 2H), 2.09 (brs, 3H), 1.99 (d, J = 2.8 Hz, 6H), 1.69 (d, J = 2.8 Hz, 6H), 1.27 (s, 6H) 24 N-adamantan-1-yl-3- (3-fluoro-benzenesulfonylamino) -3-methyl-butyrylamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.69-7.72 (m, 1H), 7.60-7.63 (m, 1H), 7.43-7.48 (m, 1H), 7.20-7.25 (m, 1H), 6.87 (s , 1H), 5.32 (s, 1H), 2.18 (s, 2H), 2.09 (brs, 3H), 1.99 (d, J = 3.2 Hz, 6H), 1.68 (t, J = 2.8 Hz, 6H), 1.27 (s, 6H) 25 N-adamantan-1-yl-3-methyl-3- (4-trifluoromethoxy-benzenesulfonylamino) -butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.93-7.96 (m, 2H), 7.29 (dd, J = 8.8, 0.8 Hz, 2H), 6.86 (s, 1H), 5.29 (s, 1H), 2.17 ( s, 2H), 2.09 (brs, 3H), 1.98 (d, J = 2.8 Hz, 6H), 1.68 (t, J = 2.8 Hz, 6H), 1.26 (s, 6H) 26 N-adamantan-1-yl-3-methyl-3- (3-trifluoromethyl-benzenesulfonylamino) -butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.18 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 7.8 Hz , 1H), 7.06 (s, 1H), 5.28 (s, 1H), 2.17 (s, 2H), 2.09 (brs, 3H), 1.98 (d, J = 3.2 Hz, 6H), 1.68 (t, J = 3.0 Hz, 6H), 1.26 (s, 6H) 27 N -adamantan-1-yl-3-methyl-3- (3-nitro-benzenesulfonylamino) -butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.76 (t, J = 2.0 Hz, 1H), 8.36-8.39 (m, 1H), 8.23-8.26 (m, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.29 (s, 1H), 5.26 (s, 1H), 2.18 (s, 2H), 2.09 (brs, 3H), 1.98 (d, J = 2.8 Hz, 6H), 1.69 (t, J = 2.8 Hz, 6H), 1.29 (s, 6H) 28 N -adamantan-1-yl-3- (2-chloro-4-cyano-benzenesulfonylamino) -3-methyl-butyrylamide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.21 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.67 (dd, J = 8.4, 1.6 Hz, 1H), 7.32 (s, 1H), 5.33 (s, 1H), 2.21 (s, 2H), 2.09 (brs, 3H), 2.01 (s, 6H), 1.69 (s, 6H), 1.25 (s, 6H) 29 N -adamantan-1-yl-3-benzenesulfonylamino-3-methyl-butyrylamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.89-7.90 (m, 2H), 7.45-7.55 (m, 3H), 6.55 (s, 1H), 5.39 (s, 1H), 2.19 (s, 2H), 2.08 (brs, 3H), 1.99 (d, J = 2.8 Hz, 6H), 1.68 (t, J = 2.8 Hz, 6H), 1.24 (s, 6H) 30 Cyclopropanecarboxylic acid [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethyl] -amide

¹ H NMR (400 MHz, CDCl ₃ ) d 6.34 (s, 1H), 5.44 (s, 1H), 2.43 (s, 2H), 2.06 (brs, 3H), 1.98 (d, J = 3.2 Hz, 6H) , 1.67 (t, J = 3.0 Hz, 6H), 1.43 (s, 6H), 1.29-1.36 (m, 1H), 0.89-0.94 (m, 2H), 0.69-0.73 (m, 2H) 31 N -adamantan-1-yl-3-methyl-3- (3-methyl-aminobutyric acid) -butyramide
¹ H NMR (400 MHz, CDCl ₃ ) d 6.45 (s, 1H), 5.42 (s, 1H), 2.39 (s, 2H), 2.08-2.12 (m, 4H), 1.98-2.01 (m, 8H), 1.69 (d, J = 2.4 Hz, 6H), 1.45 (s, 6H), 0.97 (d, J = 6.4 Hz, 6H)

< Example  32> N- Adamantan -1-yl-3- (4-amino- Benzenesulfonylamino ) -3- methyl - Butyramide  Produce

18 mg (0.041 mmol) of N-adamantan-1-yl-3-methyl-3- (4-nitro-benzenesulfonylamino) -butyramide prepared in Example 21 was dissolved in 2 ml of methanol. Pd / C, 10% 5.4 mg was added. The mixture was stirred at room temperature for 2 hours under hydrogen stream. After completion of the reaction, the mixture was filtered using a celite pad and distilled under reduced pressure to obtain 14 mg of N-adamantane-1-yl-3- (4-amino-benzenesulfonylamino) -3-methyl-butyamide (yield: 83 %) Was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J = 8.0 Hz, 2H), 6.65 (d, J = 8.8 Hz, 2H), 6.04 (s, 1H), 5.54 (s, 1H), 4.10 (s, 2H), 2.22 (s, 2H), 2.07 (brs, 3H), 2.00 (d, J = 2.8 Hz, 6H), 1.68 (s, 6H), 1.23 (s, 6H)

< Example  33> N- Adamantan -1-yl-3- (3-amino- Benzenesulfonylamino ) -3- methyl - Butyramide  Produce

20 mg (0.046 mmol) of N-adamantan-1-yl-3- (3-amino-benzenesulfonylamino) -3-methyl-butyramide prepared in Example 27 was dissolved in 2 ml of methanol. Pd / C, 10% 6 mg was added. The mixture was stirred at room temperature for 2 hours under hydrogen stream. After completion of the reaction, the mixture was filtered using a celite pad and distilled under reduced pressure to obtain 17 mg of N-adamantan-1-yl-3- (3-amino-benzenesulfonylamino) -3-methyl-butyamide (yield: 91 %) Was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.25 (dd, J = 3.2, 1.2 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.18 (t, J = 1.8 Hz, 1H), 6.77 -6.81 (m, 1H), 6.35 (s, 1H), 5.38 (s, 1H), 3.86 (s, 2H), 2.20 (s, 2H), 2.08 (brs, 3H), 2.00 (d, J = 3.2 Hz, 6H), 1.68 (s, 6H), 1.26 (s, 6H)

< Example  34> 4- [2- ( Adamantan -One- Il carbamoyl ) -1,1- Dimethyl - Ethylsulfamoyl ] -3-chloro- Benzamide  Produce

23 mg (0.051 mmol) of N-adamantan-1-yl-3- (2-chloro-4-cyano-benzenesulfonylamino) -3-methyl-butyramide prepared in Example 28 was t Dissolve in 1 mL butanol and add 14.3 mg (0.256 mmol) of potassium hydroxide. The mixture was stirred at 65 ° C. for 1 hour. After completion of the reaction, the mixture was diluted with 5 ml of ethyl acetate and washed with water and brine. Extracted with 3 × 5 ml of ethyl acetate, dried over anhydrous magnesium sulfate, distillation under reduced pressure and separation by column chromatography was carried out to obtain 4- [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethylsulfa. Moyl] -3-chloro-benzamide 9 mg (yield: 38%) was obtained.

¹ H NMR (400 MHz, MeOD) δ 8.17 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 1.2 Hz, 1H), 7.92 (dd, J = 8.4, 1.6 Hz, 1H), 2.04 ( d, J = 9.6 Hz, 9H), 1.72 (s, 6H), 1.20 (s, 6H)

< Example  35> N- [2- ( Adamantan -One- Il carbamoyl ) -1,1- Dimethyl -Ethyl] -5- fluorine 2-methyl- Benzamide  Produce

20 mg (0.07 mmol) of N-adamantan-1-yl-3-amino-3-methyl-butyamide hydrochloride prepared in Preparation Example 5 was dissolved in 1 ml of methylene chloride and 27.4 mg (0.10) of BOP-Cl mmol), 10.9 mg (0.07 mmol) of 5-fluoro-2-methylbenzoic acid and 0.02 mL (0.14 mmol) of TEA were added. The mixture was stirred at room temperature for 2 hours. After completion of the reaction methylene chloride was removed by evaporation under reduced pressure. The residue was dissolved in 5 ml of water and extracted with 3 x 5 ml of ethyl acetate. The extract was then dried over anhydrous magnesium sulfate, distilled under reduced pressure, separated by column chromatography, and extracted with N- [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethyl] -5-fluor-2. 17 mg (yield 63%) of -methyl-benzamide were obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.14 (dd, J = 8.4, 1.2 Hz, 1H), 7.10 (dd, J = 9.0, 2.6 Hz, 1H), 6.99 (s, 1H), 6.94-6.98 ( m, 1H), 5.39 (s, 1H), 2.43 (s, 2H), 2.40 (s, 3H), 2.07 (brs, 3H), 1.98 (d, J = 2.8 Hz, 6H), 1.66 (t, J = 6.0 Hz, 6H), 1.56 (s, 6H)

Through the same synthesis method as in Example 35, the compound of Examples 36 to 40 was prepared and the results are shown in Table 3 below.

Example Name of compound rescue NMR data 36 N- [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethyl] -4-methyl-benzamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.69 (d, J = 8.0 Hz, 2H), 7.33 (s, 1H), 7.22 (d, J = 8.0 Hz, 2H), 5.46 (s, 1H), 2.47 (s, 2H), 2.39 (s, 3H), 2.05 (brs, 3H), 1.91 (d, J = 2.8 Hz, 6H), 1.62 (s, 6H), 1.56 (s, 6H) 37 5-Isopropyl-isoxazole-3-carboxylic acid [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethyl] -amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.44 (s, 1H), 6.36 (s, 1H), 5.39 (s, 1H), 3.07-3.13 (m, 1H), 2.53 (s, 2H), 2.00 ( brs, 3H), 1.89 (d, J = 2.8 Hz, 6H), 1.60 (s, 6H), 1.53 (s, 6H), 1.32 (d, J = 6.8 Hz, 6H) 38 N- [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethyl] -3-chloro-2-methyl-benzamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.37 (dd, J = 8.0, 1.2 Hz, 1H), 7.26 (dd, J = 7.6, 1.2 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H) , 6.97 (s, 1H), 5.39 (s, 1H), 2.44 (s, 5H), 2.07 (brs, 3H), 1.98 (d, J = 2.8 Hz, 6H), 1.66 (t, J = 3.0 Hz, 6H), 1.56 (s, 6H) 39 N -adamantan-1-yl-3- (2-cyclopropyl-acetylamino) -3-methyl-butyrylamide

¹ H NMR (400 MHz, CDCl ₃ ) d 6.60 (s, 1H), 5.45 (s, 1H), 2.43 (s, 2H), 2.08 (d, J = 7.2 Hz, 2H), 2.06 (brs, 3H) , 1.96 (d, J = 2.8 Hz, 6H), 1.66 (t, J = 3.0 Hz, 6H), 1.44 (s, 6H), 0.92-0.99 (m, 1H), 0.58-0.63 (m, 2H), 0.17-0.20 (m, 2H) 40 N -adamantan-1-yl-3- [2- (2-methoxy-phenyl) -acetylamino] -3-methyl-butyrylamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.21-7.28 (m, 2H), 6.92-6.96 (m, 1H), 6.89 (d, J = 8.4 Hz, 2H), 6.29 (s, 1H), 5.50 ( s, 1H), 3.86 (s, 3H), 3.48 (s, 2H), 2.47 (s, 2H), 2.05 (brs, 3H), 1.87 (d, J = 2.8 Hz, 6H), 1.65 (t, J = 2.8 Hz, 6H), 1.33 (s, 6H)

< Example  41> N- Adamantan -2-yl-3- (2,6- Dichloro - Benzenesulfonylamino ) -3- methyl Preparation of Butyramide

20 mg (0.07 mmol) of N-adamantan-2-yl-3-amino-3-methyl-butyamide hydrochloride prepared in Preparation Example 8 and 17.6 mg (0.07) of 2,6-dichlorobenzenesulfonyl chloride mmol) was dissolved in 1 ml of methylene chloride. 0.02 mL (0.14 mmol) of TEA was added and stirred at room temperature for 2 hours, and then the methylene chloride was removed by evaporation under reduced pressure. After completion of the reaction, the solution was dissolved in 5 ml of water and extracted with 3 × 5 ml of ethyl acetate. Then, dried over anhydrous magnesium sulfate, distillation under reduced pressure, separation by column chromatography, and N-adamantan-2-yl-3- (2,6-dichloro-benzenesulfonylamino) -3-methyl-butyamide 18 mg (yield: 56%) were obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48 (d, J = 8.0 Hz, 2H), 7.34 (q, J = 4.6, 3.4 Hz, 1H), 6.57 (s, 1H), 6.25 (d, J = 7.6 Hz, 1H), 4.10 (d, J = 8.0 Hz, 1H), 2.49 (s, 2H), 1.97 (s, 2H), 1.86 (d, J = 11.6 Hz, 8H), 1.76 (s, 2H) , 1.68 (d, J = 12.8 Hz, 2H), 1.33 (s, 6H)

By the same synthesis method as in Example 41, the compounds of Examples 42 to 60 were prepared and the results are shown in Table 4 below.

