KR20160108281A - Compounds with cardiac myosin activating function and pharmaceutical composition containing the same for treating or preventing heart failure - Google Patents

Abstract

The present invention relates to a compound having a cardiotonic activating function and a pharmaceutical composition containing the same. The composition comprising the compound according to the present invention is effective in preventing or treating heart failure. In addition, the compound is represented by chemical formula 2 or is pharmaceutically acceptable salt thereof.

Description

TECHNICAL FIELD The present invention relates to a compound having cardiac activity and a pharmaceutical composition for preventing or treating heart failure containing the same,

TECHNICAL FIELD The present invention relates to a novel compound having a cardiac activity and a pharmaceutical composition containing the same.

Heart Failure (HF) refers to a group of diseases caused by a heart's structural or functional abnormality that causes the heart to receive blood, or the ability to shrink the blood-shrinking contractions, resulting in poor blood supply to the body's tissues . The most common and important symptom is dyspnea. Dyspnea is mainly caused by congestion of the blood in the heart, resulting in increased pressure of the ventricle, resulting in stagnation of blood in the pulmonary blood vessels entering the heart, resulting in coughing. Difficulty breathing depends on the degree of difficulty breathing during exercise, dyspnea difficulty, paroxysmal nocturnal dyspnea and progresses.

The prevalence of heart failure is expected to increase steadily due to the chronic aging of patients with past acute heart failure due to the aging of the population as the lifespan increases and the development of medical technology. However, accurate statistics on heart failure prevalence have not been reported in Korea, (Han et al., 2005, Korean Circulation Journal, 35, 357-361). In addition, worldwide, there are about 5.7 million new heart failure patients each year, which is expected to increase the number of heart failure patients (Gallagher, R. 2010. European Journal of Cardiovascular Nursing, 9, 153-160).

Medications for the treatment of heart failure include cardiotonics, diuretics, and vasodilators.

Double-cardioplegia is a drug that affects the contraction of the myocardium and strengthens the heartbeat. Conventional heart failure medication indirectly activates myocardial contraction, but its side effects are severe and its effects are limited. In addition, existing cardiomyocyte fibrils such as Dobutamine or Milrinone increase the intracellular calcium concentration and increase the contractility of cardiac cells. However, these effects on calcium concentrations have life-threatening side effects. In addition, myocardial contractile mechanisms of existing drugs increase the rate of cardiac contraction and shorten the systolic ejection time.

Therefore, it is necessary to develop a new therapeutic agent for heart failure, which directly accelerates myocardial contraction.

Amgen 's omecamtiv mecarbil is currently under development, but it needs to develop more drugs that can improve heart function with little change in oxygen consumption and systolic Ca ⁺² concentration of myocardial cells.

International Publication No. WO 2011/133882 discloses compounds that modulate skeletal muscle contractility of amino-pyridazines. Also, International Publication Nos. WO 2004/064730 and WO 2006/009726 disclose certain substituted urea derivatives that are useful in the treatment of heart failure.

WO 2011/133882 (CERTAIN AMINO-PYRIDAZINES, COMPOSITIONS THEREOF, AND METHODS OF THEIR USE, published on October 27, 2011) WO 2004/064730 (COMPOUNDS, COMPOSITIONS AND METHODS, published Aug. 4, 2004) WO 2006/009726 (COMPOUNDS, COMPOSITIONS AND METHODS, Jan. 26, 2006)

Han et al., 2005, Korean Circulation Journal, 35, 357-361. Gallagher, R. 2010. Self-management, symptom monitoring and associated factors. European Journal of Cardiovascular Nursing, 9, 153-160. Pollard, T.D. 1982. Myosin purification and characterization. Methods in Cell Biology, 24, 333-371. Vahey, M. 1983. A 72,000-mol-wt protein from tomato inhibits rabbit acto-S-1 ATPase activity. Journal Cell Biology, 96, 1761-1765. Straight, A.F. et al., 2002. Nature Cell Biology, 4, 83.

The present invention provides a compound having cardiac activity and a pharmaceutical composition for preventing or treating heart disease containing the compound.

In order to accomplish the above object, the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof as described below.

In another embodiment, the present invention also provides a compound of formula 2, or a pharmaceutically acceptable salt thereof, as described below.

In another aspect, the present invention also provides a pharmaceutical composition for the treatment and prevention of acute and chronic heart diseases comprising a compound of the formula (1) or (2) or a salt thereof. The pharmaceutical composition according to the present invention may be useful for the treatment of acute and chronic heart diseases including cardiac contractile heart failure, diastolic heart failure, or congestive heart failure through the activation of myocardial myosin ATPase.

The present invention is based on the discovery that a compound obtained through a structural activity relationship of a myocardial myosin activator containing a compound based on a urea structure and an amide structure is useful for prevention or treatment of heart disease.

Accordingly, in one aspect the present invention relates to a compound of the formula 1 EMI5.1 or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

1) when R ₁ and R ₂ do not form a ring with N ₁ (and R ₁ and R ₃ do not form a ring with N ₁ and N ₂ ), R ₁ is -C ₀ -C ₁₀ Alkyl-phenyl wherein said phenyl is optionally substituted with one or more of hydrogen, halogen, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, CO ₂ H, NO ₂ , NR'R ", NHSO ₂ CH ₃ or -SO ₂ NR'R (Wherein R 'and R "are each hydrogen or C ₁ -C ₅ alkyl); -C ₀ -C ₁₀ alkyl-heteroaryl, wherein said alkyl may be substituted with alkoxycarbonyl; -C ₀ -C ₁₀ alkyl-cycloalkyl {wherein the cycloalkyl can be replaced by OH}; -C ₀ -C ₁₀ alkyl-heterocycloalkyl; -NHCO-heteroaryl; C ₁ -C ₁₀ alkyl {wherein said alkyl can be substituted by hydroxy}; or partially hydrogenated polycyclic benzene ring {wherein the benzene ring may be substituted with one or more C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy} and ;

R ₂ is hydrogen; Or C ₁ -C ₅ alkyl; R ₃ is (C ₁ -C ₅₎ alkyl-phenyl {wherein the phenyl is one or more hydrogen, C ₁ -C ₅ alkoxy, or -SO ₂ NR'R "(R 'and R" are each hydrogen or C ₁ -C ₅ Alkyl); Or cycloalkyl; And R ₄ is hydrogen; Or C ₁ -C ₅ alkyl,

2) when R ₁ and R _{2 together} with N ₁ form a ring, the ring formed by R ₁ , R ₂ and N ₁ is a heterocycloalkyl or partially hydrogenated heteroaryl containing N, Is selected from the group consisting of one or more of hydrogen, hydroxy, -CO ₂ H, -CONH ₂ , C ₁ -C ₅ alkyl {wherein the alkyl may be substituted with one or more OH, C ₁ -C ₅ alkyl}, C ₁ -C ₅ alkoxy, {at least one hydrogen, halogen, SO ₂ NR'R be substituted by "(R 'and R" each represent a hydrogen or C ₁ -C _{5 alkyl)}, -SO 2 - (C} 1 -C 5) alkyl, SO ₂ - Heterocycloalkyl; And R ₃ and R ₄ are each as defined above, or R ₃ and R ₄ together with N ₂ may form an indole ring,

3) When R ₁ and R _{3 together} with N ₁ and N ₂ form a ring, R ₁ and R ₃ can form a tetrahydropyrimidin-2 (1H) -one ring together with two N of urea And said ring is optionally substituted with phenyl; R ₃ and R ₄ are each hydrogen or C ₁ -C ₁₀ alkyl-phenyl.

(1) when R ₁ and R ₂ do not form a ring together with N ₁ (and R ₁ and R ₃ do not form a ring together with N ₁ and N ₂ ), and R ₁ is C ₀ -C ₅ alkyl-phenyl, wherein the phenyl is optionally substituted with one or more of hydrogen, halogen, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, CO ₂ H, NO ₂ , NH ₂ , N (CH ₃ ) _2, NHSO ₂ CH _3, SO ₂ NH _2, or SO ₂ N (CH _{3) 2}} can be replaced by; 2-pyridyl-ethyl, 2-thiophenyl-methyl, 2-thio-phenylethyl, 2-furanyl-methyl, (3-imidazol-1-yl) propyl, 1- (methoxycarbonyl) -2- Pyrroleethyl, 3-morpholinopropyl, tetrahydro-2H-pyran-4-yl, (tetrahydro-2H-pyran-4-yl) methyl, N-methylpiperidin-4-yl; Cyclohexyl, cyclohexylmethyl, cyclohexylethyl, hydroxycyclohexyl; -NHCO-pyridine; 3-hydroxypropyl; Or dihydroindanyl, tetrahydronaphthyl, or tetrahydronaphthyl substituted with one or more methyl or methoxy; R ₂ is hydrogen; Or C ₁ -C ₅ alkyl; R ₃ is (C ₁ -C ₅ ) alkyl-phenyl {said phenyl may be substituted with one or more of hydrogen, halogen, C ₁ -C ₅ alkoxy, SO ₂ NH ₂ , or SO ₂ N (CH ₃ ) ₂ ; Or cyclohexyl; And R ₄ is hydrogen; Or C ₁ -C ₅ alkyl;

2) when R ₁ and R _{2 together} with N ₁ form a ring, the ring formed by R ₁ , R ₂ and N ₁ is selected from aziridine, pyrrolidine, piperidine, 1,4-dioxa- Dihydrothieno [3,2-c] pyridine, tetrahydroisoquinoline, or 6,7-dihydrothieno [3,2-c] pyridine and the ring is one or more of hydrogen, _{hydroxy, -CO 2 H, -CONH 2,} C 1 -C 5 alkyl {wherein said alkyl can be substituted with one or more OH, C ₁ -C ₅ alkoxy}, C ₁ -C ₅ alkoxy, phenyl {wherein the phenyl is one or more hydrogen, halogen, SO ₂ NH _2, or SO ₂ N (CH ₃₎ can be replaced with _{2}, SO 2 CH 3,} 4- methyl-1-ylsulphonyl, or Morpholinosulfonyl; And R ₃ and R ₄ are each as defined above, or R ₃ and R _{4 together} with N ₂ can form an indole ring;

3) When R ₁ and R _{3 together} with N ₁ and N ₂ form a ring, R ₁ and R ₃ can form a tetrahydropyrimidin-2 (1H) -one ring together with two N of urea And said ring is optionally substituted with phenyl; R ₃ and R ₄ are each hydrogen or (C ₁ -C ₅ ) alkyl-phenyl.

The term " alkyl " in the present invention refers to a straight or branched chain saturated hydrocarbon group of a single bond, for example, methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl and 1-methylpropyl.

The term " alkoxy " of the present invention refers to an oxygen group to which a single bond of a linear or branched saturated hydrocarbon is bonded, and includes, for example, methoxy, ethoxy, propoxy, n-butoxy, Propoxy and the like.

The term " cycloalkyl " in the present invention refers to a saturated, single bond saturated hydrocarbon group, and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like are available depending on the number of carbon atoms.

The term " heterocycloalkyl " in the present invention refers to a saturated monocyclic saturated hydrocarbon group containing at least one heteroatom such as N, O, or S, and includes a number and kind of heteroatoms contained in the ring, Such as aziridine, pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, tetrahydropyran and the like.

The term "heteroaryl" as used herein means an aromatic ring compound containing at least one heteroatom such as N, O, or S, and the number and type of heteroatoms contained in the ring, and the number of carbon atoms of pyridine, indole, iso And indole.

Hereinafter, the numbers given before each compound in the present specification indicate the numbers of the examples.