Example Name of compound rescue NMR data 42 N -adamantan-2-yl-3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-butyrylamide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.00 (dd, J = 8.0, 1.2 Hz, 1H), 7.57 (dd, J = 8.0, 1.2 Hz, 1H), 7.23-7.27 (m, 1H), 6.58 ( s, 1H), 6.05 (d, J = 7.6 Hz, 1H), 4.10 (d, J = 8.0 Hz, 1H), 2.75 (s, 3H), 2.38 (s, 2H), 1.95 (s, 2H), 1.88 (d, J = 2.4 Hz, 6H), 1.79 (d, J = 14.4 Hz, 4H), 1.68 (d, J = 12.8 Hz, 2H), 1.27 (s, 6H) 43 N -adamantan-2-yl-3- (4-fluoro-2-trifluoromethyl-benzenesulfonylamino) -3-methyl-butyrylamide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.33 (dd, J = 8.8, 5.2 Hz, 1H), 7.57 (dd, J = 5.0, 2.6 Hz, 1H), 7.34-7.39 (m, 1H), 6.55 ( s, 1H), 6.13 (d, J = 7.6 Hz, 1H), 4.11 (d, J = 8.0 Hz, 1H), 2.42 (s, 2H), 1.96 (s, 2H), 1.87 (d, J = 2.4 Hz, 6H), 1.79 (brt, J = 12.4 Hz, 4H), 1.67 (brd, J = 12.8 Hz, 2H), 1.31 (s, 6H) 44 N -adamantan-2-yl-3- (2-fluoro-benzenesulfonylamino) -3-methyl-butyrylamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.90-7.94 (m, 1H), 7.55-7.60 (m, 1H), 7.26-7.30 (m, 1H), 7.19-7.24 (m, 1H), 6.24 (d , J = 7.2 Hz, 1H), 6.15 (s, 1H), 4.10 (d, J = 8.0 Hz, 1H), 2.45 (s, 2H), 1.96 (s, 2H), 1.85 (brd, J = 16.0 Hz , 8H), 1.76 (s, 2H), 1.67 (brd, J = 12.8 Hz, 2H), 1.28 (s, 6H) 45 N -adamantan-2-yl-3- (4'-cyano-biphenyl-4-sulfonylamino) -3-methyl-butyrylamide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.01 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.68-7.72 (m, 4H), 6.57 (s, 1H) , 6.03 (d, J = 8.0 Hz, 1H), 4.07 (d, J = 8.0 Hz, 1H), 2.36 (s, 2H), 1.84-1.92 (m, 8H), 1.76 (d, J = 15.2 Hz, 4H), 1.64 (d, J = 12.8 Hz, 2H), 1.30 (s, 6H) 46 N -adamantan-2-yl-3-methyl-3- (toluene-2-sulfonylamino) -butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.00-8.02 (m, 1H), 7.40-7.44 (m, 1H), 7.27-7.31 (m, 2H), 6.14-6.17 (m, 2H), 4.08 (d , J = 8.0 Hz, 1H), 2.68 (s, 3H), 2.39 (s, 2H), 1.93 (s, 2H), 1.74-1.86 (m, 10H), 1.66 (d, J = 12.8 Hz, 2H) , 1.22 (s, 6H) 47 N -adamantan-2-yl-3- (4-fluoro-2-methyl-benzenesulfonylamino) -3-methyl-butyrylamide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.00-8.03 (m, 1H), 6.94-7.00 (m, 2H), 6.39 (s, 1H), 6.06 (d, J = 8.0 Hz, 1H), 4.07 ( d, J = 7.6 Hz, 1H), 2.68 (s, 3H), 2.37 (s, 2H), 1.93 (s, 2H), 1.74-1.85 (m, 10H), 1.66 (d, J = 12.4 Hz, 2H ), 1.22 (s, 6 H) 48 N -adamantan-2-yl-3- (2,4-difluoro-benzenesulfonylamino) -3-methyl-butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.88-7.95 (m, 1H), 6.91-7.00 (m, 2H), 6.36 (s, 1H), 6.09-6.11 (m, 1H), 4.08 (d, J = 8.0 Hz, 1H), 2.40 (s, 2H), 1.93 (s, 2H), 1.74-1.85 (m, 10H), 1.65 (d, J = 13.6 Hz, 2H), 1.27 (s, 6H) 49 N -adamantan-2-yl-3- (2-chloro-4-fluoro-benzenesulfonylamino) -3-methyl-butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.12 (dd, J = 9.0, 5.8 Hz, 1H), 7.24-7.27 (m, 1H), 7.07-7.12 (m, 1H), 6.44 (s, 1H), 6.17 (d, J = 7.2 Hz, 1H), 4.09 (d, J = 8.4 Hz, 1H), 2.41 (s, 2H), 1.94 (s, 2H), 1.80-1.86 (m, 8H), 1.75 (s , 2H), 1.66 (d, J = 12.4 Hz, 2H), 1.24 (s, 6H) 50 N -adamantan-2-yl-3- (4-chloro-2-fluoro-benzenesulfonylamino) -3-methyl-butyrylamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.82-7.86 (m, 1H), 7.21-7.24 (m, 2H), 6.45 (s, 1H), 6.09 (d, J = 8.4 Hz, 1H), 4.08 ( d, J = 8.0 Hz, 1H), 2.39 (s, 2H), 1.92 (s, 2H), 1.74-1.85 (m, 10H), 1.66 (d, J = 13.2 Hz, 2H), 1.28 (s, 6H ) 51 N -adamantan-2-yl-3-methyl-3- (2,4,6-trifluoro-benzenesulfonylamino) -butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 6.79 (m, 2H), 6.14 (d, J = 7.6 Hz, 1H), 4.08 (d, J = 7.6 Hz, 1H), 2.43 (s, 2H), 1.64 -1.93 (m, 14H), 1.37 (s, 6H) 52 N -adamantan-2-yl-3-benzenesulfonylamino-3-methyl-butyrylamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.92 (m, 2H), 7.52 (m, 3H), 6.17 (d, J = 7.6 Hz, 1H), 4.07 (d, J = 7.6 Hz, 1H), 2.37 (s, 2H), 1.63-1.93 (m, 14H), 1.23 (s, 6H) 53 N -adamantan-2-yl-3- (2,6-difluoro-benzenesulfonylamino) -3-methyl-butyrylamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.51 (m, 3H), 7.03 (t, J = 8.4 Hz, 2H), 6.47 s, 1H), 6.21 (d, J = 7.6 Hz, 1H), 4.09 ( d, J = 7.6 Hz, 1H), 2.47 (s, 2H), 1.64-1.94 (m, 14H), 1.36 (s, 6H) 54 N -adamantan-2-yl-3- (2-chloro-6-methyl-benzenesulfonylamino) -3-methyl-butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.41 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.41 (d , J = 7.6 Hz, 1H), 6.26 (s, 1H), 4.10 (d, J = 7.6 Hz, 1H), 2.76 (s, 3H), 2.50 (s, 2H), 1.66-1.98 (m, 14H) , 1.25 (s, 6H) 55 N -adamantan-2-yl-3-methyl-3- (2-trifluoromethyl-benzenesulfonylamino) -butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.31 (m, 1H), 7.87 (m, 1H), 7.71 (m, 2H), 6.38 (s, 1H), 6.24 (d, J = 7.6 Hz, 1H) , 4.10 (d, J = 7.6 Hz, 1H), 2.45 (s, 2H), 1.65-1.96 (m, 14H), 1.29 (s, 6H) 56 N -adamantan-2-yl-3- (3-chloro-2-methyl-benzenesulfonylamino) -butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.96 (dd, J = 7.8, 1.0 Hz, 1H), 7.56 (dd, J = 8.0, 1.2 Hz, 1H), 7.22-7.25 (m, 1H), 6.29 ( d, J = 8.0 Hz, 1H), 5.78 (d, J = 7.6 Hz, 1H), 4.01 (d, J = 7.6 Hz, 1H), 3.61-3.67 (m, 1H), 2.71 (s, 3H), 2.38 (dd, J = 14.8, 4.4 Hz, 1H), 2.18 (dd, J = 14.8, 4.8 Hz, 1H), 1.84-1.89 (m, 8H), 1.62-1.74 (m, 4H), 1.17 (d, J = 6.8 Hz, 3H) 57 N -adamantan-2-yl-3- (3-chloro-2-methyl-benzenesulfonylamino) -butyramide

1 H NMR (400 MHz, CDCl 3) d 7.98 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.23 (t, J 8.0 Hz, 1H), 6.33 (d, J = 8.0 Hz, 1H), 5.81 (d, J = 7.2 Hz, 1H), 4.03 (d, J = 8.0 Hz, 1H), 3.65 (m, 1H), 2.74 (s, 3H), 2.40 (m, 1H) , 2.21 (m, 1H), 1.60-1.92 (m, 14H), 1.19 (d, J = 7.2 Hz, 3H) 58 N -adamantan-2-yl-3- (naphthalene-2-sulfonylamino) -butyramide

1 H NMR (400 MHz, CDCl 3) d 8.45 (d, J = 1.6 Hz, 1H), 7.94-7.97 (m, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.86 (dd, J = 8.6, 1.8 Hz, 1H), 7.58-7.66 (m, 2H), 6.11 (d, J = 7.6 Hz, 1H), 5.77 (d, J = 8.0 Hz, 1H), 3.94 (d, J = 8.0 Hz, 1H) , 3.64-3.67 (m, 1H), 2.31 (dd, J = 14.8, 4.8 Hz, 1H), 2.18 (dd, J = 14.8, 5.6 Hz, 1H), 1.85 (s, 2H), 1.79 (d, J = 10.4 Hz, 5H), 1.52-1.71 (m, 7H), 1.18 (d, J = 6.4 Hz, 3H) 59 N -adamantan-2-yl-3- (naphthalene-2-sulfonylamino) -butyramide

1 H NMR (400 MHz, CDCl 3) d 7.98 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.33 (d, J = 8.0 Hz, 1H), 5.81 (d, J = 7.2 Hz, 1H), 4.03 (d, J = 8.0 Hz, 1H), 3.65 (m, 1H), 2.74 (s, 3H), 2.40 (m, 1H ), 2.21 (m, 1H), 1.60-1.92 (m, 14H), 1.19 (d, J = 7.2 Hz, 3H) 60 N -adamantan-2-yl-2- [1- (3-chloro-2-methyl-benzenesulfonylamino) -cyclopropyl] -acetamide

¹ H NMR (400 MHz, CDCl 3) d 7.98 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 6.12 (s, 1H), 5.81 (d, J = 7.6 Hz, 1H), 4.06 (d, J = 7.6 Hz, 1H), 2.63 (s, 3H), 2.33 (s, 2H), 1.63-1.91 (m, 14H), 0.78 (m, 2H), 0.56 (m, 2H)

< Example  61> N- [2- ( Adamantan -2- Il carbamoyl ) -1,1- Dimethyl -Ethyl] -3- Chloro 2-methyl- Benzamide  Produce

11.9 mg (0.070 mmol) of 3-chloro-2-methylbenzoic acid was dissolved in 1 mL of methylene chloride, and 11.3 mg (0.084 mmol) of HOBt and 16 mg (0.084 mmol) of EDCI were added thereto. After stirring for 10 minutes at room temperature, 20 mg (0.070 mmol) of N-adamantan-2-yl-3-amino-3-methyl-butyramide hydrochloride (Preparation Example 6) was added thereto. The mixture was stirred at room temperature for 3 hours. After completion of the reaction methylene chloride was removed by evaporation under reduced pressure. The residue was dissolved in 5 ml of water and extracted with 3 x 5 ml of ethyl acetate. The extract was then dried over anhydrous magnesium sulfate, distilled under reduced pressure, separated by column chromatography, and extracted with N- [2- (adamantane-2-ylcarbamoyl) -1,1-dimethyl-ethyl] -3-chloro-2. 20 mg (yield 71%) of -methyl-benzamide were obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (dd, J = 8.0, 0.8 Hz, 1H), 7.25 (dd, J = 7.6, 1.2 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H) , 6.95 (s, 1H), 6.04 (d, J = 7.2 Hz, 1H), 4.07 (d, J = 8.0 Hz, 1H), 2.60 (s, 2H), 2.46 (s, 3H), 1.85-1.91 ( m, 8H), 1.77 (d, J = 12.8 Hz, 4H), 1.65 (d, J = 13.2 Hz, 2H), 1.60 (s, 6H)

Through the same synthesis method as in Example 61, the compound of Examples 62 to 64 was prepared and the results are shown in Table 5 below.

Example Name of compound rescue NMR data 62 N -adamantan-2-yl-3- [2- (2-methoxy-phenyl) -acetylamino] -3-methyl-butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.28 (dd, J = 15.6, 1.6 Hz, 1H), 7.20 (dd, J = 7.4, 1.4 Hz, 1H), 6.90-6.96 (m, 2H), 6.27 ( d, J = 8.0 Hz, 1H), 6.16 (s, 1H), 3.99 (d, J = 7.6 Hz, 1H), 3.87 (s, 3H), 3.46 (s, 2H), 2.65 (s, 2H), 1.75-1.86 (m, 12H), 1.62-1.64 (m, 2H), 1.35 (s, 6H) 63 1-phenyl-cyclopropanecarboxylic acid [2- (adamantane-2-ylcarbamoyl) -1,1-dimethyl-ethyl] -amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.28-7.32 (m, 5H), 6.25 (d, J = 8.0 Hz, 1H), 5.43 (s, 1H), 4.01 (d, J = 8.0 Hz, 1H) , 2.67 (s, 2H), 1.80-1.90 (m, 10H), 1.76 (s, 2H), 1.66 (d, J = 12.4 Hz, 2H), 1.53 (q, J = 6.6, 3.8 Hz, 2H), 1.24 (s, 6H), 1.02 (q, J = 7.0, 3.8 Hz, 2H) 64 N- [2- (adamantane-2-ylcarbamoyl) -1,1-dimethyl-ethyl] -3,4-dichloro-benzamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.92 (d, J = 2.0 Hz, 1H), 7.88 (s, 1H), 7.60 (dd, J = 8.4, 2.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 6.03 (d, J = 7.6 Hz, 1H), 4.05 (d, J = 8.0 Hz, 1H), 2.51 (s, 2H), 1.82-1.85 (m, 8H), 1.71 (d, J = 12.0 Hz, 4H), 1.61 (d, J = 12.0 Hz, 2H), 1.57 (s, 6H)

< Example  65> 3- (3- Chloro -2- methyl - Benzenesulfonylamino ) -N- (5- Hydro City - Adamantan Yl) -3- methyl - Butyramide  Produce

160 mg (0.52 mmol) of methyl 3- (3-chloro-2-methylphenylsulfonamido) -3-methylbutanoic acid prepared in Preparation Example 3 was dissolved in 5.2 ml of methylene chloride and 160 mg (0.63 mmol) of BOP-Cl ), 105 mg (0.63 mmol) of 4-amino-adamantan-1-ol and 0.15 mL (1.05 mmol) of TEA were added. The mixture was stirred at room temperature for 12 hours. After completion of the reaction methylene chloride was removed by evaporation under reduced pressure. The residue was dissolved in 15 mL of water and extracted with 3 × 15 mL of ethyl acetate. The extract was then dried over anhydrous magnesium sulfate, distilled under reduced pressure, and separated by column chromatography to obtain 3- (3-chloro-2-methyl-benzenesulfonylamino) -N- (5-hydroxy-adamantan-2-yl. 104 mg (yield 44%) of 3--3-methyl-butyamide were obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 6.19 (s , 1H), 6.03 (d, J = 7.6 Hz, 1H), 4.04-4.06 (m, 1H), 2.72 (s, 3H), 2.41 (s, 2H), 2.15 (brs, 3H), 1.90 (d, J = 11.2 Hz, 2H), 1.71-1.79 (m, 6H), 1.53 (d, J = 12.8 Hz, 2H), 1.24 (s, 6H)

Through the same synthesis method as in Example 65, to prepare a compound of Examples 66 to 70 and the results are shown in Table 6 below.

Example Name of compound rescue NMR data 66 Z-3- (3- chloro-2-methyl-benzenesulfonylamino) - N - (5- dihydro-upon-adamantan-2-yl) -3-methyl-butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.97 (dd, J = 8.0, 1.2 Hz, 1H), 7.55 (dd, J = 8.0, 1.2 Hz, 1H), 7.22-7.26 (m, 1H), 6.42 ( s, 1H), 6.15 (d, J = 7.6 Hz, 1H), 3.93-3.95 (m, 1H), 2.72 (s, 3H), 2.38 (s, 2H), 2.14-2.20 (m, 3H), 1.60 -1.81 (m, 10H), 1.23 (s, 6H) 67 E-3- (2- chloro-6-methyl-benzenesulfonylamino) - N - (5- dihydro-upon-adamantan-2-yl) -3-methyl-butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.40 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 6.43 (d , J = 7.6 Hz, 1H), 5.93 (s, 1H), 4.06 (d, J = 7.6 Hz, 1H), 2.74 (s, 3H), 2.52 (s, 2H), 2.17 (brs, 3H), 1.76 -1.91 (m, 8H), 1.52 (d, J = 13.2 Hz, 2H), 1.22 (s, 6H) 68 3- (2-Chloro-4-fluoro-benzenesulfonylamino) - N - (5- dihydro-upon-adamantan-2-yl) -3-methyl-butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.12 (dd, J = 8.8, 6.0 Hz, 1H), 7.27 (dd, J = 8.0, 2.4 Hz, 1H), 7.09-7.14 (m, 1H), 6.23 ( d, J = 7.6 Hz, 1H), 6.14 (s, 1H), 4.04-4.06 (m, 1H), 2.45 (s, 2H), 2.16 (brs, 3H), 1.76-1.91 (m, 8H), 1.52 (d, J = 13.2 Hz, 2H), 1.23 (s, 6H) 69 3- (3-chloro-benzenesulfonylamino) - N - (5- dihydro-upon-adamantan-2-yl) -3-methyl-butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.88 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0 Hz , 1H), 6.50 (s, 1H), 6.13 (d, J = 7.6 Hz, 1H), 4.03 (d, J = 7.2 Hz, 1H), 2.38 (s, 2H), 1.89 (d, J = 12.0 Hz , 2H), 1.70-1.78 (m, 7H), 1.51 (d, J = 13.2 Hz, 2H), 1.27 (s, 6H) 70 3- (3-chloro-2-fluoro-benzenesulfonylamino) - N - (5- dihydro-upon-adamantan-2-yl) -3-methyl-butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.78-7.82 (m, 1H), 7.59-7.63 (m, 1H), 7.22 (t, J = 8.0 Hz, 1H), 6.31 (s, 1H), 6.18 ( d, J = 7.6 Hz, 1H), 4.05 (d, J = 7.2 Hz, 1H), 2.44 (s, 2H), 2.15 (s, 2H), 1.89 (d, J = 12.4 Hz, 2H), 1.73- 1.78 (m, 7H), 1.52 (d, J = 12.4 Hz, 2H), 1.28 (s, 6H)

< Example  71> Methanesulfonic acid  4- [3- (3- Chloro -2- methyl - Benzenesulfonylamino ) -3- methyl -part Tyrylamino ] - Adamantan Preparation of -1-yl ester

36 mg of 3- (3-chloro-2-methyl-benzenesulfonylamino) -N- (5-hydrocy-adamantan-2-yl) -3-methyl-butyramide prepared in Example 65 above (0.079 mmol) was dissolved in 0.012 mL (0.158 mmol) of methanesulfonyl chloride in 0.79 mL of methylene chloride. 0.022 mL (0.158 mmol) of TEA was added and stirred at room temperature for 12 hours, after which the methylene chloride was removed by evaporation under reduced pressure. After completion of the reaction, the solution was dissolved in 5 ml of water and extracted with 3 × 5 ml of ethyl acetate. After drying over anhydrous magnesium sulfate and distillation under reduced pressure, the residue was separated by column chromatography to give methanesulfonic acid 4- [3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] 18 mg (yield 42%) of tan-1-yl ester were obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (dd, J = 8.0, 1.2 Hz, 1H), 7.57 (dd, J = 8.0, 0.8 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H) , 6.11 (d, J = 7.2 Hz, 1H), 5.92 (s, 1H), 4.09-4.11 (m, 1H), 3.01 (s, 3H), 2.71 (s, 3H), 2.43 (s, 2H), 2.25-2.32 (m, 9H), 1.78 (d, J = 13.6 Hz, 2H), 1.60 (d, J = 14.0 Hz, 2H), 1.22 (s, 6H)

By the same synthesis method as in Example 71, the compound of Example 72 was prepared and the results are shown in Table 7 below.

Example Name of compound rescue NMR data 72 Methanesulfonic acid 4- [3- (2-chloro-6-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantan-1-yl ester

¹ H NMR (400 MHz, CDCl ₃ ) d 7.41 (dd, J = 7.8, 1.0 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.23 (dd, J = 7.6, 0.8 Hz, 1H) , 6.50 (d, J = 7.6 Hz, 1H), 5.76 (s, 1H), 4.09-4.11 (m, 1H), 2.74 (s, 3H), 2.54 (s, 2H), 2.28-2.35 (m, 9H ), 1.90 (d, J = 13.6 Hz, 2H), 1.58-1.61 (m, 2H), 1.21 (s, 6H)

< Example  73> 3- (3- Chloro -2- methyl - Benzenesulfonylamino ) -3- methyl -N- (5- Methylsulfanyl - Adamantan -2 days)- Butyramide  Produce

17 mg of methanesulfonic acid 4- [3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantan-1-yl ester prepared in Example 71 0.032 mmol) was dissolved in 1 ml of methanol. 44.7 mg (0.638 mmol) of sodium thiomethoxide were added and stirred at 80 ° C. for 12 hours. After completion of the reaction, methanol was removed by evaporation under reduced pressure. The residue was diluted with 5 ml of ethyl acetate, washed with an aqueous calcium carbonate solution and extracted with 3 × 5 ml of ethyl acetate. The extract was then dried over anhydrous magnesium sulfate, distilled under reduced pressure and separated by column chromatography to obtain 3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-N- (5-methylsulfanyl-adama). 10.8 mg (yield: 69%) of tan-2-yl) -butyramide were obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (dd, J = 8.0, 0.8 Hz, 1H), 7.55 (dd, J = 8.0, 0.8 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H) , 6.25 (s, 1H), 6.04 (d, J = 7.2 Hz, 1H), 4.02-4.04 (m, 1H), 3.24 (s, 3H), 2.72 (s, 3H), 2.40 (s, 2H), 2.16 (brs, 3H), 1.91 (d, J = 12.0 Hz, 2H), 1.71-1.80 (m, 6H), 1.53 (d, J = 12.8 Hz, 2H), 1.24 (s, 6H)

By the same synthesis method as in Example 73, to prepare a compound of Example 74 shown in Table 8.