More specifically, the compound of formula (1) of the present invention is as follows:

1. (R) -2-Phenyl-N - (3-phenylpropyl) aziridine-1-carboxamide;

4. 1-Phenethyl-3- (3-phenylpropyl) urea;

5. 1,3-Bis (3-phenylpropyl) urea;

7. 4-Phenyl-N- (4-phenylbutyl) piperidine-1-carboxamide;

8. 1- (2,3-Dihydro-1H-inden-1-yl) -3- (3-phenylpropyl) urea;

12. 2-Phenyl-N- (4-phenylbutyl) pyrrolidine-1-carboxamide;

13. 2-Phenyl-N- (4-phenylbutyl) piperidine-1-carboxamide;

16. 1- (4-Nitrophenethyl) -3- (3-phenylpropyl) urea;

18. 1-Methyl-1-phenethyl-3- (3-phenylpropyl) urea;

19. 1,3-Dimethyl-1-phenethyl-3- (3-phenylpropyl) urea;

20. 3- (Hydroxymethyl) -N- (3-phenylpropyl) piperidine-1-carboxamide;

22. 1- (Cyclohexylmethyl) -3- (3-phenylpropyl) urea;

23. 1- (2-Cyclohexylethyl) -3- (3-phenylpropyl) urea;

24. 1- (4-Aminophenethyl) -3- (3-phenylpropyl) urea;

25. N - (4- (2- (3- (3-Phenylpropyl) ureido) ethyl) phenyl) methanesulfonamide;

27. 2-Isonicotinoyl-N- (3-phenylpropyl) hydrazinecarboxamide;

30. 4- (Hydroxymethyl) -N- (3-phenylpropyl) piperidine-1-carboxamide;

31. 3- (Methoxymethyl) -N- (3-phenylpropyl) piperidine-1-carboxamide;

32. 4- (2-Hydroxyethyl) -N- (3-phenylpropyl) piperidine-1-carboxamide;

34. 4- (Hydroxymethyl) -N-phenethylpiperidine-1-carboxamide;

35. 3-Hydroxy-N- (3-phenylpropyl) piperidine-1-carboxamide;

36. N, N-Dimethyl-4- (2- (3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide;

38. N-phenethyl-4-phenylpiperidine-1-carboxamide;

40. 4-Benzyl-N-phenethylpiperazine-1-carboxamide;

41. 4- (2- (1,3-Dimethyl-3- (3-phenylpropyl) ureido) ethyl) N, N-dimethylbenzenesulfonamide;

42. 4-Hydroxy-N- (3-phenylpropyl) piperidine-1-carboxamide;

43. 4-Methyl-N- (3-phenylpropyl) piperazine-1-carboxamide;

44. 4-Methoxy-N- (3-phenylpropyl) piperidine-1-carboxamide;

45. 4-Methoxy-N-methyl-N- (3-phenylpropyl) piperidine-1-carboxamide;

48. 3-Phenyl-N- (3-phenylpropyl) piperidine-1-carboxamide;

49. 1- (2,3-Dihydro-1H-inden-2-yl) -3- (3-phenylpropyl) urea;

50. 1,3-Bis (3-phenylpropyl) tetrahydropyrimidin-2 (1H) -one;

52. 1- (3-Phenylpropyl) -3- (thiophen-2-ylmethyl) urea;

53. 1- (4-Methylphenethyl) -3- (3-phenylpropyl) urea;

54. 1- (3-Cyclohexylpropyl) -3-phenethyl urea;

56. 1- (2-Cyclohexylethyl) -3- (3-cyclohexylpropyl) urea;

58. 2-Phenyl-N- (3-phenylpropyl) piperidine-1-carboxamide;

59. 4- (3- (3-Phenylpropyl) ureido) benzenesulfonamide;

60. 4- (2- (3- (3-Phenylpropyl) ureido) ethyl) benzenesulfonamide;

61. 4 - ((3- (3-Phenylpropyl) ureido) methyl) benzenesulfonamide;

63. 4- (3- (3-Phenylpropyl) ureido) benzoic acid;

64. 1- (3-Chloro-2-fluorophenyl) -3- (3-phenylpropyl) urea;

68. 1- (2-tert-Butylphenyl) -3- (3-phenylpropyl) urea;

69. 1- (2-Isopropylphenyl) -3- (3-phenylpropyl) urea;

70. N- (3-phenylpropyl) -6,7-dihydrothieno [3,2-c] pyridin-5 (4H) -carboxamide;

71. 1-Benzyl-4-phenyltetrahydropyrimidin-2 (1H) -one;

72. 4-Phenyl-1- (3-phenylpropyl) tetrahydropyrimidin-2 (1H) -one;

73. 4-Methylsulfonyl-N- (3-phenylpropyl) piperazine-1-carboxamide;

76. 4- (Methoxymethyl) -N- (3-phenylpropyl) piperidine-1-carboxamide;

78. 4- (2- (1-Ethyl-3- (3-phenylpropyl) ureido) ethyl) -N, N-dimethylbenzenesulfonamide;

79. 4- (2- (1,3-Diethyl-3- (3-phenylpropyl) ureido) ethyl) -N, N-dimethylbenzenesulfonamide;

80. 4- (2- (1-Isopropyl-3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide;

81. 4- (2 (1-Isopropyl-3- (3-phenylpropyl) ureido) ethyl) -N, N-dimethylbenzenesulfonamide;

82. 4- (2 (1-Isopropyl-3-methyl-3- (3-phenylpropyl) ureido) ethyl) -N, N-dimethylbenzenesulfonamide;

83. 1 - ((lH-Indol-5-yl) methyl) -3- (3-phenylpropyl) urea;

84. 6,7-Dimethoxy-1-methyl-N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -carboxamide;

85. N-phenethyl-1-phenyl-1,2,3,4-tetrahydroisoquinolin-2 (1H) -carboxamide;

86. N- (3,4-Dimethoxyphenethyl) -1-phenyl-1,2,3,4-tetrahydroisoquinolin-2 (1H) -carboxamide;

87. 4- (2- (1-Methyl-3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide;

88. 1- (2- (Furan-2-yl) ethyl) -3- (3-phenylpropyl) urea;

90. N, N-Dimethyl-4 - ((3- (3-phenylpropyl) ureido) methyl) benzenesulfonamide;

91. 4 - ((1,3-Dimethyl-3- (3-phenylpropyl) ureido) methyl) -N, N-dimethylbenzenesulfonamide;

92. 1- (3-1H-imidazol-1-yl) propyl) -3-phenethyl urea;

93. 1- (3-Morpholinopropyl) -3-phenethyl urea;

94. 1-Phenyl-N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -carboxamide;

95. 1- (4-Chlorophenyl) -7-methoxy-N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -carboxamide;

96. N- (3-Phenylpropyl) -7-sulfamoyl-1,2,3,4-tetrahydroisoquinolin-2 (1H) -carboxamide;

97. 7- (N, N-Dimethylsulfamoyl) -N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -carboxamide;

98. 7- (4-Methylpiperazin-1-ylsulfonyl) -N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -carboxamide;

99. 7- (Morpholinosulfonyl) -N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -carboxamide;

100. N, N-Dimethyl-4- (2- (1-methyl-3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide;

101. 4- (2- (3-Methyl-3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide;

102. N, N-Dimethyl-4- (2- (3-methyl-3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide;

103. 7- (N, N-Dimethylsulfamoyl) -N-methyl-N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -carboxamide;

104. N- (3-Phenylpropyl) -1,2,3,4-tetrahydroquinoline-1 (2H) -carboxamide;

105. N- (4-Phenylbutyl) -1,2,3,4-tetrahydroquinoline-1 (2H) -carboxamide;

106. N- (4-Phenylbutyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -carboxamide;

108. N-methyl-N- (4-phenylbutyl) indoline-1-carboxamide;

109. N-methyl-N- (3-phenylpropyl) indoline-1-carboxamide;

111. N-methyl-N- (3-phenylpropyl) isoindoline-2-carboxamide;

116. N-methyl-N- (4-phenylbutyl) isoindoline-2-carboxamide;

117. 1- (4-Isopropylphenethyl) -3- (3-phenylpropyl) urea;

118. 1- (2-Morpholinethyl) -3- (3-phenylpropyl) urea;

119. 1- (2,4-Dichlorophenethyl) -3- (3-phenylpropyl) urea;

120. 4- (2- (3- (3-Phenylpropyl) ureido) ethyl) benzoic acid;

121. N-Methyl-N- (3-phenylpropyl) -1,2,3,4-tetrahydroquinoline-1 (2H) -carboxamide;

122. N-methyl-N- (4-phenylbutyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -carboxamide;

124. N-Methyl-N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -carboxamide;

127. 1- (3,4-Dimethoxybenzyl) -3- (3-phenylpropyl) urea;

128. N- (4- (N, N-dimethylsulfamoyl) phenethyl) -4-phenylpiperidine-1-carboxamide;

129. 4- (4- (N, N-dimethylsulfamoyl) phenyl) -N- (3-phenylpropyl) piperidine-1-carboxamide;

131. Methyl 2- (3-cyclohexylureido) -3- (1H-indol-3-yl) propanoate;

132. N- (3-phenylpropyl) -5-sulfamoylindoline-1-carboxamide;

133. (5- (N, N-Dimethylsulfamoyl) -N-methyl-N- (3-phenylpropyl) indoline-1-carboxamide;

134. 1- (6-Methylpyridin-3-yl) -3- (3-phenylpropyl) urea;

135. 1- (3-Phenylpropyl) -3 - ((tetrahydro-2H-pyran-4-yl) methyl) urea;

136. Methyl 3- (1H-indol-3-yl) -2- (3-phenethylureido) propanoate;

137. 4- (2- (3- (3- (4-Methoxyphenyl) propyl) ureido) ethyl) benzenesulfonamide;

138. 4-Hydroxy-N- (3- (4-methoxyphenyl) propyl) piperidine-1-carboxamide;

139. 4- (4- (N, N-dimethylsulfamoyl) phenyl) piperidine-N-phenethyl-1-carboxamide;

140. N-Benzyl-4- (4- (N, N-dimethylsulfamoyl) phenylpiperidine-1-carboxamide;

141. Methyl 3- (1H-indol-3-yl) -2- (3- (3-phenylpropyl) ureido) propanoate;

142. 4- (Hydroxymethyl) -N- (3- (4-methoxyphenyl) propyl) piperidine-1-carboxamide;

145. N- (3- (4-Methoxyphenyl) propyl) piperidine-1-carboxamide;

147. N- (3- (4-Methoxyphenyl) propyl) -4-phenylpiperidine-1-carboxamide;

150. 4- (4- (N, N-dimethylsulfamoyl) phenyl) -N- (3- (4-methoxyphenyl) propyl) piperidine-1-carboxamide;

151. 4- (2- (3- (3- (4-Chlorophenyl) propyl) ureido) ethyl) benzenesulfonamide;

152. 1- (3- (4-Chlorophenyl) propyl) -3- (tetrahydro-2H-pyran-4-yl) urea;

154. N- (3- (4-Chlorophenyl) propyl) -4-hydroxypiperidine-1-carboxamide;

155. 4-Hydroxy-N- (4-phenylbutyl) piperidine-1-carboxamide;

156. 4- (2- (3- (4-Phenylbutyl) ureido) ethyl) benzenesulfonamide;

157. N- (4-phenylbutyl) morpholine-4-carboxamide;

158. 1- (4-Phenylbutyl) -3- (tetrahydro-2H-pyran-4-yl) urea;

159. 4- (4-Chlorophenyl) -4-hydroxy-N- (3-phenylpropyl) piperidine-1-carboxamide;

160. N- (3-phenylpropyl) -1,4-dioxa-8-azaspiro [4.5] decane-8-carboxamide;

161. 1- (4-Fluorobenzyl) -3- (4-phenylbutyl) urea;

162. 4- (2- (3- (4-Methoxyphenyl) ureido) ethyl) benzenesulfonamide;

163. 1- (2-morpholinoethyl) -3- (4-phenylbutyl) urea;

164. 4- (Hydroxymethyl) -N- (4-phenylbutyl) piperidine-1-carboxamide;

165. 1- (3,4-Dimethoxyphenethyl) -3- (4-phenylbutyl) urea;

166. N- (4-Phenylbutyl) piperidine-1-carboxamide;

167. 4- (4-Chlorophenyl) -4-hydroxy-N- (4-phenylbutyl) piperidine-1-carboxamide;

168. 4-Hydroxy-N- (4-methoxyphenethyl) piperidine-1-carboxamide;

169. 4- (2- (3- (4-Fluorophenethyl) ureido) ethyl) benzenesulfonamide;

171. 1- (3-Fluoro-4-morpholinophenyl) -3- (4-fluorophenethyl) urea;

172. 3- (3-Fluoro-4-morpholinophenyl) -1-methyl-1-phenethyl urea;

173. 1- (3-Methoxyphenethyl) -3- (3-phenylpropyl) urea;

174. 1- (3-Fluoro-4-morpholinophenyl) -3- (3-phenylpropyl) urea;

175. 4- (2- (3- (3-Fluoro-4-morpholinophenyl) -1-methylureido) ethyl) -N, N-dimethylbenzenesulfonamide;

176. N- (4- (N, N-dimethylsulfamoyl) benzyl) -4-phenylpiperidine-1-carboxamide;

177. 4- (4- (N, N-dimethylsulfamoyl) phenyl) -N- (tetrahydro-2H-pyran-4-yl) piperidine-1-carboxamide;

178. N- (3- (4- (N, N-dimethylsulfamoyl) phenyl) propyl-4-hydroxypiperidine-1-carboxamide;

179. 4-Methoxy-2- (2- (3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide;

180. 4- (3- (3-Benzylureido) propyl) -N, N-dimethylbenzenesulfonamide;

182. N- (3- (4-N, N-dimethylsulfamoyl) phenyl) propyl) morpholine-4-carboxamide;

183. N, N-Dimethyl-4- (3- (3- (tetrahydro-2H-pyran-4-yl) ureido) propyl) benzenesulfonamide;

184. 1-Oxo-N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinolin-2- (1H) -carboxamide;

185. 1- (1-Methylpiperidin-4-yl) -3- (3-phenylpropyl) urea;

301. 4- (2- (3- (3- (4-Fluorophenyl) propyl) ureido) ethyl) benzenesulfonamide;

302. 4- (2- (3- (3- (4-Fluorophenyl) propyl) ureido) ethyl) -N, N-dimethylbenzenesulfonamide;

303. N- (3- (4-Fluorophenyl) propyl) -4-hydroxypiperidine-1-carboxamide;

304. 1- (3- (4-Fluorophenyl) propyl) -3- (tetrahydro-2H-furan-4-yl) urea;

305. 1-Benzyl-3- (3- (4-fluorophenyl) propyl) urea;

306. 4- (Dimethylamino) -N- (3-phenylpropyl) piperidine-1-carboxamide;

307. 6- (N, N-Dimethylsulfamoyl) -N- (3-phenylpropyl) -3,4-dihydroquinoline-1 (2H) -carboxamide;

308. 3- (Hydroxymethyl) -N-methyl-N- (3-phenylpropyl) piperidine-1-carboxamide;

309. 6- (N, N-Diethylsulfamoyl) -N- (3-phenylpropyl) -3,4-dihydroquinoline-1 (2H) -carboxamide;

310. 5- (N, N-Diethylsulfamoyl) -N- (3-phenylpropyl) indoline-1-carboxamide;

311. 5- (N, N-Diethylsulfamoyl) -N-methyl-N- (3-phenylpropyl) indoline-1-carboxamide;