Example Name of compound rescue NMR data 74 3- (2-Chloro-6-methyl-benzenesulfonylamino) -3-methyl- N- (5-methylsulfanyl-adamantan-2-yl) -butyramide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.40 (d, J = 7.2 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 6.42 (d , J = 7.6 Hz, 1H), 5.94 (s, 1H), 4.04-4.06 (m, 1H), 3.24 (s, 3H), 2.74 (s, 3H), 2.52 (s, 2H), 2.19 (brs, 3H), 1.77-1.92 (m, 8H), 1.53 (d, J = 13.2 Hz, 2H), 1.22 (s, 6H)

< Example  75> 4- [3- (3- Chloro -2- methyl -benzene- Sulfonylamino ) -3- methyl - Butyrylamino ] Adamantan -1 day- Ethanechiate  Produce

Methanesulfonic acid 4- [3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantan-1-yl ester prepared in Example 71 (39 mg ( 0.073 mmol) was dissolved in 0.3 ml (excess) of thioacetic acid and stirred at 70 ° C. for 16 hours. After completion of the reaction the thioacetic acid was removed by evaporation under reduced pressure. The residue was dissolved in 5 ml of water and extracted with 3 x 5 ml of methylene chloride. The extract was then dried over anhydrous magnesium sulfate, distilled under reduced pressure, separated by column chromatography, and then extracted with 4- [3- (3-chloro-2-methyl-benzene-sulfonylamino) -3-methyl-butyrylamino] adamantane. 37.5 mg (yield: 32%) of 1-yl-ethanechioate were obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 6.22 (s , 1H), 6.08 (d, J = 7.6 Hz, 1H), 4.13 (t, J = 3.8 Hz, 1H), 2.72 (s, 3H), 2.40 (s, 2H), 2.18-2.26 (m, 9H) , 2.02-2.08 (m, 3H), 1.78 (d, J = 13.2 Hz, 2H), 1.68 (d, J = 13.2 Hz, 2H), 1.23 (s, 6H)

< Example  76> 3- (3- Chloro -2- methyl -benzene- Sulfonylamino ) -3- methyl -N- (5- Methylsulfo Neil- Adamantan -2 days) Butanamide  Produce

E-3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-N- (5-methylsulfanyl-adamantan-2-yl) -butyr prepared in Example 73 above. 19 mg (0.039 mmol) of amide was dissolved in 1 ml of acetic acid, and then 18.1 mg (0.118 mmol) of NaBO 3 · 4H 2 O was added thereto, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, 2 ml of toluene was added and then removed by evaporation under reduced pressure. The residue was dissolved in 5 ml of water and extracted with 3 x 5 ml of ethyl acetate. The extract was then dried over anhydrous magnesium sulfate, distilled under reduced pressure, separated by column chromatography, and then 3- (3-chloro-2-methyl-benzene-sulfonylamino) -3-methyl-N- (5-methylsulfonyl-a Tantan-2-yl) butanamide 20.2 mg (yield: 55%) were obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.25 (t , J = 8.0 Hz, 1H), 5.82 (s, 1H), 4.09 (d, J = 6.8 Hz, 1H), 2.77 (s, 3H), 2.71 (s, 3H), 2.46 (s, 2H), 2.13 -2.24 (m, 7H), 2.06 (s, 2H), 1.88 (d, J = 13.6 Hz, 2H), 1.64 (d, J = 13.6 Hz, 2H), 1.23 (s, 6H)

By the same synthesis method as in Example 76, to prepare a compound of Examples 77 and 78 are shown in Table 9.

Example Name of compound rescue NMR data 77 3- (3-Chloro-2-fluoro-benzene-sulfonylamino) -3-methyl- N- (5-methylsulfonyl-adamantan-2-yl) butanamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.78-7.82 (m, 1H), 7.61-7.65 (m, 1H), 7.21-7.25 (m, 1H), 6.33 (d, J = 7.6 Hz, 1H), 5.84 (s, 1H), 4.09 (d, J = 7.6 Hz, 1H), 2.77 (s, 3H), 2.50 (s, 2H), 2.11-2.25 (m, 7H), 2.07 (d, J = 2.4 Hz , 2H), 1.19 (d, J = 13.6 Hz, 2H), 1.64 (d, J = 13.6 Hz, 2H), 1.27 (s, 6H) 78 3- (3-Chloro-2-methyl-benzene-sulfonylamino) -3-methyl- N- (5-methylsulfonyl-adamantan-2-yl) butanamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.97 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 6.31 (d , J = 7.6 Hz, 1H), 6.06 (s, 1H), 4.08 (d, J = 7.2 Hz, 1H), 2.71 (s, 3H), 2.45 (s, 2H), 2.41 (s, 3H), 2.19 -2.23 (m, 3H), 1.83-2.00 (m, 8H), 1.65 (d, J = 13.2 Hz, 2H), 1.23 (s, 6H)

< Example  79> 4- [3- (3- Chloro -2- methyl - Benzenesulfonylamino ) -3- Butyryl  Amino]- Adamantan -One- Carboxylic  Produce

50 mg (0.106 mmol) of 4- [3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid methyl ester prepared in Preparation Example 18 ) Was dissolved in 0.6 mL of THF and ethanol 1: 1 mixture, and 0.6 mL of 2N NaOH aqueous solution was added thereto. After stirring overnight at room temperature, the solution was acidified with 1N HCl aqueous solution, extracted with ethyl acetate, dried over Na ₂ SO _4, and the solvent was evaporated under reduced pressure to give E-4- [3- (3-chloro-2-methyl-benzenesulfonylamino 47 mg (yield: 92%) of 3--3-methyl-butyrylamino] -adamantane-1-carboxylic acid were obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 6.25 (s , 1H), 6.21 (d, J = 7.6 Hz, 1H), 4.14 (m, 1H), 2.74 (s, 3H), 2.45 (s, 2H), 1.63-2.09 (m, 13H), 1.27 (s, 6H)

< Example  80> 4- [3- (3- Chloro -2- methyl - Benzenesulfonylamino ) -3- methyl - Butyrylamino ] - Adamantan -One- Carboxylic acid  Preparation of amide

47 mg (0.10 mmol) of 4- [3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid prepared in Example 79 was prepared. Dissolved in 3 ml of methylene chloride, 16 mg (0.116 mmol) of HOBt and 22 mg (0.116 mmol) of EDCI were added thereto, and after stirring for 1 hour at room temperature, 3 ml of 30% aqueous ammonia was added, followed by stirring at room temperature for 20 hours. Extraction with methylene chloride, washing with brine, drying with Na ₂ SO ₄ , and separation with column chromatography 4- [3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-butyrylamino 27 mg (yield: 58%) of] -adamantane-1-carboxylic acid amide were obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 6.32 (s , 1H), 6.20 (d, J = 7.6 Hz, 1H), 5.63 (brs, 1H), 5.42 (br, 1H), 4.07 (d, J = 7.6 Hz, 1H), 2.72 (s, 3H), 2.42 (s, 2H), 1.61-1.18 (m, 13H), 1.24 (s, 6H)

Through the same synthesis method as in Example 80, the compounds of Examples 81 to 127 were prepared, and the results are shown in Table 10 below.