312. 5- (N, N-Diethylsulfamoyl) -N-ethyl-N- (3-phenylpropyl) indoline-1-carboxamide;

313. Methyl 4- (3-phenylpropylcarbamoyl) piperazine-1-carboxylate;

314. Methyl 4- (methyl (3-phenylpropyl) carbamoyl) piperazine-1-carboxylate;

316. 1- (3-Phenylpropyl) -3- (piperidin-4-ylmethyl) urea;

317. Methyl 4- (1- (3-phenylpropylcarbamoyl) indolin-5-ylsulfonyl) piperazine-1-carboxylate;

318. Methyl 4- (1- (phenethylcarbamoyl) indolin-5-ylsulfonyl) piperazine-1-carboxylate;

336. 1- (9H-Carbazol-3-yl) -3-phenylpropylurea;

337. 1- (9H-Carbazol-3-yl) -3-phenylbutyramide;

338. 1- (9H-Carbazol-3-yl) -3-cyclohexylurea;

339. 1- (9H-Carbazol-3-yl) -3-phenethyl urea;

340. 1- (9H-Carbazol-3-yl) -3-propylurea;

341. 1- (9H-Carbazol-3-yl) -3-benzylurea;

342. 1- (9H-Carbazol-3-yl) -3- (4-methoxyphenethyl) urea;

343. 1- (9H-Carbazol-3-yl) -3-furfurylurea;

344. 1- (9H-Carbazol-3-yl) -3- (4-nitrophenyl) urea;

345. 1- (9H-Carbazol-3-yl) -3-hexyl urea;

346. 1- (9H-Carbazol-3-yl) -3-nonyl urea;

347. 1- (9H-Carbazol-3-yl) -3- (3-nitrophenyl) urea;

348. 1- (9H-Carbazol-3-yl) -3- (4-chlorophenyl) urea;

349. 1- (9H-Carbazol-3-yl) -3- (2-nitrophenyl) urea;

350. 1- (9H-Carbazol-3-yl) -3- (4-ethylphenyl) urea;

351. 1- (9H-Carbazol-3-yl) -3-phenylurea;

352. 1- (9H-Carbazol-3-yl) -3- (4-acetoxyphenyl) urea;

353. 1- (9-Methyl-9H-carbazol-3-yl) -3-phenylpropylurea;

354. 1- (9-Methyl-9H-carbazol-3-yl) -3-phenylbutyramide;

355. 1- (9-Methyl-9H-carbazol-3-yl) -3-cyclohexylurea;

356. 1- (9-Methyl-9H-carbazol-3-yl) -3-phenethyl urea;

357. 1- (9-Methyl-9H-carbazol-3-yl) -3-propylurea;

358. 1- (9-Methyl-9H-carbazol-3-yl) -3-benzylurea;

359. 1- (9-Methyl-9H-carbazol-3-yl) -3- (4-methoxyphenethyl) urea;

360. 1- (9-Methyl-9H-carbazol-3-yl) -3-furfurylurea;

361. 1- (9-Methyl-9H-carbazol-3-yl) -3- (4-nitrophenyl) urea;

362. 1- (9-Methyl-9H-carbazol-3-yl) -3-hexyl urea;

363. 1- (9-Methyl-9H-carbazol-3-yl) -3-nonyl urea;

364. 1- (9-Methyl-9H-carbazol-3-yl) -3- (3-nitrophenyl) urea;

365. 1- (9-Methyl-9H-carbazol-3-yl) -3- (4-chlorophenyl) urea;

366. 1- (9-Methyl-9H-carbazol-3-yl) -3- (2-nitrophenyl) urea;

367. 1- (9H-Carbazol-3-yl) -3- (4-ethylphenyl) urea;

368. 1- (9-Methyl-9H-carbazol-3-yl) -3-phenylurea; And

369. At least one compound selected from the group consisting of 1- (9-methyl-9H-carbazol-3-yl) -3- (4-acetoxyphenyl) urea.

In one particular embodiment, the compound of formula 1 is as follows:

20. 3- (Hydroxymethyl) -N- (3-phenylpropyl) piperidine-1-carboxamide;

27. 2-Isonicotinoyl-N- (3-phenylpropyl) hydrazinecarboxamide;

30. 4- (Hydroxymethyl) -N- (3-phenylpropyl) piperidine-1-carboxamide;

35. 3-Hydroxy-N- (3-phenylpropyl) piperidine-1-carboxamide;

36. N, N-Dimethyl-4- (2- (3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide;

42. 4-Hydroxy-N- (3-phenylpropyl) piperidine-1-carboxamide;

90. N, N-Dimethyl-4 - ((3- (3-phenylpropyl) ureido) methyl) benzenesulfonamide;

100. N, N-dimethyl-4- (2- (1-methyl-3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide;

102. N, N-Dimethyl-4- (2- (3-methyl-3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide;

103. 7- (N, N-Dimethylsulfamoyl) -N-methyl-N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H) -carboxamide;

104. N- (3-Phenylpropyl) -1,2,3,4-tetrahydroquinoline-1 (2H) -carboxamide;

109. N-methyl-N- (3-phenylpropyl) indoline-1-carboxamide;

118. 1- (2-Morpholinethyl) -3- (3-phenylpropyl) urea;

135. 1- (3-Phenylpropyl) -3 - ((tetrahydro-2H-pyran-4-yl) methyl) urea;

301. 4- (2- (3- (3- (4-Fluorophenyl) propyl) ureido) ethyl) benzenesulfonamide;

302. 4- (2- (3- (3- (4-Fluorophenyl) propyl) ureido) ethyl) -N, N-dimethylbenzenesulfonamide;

303. N- (3- (4-Fluorophenyl) propyl) -4-hydroxypiperidine-1-carboxamide;

304. 1- (3- (4-Fluorophenyl) propyl) -3- (tetrahydro-2H-furan-4-yl) urea;

305. 1-Benzyl-3- (3- (4-fluorophenyl) propyl) urea;

306. 4- (Dimethylamino) -N- (3-phenylpropyl) piperidine-1-carboxamide;

307. 6- (N, N-Dimethylsulfamoyl) -N- (3-phenylpropyl) -3,4-dihydroquinoline-1 (2H) -carboxamide;

308. 3- (Hydroxymethyl) -N-methyl-N- (3-phenylpropyl) piperidine-1-carboxamide;

309. 6- (N, N-Diethylsulfamoyl) -N- (3-phenylpropyl) -3,4-dihydroquinoline-1 (2H) -carboxamide;

310. 5- (N, N-Diethylsulfamoyl) -N- (3-phenylpropyl) indoline-1-carboxamide;

311. 5- (N, N-Diethylsulfamoyl) -N-methyl-N- (3-phenylpropyl) indoline-1-carboxamide;

312. 5- (N, N-Diethylsulfamoyl) -N-ethyl-N- (3-phenylpropyl) indoline-1-carboxamide;

313. Methyl 4- (3-phenylpropylcarbamoyl) piperazine-1-carboxylate;

314. Methyl 4- (methyl (3-phenylpropyl) carbamoyl) piperazine-1-carboxylate;

316. 1- (3-Phenylpropyl) -3- (piperidin-4-ylmethyl) urea;

317. Methyl 4- (1- (3-phenylpropylcarbamoyl) indolin-5-ylsulfonyl) piperazine-1-carboxylate;

318. Methyl 4- (1- (phenethylcarbamoyl) indolin-5-ylsulfonyl) piperazine-1-carboxylate;

336. 1- (9H-Carbazol-3-yl) -3-phenylpropylurea;

337. 1- (9H-Carbazol-3-yl) -3-phenylbutyramide;

338. 1- (9H-Carbazol-3-yl) -3-cyclohexylurea;

339. 1- (9H-Carbazol-3-yl) -3-phenethyl urea;

340. 1- (9H-Carbazol-3-yl) -3-propylurea;

341. 1- (9H-Carbazol-3-yl) -3-benzylurea;

342. 1- (9H-Carbazol-3-yl) -3- (4-methoxyphenethyl) urea;

343. 1- (9H-Carbazol-3-yl) -3-furfurylurea;

344. 1- (9H-Carbazol-3-yl) -3- (4-nitrophenyl) urea;

345. 1- (9H-Carbazol-3-yl) -3-hexyl urea;

346. 1- (9H-Carbazol-3-yl) -3-nonyl urea;

347. 1- (9H-Carbazol-3-yl) -3- (3-nitrophenyl) urea;

348. 1- (9H-Carbazol-3-yl) -3- (4-chlorophenyl) urea;

349. 1- (9H-Carbazol-3-yl) -3- (2-nitrophenyl) urea;

350. 1- (9H-Carbazol-3-yl) -3- (4-ethylphenyl) urea;

351. 1- (9H-Carbazol-3-yl) -3-phenylurea;

352. 1- (9H-Carbazol-3-yl) -3- (4-acetoxyphenyl) urea;

353. 1- (9-Methyl-9H-carbazol-3-yl) -3-phenylpropylurea;

354. 1- (9-Methyl-9H-carbazol-3-yl) -3-phenylbutyramide;

355. 1- (9-Methyl-9H-carbazol-3-yl) -3-cyclohexylurea;

356. 1- (9-Methyl-9H-carbazol-3-yl) -3-phenethyl urea;

357. 1- (9-Methyl-9H-carbazol-3-yl) -3-propylurea;

358. 1- (9-Methyl-9H-carbazol-3-yl) -3-benzylurea;

359. 1- (9-Methyl-9H-carbazol-3-yl) -3- (4-methoxyphenethyl) urea;

360. 1- (9-Methyl-9H-carbazol-3-yl) -3-furfurylurea;

361. 1- (9-Methyl-9H-carbazol-3-yl) -3- (4-nitrophenyl) urea;

362. 1- (9-Methyl-9H-carbazol-3-yl) -3-hexyl urea;

363. 1- (9-Methyl-9H-carbazol-3-yl) -3-nonyl urea;

364. 1- (9-Methyl-9H-carbazol-3-yl) -3- (3-nitrophenyl) urea;

365. 1- (9-Methyl-9H-carbazol-3-yl) -3- (4-chlorophenyl) urea;

366. 1- (9-Methyl-9H-carbazol-3-yl) -3- (2-nitrophenyl) urea;

367. 1- (9H-Carbazol-3-yl) -3- (4-ethylphenyl) urea;

368. 1- (9-Methyl-9H-carbazol-3-yl) -3-phenylurea; And

369. At least one compound selected from the group consisting of 1- (9-methyl-9H-carbazol-3-yl) -3- (4-acetoxyphenyl) urea.

The compounds of formula (I) disclosed in the present invention include stereoisomers thereof. The term " stereoisomer " of the present invention refers to an isomer produced by a different arrangement of atoms or atoms within a molecule, including both optical isomers and geometric isomers. An optical isomer is a pair of enantiomers in which four atoms or atoms bonded to an asymmetric carbon atom form a pair of enantiomers depending on the manner of coupling. When two asymmetric carbon atoms are present in a molecule, the stereoisomer becomes a diastereomer. Isomers. It is also a geometric isomer when unsaturated hydrocarbons are present, including all possible geometric isomers.

The compounds of formula I disclosed herein also include pharmaceutically acceptable acid addition or base addition salts thereof, solvates thereof.

 Pharmaceutically acceptable acid addition salts comprise a therapeutically active non-toxic addition salt which may be formed by a compound of formula (1), which salt is prepared by reacting a compound of formula (1) in base form with an appropriate acid, Lt; RTI ID = 0.0 > free acid. ≪ / RTI > Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propionate, naphthalene-1, < / RTI > < RTI ID = 0.0 & -Sulfonate, naphthalene-2-sulfonate or mandelate.

Conversely, the acid addition salt can be converted to the free base form by treatment with an appropriate base.

Also included are quaternary ammonium salts of the compound derivatives of formula (I) disclosed in the present invention. The quaternary ammonium salt can be obtained by reacting a basic nitrogen present in the compound of formula (I) with a suitable quaternizing agent. The quaternizing agents include alkyl halides, aryl halides, or aryl alkyl halides, such as methyl iodide, benzyl iodide, alkylcfluoromethanesulfonate, alkyl methanesulfonate, and alkyl p-toluenesulfonate . The quaternary ammonium salt has a positively charged nitrogen, and the pharmaceutically acceptable counter ions include chloro, bromo, iodo, trifluoroacetate and acetate ions.

Conversely, the compound in the form of the salt may be converted to the free form by treatment with an appropriate acid.

The acid addition salt according to the present invention can be obtained by a conventional method, for example, by dissolving a derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, , Or may be prepared by drying, or by distillation of the solvent and excess acid under reduced pressure, followed by drying or crystallization in an organic solvent.

In addition, the present invention includes all possible solvates which can be prepared from the compound derivatives of the formula (1) disclosed in the present invention, and the solvates include, for example, hydrates, alcoholates and the like.

In another aspect, the invention relates to a compound of formula 2: < EMI ID = 2.1 > or a pharmaceutically acceptable salt thereof.

(2)

In Formula 2, R ₅ is cycloalkyl (the cycloalkyl may be substituted with hydrogen or phenyl); - (C ₁ -C ₅ ) alkyl-cycloalkyl; -Alkyl (C ₁ -C ₁₀₎ - phenyl; Heterocycloalkyl; Heteroaryl (which may be substituted with one or more of hydrogen or (C ₁ -C ₅ ) alkoxy); - (C ₁ -C ₅ ) alkyl-NRaRb wherein Ra is hydrogen or (C ₁ -C ₅ ) alkyl; Rb is arylalkyl, phenyl {optionally substituted with one or more hydrogen, halogen, - (C ₁ -C ₅ ) alkyl or - (C ₁ -C ₅ ) alkoxy} or - (C ₁ -C ₅ ) alkyl-cycloalkyl }; Arylalkenyl; - (C ₁ -C ₅ ) alkyl-S-Rc; Or - (C ₁ -C ₅ ) alkyl-O-Rc {wherein Rc is arylalkyl or phenyl}; R ₆ is hydrogen or (C ₁ -C ₅₎ alkyl; R ₇ is - (C ₀ -C ₁₀ ) phenyl {said phenyl is optionally substituted with one or more of hydrogen, halogen, (C ₁ -C ₅ ) alkyl, (C ₁ -C ₅ ) alkoxy or SO ₂ NR'R " And R " are each hydrogen or (C ₁ -C ₅ ) alkyl; Heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with hydroxy or arylalkyl; - (C ₁ -C ₅ ) alkyl, wherein said alkyl may be substituted with arylalkoxy; Or a partially hydrogenated polycyclic benzene ring.

In particular, R < ₅ > is 2-phenyl-cyclopropyl; Cyclohexylmethyl or cyclohexylethyl; - (C ₁ -C ₅ ) alkyl-phenyl; Tetrahydropyran substituted with hydroxy or benzyl, morpholine or piperidine; An indole substituted with one or more hydrogen or methoxy; - (C ₁ -C ₅ ) alkyl-NRaRb wherein Ra is hydrogen or (C ₁ -C ₅ ) alkyl; Rb is benzyl, phenylethyl, phenyl {optionally substituted with one or more hydrogen, halogen, tert-butyl or methoxy} or - (C ₁ -C ₅ ) alkyl-cyclohexyl}; Arylalkenyl; - (C ₁ -C ₅ ) alkyl-S-Rc; Or - (C ₁ -C ₅ ) alkyl-O-Rc {wherein Rc is phenyl, benzyl or phenylethyl}; R ₆ is hydrogen or (C ₁ -C ₅₎ alkyl; R ₇ is - (C ₀ -C ₁₀ ) phenyl, wherein the phenyl is optionally substituted with one or more of hydrogen, halogen, (C ₁ -C ₅ ) alkyl, (C ₁ -C ₅ ) alkoxy, SO ₂ NH ₂ or SO ₂ N ₃ ) replaceable with ₂ }; Tetrahydropyran substituted with hydrogen, hydroxy or benzyl, morpholine or piperazine; - (C ₁ -C ₅ ) alkyl substituted by benzyloxy; Or dihydroindane.

More specifically, the compound of formula (2) disclosed in the present invention is as follows:

190. 5-Phenyl-N- (tetrahydro-2H-pyran-4-yl) pentanamide;

193. 1- (4-Hydroxypiperidin-1-yl) -5-phenylpentan-1-one;

196. N- (4-methylphenethyl) -5-phenylpentanamide;

197. N- (2-fluorophenethyl) -5-phenylpentanamide;

198. N- (4- (N, N-dimethylsulfamoyl) phenethyl-N-methyl-5-phenylpentanamide;

199. N-methyl-N-phenethyl-5-phenylpentanamide;

201. N- (2,3-Dihydro-1H-inden-2-yl) -5-phenylpentanamide;

205. 6-Methoxy-N- (3-phenylpropyl) -1H-indole-2-carboxamide;

206. (4-Benzylpiperazin-1-yl) (6-methoxy-1H-indol-2-yl) methanone;

207. N- (4- (N, N-dimethylsulfamoyl) phenethyl) -5-phenylpentanamide;

212. 2- (Methyl (phenyl) amino) -N- (3-phenylpropyl) acetamide;

213. 2- (Benzyl (methyl) amino) -N- (3-phenylpropyl) acetamide;

214. 2- (Benzyloxy) -N- (3-phenylpropyl) acetamide;

218. 2-Phenethoxy-N-phenylacetamide;

219. 3- (Benzylamino) -N-phenethylpropanamide;

220. 3- (Benzyl (methyl) amino) -N-phenethylpropanamide;

222. N-phenethyl-4- (phenylamino) butanamide;

223. 4- (Methyl (phenyl) amino) -N-phenethylbutanamide;

224. 3- (Phenylamino) -N- (3-phenylpropyl) propanamide;

225. 3- (Methyl (phenyl) amino) -N- (3-phenylpropyl) propanamide;

226. 2- (Phenylamino) -N- (4-phenylbutyl) acetamide;

227. 2- (Methyl (phenyl) amino) -N- (4-phenylbutyl) acetamide;

229. 2- (Benzylamino) -N- (3-phenylpropyl) acetamide;

230. 2- (Benzyl (methyl) amino) -N- (4-phenylbutyl) acetamide;

231. 2- (Benzylthio) -N- (4-phenylbutyl) acetamide;

232. 2- (Benzyloxy) -N- (4-phenylbutyl) acetamide;

233. 3- (Benzyloxy) -N-phenethylpropanamide;

234. 2- (Benzylamino) -N- (4-phenylbutyl) acetamide;

238. 2- (Benzyloxy) -N-phenylacetamide;

239. 2- (Benzyl (methyl) amino) -N-phenylacetamide;

240. N- (2- (Benzyloxy) ethyl) -3-phenylpropanamide;

242. N-benzyl-4- (benzyloxy) -N-methylbutanamide;

243. 4- (Benzyloxy) -N-phenethylbutanamide;

244. 4- (Benzyloxy) -N-methyl-N-phenethylbutanamide;

245. 2- (4-Methoxybenzylamino) -N- (3-phenylpropyl) acetamide;

246. 2- (4-Chlorobenzylamino) -N- (3-phenylpropyl) acetamide;

247. 2- (4-tert-Butylbenzylamino) -N- (3-phenylpropyl) acetamide;

248. 2- (cyclohexylmethylamino) -N- (3-phenylpropyl) acetamide; and

249. 2- (4-Fluorobenzylamino) -N- (3-phenylpropyl) acetamide;

319. 4- (4- (N, N-Dimethylsulfamoyl) phenyl-N- (3-phenylpropyl) butanamide;

320. 4- (4- (N, N-dimethylsulfamoyl) phenyl-N-methyl-N- (3-phenylpropyl) butanamide;

321. 5-Phenyl-N- (4-sulfamoylbenzyl) pentanamide;

322. N- (4- (N, N-dimethylsulfamoyl) benzyl) -5-phenylpentanamide;

323. N- (4- (N, N-dimethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide;

324. N, N-Dimethyl-4- (4-oxo-4- (4-phenylpiperidin-1-yl) butyl) benzenesulfonamide;

325. N, N-Dimethyl-4- (4-oxo-4- (4-phenylpiperazin-1-yl) butyl) benzenesulfonamide;

326. N- (4- (N, N-dimethylsulfamoyl) benzyl) -N-ethyl-5-phenylpentanamide;

327. N- (4- (N, N-dimethylsulfamoyl) phenethyl) -N-ethyl-5-phenylpentanamide;

328. N-methyl-N- (4- (morpholinosulfonyl) benzyl) -5-phenylpentanamide;

329. N-methyl-N- (4- (morpholinosulfonyl) benzyl) -4-phenylbutanamide;

330. N- (4- (N, N-diethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide;

331. N- (4- (N-ethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide;

332. N-methyl-N- (4- (N-methylsulfamoyl) benzyl) -5-phenylpentanamide;

333. N-methyl-N- (4- (N-morpholinosulfonyl) phenethyl) -5-phenylpentanamide;

334. N-methyl-N- (4- (N-methylsulfamoyl) phenethyl) -5-phenylpentanamide; And

335. At least one compound selected from the group consisting of N- (4- (N, N-dimethylsulfamoyl) phenethyl) -N-methyl-5-phenylpentanamide.

More particularly, the compounds of formula 2 are as follows:

190. 5-Phenyl-N- (tetrahydro-2H-pyran-4-yl) pentanamide;

198. N- (4- (N, N-dimethylsulfamoyl) phenethyl-N-methyl-5-phenylpentanamide;

223. 4- (Methyl (phenyl) amino) -N-phenethylbutanamide;

319. 4- (4- (N, N-Dimethylsulfamoyl) phenyl-N- (3-phenylpropyl) butanamide;

320. 4- (4- (N, N-dimethylsulfamoyl) phenyl-N-methyl-N- (3-phenylpropyl) butanamide;

321. 5-Phenyl-N- (4-sulfamoylbenzyl) pentanamide;

322. N- (4- (N, N-dimethylsulfamoyl) benzyl) -5-phenylpentanamide;

323. N- (4- (N, N-dimethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide;

324. N, N-Dimethyl-4- (4-oxo-4- (4-phenylpiperidin-1-yl) butyl) benzenesulfonamide;

325. N, N-Dimethyl-4- (4-oxo-4- (4-phenylpiperazin-1-yl) butyl) benzenesulfonamide;

326. N- (4- (N, N-dimethylsulfamoyl) benzyl) -N-ethyl-5-phenylpentanamide;

327. N- (4- (N, N-dimethylsulfamoyl) phenethyl) -N-ethyl-5-phenylpentanamide;

328. N-methyl-N- (4- (morpholinosulfonyl) benzyl) -5-phenylpentanamide;

329. N-methyl-N- (4- (morpholinosulfonyl) benzyl) -4-phenylbutanamide;

330. N- (4- (N, N-diethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide;

331. N- (4- (N-ethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide;

332. N-methyl-N- (4- (N-methylsulfamoyl) benzyl) -5-phenylpentanamide;

333. N-methyl-N- (4- (N-morpholinosulfonyl) phenethyl) -5-phenylpentanamide;

334. N-methyl-N- (4- (N-methylsulfamoyl) phenethyl) -5-phenylpentanamide; And

335. At least one compound selected from the group consisting of N- (4- (N, N-dimethylsulfamoyl) phenethyl) -N-methyl-5-phenylpentanamide.

The compounds of formula (2) disclosed in the present invention also include the stereoisomers thereof as described above. Also encompassed are pharmaceutically acceptable acid addition or base addition salts, solvates thereof, acid or base addition salts, solvates thereof, as described above. Also included are quaternary ammonium salts of the compound derivatives of Formula 2, which are also as described above.

In another aspect, the present invention also relates to a pharmaceutical composition for preventing or treating heart failure comprising the compound of the above formula (1) or (2) or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (1) or Can be referred to above.

Also in one embodiment the composition according to the invention comprises, in one embodiment, one or more compound compounds, preferably selected from the group consisting of the title compounds of Examples 1 to 369, or a pharmaceutically acceptable salt thereof, . More preferably 2, 3, 6, 9, 10, 11, 14, 15, 17, 21, 26, 28, 29, 33, 37, 39, 46, 47, 51, 55, 57, 144, 146, 148, 149, 153, 170, 181, 186, 176, 177, 187, 188, 189, 191, 192, 194, 195, 200, 202, 203, 204, 208, 209, 210, 211, 215, 216, 217, 221, 228, 235, 236, 237, 369, < / RTI > or a pharmaceutically acceptable salt thereof.

Also, as described above, the compound of formula (1) or (2) contained in the composition of the present invention includes a stereoisomer thereof. Also encompassed are pharmaceutically acceptable acid addition or base addition salts, solvates thereof, acid or base addition salts, solvates thereof, as described above. Also included are quaternary ammonium salts of the compound derivatives of Formulas 1 and 2, which are also as described above.

The compound according to any one of formulas 1 and 2 according to the present invention as described above has an effect of activating cardiac myosin. Although not limited to this theory, the compounds according to the present invention and the pharmaceutical compositions containing them increase the activity of myosin ATPase (an enzyme that hydrolyzes adenosine triphosphate (ADP) to adenosine diphosphate) To regulate, especially increase, the contractile capacity of the heart muscle. The heart muscle consists of a sarcomere of micrometer size, each of which consists of myosin filaments and actin filaments. Myosin is composed of tail and hair structure. It forms another myosin and filament through tail structure. Head structure is connected with actin, so that if actin filament and myosin filament slip together, heart muscle contracts. In this process, ATP bound to myosin head structure is hydrolyzed and used as energy. Thus, increased ATP hydrolysis may increase muscle contraction or its rate.

Therefore, the compounds according to the present invention for increasing the activity of ATPase and the pharmaceutical compositions containing them do not increase intracellular calcium concentration, unlike conventional inotropic muscle contraction control. Increased calcium concentrations may increase the rate of contraction of the heart and shorten the duration of systolic depression, leading to serious side effects. Cardiac myosin activator is a mechanism that directly stimulates the activity of myosin, which is an exercise protein, and has almost no effect on changes in intracellular calcium. The myosin activator accelerates the rate-limiting step of myosin and converts the cycle toward a force-producing state. This mechanism of myocardial contraction does not increase the rate of myocardial contraction but prolongs systolic ejection time and increases cardiac contractility and cardiac function in a more oxygen-efficient manner.

Therefore, the compounds according to the present invention and the pharmaceutical compositions containing them can be usefully used for prevention or treatment of heart failure.

In the present invention, heart failure refers to a phenomenon in which the function of the heart does not satisfy the cardiac output required by the body. The heart failure refers to a phenomenon in which the cardiac output required by the body is not satisfied, such as shortness of breath, hand foot swelling, helplessness, fatigue, sleeping disorders due to dyspnea, Symptoms of memory loss are accompanied by symptoms.