Example Name of compound rescue NMR data 81 4- [3- (2-Chloro-6-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.41 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.56 (d , J = 7.6 Hz, 1H), 6.06 (s, 1H), 5.67 (brs, 1H), 5.52 (brs, 1H), 4.10 (d, J = 7.6 Hz, 1H), 2.76 (s, 3H), 2.54 (s, 2H), 1.62-2.19 (m, 13H), 1.24 (s, 6H) 82 4- [3- (2-Chloro-4-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.11 (m, 1H), 7.28 (m, 1H), 7.11 (m, 1H), 6.53 (d, J = 7.6 Hz, 1H), 6.25 (s, 1H) , 5.81 (br, 1H), 5.50 (br, 1H), 4.06 (d, J = 7.6 Hz, 1H), 2.48 (s, 2H), 1.61-2.18 (m, 13H), 1.23 (s, 6H) 83 4- [3- (4-Chloro-2-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.86 (t, J = 8.0 Hz, 1H), 7.27 (m, 2H), 6.29 (m, 2H), 5.67 (brs, 1H), 5.50 (brs, 1H) , 4.08 (m, 1H), 2.47 (s, 2H), 1.62-2.11 (m, 13H), 1.29 (s, 6H) 84 4- [3- (2-Fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.88-7.92 (m, 1H), 7.54-7.60 (m, 1H), 7.23-7.29 (m, 1H), 7.18-7.22 (m, 1H), 6.36 (d , J = 8.0 Hz, 1H), 5.82 (s, 1H), 5.60 (brs, 1H), 5.30 (brs, 1H), 4.08 (t, J = 3.8 Hz, 1H), 2.49 (s, 2H), 2.11 (s, 2H), 1.96-2.05 (m, 5H), 1.87-1.91 (m, 4H), 1.63 (d, J = 13.2 Hz, 2H), 1.25 (s, 6H) 85 4- [3- (2- (trifluoromethyl) -benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.29 (t, J = 4.4 Hz, 1H), 7.86 (t, J = 4.4 Hz, 1H), 7.66-7.72 (m, 2H), 6.32 (d, J = 7.6 Hz, 1H), 5.93 (s, 1H), 5.60 (brs, 1H), 5.30 (brs, 1H), 4.09 (d, J = 7.2 Hz, 1H), 2.49 (s, 1H), 2.11 (s, 2H), 1.86-2.05 (m, 9H), 1.63 (d, J = 13.2 Hz, 2H), 1.27 (s, 6H) 86 4- [3- (2-Chloro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.11 (dd, J = 8.0, 1.2 Hz, 1H), 7.48-7.54 (m, 2H), 7.39-7.44 (m, 1H), 6.44 (d, J = 7.6 Hz, 1H), 5.85 (s, 1H), 5.60 (brs, 1H), 5.49 (brs, 1H), 4.07-4.09 (m, 1H), 2.50 (s, 2H), 2.12 (s, 2H), 1.96 -2.06 (m, 5H), 1.90-1.93 (m, 4H), 1.63 (d, J = 12.4 Hz, 2H), 1.22 (s, 6H) 87 4- [3- (2-Methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, DMSO) d 7.89 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.35-7.40 (m, 2H), 7.00 (s, 1H), 6.74 (s, 1H), 3.81 (m, 1H), 3.34 (s, 3H), 2.59 (s, 2H), 1.73-1.90 (m, 12H), 1.39 (d, J = 10.0 Hz, 2H), 1.12 (s, 6H) 88 4- [3- (3-Chloro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.90 (t, J = 1.8 Hz, 1H), 7.77-7.80 (m, 1H), 7.50-7.53 (m, 1H), 7.43 (t, J = 8.0 Hz, 1H), 6.36 (s, 1H), 6.13 (d, J = 7.2 Hz, 1H), 5.61 (brs, 1H, 5.33 (brs, 1H), 4.07 (t, J = 3.8 Hz, 1H), 2.40 (s , 2H), 2.09 (s, 2H), 1.97-2.04 (m, 5H), 1.91 (d, J = 2.4 Hz, 2H), 1.81 (d, J = 13.6 Hz, 2H), 1.62 (d, J = 13.6 Hz, 2H), 1.28 (s, 6H) 89 4- [3- (3-Fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, DMSO) d 7.81 (s, 1 H), 7.59-7.69 (m, 3 H), 7.49-7.50 (m, 1 H), 7.00 (s, 1 H), 6.74 (s, 1 H). 3.79 (s, 1H), 2.51 (s, 2H), 1.73-1.91 (m, 12H), 1.39 (d, J = 11.2 Hz, 2H), 1.12 (s, 6H) 90 4- [3- (3- (trifluoromethyl) -benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.17 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 7.6 Hz , 1H), 6.63 (s, 1H), 6.20 (d, J = 6.8 Hz, 1H), 5.72 (s, 1H), 4.06 (d, J = 7.2 Hz, 1H), 2.39-2.41 (m, 2H) , 2.08-2.04 (m, 7H), 2.00-1.96 (m, 2H), 1.95 (t, J = 5.4 Hz, 2H), 1.61 (d, J = 13.2 Hz, 2H), 1.27 (s, 6H) 91 4- [3- (3-Methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.68-7.71 (m, 2H), 7.36-7.37 (m, 2H), 6.33 (d, J = 7.6 Hz, 1H), 5.63 (brs, 1H), 5.38 ( brs, 1H), 4.07 (d, J = 7.2 Hz, 1H), 2.45 (s, 2H), 2.42 (s, 3H), 1.90-2.04 (m, 9H), 1.86 (d, J = 13.6 Hz, 2H ), 1.62 (d, J = 14.0 Hz, 2H), 1.21 (s, 6H) 92 4- [3- (4-Fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.90-7.93 (m, 2H), 7.14-7.19 (m, 2H), 6.17-6.18 (m, 2H), 5.61 (brs, 1H), 5.31 (brs, 1H ), 4.06 (d, J = 7.6 Hz, 1H), 2.41 (s, 2H), 1.81-2.09 (m, 9H), 1.82 (d, J = 13.6 Hz, 2H), 1.62-1.64 (m, 2H) , 1.26 (s, 6H) 93 4- [3- (4- (trifluoromethyl) -benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.04 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 6.83 (s, 1H), 6.27 (d, J = 8.0 Hz , 1H), 5.75 (brs, 2H), 4.06 (d, J = 7.6 Hz, 2H), 2.40 (s, 2H), 1.80-2.07 (m, 11H), 1.60 (d, J = 12.8 Hz, 2H) , 1.27 (s, 6H) 94 4- [3- (pyridine-3-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 9.13 (s, 1H), 8.78 (s, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.43-7.46 (m, 1H), 6.63 (s, 1H), 6.12 (d, J = 7.6 Hz, 1H), 5.65 (brs, 1H), 5.50 (brs, 1H), 4.06 (t, J = 3.8 Hz, 1H), 2.41 (s, 2H), 1.96- 2.08 (m, 7H), 1.90 (s, 2H), 1.81 (d, J = 13.0 Hz, 2H), 1.62 (d, J = 13.0 Hz, 2H), 1.29 (s, 6H) 95 4- [3- (6-Trifluoromethyl-pyridine-3-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 9.22 (d, J = 2.4 Hz, 1H), 8.40 (dd, J = 8.2, 1.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.20 (s, 1H), 6.07 (d, J = 7.6 Hz, 1H), 5.69 (brs, 1H), 5.55 (brs, 1H), 4.08 (d, J = 7.2 Hz, 1H), 2.40 (s, 2H) , 1.92-2.09 (m, 7H), 1.63-1.81 (m, 6H), 1.33 (s, 6H) 96 4- [3- (2-Chloro-4-cyano-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.22 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.70 (dd, J = 8.4, 1.6 Hz, 1H), 6.79 (s, 1H), 6.12 (d, J = 8.0 Hz, 1H), 5.60 (brs, 1H), 5.32 (brs, 1H), 4.08 (t, J = 3.8 Hz, 1H), 2.42
(s, 2H), 2.10 (s, 2H), 2.00-2.05 (m, 5H), 1.91 (d, J = 2.4 Hz, 2H), 1.82 (d, J = 13.2 Hz, 1H), 1.64 (d, J = 13.2 Hz, 1H), 1.26 (s, 6H) 97 4- [3- (4-carbamoyl-2-chloro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, DMSO) d 8.25 (brs, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H), 8.04 (brs, 1H), 7.96 ( dd, J = 8.0, 1.6 Hz, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.73 (brs, 1H), 7.00 (brs, 1H), 6.73 (brs, 1H), 3.82 (d, J = 6.0 Hz, 1H), 2.39 (s, 2H), 1.77-1.91 (m, 9H), 1.73 (s, 2H), 1.40 (d, J = 10.8 Hz, 2H), 1.14 (s, 6H) 98 4- [3- (2,3-Dichloro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.05 (dd, J = 8.0, 1.6 Hz, 1H), 7.67 (dd, J = 8.0, 1.6 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H) , 6.03 (d, J = 7.2 Hz, 1H), 6.26 (s, 1H), 5.61 (brs, 1H), 5.35 (brs, 1H), 4.08 (d, J = 7.2 Hz, 1H), 2.46 (s, 2H), 2.11 (s, 2H), 1.97-2.06 (m, 5H), 1.85-1.91 (s, 4H), 1.63 (d, J = 13.6 Hz, 2H), 1.25 (s, 6H) 99 4- [3- (3,5-Dichloro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.77 (d, J = 2.0 Hz, 2H), 7.51 (t, J = 2.0 Hz, 1H), 6.66 (s, 1H), 6.01 (d, J = 7.2 Hz , 1H), 5.59 (brs, 1H), 5.30 (brs, 1H), 4.07 (d, J = 7.2 Hz, 1H), 2.38 (s, 2H), 2.09 (s, 2H), 2.00-2.05 (m, 5H), 7.91 (s, 2H), 1.78 (d, J = 12.8 Hz, 2H), 1.64 (d, J = 12.8 Hz, 2H), 1.31 (s, 6H) 100 4- [3- (3-Chloro-4-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.98 (dd, J = 6.6, 2.2 Hz, 1H), 7.78-7.82 (m, 1H), 7.24 (t, J = 8.4 Hz, 1H), 6.48 (s, 1H), 6.07 (d, J = 7.2 Hz, 1H), 5.61 (brs, 1H), 5.30 (brs, 1H), 4.06 (d, J = 7.6 Hz, 1H), 2.39 (s, 2H), 2.09 ( s, 2H), 1.97-2.05 (m, 5H), 1.91 (s, 2H), 1.79 (d, J = 13.2 Hz, 2H), 1.63 (d, J = 13.2 Hz, 2H), 1.29 (s, 6H ) 101 4- [3- (3-Chloro-4-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.87 (d, J = 1.6 Hz, 1H), 7.67 (dd, J = 8.0, 2.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 6.18 (s, 1H), 5.63 (brs, 1H), 5.37 (brs, 1H), 4.07 (d, J = 7.6 Hz, 1H), 2.44 (s, 3H) , 2.42 (s, 2H), 2.09 (s, 2H), 1.97-2.04 (m, 5H), 1.91 (s, 2H), 1.83 (d, J = 13.6 Hz, 2H), 1.62 (d, J = 13.6 Hz, 2H), 1.27 (s, 6H) 102 4- [3- (3-Chloro-2-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.78-7.82 (m, 1H), 7.59-7.63 (m, 1H), 7.22 (t, J = 8.0 Hz, 1H), 6.21-6.24 (m, 2H), 5.61 (brs, 1H), 5.30 (brs, 1H), 4.08 (d, J = 7.2 Hz, 1H), 2.46 (s, 2H), 2.10 (s, 2H), 2.00-2.05 (m, 5H), 1.83 -1.91 (m, 4H), 1.62 (d, J = 13.6 Hz, 2H), 1.28 (s, 6H) 103 4- [3- (5-Chloro-2-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.88 (dd, J = 6.0, 2.8 Hz, 1H), 7.49-7.53 (m, 1H), 7.16 (t, J = 9.2 Hz, 1H), 6.22-6.23 ( m, 2H), 5.60 (brs, 1H), 5.33 (brs, 1H), 4.07 (d, J = 8.0 Hz, 1H), 2.46 (s, 2H), 2.09 (s, 2H), 1.97-2.05 (m , 5H), 1.83-1.91 (m, 4H), 1.62 (d, J = 13.2 Hz, 2H), 1.29 (s, 6H) 104 4- [3- (2-Fluoro-3-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide ¹ H NMR (400 MHz, CDCl ₃ ) d 7.71 (t, J = 6.8 Hz, 1H), 7.41 (t, J = 6.8 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 6.41 (d , J = 7.6 Hz, 1H), 5.68 (s, 1H), 5.59 (brs, 1H), 5.28 (brs, 1H), 4.08 (d, J = 7.6 Hz, 1H), 2.50 (S, 2H), 2.34 (d, J = 2.0 Hz, 3H), 2.11 (s, 2H), 1.96-2.05 (m, 5H), 1.88-1.91 (m, 4H), 1.62 (d, J = 12.8 Hz, 2H), 1.25 ( s, 6 H) 105 4- [3- (2-Fluoro-4-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.76 (t, J = 7.8 Hz, 1H), 7.00-7.07 (m, 2H), 6.46 (d, J = 7.6 Hz, 1H), 5.78 (s, 1H) , 5.65 (brs, 1H), 5.45 (brs, 1H), 4.07 (d, J = 7.6 Hz, 1H), 2.49 (s, 2H), 2.42 (s, 3H), 1.90-2.10 (m, 11H), 1.61 (d, J = 13.2 Hz, 2H), 1.24 (s, 6H) 106 4- [3- (2-Fluoro-5-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.69 (dd, J = 6.8, 2.0 Hz, 1H), 7.32-7.36 (m, 1H), 7.08 (dd, J = 9.8, 8.6 Hz, 1H), 6.44 ( d, J = 7.6 Hz, 1H), 5.78 (s, 1H), 5.63 (brs, 1H), 5.38 (brs, 1H), 4.08 (t, J = 3.8 Hz, 1H), 2.49 (s, 2H), 2.38 (s, 3H), 2.10 (s, 2H), 1.88-2.05 (m, 9H), 1.62 (d, J = 13.2 Hz, 2H), 1.25 (s, 6H) 107 4- [3- (2-Fluoro-5-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.36-7.41 (m, 1H), 7.03-7.09 (m, 2H), 6.45 (d, J = 8.0 Hz, 1H), 5.80 (s, 1H), 5.70 ( brs, 1H), 5.64 (brs, 1H), 4.08 (d, J = 7.6 Hz, 1H), 2.69 (s, 3H), 2.53 (s, 2H), 1.91-2.12 (m, 11H), 1.62 (d , J = 12.8 Hz, 2H), 1.26 (s, 6H) 108 4- [3- (3-Fluoro-4-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.52-7.59 (m, 2H), 7.30 (t, J = 7.6 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 6.15 (s, 1H) , 5.63 (brs, 1H), 5.38 (brs, 1H), 4.06 (d, J = 7.6 Hz, 1H), 2.42 (s, 2H), 2.34 (s, 3H), 2.09 (s, 2H), 1.97- 2.04 (m, 5H), 1.90 (d, J = 2.0 Hz, 2H), 1.83 (d, J = 13.2 Hz, 2H), 1.62 (d, J = 13.2 Hz, 2H), 1.26 (s, 6H) 109 4- [3- (3,4-Difluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.68-7.77 (m, 2H), 7.29 (t, J = 9.6 Hz, 1H), 6.66 (s, 1H), 6.20 (d, J = 7.6 Hz, 1H) , 5.70 (brs, 1H), 5.55 (brs, 1H), 4.06 (t, J = 3.6 Hz, 1H), 2.40 (s, 2H), 2.08 (s, 2H), 1.96-2.04 (m, 5H), 1.90 (s, 2H), 1.81 (d, J = 13.6 Hz, 2H), 1.62 (d, J = 13.6 Hz, 2H), 1.27 (s, 6H) 110 4- [3- (2,3-Difluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.65-7.69 (m, 1H), 7.36-7.43 (m, 1H), 7.19-7.25 (m, 1H), 6.30 (s, 1H), 6.25 (d, J = 7.6 Hz, 1H), 5.63 (brs, 1H), 5.42 (brs, 1H), 4.08 (d, J = 7.6 Hz, 1H), 2.46 (s, 2H), 2.10 (s, 2H), 1.90-2.05 (m, 7H), 1.85 (d, J = 13.6 Hz, 2H), 1.63 (d, J = 14.0 Hz, 2H), 1.29 (s, 6H) 111 4- [3- (2,4-Difluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, DMSO) d 7.87-7.95 (m, 3H), 7.54 (s, 1H), 7.26 (s, 1H), 7.01 (s, 1H), 6.74 (s, 1H), 3.79 (s , 1H), 2.52 (s, 2H), 1.67-1.91 (m, 11H), 1.39 (d, J = 12.0 Hz, 2H), 1.16 (s, 6H) 112 4- [3- (2,5-Difluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.62-7.63 (m, 1H), 7.18-7.29 (m, 2H), 6.28-6.34 (m, 2H), 5.66 (brs, 1H), 5.48 (brs, 1H ) 4.08 (s, 1H), 2.47 (s, 2H), 1.85-2.10 (m, 11H), 1.61-1.70 (m, 2H), 1.29 (s, 6H) 113 4- [3- (2,6-Difluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.47-7.54 (m, 1H), 7.02 (t, J = 8.6 Hz, 2H), 6.27 (t, J = 7.6 Hz, 1H), 5.99 (s, 1H) , 5.58 (brs, 1H), 5.26 (brs, 1H), 4.07 (t, J = 7.6 Hz, 1H), 2.52 (s, 2H), 2.10 (s, 2H), 1.95-2.05 (m, 5H)) , 1.86-1.90 (m, 4H), 1.61 (d, J = 13.2 Hz, 2H), 1.34 (s, 6H) 114 4- [3- (3,5-Difluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.42-7.45 (m, 2H), 6.96-7.01 (m, 1H), 6.68 (s, 1H), 6.06 (d, J = 7.6 Hz, 1H), 5.63 ( brs, 1H), 5.57 (brs, 1H), 4.07 (d, J = 7.6 Hz, 1H), 2.39 (s, 2H), 2.00-2.08 (m, 7H), 1.90-1.91 (m, 2H), 1.79 (d, J = 13.2 Hz, 2H), 1.63 (d, J = 12.8 Hz, 2H), 1.30 (s, 6H) 115 4- [3- (4-Fluoro-2- (trifluoromethyl) -benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.29-8.33 (m, 1H), 7.56 (dd, J = 8.8, 2.8 Hz, 1H), 7.34-7.39 (m, 1H), 6.19 (d, J = 7.6 Hz, 1H), 6.09 (s, 1H), 5.57 (brs, 1H), 5.22 (brs, 1H), 4.09 (d, J = 7.6 Hz, 1H), 2.46 (s, 2H), 2.11 (s, 2H ), 2.00-2.05 (m, 5H), 1.91 (d, J = 2.4 Hz, 2H), 1.84 (d, J = 13.0 Hz, 2H), 1.63 (d, J = 13.0 Hz, 2H), 1.28 (s , 6H) 116 4- [3- (2-Fluoro-5- (trifluoromethyl) -benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.18-8.21 (m, 1H), 7.82-7.86 (m, 1H), 7.34 (t, J = 9.0 Hz, 1H), 6.57 (s, 1H), 6.21 ( d, J = 8.0 Hz, 1H), 5.65 (brs, 1H), 5.46 (brs, 1H), 4.08 (t, J = 3.8 Hz, 1H), 2.45 (s, 2H), 2.09 (s, 2H), 1.96-2.05 (m, 5H), 1.90 (s, 2H), 1.84 (d, J = 13.2 Hz, 2H), 1.63 (d, J = 13.2 Hz, 2H), 1.29 (s, 6H) 117 4- [3- (2-Chloro-4- (trifluoromethyl) -benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.24 (d, J = 8.4 Hz, 1H), 7.78 (s, 1H), 7.67 (dd, J = 8.4, 1.2 Hz, 1H), 6.71 (s, 1H) , 6.28 (d, J = 7.6 Hz, 1H), 5.67 (brs, 1H), 5.56 (brs, 1H), 4.08 (t, J = 3.8 Hz, 1H), 2.45 (s, 2H), 2.10 (s, 2H), 1.96-2.05 (m, 5H), 1.90 (s, 2H), 1.85 (d, J = 13.2 Hz, 2H), 1.63 (d, J = 13.2 Hz, 2H), 1.26 (s, 6H) 118 4- [3- (2,4,6-Trifluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 6.77-6.82 (m, 2H), 6.42 (s, 1H), 6.27 (d, J = 7.6 Hz, 1H), 5.68 (brs, 2H), 4.07 (d, J = 7.6 Hz, 1H), 2.49 (s, 2H), 1.95-2.09 (m, 7H), 1.84-1.90 (m, 4H), 1.61 (d, J = 12.8 Hz, 2H), 1.35 (s, 6H ) 119 4- [3- (2,3,4,5,6-pentafluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, DMSO) d 8.42 (brs, 1H), 7.87 (brs, 1H), 7.01 (s, 1H), 6.74 (s, 1H), 3.78 (d, J = 6.8 Hz, 1H), 2.41 (s, 2H), 1.73-1.91 (m, 11H), 1.37-1.41 (m, 2H), 1.26 (s, 6H) 120 4- [3-naphthalene-sulfonylamino-3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.46 (s, 1H), 7.86-7.97 (m, 4H), 7.52-7.66 (m, 2H), 6.22 (d, J = 6.8 Hz, 1H), 5.99 ( s, 1H), 5.58 (brs, 1H), 5.23 (brs, 1H), 4.07 (t, J = 3.8 Hz, 1H), 1.96-2.09 (m, 7H), 1.90 (s, 2H), 1.83 (d , J = 13.2 Hz, 2H), 1.60 (d, J = 13.2 Hz, 2H), 1.26 (s, 6H) 121 4- [3- (4'-Cyano- [1,1-biphenyl] -4-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, DMSO) d 7.91-7.99 (m, 8H), 7.75-7.79 (m, 2H), 6.98 (s, 1H), 6.72 (s, 1H), 3.80 (s, 1H), 2.39 (s, 2H), 1.72-1.91 (m, 11H), 1.31 (d, J = 11.6 Hz, 2H), 1.17 (s, 6H) 122 4- [3- (4'-Fluoro- [1,1-biphenyl] -4-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.87-7.90 (m, 2H), 7.57-7.64 (m, 2H), 7.48-7.52 (m, 2H), 7.07-7.13 (m, 2H), 6.32-6.34 (m, 1H), 6.25-6.27 (m, 1H), 5.68 (brs, 2H), 4.01 (s, 1H), 2.38 (s, 2H), 1.79-2.03 (m, 11H), 1.54 (d, J = 13.2 Hz, 2H), 1.17 (s, 6H) 123 4- [3- (2 ', 4'-Difluoro- [1,1-biphenyl] -4-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.94-7.97 (m, 2H), 7.62 (dd, J = 8.4, 1.6 Hz, 2H), 7.40-7.46 (m, 1H), 6.92-7.03 (m, 2H ), 6.31 (d, J = 8.0 Hz, 1H), 6.22 (s, 1H), 5.75 (brs, 1H), 5.68 (brs, 1H), 4.08 (d, J = 7.6 Hz, 1H), 2.46 (s , 2H), 1.90-2.10 (m, 9H), 1.86 (d, J = 13.6 Hz, 2H), 1.62 (d, J = 13.2 Hz, 2H), 1.29 (s, 6H) 124 4- [3- (2 ', 3,, 4'-Trifluoro- [1,1-biphenyl] -4-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amides