Heart failure in which the compounds and compositions of the present invention are effective may be used for the treatment of cardiovascular diseases, myocardial infarction, hypertension, heart valve disease, myocardial diseases (for example, definitive cardiomyopathy , Hypertrophic cardiomyopathy) or myocarditis, endocarditis, congenital heart disease, chronic lung disease, diabetes or heart failure due to arrhythmia. It also includes cardiac contractile heart failure, diastolic heart failure or congestive heart failure. Systolic heart failure is a traditional heart failure in which the cardiac output from the heart is reduced due to the heart's inability to maintain its normal function of contraction and the ventricular volume is increased over time because the ventricular blood is not properly emptied, Diastolic heart failure is a heart failure in which ventricular relaxation is poor and an increase in ventricular pressure during diastole is a problem. In one embodiment, there is an effect on systolic heart failure.

The term " prophylactic " as used herein refers to any act that inhibits or delays the onset of a related disorder upon administration of a composition according to the present invention. It will be apparent to those skilled in the art that the composition of the present invention can prevent such diseases when administered before or at the onset of symptoms.

As used herein, the term " treatment " means any action that improves or alleviates the symptoms of a related disease upon administration of the composition according to the present invention, and the treatment includes alleviation or amelioration. Those skilled in the art will be able to ascertain the precise criteria of the disease by referring to the data presented by the Korean Medical Association, etc., and to judge the degree of improvement, improvement, and treatment of the disease.

In another aspect, the present invention relates to a method for treating or preventing heart failure, comprising administering a composition according to the present invention to a subject in need of treatment for heart failure, in an amount effective for treatment of heart failure.

The term " individual " of the present invention means a subject in need of treatment of a disease, and more particularly, a human or non-human primate, mouse, rat, dog, cat, Of mammals.

The term " therapeutically effective amount " of the present invention refers to the amount of a compound according to the present invention or a pharmaceutical composition containing it sufficient to treat, inhibit, alleviate or prevent heart failure as described above and is applied to any drug (Benefit / risk ratio). However, the total daily dose may be determined by the physician's reasonable opinion. In addition, the daily dose of a particular patient may also vary depending on a variety of factors, such as the type of specific disease, the severity of the disease, the type of the particular drug administered, the type of composition used, the age, body weight, general health, , The time of administration, the route of administration, the absorption, distribution and excretion of the drug, the duration of the administration, the type of other drug used, and the like. Further, when the initial drug is administered, administration is started in an amount less than that required for the desired effect, and the dose is gradually increased until the desired effect is obtained.

The pharmaceutical composition according to the present invention can be formulated in a suitable form together with a commonly used pharmaceutically acceptable carrier. &Quot; Pharmaceutically acceptable " refers to compositions which are physiologically acceptable and which, when administered to humans, do not normally cause allergic reactions such as gastrointestinal disorders, dizziness, or the like. Examples of pharmaceutically acceptable carriers include, for example, water, suitable oils, saline, aqueous carriers for parenteral administration such as aqueous glucose and glycols, and the like.

The composition according to the present invention may further comprise a stabilizer and a preservative. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. In addition, the composition according to the present invention may contain various additives such as a suspending agent, a solubilizer, a stabilizer, an isotonic agent, a preservative, an adsorption inhibitor, an interface activator, a diluent, an excipient, a pH adjuster, An antioxidant, and the like. Pharmaceutically acceptable carriers and formulations suitable for the present invention, including those exemplified above, are described in detail in Remington ' s Pharmaceutical Sciences, Current Edition. May be prepared in unit dosage form or may be manufactured by intrusion into a multi-dose container. In the pharmaceutical composition, the compound of the present invention is present in an amount of 0.0001 to 10% by weight, preferably 0.001 to 1% by weight, based on the total weight of the total composition.

The method of administering the pharmaceutical composition of the present invention can be easily selected according to the formulation, and can be formulated and administered to mammals such as livestock, humans, and the like in various routes, the following oral or parenteral administration forms.

Examples of formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs and troches, , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants (such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols). 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.

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used. In order to formulate the formulation for parenteral administration, the indole derivative of the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof may be sterilized and / or supplemented with a preservative, a stabilizer, a hydrating agent or an emulsifying accelerator, a salt for controlling osmotic pressure and / , And other therapeutically useful substances in water to prepare solutions or suspensions, which may be prepared in ampoules or vial unit dosage forms.

The preferred dosage of the pharmaceutical composition comprising the compound of formula (I) or (II) as an active ingredient of the present invention for the human body depends on the condition and the weight of the patient, the degree of the disease, the drug form, And the like. Preferably, however, the compound of the present invention is administered at a daily dose of 0.001 to 100 mg / kg body weight, more preferably 0.01 to 30 mg / kg body weight. The administration may be carried out once a day or divided into several doses. The dose may vary depending on various conditions such as the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate and severity of disease, Are obvious to those skilled in the art, and thus the dosage amounts are not intended to limit the scope of the invention in any way. The number of administrations can be administered once or several times a day within a desired range, and the administration period is not particularly limited.

The compound of the present invention is effective for activating myocardial myosin ATPase, and is also capable of activating myosin of cardiac muscle, which enables continuous changes in ventricular contractility and relaxation function with little change in heart rate as the concentration of the drug increases. Thereby being useful as a drug for the treatment and prevention of acute and chronic heart diseases.

FIG. 1 shows a photograph of the echocardiographic machine and the compound injection experiment for verifying the cardiac effect of each example compound according to an embodiment of the present invention.
Figure 2 shows M-mode echocardiograms of 25 example compounds according to one embodiment of the invention.

Hereinafter, embodiments are provided to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited to the following examples.

Example

Experimental preparation and instrumentation

1. Analysis equipment

The equipment used to identify the structure of the product obtained in this experiment is as follows. The FT-IR spectrum was measured using a Nicolet-380 model. Nuclear magnetic resonance spectrum (1 H-NMR, manufacturer JEOL, model name JNM-AL 400 NMR) was 400 MHz, and solvents were CDCl ₃ and DMSO-d ₆ . The coupling constant (J) is expressed in Hz.

2. TLC and column chromatography

Silica gel (Merck F254) from Merck was used for thin layer chromatography (TLC) and silica (Merck EM 9385, 230-400 mesh) was used for column chromatography. Further, in order to identify the substance separated on TLC, the plate was heated by UV lamp (= 254 nm) or immersed in anisaldehyde, potassium permanganate (KMnO4) color development reagent, and the plate was confirmed by heating.

3. Reagents used

Sigma-Aldrich, Lancaster and Fluka were purchased from Sigma-Aldrich and Merck. The solvents used in the reaction were Sigma-Aldrich, (Merck) and Junsei Chemical Co. (1) were used without purification. The tetrahydrofuran (THF) used in the solvent was used when the Na metal and benzophenone were added in an argon stream and the solution became blue by heating under reflux. Further, dichloromethane (CH ₂ Cl ₂ ) was prepared by adding calcium hydride (CaH ₂ ) in an argon stream and heating and refluxing. Ethyl acetate and hexane were purified by refluxing in an argon stream and used.

Example 1. (R) -2-Phenyl- N - (3-phenylpropyl) aziridine-1-carboxamide

3-phenylpropyl isocyanate (0.645 mmol) was added to an acetonitrile solution (5 ml) of 2-phenyl aziridine (R-form) (0.710 mmol) and the mixture was stirred at room temperature for 8 hours. The resulting mixture was partitioned into an aqueous layer and an ethyl acetate layer. The organic layer solution was dried over anhydrous sodium sulfate (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure. The crude mixture was subjected to column chromatography to give the pure title compound.

Example 2. Preparation of 1- (3-phenylpropyl) -3- (1,2,3,4-tetrahydronaphthalen-1-yl) urea (S +

(S) -1-amino-1,2,3,4-tetrahydronaphthalene instead of 2-phenyl aziridine in the same manner as in Example 1, the title compound was synthesized Respectively.

Example 3. l-Benzyl-3- (3-phenylpropyl) urea

The title compound was synthesized by following the procedure of Example 1 while using benzylamine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 4. 1-Phenethyl-3- (3-phenylpropyl) urea

The title compound was synthesized by following the procedure of Example 1 while using 2-phenylethylamine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 5. Synthesis of 1,3-bis (3-phenylpropyl) ureas

The title compound was synthesized by following the procedure of Example 1 while using 3-phenylpropylamine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 6. 4-Phenyl- N - (3-phenylpropyl) piperidine-1-carboxamide

The title compound was synthesized by following the procedure of Example 1 while using 4-phenylpiperidine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 7. < RTI ID = 0.0 > N - (4-phenylbutyl) piperidine-1-carboxamide

4-Phenylbutylamine (3.52 mmol) and N, N-diisopropylethylamine (DIPEA, 7.04 mmol) were added to a THF solution of triphosgene (1.41 mmol) at 0 ° C. After stirring the reaction mixture at the same temperature for 30 minutes, 4-phenylpiperidine (3.52 mmol) was added. After allowing the temperature to slowly rise to room temperature, the reaction mixture was stirred for an additional 8 hours. After the reaction was complete, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO _4, filtered and evaporated under reduced pressure. The crude mixture was subjected to column chromatography to obtain the pure title compound.

Example 8 l- (2,3-dihydro-1H-inden-l-yl) -3- (3-phenylpropyl) urea

The title compound was synthesized by following the procedure of Example 1 while using 2-aminoindane instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 9. l- (2,3-dihydro-1H-inden-1-yl) -3- (4-phenylbutyl) urea

The title compound was synthesized by following the procedure of Example 7 while using 2-aminoindane instead of 4-phenylpiperidine in the preparation method of Example 7.?

Example 10. N- (3-phenylpropyl) indoline-1-carboxamide

The title compound was synthesized by following the procedure of Example 1 while using indoline in place of 2-phenyl aziridine in the production method of Example 1.?

Example 11 Synthesis of 1- (4-phenylbutyl) -3- (1,2,3,4-tetrahydronaphthalen-1-yl) urea (S +

The title compound was synthesized by following the procedure of Example 7 while using (S) -1,2,3,4-tetrahydronaphthylamine instead of 4-phenylpiperidine in the preparation method of Example 7 .

Example 12. 2-Phenyl-N- (4-phenylbutyl) pyrrolidine-1-carboxamide

The title compound was synthesized by following the procedure of Example 7 while using 2-phenylpyrrolidine instead of 4-phenylpiperidine in the preparation method of Example 7.

Example 13. 2-Phenyl-N- (4-phenylbutyl) piperidine-1-carboxamide

The title compound was synthesized by following the procedure of Example 7 while using 2-phenylpiperidine instead of 4-phenylpiperidine in the preparation method of Example 7.?

Example 14. Preparation of 1- (1-phenylethyl) -3- (3-phenylpropyl) urea (S-)

The title compound was synthesized by following the procedure of Example 1 while using (S) -1-phenylethylamine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 15 1- (3-Phenylpropyl) -3- (2- (pyridin-2-yl) ethyl) urea

The title compound was synthesized by the same method as in Example 1, except that 2-pyridylethylamine was used instead of 2-phenyl aziridine in the production method of Example 1.

Example 16. Preparation of 1- (4-nitrophenethyl) -3- (3-phenylpropyl) urea

The title compound was synthesized by following the procedure of Example 1 while using 4-nitrophenylethylamine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 17. Preparation of 1- (4- (dimethylamino) phenethyl) -3- (3-phenylpropyl) urea

(4-aminophenyl) -3- (3-phenylpropyl) urea hydrochloride was obtained in the same manner as in Example 1, except that 4-aminophenylethylamine was used instead of 2- . K ₂ CO ₃ (0.37 mmol) and CH ₃ I (1.36 mmol) were added to an acetone solution (8 ml) of the urea (0.34 mmol) and refluxed for 2 hours. The reaction mixture was filtered and purified by column chromatography to give the title compound.

Example 18. Methyl-1-phenethyl-3- (3-phenylpropyl) urea

The title compound was synthesized by following the procedure of Example 1 while using N-methyl-2-phenylethylamine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 19. Synthesis of 1,3-dimethyl-1-phenethyl-3- (3-phenylpropyl) urea

To the suspension of NaH (4.05 mmol) in cold DMF (5 ml), the compound of Example 18 (0.68 mmol) was added, and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was then cooled and then CH ₃ I (0.75 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Saturated NH ₄ Cl solution was added to neutralize excess NaH and extracted with ethyl acetate. And drying the organic solution over anhydrous Na ₂ SO _4, filtered and evaporated under reduced pressure. The crude mixture was subjected to column chromatography to obtain pure title compound.

Example 20. 3- (hydroxymethyl) -N- (3-phenylpropyl) piperidine-1-carboxamide

The title compound was synthesized by following the procedure of Example 1 while using 3-hydroxymethylpiperidine instead of 2-phenylaziridine in the same manner as in Example 1.

Example 21. Preparation of 4- (2- (3-phenylureido) ethyl) benzenesulfonamide

In the same manner as in Example 1, except for using 4- (2-aminoethyl) benzenesulfonamide instead of 2-phenyl aziridine and phenyl isocyanate in place of 3-phenylpropyl isocyanate, the title compound Were synthesized.

Example 22. Preparation of 1- (cyclohexylmethyl) -3- (3-phenylpropyl) urea

The title compound was synthesized by following the procedure of Example 1 while using cyclohexylmethylamine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 23. Preparation of 1- (2-cyclohexylethyl) -3- (3-phenylpropyl) urea

The title compound was synthesized by following the procedure of Example 1 while using 2-cyclohexylethylamine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 24. l- (4-Aminophenethyl) -3- (3-phenylpropyl) urea

The title compound was synthesized by following the procedure of Example 1 while using 4-aminophenylethylamine instead of 2-phenylaziridine in the same manner as in Example 1.