¹ H NMR (400 MHz, CDCl ₃ ) d 7.95 (t, J = 7.8 Hz, 1H), 7.36-7.47 (m, 3H), 6.94-7.04 (m, 2H), 6.43 (d, J = 7.6 Hz, 1H), 6.18 (s, 1H), 5.99 (brs, 1H), 5.73 (brs, 1H), 4.09 (d, J = 7.6 Hz, 1H), 2.51 (s, 2H), 1.96-2.11 (m, 7H ), 1.89 (d, J = 10.8 Hz, 4H), 1.62 (d, J = 13.2 Hz, 2H), 1.28 (s, 6H) 125 4- [3- (4'-Methyl- [1,1-biphenyl] -4-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.92-7.95 (m, 2H), 7.66-7.69 (m, 2H), 7.50-7.52 (m, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.43 (d, J = 8.0 Hz, 1H), 6.28 (s, 1H), 5.72 (brs, 1H), 5.62 (brs, 1H), 4.07 (d, J = 7.6 Hz, 1H), 2.46 (s, 2H ), 2.41 (s, 3H), 1.95-2.15 (m, 7H), 1.85-1.90 (m, 4H), 1.60 (d, J = 13.2 Hz, 2H), 1.27 (s, 6H) 126 4- [3- (4-cyclohexylphenyl-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.79 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 6.55 (d, J = 8.0 Hz, 1H), 6.02 (s , 1H), 5.79-5.81 (m, 2H), 4.05 (d, J = 7.6 Hz, 1H), 2.56 (s, 1H), 2.47 (s, 2H), 1.98-2.08 (m, 6H), 1.96- 1.89 (m, 9H), 1.77 (d, J = 12.4 Hz, 2H), 1.59 (d, J = 12.8 Hz, 2H), 1.39 (d, J = 4.8 Hz, 4H), 1.24 (s, 6H) 127 4- [3- (6-Morpholinopyridine-3-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 8.62 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 9.0, 2.6 Hz, 1H), 6.60 (d, J = 9.2 Hz, 1H), 6.33 (d, J = 7.6 Hz, 1H), 5.80 (brs, 1H), 5.62 (brs, 1H), 5.49 (s, 1H), 4.06 (d, J = 7.6 Hz, 1H), 3.81 (t, J = 5.0 Hz, 4H), 3.65 (t, J = 5.0 Hz, 4H), 2.47 (s, 2H), 2.05-2.09 (m, 7H), 1.85-1.91 (m, 4H), 1.62 (d, J = 13.2 Hz, 2H), 1.28 (s, 6H)

< Example  128> 4- [3- (3- Chloro -2- methyl -benzene- Sulfonylamino ) -3- methyl - Butyrylamino ] -N- methyl - Adamantan -One- Carboxylic acid  amides

20 mg (0.041 mmol) of E-4- [3- (3-chloro-2-methyl-benzenesulfonylamino) -3-butyrylamino] -adamantane-1-carboxylic acid prepared in Example 79 was prepared. Dissolve in 0.5 ml of dimethylacetamide, add 14.6 mg (0.045 mmol) of TBTU and 10.7 mg (0.083 mmol) of DIEA, stir for 10 minutes at room temperature, add 0.042 ml of methylamine (2.0 M solution in THF), and then add 20 ml at room temperature. Stirred for time. Extraction with ethyl acetate, drying with Na2SO4, column chromatography to separate 4- [3- (3-chloro-2-methyl-benzene-sulfonylamino) -3-methyl-butyrylamino] -N-methyl- 20.5 mg of adamantane-1-carboxylic acid amide (yield: 63%) were obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (dd, J = 8.0, 0.8 Hz, 1H), 7.55 (dd, J = 8.0, 1.2 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H) , 6.28 (s, 1H), 6.15 (d, J = 7.6 Hz, 1H), 5.62 (d, J = 4.0 Hz, 1H), 4.06 (t, J = 3.6 Hz, 1H), 2.80 (d, J = 4.8 Hz, 3H), 2.72 (s, 3H), 2.41 (s, 2H), 2.02-2.08 (m, 7H), 1.88 (d, J = 2.8 Hz, 2H), 1.81 (d, J = 13.6 Hz, 2H), 1.61 (d, J = 13.6 Hz, 1H), 1.24 (s, 6H)

By the same synthesis method as in Example 128, to prepare a compound of Examples 129 and 130 are shown in Table 11.