Example 25. N- (4- (2- (3- (3-Phenylpropyl) ureido) ethyl) phenyl) methanesulfonamide

The compound of Example 17 (0.1 mmol) was dissolved in methylene chloride and cooled to 0 ° C. To the solution was added TEA (0.15 mmol) followed by methanesulfonyl chloride (0.12 mmol). The reaction mixture was stirred for 1 hour and then allowed to warm to room temperature. The reaction was monitored by TLC. After the reaction was completed, water was added to the reaction mixture and extracted with ethyl acetate. The aqueous layer was extracted once more with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography to obtain the title compound.

Example 26. l- (4-chlorophenethyl) -3- (3-phenylpropyl) urea

The title compound was synthesized by following the procedure of Example 1 while using 4-chlorophenylethylamine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 27. 2-isonicotinoyl-N- (3-phenylpropyl) hydrazinecarboxamide

(Aldirch, USA) instead of 2-phenyl aziridine in the same manner as in Example 1, the title compound was synthesized.

Example 28. 1- (2-methoxyphenethyl) -3- (3-phenylpropyl) urea

The title compound was synthesized by following the procedure of Example 1 while using 2-methoxyphenylethylamine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 29. l- (3,4-dimethoxyphenethyl) -3- (3-phenylpropyl) urea

The title compound was synthesized by following the procedure of Example 1 while using 3,4-dimethoxyphenylethylamine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 30. 4- (hydroxymethyl) -N- (3-phenylpropyl) piperidine-1-carboxamide

The title compound was synthesized by following the procedure of Example 1 while using 4-hydroxymethylpiperidine instead of 2-phenylaziridine in the same manner as in Example 1.

Example 31. 3- (methoxymethyl) -N- (3-phenylpropyl) piperidine-1-carboxamide

To a suspension of NaH (1.20 mmol) in cold DMF (5 ml) was added the compound of Example 20 (1.0 mmol) and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was then cooled and CH ₃ I (1.20 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Saturated NH ₄ Cl solution was added to remove excess NaH and extracted with ethyl acetate. The organic layer solution was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by column chromatography to give pure title compound.

Example 32. 4- (2-hydroxyethyl) -N- (3-phenylpropyl) piperidine-1-carboxamide

The title compound was synthesized by following the procedure of Example 1 while using 4- (2-hydroxyethyl) piperidine instead of 2-phenylaziridine in the same manner as in Example 1.

Example 33. 3- (hydroxymethyl) -N-phenethylpiperidine-1-carboxamide

In the same manner as in Example 1, except that 3- (2-hydroxymethyl) piperidine was used instead of 2-phenyl aziridine and 2-phenylethyl isocyanate was used instead of 3-phenylpropyl isocyanate The title compound was synthesized.

Example 34. 4- (hydroxymethyl) -N-phenethylpiperidine-1-carboxamide

In Example 1, 4- (2-hydroxymethyl) piperidine was used instead of 2-phenyl aziridine, and 2-phenylethyl isocyanate was used instead of 3-phenylpropyl isocyanate in the same manner as in Example 1 The title compound was synthesized.

Example 35. Preparation of 3-hydroxy-N- (3-phenylpropyl) piperidine-1-carboxamide

The title compound was synthesized by following the procedure of Example 1 while using 3-hydroxypiperidine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 36. N, N-Dimethyl-4- (2- (3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide

1. Preparation of 4- (2- (3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide

(2- (3- (3-phenylpropyl) -1H-pyrazolo [3,4-c] pyridin-4-yl) -methanone was obtained in the same manner as in Example 1, Yl) ethyl) benzenesulfonamide.

2. Preparation of N, N-dimethyl-4- (2- (3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide

To the suspension of NaH (2.20 mmol) in cold DMF (5 ml) was added the above sulfonamide (1.00 mmol) and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was then cooled and CH ₃ I (2.20 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Saturated NH ₄ Cl solution was added to remove excess NaH and extracted with ethyl acetate. The organic layer solution was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by column chromatography to give pure title compound.

Example 37 N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinolin-2- (1H) -carboxamide

The title compound was synthesized by following the procedure of Example 1 while using 1,2,3,4-tetrahydroisoquinoline instead of 2-phenylaziridine in the same manner as in Example 1.

Example 38. N-phenethyl-4-phenylpiperidine-1-carboxamide

In the same manner as in Example 1, except that 4-phenylpiperidine was used instead of 2-phenyl aziridine and 2-phenylethyl isocyanate was used instead of 3-phenylpropyl isocyanate in the production method of Example 1, the title compound was synthesized Respectively.

Example 39 N-phenethyl-4-phenylpiperazine-1-carboxamide

The title compound was synthesized by following the procedure of Example 1 while using 4-phenylpiperazine instead of 2-phenyl aziridine and 2-phenylethyl isocyanate instead of 3-phenylpropyl isocyanate in the production method of Example 1 .

Example 40. 4-benzyl-N-phenethylpiperazine-1-carboxamide

Piperazine (35 mmol) was dissolved in THF. To the solution was added benzyl bromide (5.8 mmol) and refluxed for 2 hours. The reaction was monitored by TLC. After the reaction was complete, water was added to the mixture and extracted with ethyl acetate. The organic layer was concentrated and purified by column chromatography. The above-obtained benzylpiperazine was used instead of 2-phenyl aziridine in the same manner as in Example 1, except that 2-phenylethyl isocyanate was used instead of 3-phenylpropyl isocyanate to synthesize the title compound.

Example 41. 4- (2- (1,3-Dimethyl-3- (3-phenylpropyl) ureido) ethyl) -N, N-dimethylbenzenesulfonamide

To a suspension of NaH (1.10 mmol) in cold DMF (5 ml) was added the compound of example 36 (0.55 mmol) and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was then cooled and then CH ₃ I (1.10 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Saturated NH ₄ Cl solution was added to remove excess NaH and extracted with ethyl acetate. The organic layer solution was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by column chromatography to give pure title compound.

Example 42. 4-hydroxy-N- (3-phenylpropyl) piperidine-1-carboxamide

The title compound was synthesized by following the procedure of Example 1 while using 4-hydroxypiperidine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 43. 4-Methyl-N- (3-phenylpropyl) piperazine-1-carboxamide

The title compound was synthesized by following the procedure of Example 1 while using 4-methylpiperazine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 44. 4-methoxy-N- (3-phenylpropyl) piperidine-1-carboxamide

To a suspension of NaH (0.63 mmol) in cold THF (5 ml) was added the compound of Example 42 (0.58 mmol) and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was then cooled and then CH ₃ I (0.63 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC. Saturated NH ₄ Cl solution was added to neutralize excess NaH and extracted with ethyl acetate. The organic layer solution was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by column chromatography to give pure title compound.

Example 45. Preparation of 4-methoxy-N-methyl-N- (3-phenylpropyl) piperidine-

To a suspension of NaH (3.44 mmol) in cold DMF (5 ml) was added the compound of Example 42 (0.58 mmol) and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was then cooled and CH ₃ I (1.15 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Saturated NH ₄ Cl solution was added to neutralize excess NaH and extracted with ethyl acetate. The organic layer solution was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude mixture was purified by column chromatography to give pure title compound.

Example 46. l- (3-phenylpropyl) -3- (tetrahydro-2H-pyran-4-yl) urea

The title compound was synthesized by following the procedure of Example 1 while using 4-aminotetrahydropyran instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 47 N- (3-phenylpropyl) morpholine-4-carboxamide

The title compound was synthesized by following the procedure of Example 1 while using morpholine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 48. 3-Phenyl-N- (3-phenylpropyl) piperidine-1-carboxamide

3-Phenylpyridine (3.48 mmol, 0.5 ml) was dissolved in acetic acid, and Pt / C (10%, 20 mg) was added thereto under a stream of N ₂ . The reaction mixture was hydrogenated at 55 psi for 20 hours. Completeness of the reaction was checked by TLC. The reaction mixture was filtered through celite and concentrated in vacuo. The crude mixture was purified by column chromatography. The yield was 26% (150 mg of 3-phenylpiperidine).

Then, in the production method of Example 1, the title compound was synthesized by conducting the same procedure as in Example 1 using 3-phenylpiperidine obtained above in place of 2-phenyl aziridine.

Example 49. 1- (2,3-dihydro-1H-inden-2-yl) -3- (3-phenylpropyl) urea

The title compound was synthesized by following the procedure of Example 1 while using 2-aminoindan in place of 2-phenylaziridine in the preparation method of Example 1.?

Example 50. 1,3-bis (3-phenylpropyl) tetrahydropyrimidin-2 (1H) -one

Tetrahydropyrimidinone (3.30 mmol) was added to the suspension of NaH (3.60 mmol) in cold THF (5 ml) and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was then cooled and then 3-phenylpropyl bromide (3.30 mmol) was added. The reaction mixture was refluxed for an additional 5 h. The reaction was monitored by TLC. Saturated NH ₄ Cl solution was added to neutralize excess NaH and extracted with ethyl acetate. The crude mixture was purified by column chromatography to give pure title compound.

Example 51. 1- (2-fluorophenethyl) -3- (3-phenylpropyl) urea

The title compound was synthesized by following the procedure of Example 1 while using 2-fluorophenylethylamine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 52. l- (3-phenylpropyl) -3- (thiophen-2-ylmethyl) urea

The title compound was synthesized by following the procedure of Example 1 while using 2-aminomethylthiophene instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 53. l- (4-methylphenethyl) -3- (3-phenylpropyl) urea

The title compound was synthesized by following the procedure of Example 1 while using 4-methylphenylethylamine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 54. 1- (3-cyclohexylpropyl) -3-phenethyl urea

3-Cyclohexylpropan-1-ol (10 mmol) was refluxed overnight with bromic acid (10 mmol). After adding ice water, the reaction mixture was extracted with ethyl acetate to obtain 3- (bromopropyl) cyclohexane. The crude mixture was reacted with phthalimide (15 mmol) in THF solution (20 ml) to obtain a white solid phthalimide derivative. This was filtered and then reacted with hydrazine (98%, 63 mmol) in anhydrous ethanol (15 ml) at 60 ° C for 10 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate to give a 3-cyclohexylpropylamine compound.

Then, in the production method of Example 1, 3-cyclohexylpropylamine obtained as described above was used instead of 2-phenyl aziridine in the same manner as in Example 1 except that 2-phenylethyl isocyanate was used instead of 3-phenylpropyl isocyanate The title compound was synthesized.

Example 55. l- (3-phenylpropyl) -3- (2- (thiophen-2-yl) ethyl) urea

The title compound was synthesized by following the procedure of Example 1 while using 2- (2-aminoethyl) thiophene instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 56. 1- (2-cyclohexylethyl) -3- (3-cyclohexylpropyl) urea

An acetonitrile solution (25 ml) of 2-cyclohexenylethanamine (10 mmol) and CDI (carbodiimidazole) (10 mmol) was refluxed for 3 hours. The mixture was diluted with water and extracted with ethyl acetate to give N- (2-cyclohexylethyl) -1H-imidazole-1-carboxamide. The carboxamide (5 mmol) was refluxed with 3-cyclohexylpropylamine in an acetonitrile solution for 3 hours to give 1- (2-cyclohexylethyl) -3- (3-cyclohexylpropyl) urea. The urea was dissolved in methanol and hydrogenated at room temperature for 3 hours using Pd / C to obtain the title compound. Pd / C was filtered through celite and the organic solution was concentrated under reduced pressure. The crude mixture was subjected to column chromatography to obtain pure title compound.

Example 57. l-cyclohexyl-3- (3-phenylpropyl) urea

The title compound was synthesized by following the procedure of Example 1 while using cyclohexylamine instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 58. 2-phenyl-N- (3-phenylpropyl) piperidine-1-carboxamide

Under argon flow, piperidine (58 mmol) was added all at 20 占 폚 in a dry diethyl ether solution (150 ml) slurry of N-chlorosuccinimide (103 mmol). After 1 hour, the mixture was filtered and the solid was washed with diethyl ether (20 ml). The combined diethyl ether layers were washed with water (2 x 50 ml) and brine (40 ml) and dried with potassium carbonate, sodium sulphate and 4 Å molecular sieve for 1 hour. The solution was filtered and then added to a stirred solution of phenyllithium (1.8 M in 7: 3 cyclohexane: Et ₂ O, 80 ml, 144 mmol) at a rate that kept the internal temperature between 30-35 ° C under argon . The dark mixture was cooled (ice bath) and water (2 ml) was added. After 10 minutes, the solution turned pale yellow. After another 30 min, the mixture was diluted with water (20 ml) and diethyl ether (40 ml). The aqueous layer was extracted again with diethyl ether (30 ml) and the ether layers were combined and dried over sodium sulfate. The reaction mixture was concentrated and subjected to column chromatography to obtain pure 2-phenylpiperidine.

The title compound was synthesized by following the procedure of Example 1 while using 2-phenylpiperidine obtained above instead of 2-phenylaziridine in the same manner as in Example 1.

Example 59. 4- (3- (3-phenylpropyl) ureido) benzenesulfonamide

The title compound was synthesized by following the procedure of Example 1 while using 4-aminobenzenesulfonamide instead of 2-phenyl aziridine in the same manner as in Example 1.