Example Name of compound rescue NMR data 129 4- [3- (3-Chloro-2-methyl-benzene-sulfonylamino) -3-methyl-butyrylamino] -N, N -dimethyl-adamantane-1-carboxylic acid amide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.97 (dd, J = 8.0, 1.2 Hz, 1H), 7.55 (dd, J = 8.0, 0.8 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H) , 6.27 (s, 1H), 6.12 (d, J = 7.2 Hz, 1H), 4.08 (d, J = 7.2 Hz, 1H), 3.07 (s, 6H), 2.72 (s, 3H), 2.41 (s, 2H), 2.20 (d, J = 12.0 Hz, 2H), 2.03-2.11 (m, 7H), 1.79 (d, J = 13.6 Hz, 2H), 1.62 (d, J = 13.6 Hz, 2H), 1.24 ( s, 6 H) 130 3- (2-Chloro-2-methyl-benzene-sulfonylamino) -3-methyl- N- (5- (pyrrolidine-1-carbonyl) adamantan-2-yl) butanamide

¹ H NMR (400 MHz, CDCl ₃ ) d 7.99 (dd, J = 8.0, 1.2 Hz, 1H), 7.55 (dd, J = 8.0, 0.8 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H) , 6.30 (s, 1H), 6.10 (d, J = 7.6 Hz, 1H), 4.08 (d, J = 7.6 Hz, 1H), 3.60 (brs, 4H), 2.72 (s, 3H), 2.40 (s, 2H), 2.01-2.17 (m, 9H), 1.85 (brs, 4H), 1.78 (d, J = 13.6 Hz, 2H), 1.63 (d, J = 13.6 Hz, 2H), 1.24 (s, 6H)

< Experimental Example  1> 11β- HSD1  Inhibitory effect test

In order to investigate the inhibitory activity of 11β-HSD1 of the compounds of the present invention, the following experiment was performed.

Various concentrations of test compounds dissolved in DMSO were diluted with pH 6.0 tris 20 mM EDTA 5 mM buffer, followed by addition of 160 nM of substrate cortisone (C2755, Sigma) and 200 μM of coenzyme NADPH (N1630, Sigma). A lOμl total volume reaction mixture was made by adding 11β-HSD1 as a microsomal fraction (M0317, Sigma) isolated from human liver and an 11β-HSD1 enzyme assay was performed on 384-well microtiter plates. After 2 hours of reaction at 37 ° C, 5 μl of europium cryptate-labeled anti-cortisol antibody and 5 μl of XL665-label cortisol were added using a cortisol assay (62CO2PEB, Cis bio). After additional reaction at room temperature for 2 hours, a homogeneous time-resolved fluorescence (HTRF) signal was measured. In each assay, the cortisol production was estimated by standard curves generated with several known concentrations of cortisol. Compound-free cortisol production was provided as a control and percent inhibition by the test compound at each concentration was calculated. Using inhibition curves calculated as the percentage of inhibition versus the concentration of the test compound, a 50% degree of inhibition (IC ₅₀ ) value of the compound for 11β-HSD1 was obtained and the results are shown in Table 12 below.

Example human IC ₅₀ (μM) Example human IC ₅₀ (μM) One 3.8 2 0.193 3 0.39 4 3.3 5 2.26 6 3.9 7 3.5 8 0.159 9 31 10 0.152 11 10.4 12 2.7 13 2.6 14 1.033 15 0.08 16 1.745 17 1.336 18 0.493 19 1.189 20 0.595 21 1.88 22 2.04 23 0.396 24 0.556 25 0.651 26 0.415 27 1.498 28 0.65 29 3.0 30 8.55 31 3.73 32 0.766 33 6.66 34 25 35 1.407 36 0.551 37 8.172 38 0.416 39 2.7 40 0.307 41 0.0017 42 0.004 43 0.0108 44 0.00503 45 0.00568 46 0.00308 47 0.0064 48 0.067 49 0.0050 50 0.0052 51 0.0058 52 0.0058 53 0.0054 54 0.0018 55 0.0072 56 0.0877 57 0.0531 58 1.0 59 0.112 60 0.0012 61 0.0162 62 0.0192 63 0.0307 64 0.0121 65 0.0085 66 0.0245 67 0.0018 68 0.0091 69 0.01 70 0.01 71 0.0047 72 0.0015 73 0.0007 74 0.0004 75 0.01 76 0.05 77 0.08 78 0.02 79 0.0573 80 0.00086 81 0.0007 82 0.0011 83 0.0013 84 0.0019 85 0.0009 86 0.0021 87 0.0022 88 0.0008 89 0.0021 90 0.0037 91 0.0006 92 0.001 93 0.0012 94 0.0063 95 0.0141 96 0.0017 97 0.0028 98 0.0007 99 0.0006 100 0.0009 101 0.0009 102 0.084 103 0.0011 104 0.0018 105 0.0013 106 0.0011 107 0.0013 108 0.0013 109 0.0024 110 0.0012 111 0.0072 112 0.0016 113 0.0068 114 0.0012 115 0.0009 116 0.0021 117 0.0016 118 0.0011 119 0.0038 120 0.0019 121 0.0011 122 0.0007 123 0.0006 124 0.0013 125 0.0007 126 0.0018 127 0.0254 128 0.186 129 0.233 130 3.436

As shown in Table 12, the compounds according to the present invention can be confirmed that the inhibitory activity of the inhibitory activity against 11β-HSD1 is 0.0004 to 5.8 μM, especially Examples 74, 80, 81, 85, 88, 91 , 98, 99, 100, 101, 115, 122, 123 and 125 showed an inhibitory activity of less than 0.0010 μM activity against 11β-HSD1. Thus, prevention or treatment of diseases caused by abnormally activated 11β-HSD1, such as insulin-independent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and diseases mediated by excessive glucocorticoid action This can be useful for.

Meanwhile, the compound represented by Formula 1 according to the present invention can be formulated into various forms according to the purpose. The following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

< Formulation example  1> Sanje  Produce

2 g of a compound of formula 1

1 g lactose

The above components were mixed and packed in airtight bags to prepare powders.

< Formulation example  2> Preparation of tablets

100 mg of compound of Formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg of magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

< Formulation example  3> Preparation of capsules

100 mg of compound of Formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg of magnesium stearate

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

< Formulation example  4> Preparation of injection

100 mg of compound of Formula 1

180 mg mannitol

Na ₂ HPO ₄ 2H ₂ O 26 mg

2974 mg of distilled water

According to a conventional method for preparing an injection, an injection was prepared by containing the above components in the contents shown.

Claims (8)

A compound having an inhibitory activity of the 11β-HSD1 enzyme represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

(In the formula 1,
X is carbonyl or sulfonyl;
R ¹ is C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl, 5-6 membered heteroaryl containing one or more heteroatoms of N or O in the ring, C ₆ -C ₁₀ aryl C ₁ ~ C ₃ is a linear or branched alkyl or C of ₃ ~ C ₆ cycloalkyl C ₁ ~ C ₃ straight or branched alkyl;
In this case, the aryl is unsubstituted or substituted by one or more halogens, unsubstituted or straight or branched chain of a C ₁ substituted with one or more halogen ~ C ₄ alkyl, straight or branched chain of a C ₁ ~ C ₄ substituted with an unsubstituted or at least one halogen C ₆ -C ₁₀ aryl substituted with alkoxy, nitro, amino, cyano, formamide, unsubstituted or one or more cyano, halogen, C ₁ -C ₄ straight or branched alkyl, and C ₃ -C ₆ cycloalkyl Substituted with a substituent selected from the group consisting of;
The heteroaryl is unsubstituted or substituted with methyl, ethyl, isopropyl, trifluoromethyl or morpholinopyridine;
R ² and R ³ are each independently one hydrogen and the other adamantyl,
The adamantyl is unsubstituted or hydroxy, methylsulfonyl, C ₁ to C ₄ straight or branched chain alkylsulfanyl, formamide, methylformamide, dimethylformamide, pyrrolidinecarbonyl, ethanethioate and carboxyl. Substituted with a substituent selected from the group consisting of carboxyl;
R ⁴ and R ⁵ may each independently form C ₃ -C ₆ cycloalkyl with C ₁ -C ₄ straight or branched alkyl, or with the carbon atom or adjacent nitrogen atom to which they are attached).
delete The method of claim 1,
X is carbonyl or sulfonyl;
R ¹ is isooxazolyl substituted with cyclopropyl, phenyl, morpholinyl, pyridinyl, isopropyl, phenylmethyl, phenylcyclopropyl, cyclopropyl methyl, naphthalenyl;
Wherein the phenyl is unsubstituted or one or more of F, Cl, methyl, t-butyl, methoxy, nitro, amino, cyano, trifluoromethyl, trifluoromethoxy, formamide, cyanophenyl, fluorophenyl, di Substituted with a substituent selected from the group consisting of fluorophenyl, methylphenyl and cyclohexyl;
The heteroaryl is unsubstituted or substituted with isopropyl, trifluoromethyl or morpholinopyridine;
R ² and R ³ are each independently one hydrogen and the other adamantyl,
Wherein the adamantyl is unsubstituted or selected from the group consisting of hydroxy, methylsulfonyl, methylsulfanyl, formamide, methylformamide, dimethylformamide, pyrrolidinecarbonyl, ethylthioate and carboxyl Substituted with a substituent;
R ⁴ and R ⁵ are each independently hydrogen or methyl, or a compound having a inhibitory activity of 11β-HSD1 enzyme, or a pharmaceutically acceptable salt thereof, characterized in that they form cyclopropyl together with the carbon atom to which they are attached.
The compound of claim 1, wherein
15) N-adamantan-1-yl-3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-butyrylamide;
16) 3- (3-chloro-2-methyl-benzenesulfonylamino) -N- (3-hydroxy-adamantan-1-yl) -3-methyl-butyramide;
17) N-adamantan-1-yl-3- (4-t-butyl-benzenesulfonylamino) -3-methyl-butyramide;
18) N-adamantan-1-yl-3-methyl-3- (naphthalene-2-sulfonylamino) -butyramide;
19) N-adamantan-1-yl-3- (4-methoxy-benzenesulfonylamino) -3-methyl-butyramide;
20) N-adamantan-1-yl-3-methyl-3- (toluene-4-sulfonylamino) -butyramide;
21) N-adamantan-1-yl-3-methyl-3- (4-nitro-benzenesulfonylamino) -butyramide;
22) N-adamantan-1-yl-3-methyl-3-phenylmethanesulfonylamino-butyramide;
23) N-adamantan-1-yl-3- (3-chloro-benzenesulfonylamino) -3-methyl-butyramide;
24) N-adamantan-1-yl-3- (3-fluoro-benzenesulfonylamino) -3-methyl-butyramide;
25) N-adamantan-1-yl-3-methyl-3- (4-trifluoromethoxy-benzenesulfonylamino) -butyramide;
26) N-adamantan-1-yl-3-methyl-3- (3-trifluoromethyl-benzenesulfonylamino) -butyramide;
27) N-adamantan-1-yl-3-methyl-3- (3-nitro-benzenesulfonylamino) -butyramide;
28) N-adamantan-1-yl-3- (2-chloro-4-cyano-benzenesulfonylamino) -3-methyl-butyrylamide;
29) N-adamantan-1-yl-3-benzenesulfonylamino-3-methyl-butyrylamide;
30) cyclopropanecarboxylic acid [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethyl] -amide;
31) N-adamantan-1-yl-3-methyl-3- (3-methyl-aminobutyric acid) -butyramide;
32) N-adamantan-1-yl-3- (4-amino-benzenesulfonylamino) -3-methyl-butyrylamide;
33) N-adamantan-1-yl-3- (3-amino-benzenesulfonylamino) -3-methyl-butyrylamide
34) 4- [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethylsulfamoyl] -3-chloro-benzamide;
35) N- [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethyl] -5-fluoro-2-methyl-benzamide;
36) N- [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethyl] -4-methyl-benzamide;
37) 5-isopropyl-isoxazole-3-carboxylic acid [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethyl] -amide;
38) N- [2- (adamantane-1-ylcarbamoyl) -1,1-dimethyl-ethyl] -3-chloro-2-methyl-benzamide;
39) N-adamantan-1-yl-3- (2-cyclopropyl-acetylamino) -3-methyl-butyramide;
40) N-adamantan-1-yl-3- [2- (2-methoxy-phenyl) -acetylamino] -3-methyl-butyramide;
41) N-adamantan-2-yl-3- (2,6-dichloro-benzenesulfonylamino) -3-methyl-butyrylamide;
42) N-adamantan-2-yl-3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-butyramide;
43) N-adamantan-2-yl-3- (4-fluoro-2-trifluoromethyl-benzenesulfonylamino) -3-methyl-butyramide;
44) N-adamantan-2-yl-3- (2-fluoro-benzenesulfonylamino) -3-methyl-butyramide;
45) N-adamantan-2-yl-3- (4′-cyano-biphenyl-4-sulfonylamino) -3-methyl-butyramide;
46) N-adamantan-2-yl-3-methyl-3- (toluene-2-sulfonylamino) -butyramide;
47) N-adamantan-2-yl-3- (4-fluoro-2-methyl-benzenesulfonylamino) -3-methyl-butyramide;
48) N-adamantan-2-yl-3- (2,4-difluoro-benzenesulfonylamino) -3-methyl-butyrylamide;
49) N-adamantan-2-yl-3- (2-chloro-4-fluoro-benzenesulfonylamino) -3-methyl-butyramide;
50) N-adamantan-2-yl-3- (4-chloro-2-fluoro-benzenesulfonylamino) -3-methyl-butyrylamide;
51) N-adamantan-2-yl-3-methyl-3- (2,4,6-trifluoro-benzenesulfonylamino) -butyramide;
52) N-adamantan-2-yl-3-benzenesulfonylamino-3-methyl-butyrylamide;
53) N-adamantan-2-yl-3- (2,6-difluoro-benzenesulfonylamino) -3-methyl-butyrylamide;
54) N-adamantan-2-yl-3- (2-chloro-6-methyl-benzenesulfonylamino) -3-methyl-butyramide;
55) N-adamantan-2-yl-3-methyl-3- (2-trifluoromethyl-benzenesulfonylamino) -butyramide;
56) N-adamantan-2-yl-3- (3-chloro-2-methyl-benzenesulfonylamino) -butyramide;
57) N-adamantan-2-yl-3- (3-chloro-2-methyl-benzenesulfonylamino) -butyramide;
58) N-adamantan-2-yl-3- (naphthalene-2-sulfonylamino) -butyramide;
59) N-adamantan-2-yl-3- (naphthalene-2-sulfonylamino) -butyramide;
60) N-adamantan-2-yl-2- [1- (3-chloro-2-methyl-benzenesulfonylamino) -cyclopropyl] -acetamide;
61) N- [2- (adamantane-2-ylcarbamoyl) -1,1-dimethyl-ethyl] -3-chloro-2-methyl-benzamide;
62) N-adamantan-2-yl-3- [2- (2-methoxy-phenyl) -acetylamino] -3-methyl-butyramide;
63) 1-phenyl-cyclopropanecarboxylic acid [2- (adamantane-2-ylcarbamoyl) -1,1-dimethyl-ethyl] -amide;
64) N- [2- (adamantane-2-ylcarbamoyl) -1,1-dimethyl-ethyl] -3,4-dichloro-benzamide;
65) 3- (3-chloro-2-methyl-benzenesulfonylamino) -N- (5-hydrocy-adamantan-2-yl) -3-methyl-butyrylamide;
66) 3- (3-chloro-2-methyl-benzenesulfonylamino) -N- (5-hydrocy-adamantan-2-yl) -3-methyl-butyramide;
67) 3- (3-chloro-6-methyl-benzenesulfonylamino) -N- (5-hydrocy-adamantan-2-yl) -3-methyl-butyramide;
68) 3- (2-chloro-4-fluoro-benzenesulfonylamino) -N- (5-hydrocy-adamantan-2-yl) -3-methyl-butyramide;
69) 3- (3-chloro-benzenesulfonylamino) -N- (5-hydrocy-adamantan-2-yl) -3-methyl-butyramide;
70) 3- (3-chloro-2-fluoro-benzenesulfonylamino) -N- (5-hydrocy-adamantan-2-yl) -3-methyl-butyramide;
71) methanesulfonic acid 4- [3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantan-1-yl ester;
72) methanesulfonic acid 4- [3- (2-chloro-6-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantan-1-yl ester;
73) 3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-N- (5-methylsulfanyl-adamantan-2-yl) -butyramide;
74) 3- (2-chloro-6-methyl-benzenesulfonylamino) -3-methyl-N- (5-methylsulfanyl-adamantan-2-yl) -butyramide;
75) 4- [3- (3-Chloro-2-methyl-benzene-sulfonylamino) -3-methyl-butyrylamino] adamantan-1-yl-ethanechiate;
76) 3- (3-chloro-2-methyl-benzene-sulfonylamino) -3-methyl-N- (5-methylsulfonyl-adamantan-2-yl) butanamide;
77) 3- (3-chloro-2-fluoro-benzene-sulfonylamino) -3-methyl-N- (5-methylsulfonyl-adamantan-2-yl) butanamide;
78) 3- (3-chloro-2-methyl-benzene-sulfonylamino) -3-methyl-N- (5-methylsulfonyl-adamantan-2-yl) butanamide;
79) 4- [3- (3-chloro-2-methyl-benzenesulfonylamino) -3-butyrylamino] -adamantane-1-carboxylic acid;
80) 4- [3- (3-chloro-2-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
81) 4- [3- (2-chloro-6-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
82) 4- [3- (2-chloro-4-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
83) 4- [3- (4-chloro-2-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
84) 4- [3- (2-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
85) 4- [3- (2-trifluoromethyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
86) 4- [3- (2-chloro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
87) 4- [3- (2-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
88) 4- [3- (3-chloro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
89) 4- [3- (3-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
90) 4- [3- (3-trifluoromethyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
91) 4- [3- (3-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
92) 4- [3- (4-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
93) 4- [3- (4-trifluoromethyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
94) 4- [3- (pyridine-3-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
95) 4- [3- (6-trifluoromethyl-pyridine-3-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
96) 4- [3- (2-chloro-4-cyano-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
97) 4- [3- (4-carbamoyl-2-chloro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
98) 4- [3- (2,3-dichloro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
99) 4- [3- (3,5-Dichloro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
100) 4- [3- (3-chloro-4-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
101) 4- [3- (3-chloro-4-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
102) 4- [3- (3-chloro-2-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
103) 4- [3- (5-chloro-2-fluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
104) 4- [3- (2-fluoro-3-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
105) 4- [3- (2-Fluoro-4-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
106) 4- [3- (2-Fluoro-5-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
107) 4- [3- (2-Fluoro-5-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
108) 4- [3- (3-fluoro-4-methyl-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
109) 4- [3- (3,4-difluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
110) 4- [3- (2,3-difluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
111) 4- [3- (2,4-Difluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
112) 4- [3- (2,5-difluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
113) 4- [3- (2,6-difluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
114) 4- [3- (3,5-difluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
115) 4- [3- (4-Fluoro-2- (trifluoromethyl) -benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
116) 4- [3- (2-Fluoro-5- (trifluoromethyl) -benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
117) 4- [3- (2-Chloro-4- (trifluoromethyl) -benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
118) 4- [3- (2,4,6-trifluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
119) 4- [3- (2,3,4,5,6-pentafluoro-benzenesulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
120) 4- [3-naphthalene-sulfonylamino-3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
121) 4- [3- (4'-cyano- [1,1'-biphenyl] -4-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
122) 4- [3- (4'-fluoro- [1,1'-biphenyl] -4-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
123) 4- [3- (2 ', 4'-difluoro- [1,1'-biphenyl] -4-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amides;
124) 4- [3- (2 ', 3,4'-trifluoro- [1,1'-biphenyl] -4-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1 Carboxylic acid amides;
125) 4- [3- (4'-methyl- [1,1'-biphenyl] -4-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
126) 4- [3- (4-cyclohexylphenyl-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
127) 4- [3- (6-morpholinopyridine-3-sulfonylamino) -3-methyl-butyrylamino] -adamantane-1-carboxylic acid amide;
128) 4- [3- (3-chloro-2-methyl-benzene-sulfonylamino) -3-methyl-butyrylamino] -N-methyl-adamantane-1-carboxylic acid amide;
129) 4- [3- (3-chloro-2-methyl-benzene-sulfonylamino) -3-methyl-butyrylamino] -N, N-dimethyl-adamantane-1-carboxylic acid amide; And
130) 3- (2-chloro-2-methyl-benzene-sulfonylamino) -3-methyl-N- (5- (pyrrolidine-1-carbonyl) adamantan-2-yl) butanamide A compound having an inhibitory activity of an 11β-HSD1 enzyme selected from the group consisting of or a pharmaceutically acceptable salt thereof.
As shown in Scheme 1, the inhibitory activity of the 11β-HSD1 enzyme of claim 1 comprising the step of preparing a compound of Formula 1 by reacting a substituted sulfonyl or acetyl halide of Formula 3 with an amine derivative of Formula 2 Preparation of Compounds Having:
[Reaction Scheme 1]

(In Scheme 1, R ¹ to R ⁵ , and X are as defined in Formula 1 of claim 1).
As shown in Scheme 2, a method for preparing a compound having an inhibitory activity of the 11β-HSD1 enzyme of claim 1 comprising the step of preparing a compound of Formula 1 by reacting a carboxylic acid of Formula 5 with an amine derivative of Formula 4 :
[Reaction Scheme 2]

(In Scheme 2, R ¹ to R ⁵ , and X are as defined in Formula 1 of claim 1).
Insulin-independent type 2 diabetes, insulin resistance, obesity, glaucoma, arteriosclerosis, hypertension, dyslipidemia, dementia and osteoporosis containing the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition for preventing or treating a disease caused by the overactivity of 11β-HSD1. delete