Example 60. 4- (2- (3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide

In the same manner as in Example 1, except for using 4- (2-aminoethyl) benzenesulfonamide in place of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 61. 4 - ((3- (3-phenylpropyl) ureido) methyl) benzenesulfonamide

In the same manner as in Example 1, except for using 4- (2-aminomethyl) benzenesulfonamide instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 62. 1- (4-methoxybenzyl) -3- (3-phenylpropyl) urea

In the same manner as in Example 1, except that 4-methoxybenzylamine was used instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 63. 4- (3- (3-phenylpropyl) ureido) benzoic acid

In the same manner as in Example 1, except that 4-aminobenzoic acid was used instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 64. l- (3-chloro-2-fluorophenyl) -3- (3-phenylpropyl) urea

In the same manner as in Example 1, except for using 3-chloro-2-fluoroaniline instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 65. 1- (2,4-dichlorophenyl) -3- (3-phenylpropyl) urea

In the same manner as in Example 1, except that 2,4-dichloroaniline was used instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 66. 1- (3,5-Dichlorophenyl) -3- (3-phenylpropyl) urea

In the same manner as in Example 1, except that 3,5-dichloroaniline was used instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 67. Phenyl-3- (3-phenylpropyl) urea

In the same manner as in Example 1, except that aniline was used in place of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 68. 1- (2-tert-butylphenyl) -3- (3-phenylpropyl) urea

In the same manner as in Example 1, except that 2-tert-butylaniline was used instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 69. l- (2-isopropylphenyl) -3- (3-phenylpropyl) urea

In the same manner as in Example 1, except for using 2-isopropylaniline instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 70. N- (3-phenylpropyl) -6,7-dihydrothieno [3,2-c] pyridine-5 (4H) -carboxamide

In the same manner as in Example 1, except that 6,7-dihydrothieno [3,2-c] pyridine was used instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 71. l-benzyl-4-phenyltetrahydropyrimidin-2 (lH) -one

1. Synthesis of 2-chloro-4-phenylpyrimidine

Phenylboronic acid (1 eq) and 2,4-dichloropyrimidine (1 eq) were added to tetrahydrofuran, to which 10% sodium bicarbonate (1 eq) was added. Nitrogen was bubbled into the mixture to remove oxygen while the reaction mixture was well stirred. 0.05 equivalent of palladium tetrakis was added to the mixture and stirred well. The mixture was then refluxed under a stream of nitrogen for 24 hours. After the reaction was complete, the mixture was worked up with ethyl acetate and water to give a yellow solid crude product. The solid was purified by column chromatography to obtain white solid crystals. TLC was observed at Rf: 05 (ethyl acetate: hexane)

2. Synthesis of 4-phenylpyrimidin-2 (1H) -one

To the obtained 2-chloro-4-phenylpyrimidine was added concentrated hydrochloric acid (~ 10 N) and stirred well. The homogeneous mixture was refluxed for 1 hour. The reaction mixture was poured into 10% aqueous sodium carbonate solution. The white precipitate was filtered off and dried to give a white solid. TLC was observed at Rf: 02 (chloroform: methanol (9.5: 0.5)).

3. Synthesis of 4-phenyltetrahydropyrimidin-2 (1H) -one

Ammonium formate was added to the tetrahydrofuran methanol solution of 4-phenylpyrimidin-2 (1H) -one obtained above, and the mixture was heated to 60 ° C to obtain a homogeneous solution. After cooling the mixture, palladium carbonate (10% wt) was added and refluxed for 2 hours. The reaction mixture was filtered through Celite 450 and the filtrate was concentrated to give a crude solid. The solid was worked up with ethyl acetate and water and concentrated to give a white solid. TLC was observed at R f: 026 (chloroform: methanol (9.5: 0.5)

4. Synthesis of 1-benzyl-4-phenyltetrahydropyrimidin-2 (1H) -one

To a tetrahydrofuran solution of 4-phenyltetrahydropyrimidin-2 (1H) -one in a nitrogen stream was added LiHMDS (1 M sol) at -20 占 폚. Benzyl chloride was added dropwise at the same temperature after 1 hour from the dissolution of 4-phenyltetrahydropyrimidin-2 (1H) -one. After 20 minutes, it slowly rose to room temperature. And the mixture was refluxed under a nitrogen stream for 5 hours. The reaction mixture was worked up with an aqueous solution of ethyl acetate and 5% ammonium chloride, washed with water and brine. The organic layer was concentrated and subjected to column chromatography to obtain the title compound.

Example 72. 4-phenyl-l- (3-phenylpropyl) tetrahydropyrimidin-2 (lH) -one

3-Bromopropylbenzene was stirred in acetone with potassium iodide. The mixture was refluxed for 1 hour and then concentrated in a vacuum rotary evaporator to give a brown liquid. The title compound was obtained by following the procedure of 4 in Example 71 above, using the brown liquid obtained above instead of benzyl chloride.

Example 73. 4-methylsulfonyl-N- (3-phenylpropyl) piperazine-1-carboxamide

1. Synthesis of mono-Boc piperazine

To a cold methylene chloride solution (10 ml) of piperazine (30.23 mmol, 2.60 g) was added methylene chloride solution (10 ml) of BOC anhydride (1.50 mmol) and the mixture was stirred at 0 ° C for 1 hour. After the reaction was completed, water was added and the aqueous K ₂ CO ₃ solution was then added to make the reaction mixture basic. All of the reaction mixture was extracted with methylene chloride and the product was isolated by column chromatography.

2. Synthesis of tert-butyl 4- (methylsulfonyl) piperazine-1-carboxylate

Triethylamine was added to a cold methylene chloride solution (10 ml) of mono-Boc-piperazine (2.68 mmol) and the mixture was stirred at 0 ° C for 5 minutes. Methanesulfonyl chloride (3.23 mmol) was slowly added to the reaction mixture and stirred at 0 < 0 > C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, water was added and extracted with ethyl acetate. The product was purified by column chromatography.

3. Synthesis of 1- (methylsulfonyl) piperazine hydrochloride

tert-Butyl 4 (methylsulfonyl) piperazine-1-carboxylate (1.52 mmol) was dissolved in methanol (5 ml) and then cooled. After addition of 4M HCl in dioxane solution, the reaction mixture was stirred at room temperature for 3 hours. As the product was formed, a white precipitate was formed, which was concentrated and used in the next step.

4. Synthesis of 4-methylsulfonyl-N- (3-phenylpropyl) piperazine-1-carboxamide

1- (Methylsulfonyl) piperazine hydrochloride (1.07 mmol) was added to acetonitrile (5 ml) and potassium carbonate (1.16 mmol) was added followed by 3-phenylpropyl isocyanate (1.07 mmol). The reaction mixture was stirred at room temperature for 8 hours. After the reaction was completed, water was added and extracted with ethyl acetate. The organic layer was concentrated and purified by column chromatography to give the title compound.

Example 74. l- (3-hydroxypropyl) -3- (3-phenylpropyl) urea

In the same manner as in Example 1, except that 3-aminopropanol was used instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 75. 1- (3-phenylpropylcarbamoyl) piperidine-4-carboxylic acid

Bis (trimethylsilyl) acetamide (1.20 mmol) was added to an acetonitrile solution (5 ml) of piperidine-4-carboxylic acid (1.20 mmol) and the mixture was stirred at room temperature for 10 minutes. To the mixture was added 3-phenylpropyl isocyanate (1.00 mmol) and the mixture was stirred at room temperature for 8 hours. After the reaction was completed, water was added to the mixture, and the mixture was partitioned into an aqueous layer and an ethyl acetate layer. The organic layer was dried over anhydrous Na ₂ SO ₄ solution and was filtered and evaporated under reduced pressure. The crude mixture was subjected to column chromatography to give pure title compound.

Example 76. 4- (methoxymethyl) -N- (3-phenylpropyl) piperidine-1-carboxamide

Of the preparation methods of Example 44, the reactions were carried out in the same manner as in Example 44 using the compound of Example 30 instead of the compound of Example 42 to obtain the title compound.

Example 77. 2-phenyl-N- (3-phenylpropyl) pyrrolidine-1-carboxamide

In the same manner as in Example 1, except that 2-phenylpyrrolidine was used instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

≪ * >

Example 78. 4- (2- (1-ethyl-3- (3-phenylpropyl) ureido) ethyl) -N, N- dimethylbenzenesulfonamide

To a suspension of NaH (3.08 mmol) in DMF (8 ml), the compound of Example 36 (0.51 mmol) was added at 0 ° C, and the mixture was stirred at room temperature for 45 minutes. The solution was allowed to cool more then ethyl iodide (2.06 mmol) was added and stirred at room temperature for 15 hours. After the reaction was completed, the reaction mixture was added with saturated NH ₄ Cl and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ solution and was filtered and evaporated under reduced pressure. The crude mixture was subjected to column chromatography to obtain pure title compound.

Example 79. 4- (2- (1,3-diethyl-3- (3-phenylpropyl) ureido) ethyl) -N, N-dimethylbenzenesulfonamide

The crude mixture obtained in the same manner as in Example 78 was subjected to column chromatography to obtain pure title compound.

≪ * >

Example 80. 4- (2- (1-isopropyl-3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide

In the same manner as in Example 1, except for using 4- (2-isopropylamino) ethylbenzenesulfonamide in place of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 81. 4- (2- (1-isopropyl-3- (3-phenylpropyl) ureido) ethyl) -N, N- dimethylbenzenesulfonamide

To a suspension of NaH (0.66 mmol) in cold DMF (5 ml), the compound of Example 80 (0.30 mmol) was added and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was then cooled and then CH ₃ I (0.66 mmol) was added. The reaction mixture was stirred at room temperature for a further 6 hours. Saturated NH ₄ Cl solution was added to neutralize excess NaH and extracted with ethyl acetate. The product was purified by column chromatography to give the title compound.

Example 82. 4- (2- (1-Isopropyl-3-methyl-3- (3-phenylpropyl) ureido) ethyl) -N, N-dimethylbenzenesulfonamide

To a suspension of 5 ml of cold NaH (0.66 mmol) was added the compound of Example 81 (0.30 mmol) and the mixture was stirred at room temperature for 45 minutes. That then after cooling the reaction mixture was added CH ₃ I (1.00 mmol). The reaction mixture was stirred at room temperature for a further 15 hours. Saturated NH ₄ Cl solution was added to neutralize excess NaH and extracted with ethyl acetate. The product was purified by column chromatography to give the title compound.

Example 83. 1 - ((lH-indol-5-yl) methyl) -3- (3-phenylpropyl) urea

In the same manner as in Example 1, except that 5-aminomethylindole was used instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 84. Synthesis of 6,7-dimethoxy-1-methyl-N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinoline-2 (1H)

1. Preparation of 6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline

Sodium borohydride was added in small portions to a methanol solution (15 ml) of 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline (5.61 mmol) at room temperature for 20-30 minutes. The reaction mixture was then stirred for 3-4 hours. After the reaction is complete (TLC EA: hexane = 3: 7), the solvent is distilled off and 10 ml of water + conc. 5 ml of HCl was added to the reaction mixture. The reaction mixture was then extracted with methylene chloride. The aqueous layer was basified with 1N KOH and extracted with ethyl acetate. The solvent was evaporated to give a dark yellow residue which was used in the next step without purification.

2. Preparation of 6,7-dimethoxy-1-methyl-N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinoline-2 (1H) -carboxamide

A THF solution (10 ml) of 6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline (0.72 mmol) and 3-phenylpropyl isocyanate (0.72 mmol) Lt; RTI ID = 0.0 > 45 C < / RTI > until termination of the reaction. The reaction mixture was partitioned between 1N HCl solution and water and the organic layer was extracted with ethyl acetate. The solvent was evaporated and column chromatography (ethyl acetate: hexane) was performed to give the title compound.

Example 85. N-phenethyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2 (1H) -carboxamide

1. Preparation of 1-phenyl-1,2,3,4-tetraisoquinoline

Benzoyl chloride (33.05 mmol) was slowly added to a dichloromethane solution (40 ml) of phenylethylamine (33.05 mmol) and TEA (49.58 mmol) at 20 ° C, and the mixture was stirred until the reaction was terminated. Water was added and the organic layer was washed successively with 1N HCl, brine and water. The solvent was evaporated to give a white solid.

Xylene (80 ml), P ₂ O ₅ (132.2 mmol) and POCl ₃ (66.10 mmol) were added to the solid and refluxed for 6 hours. After cooling to room temperature, water was added, the aqueous layer was made basic with NaOH solution, extracted with dichloromethane, and the solvent was evaporated to obtain a residue. Sodium borohydride (33.31 mmol) was added in small portions to the methanol solution of the residue (22.21 mmol) at room temperature for 20-30 min. The reaction mixture was then stirred for 3-4 hours. After the reaction is complete (TLC EA: hexane = 3: 7), the solvent is distilled off and 10 ml of water + conc. 5 ml of HCl was added to the reaction mixture. The reaction mixture was then extracted with methylene chloride. The aqueous layer was basified with 1N KOH and extracted with ethyl acetate. The solvent was evaporated to give a dark yellow residue which was used in the next step without purification.

2. Preparation of N-phenethyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2 (1H) -carboxamide

A THF solution (20 ml) of 6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline (1.50 mmol) and 3-phenylethyl isocyanate (1.12 mmol) Lt; RTI ID = 0.0 > 45 C < / RTI > until termination of the reaction. The reaction mixture was partitioned between 1N HCl solution and water and the organic layer was extracted with ethyl acetate. Evaporation of the solvent followed by column chromatography (EA: hexane) gave the title compound.

Example 86. N- (3,4-dimethoxyphenethyl) -1-phenyl-1,2,3,4-tetrahydroisoquinoline-2 (1H) -carboxamide

A THF solution (10 ml) of 3,4-dimethoxyphenethylamine (1.1 mmol) and DIPEA (2.2 mmol) was slowly added to a THF solution (10 ml) of triphosgene (0.44 mmol) And stirred for 30-45 minutes. Then, a solution of 1-phenyl-1,2,3,4-tetrahydroisoquinoline (1.1 mmol) in THF (10 ml) was added and stirred overnight. The salt was filtered, and the filtrate was evaporated, and column chromatography (EA: Hexane) was carried out to obtain the title compound.

Example 87. 4- (2- (1-methyl-3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide

1. Preparation of 4- (2- (methylamino) ethyl) benzenesulfonamide

Formaldehyde solution (35%, 5.0 mmol) and freshly activated zinc powder (1.00 ml) were added to acetic acid (1.1 ml, 20 mmol) and water solution (5 ml) of 4- (2- aminoethyl) benzenesulfonamide g) was added and the reaction mixture was stirred overnight. After the product formed, excess water was added and extracted with ethyl acetate. The crude product was used in the next step without purification.

2. Preparation of 4- (2- (1-methyl-3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide

In the same manner as in Example 1, except for using 4- (2- (methylamino) ethyl) benzenesulfonamide obtained in the same manner as in Example 1, the title compound was obtained instead of 2-phenyl aziridine.

Example 88. l- (2- (furan-2-yl) ethyl) -3- (3-phenylpropyl) urea

1. Synthesis of (E) -2- (2-nitrovinyl) furan

NaOH (1.1 M, 5 ml) was added to a methanol solution (10 ml) of furfural (12.00 mmol) and nitromethane (12.00 mmol) and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, the pH was adjusted to neutral by adding water and adding dilute HCl solution. The reaction mixture was extracted with ethyl acetate. The product was purified by column chromatography.

2. Preparation of 2- (furan-2-yl) ethanamine

Lithium aluminum hydride (2M solution under THF, 25.90 mmol) was added at 0 ° C to a dry THF solution (10 ml) of (E) -2- (2-nitrovinyl) furan (4.32 mmol) Lt; / RTI > After the reaction was completed, ethyl acetate was added to dilute the reaction mixture, water was added, and the mixture was made basic with 10% NaOH solution. The mixture was extracted with ethyl acetate and then purified by column chromatography to give the product.

3. Preparation of 1- (2- (furan-2-yl) ethyl) -3- (3-phenylpropyl) urea

In the same manner as in Example 1, except that 2- (furan-2-yl) ethanamine (2.70 mmol) was used instead of 2-phenyl aziridine in the preparation method of Example 1 (3-phenylpropyl isocyanate, 2.70 mmol) to give the title compound.

Example 89. l- (furan-2-ylmethyl) -3- (3-phenylpropyl) urea

In the same manner as in Example 1, except that 2-aminomethylfuran was used instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

The reaction schemes of Examples 90 and 91

Example 90. N, N-Dimethyl-4 - ((3- (3-phenylpropyl) ureido) methyl) benzenesulfonamide

(3- (3-phenylpropyl) ureido) methyl) piperidine was performed in the same manner as in Example 1, except that 4-aminomethylbenzenesulfonamide was used instead of 2- Benzenesulfonamide. Thereafter, methylation was carried out in the same manner as in Example 36-2 to obtain the title compound.

Example 91. 4 - ((1,3-dimethyl-3- (3-phenylpropyl) ureido) methyl) -N, N-dimethylbenzenesulfonamide

In the same manner as in Example 1, except for using the compound of Example 90 instead of the compound of Example 36, the title compound was obtained.

Example 92. l- (3-1H-imidazol-l-yl) propyl) -3-phenethylurea

The procedure of Example 1 was repeated except that 1- (3-aminomethyl) imidazole was used in place of 2-phenyl aziridine and 2-phenylethyl isocyanate instead of 3-phenylpropyl isocyanate The title compound was obtained.

Example 93. 1- (3-morpholinopropyl) -3-phenethyl urea

The procedure of Example 1 was repeated except that 1- (3-aminomethyl) imidazole was used in place of 2-phenyl aziridine and 2-phenylethyl isocyanate instead of 3-phenylpropyl isocyanate The title compound was obtained.

Example 94. l-phenyl-N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinolin-2 (lH) -carboxamide

In the same manner as in Example 1, except that 1-phenyl-1,2,3,4-tetrahydroisoquinoline was used instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 95. l- (4-chlorophenyl) -7-methoxy-N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinolin-

1. 1- (4-Chlorophenyl) -7-methoxy-1,2,3,4-tetrahydroisoquinoline

4-Chlorobenzoyl chloride (16.53 mmol) was slowly added dropwise to a solution of 4-methoxyphenylethylamine (16.53 mmol) and TEA (24.80 mmol) in dichloromethane (25 ml) at 20 ° C, Lt; / RTI > Water was added and the organic layer was washed successively with 1N HCl, brine and water. The solvent was evaporated to give a white solid.

Xylene (40 ml), P ₂ O ₅ (66.12 mmol) and POCl ₃ (33.06 mmol) were added to the solid and refluxed for 6 hours. After cooling to room temperature, water was added, the aqueous layer was made basic with NaOH solution, extracted with dichloromethane, and the solvent was evaporated to obtain a residue. Sodium borohydride (6.62 mmol) was slowly added to the methanol solution of the residue (4.41 mmol) at room temperature for 20-30 min. The reaction mixture was then stirred for 3-4 hours. After the reaction is complete (monitored by TLC EA / hexane 3: 7), the solvent is evaporated and 10 ml of conc. 15 ml of HCl was added, followed by extraction with dichloromethane. The aqueous layer was basified with 1N KOH and extracted with ethyl acetate. The solvent was evaporated to give a dark yellow residue which was used in the next step without further purification.

2. Preparation of 1- (4-chlorophenyl) -7-methoxy-N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinoline-2 (1H) -carboxamide

A THF solution (10 ml) of 1- (4-chlorophenyl) -7-methoxy-1,2,3,4-tetrahydroisoquinoline (0.38 mmol) and 3-phenylisocyanate (0.38 mmol) Lt; RTI ID = 0.0 > 40-45 C < / RTI > until the reaction is complete. The reaction mixture was partitioned between 1N HCl solution and water and extracted with ethyl acetate. The solvent was evaporated and purified by column chromatography (EA: hexane) to give the title compound.

Example 96. N- (3-phenylpropyl) -7-sulfamoyl-l, 2,3,4-tetrahydroisoquinolin-2 (lH) -carboxamide

1. 1,2,3,4-Tetrahydroisoquinoline-7-sulfonamide

A mixture of tetrahydroisoquinoline (26.3 mmol) and acetic anhydride (97.9 mmol) was stirred at room temperature. After the reaction was completed, the reaction was concentrated and water was added. The pH of the reaction was then adjusted to 8 with K ₂ CO ₃ and extracted with dichloromethane. The organic layer was washed with 1N HCl, water and brine, dried, and the solvent was evaporated to obtain an acetylisoquinoline compound.

A dichloromethane solution (10 ml) of the obtained acetyl isoquinoline crude compound (18.54 mmol) and chlorosulfonic acid (34.52 mmol) was stirred at -10 ° C for 1-2 hours and then refluxed for 2 hours. The mixture was cooled to 10 ° C in ice, the reaction was quenched, extracted with dichloromethane and concentrated to obtain 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride.

The product (1.8 mmol) was dissolved in acetone (15 ml), cooled to 0-5 ° C, and an aqueous ammonia solution (85.25 mol) was added and stirred for 2-3 hours. The salt was filtered off, water was added and extracted with ethyl acetate. Dried and concentrated to give a residue.

The residue was dissolved in butanol (5 ml), 3N HCl (30 ml) was added, and the mixture was refluxed for 3-6 hours to remove the acetyl group. The solvent was then distilled off and water was added. The pH was adjusted to 9. Extraction with dichloromethane and drying over sodium sulfate. The organic layer was concentrated to obtain 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide.

2. Preparation of N- (3-phenylpropyl) -7-sulfamoyl-1,2,3,4-tetrahydroisoquinoline-2 (1H) -carboxamide

The THF solution (30 ml) of 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (3.76 mmol) and 3-phenylisocyanate (3.33 mmol) obtained above was reacted at 40-45 ° C Lt; / RTI > The reaction mixture was partitioned between 1N HCl solution and water and extracted with ethyl acetate. The solvent was evaporated and purified by column chromatography (EA: hexane) to give the title compound.

Example 97. 7- (N, N-dimethylsulfamoyl) -N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinolin-2 (1H)

The compound of Example 96 (0.53 mmol) was dissolved in THF solution (20 ml) and sodium hydride (1.17 mmol) was slowly added at room temperature. The mixture was stirred for 30-45 minutes until sodium salt was formed. Methyl iodide (1.17 mmol) was then added and stirred until the reaction was complete. The whole reaction mixture was adsorbed onto silica gel and subjected to column chromatography (EA: hexane) to obtain pure title compound.

Example 98. 7- (4-methylpiperazin-1-ylsulfonyl) -N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinoline- 2 (1H) -carboxamide

1. Preparation of 7- (4-methylpiperazin-1-ylsulfonyl) -1,2,3,4-tetrahydroisoquinoline

2-Acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride (2.736 mmol) obtained in Intermediate Step 1 of Example 96 was dissolved in THF (20 ml) 15 < 0 > C. To this was slowly added a mixture of TEA (5.47 mmol) and N-methylpiperazine (8.22 mmol). The reaction mixture was stirred for a further 2-3 hours until the piperazine scaffold was coupled. After removal of the solvent, water + 1N HCl solution was added and extracted with dichloromethane. And dried over sodium sulfate to obtain an acetylated piperazine compound.

The acetylated piperazine compound was dissolved in butanol (5 ml), 3N HCl was added, and the mixture was refluxed for 3-6 hours to release the acetyl group. The solvent was then removed and water was added. The pH was adjusted to 9. Extraction with dichloromethane followed by drying over sodium sulfate. The organic layer was concentrated to obtain N-methylpiperazine sulfonamide isoquinoline compound free from acetyl group.

2. Preparation of 7- (4-methylpiperazin-1-ylsulfonyl) -N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinoline-2 (1H) -carboxamide

A THF solution (20 ml) of 7- (4-methylpiperazin-1-ylsulfonyl) -1,2,3,4-tetrahydroisoquinoline (1.7 mmol) and 3-phenylisocyanate (1.5 mmol) Was stirred at 40-45 < 0 > C until the reaction was complete. The reaction mixture was partitioned between 1N HCl solution and water and extracted with ethyl acetate. The solvent was evaporated and purified by column chromatography (EA: hexane) to give the title compound.

Example 99. 7- (morpholinosulfonyl) -N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinoline-2 (1H) -carboxamide

In the same manner as in Example 98, except for using morpholine instead of N-methylpiperazine, the procedure of Example 98 was repeated to give the title compound.

Example 100. N, N-Dimethyl-4- (2- (1-methyl-3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide

1. Preparation of N- (4-sulfamoylphenethyl) acetamide

To the cold dichloromethane solution (20 ml) of 4- (2-aminoethyl) benzenesulfonamide (10 mmol) was added triethylamine (15 mmol) at 0 ° C. After stirring for 5 minutes, acetyl chloride (15 mmol) was added at 0 ° C, and the mixture was stirred at room temperature for about 3 hours. After the reaction was completed, water was added and extracted with dichloromethane. The organic layer was washed with a dilute hydrochloric acid solution to remove any residual amines and then concentrated. The next step was used without further purification.

2. Preparation of N- (4- (N, N-dimethylsulfamoyl) phenethyl) -N-methylacetamide

To the suspension of NaH (16.20 mmol) in DMF (8 ml) was added N- (4-sulfamoylphenethyl) acetamide (5.40 mmol) at 0 ° C and the mixture was stirred at room temperature for 45 minutes. The solution was allowed to cool more then methyl iodide (16.20 mmol) was added and stirred at room temperature for 3 hours. After the reaction was terminated, saturated NH ₄ Cl solution was added and the reaction mixture was extracted with ethyl acetate. The obtained product was purified by column chromatography.

3. Preparation of N, N-dimethyl-4- (2- (methylamino) ethyl) benzenesulfonamide

N- (4- (N, N-dimethylsulfamoyl) phenethyl) -N-methylacetamide obtained above was dissolved in n-butanol (3 ml) and 3N HCl (100 ml) was added. The reaction mixture was refluxed for 8 hours. After the reaction was completed, the aqueous layer after the solution was extracted three times with diethyl ether and neutralized by solid K ₂ CO _3. This was extracted again with ethyl acetate to give the amine crude product which was used in the next step without further purification.

4. Preparation of N, N-dimethyl-4- (2- (1-methyl-3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide

An acetonitrile solution of the amine compound (0.826 mmol) obtained in the above step 3 and 3-phenylpropyl isocyanate (0.826 mmol) was stirred for 8 hours. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography to obtain pure title compound.

The reaction equations of Examples 101 and 102

Example 101. 4- (2- (3-Methyl-3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide

The reaction was carried out in the same manner as in 1 to 3 of Example 100 using 3-aminopropylbenzene instead of 4- (2-aminoethyl) benzenesulfonamide in Step 1 of Example 100 to obtain 3- (N-methyl Amino) propylbenzene.

Thereafter, 3- (N-methylamino) propylbenzene was used instead of 4-phenylbutylamine and 4- (2-aminoethyl) benzenesulfonamide was used instead of 4-phenylpiperidine in the production method of Example 7 The title compound was obtained.

Example 102. N, N-Dimethyl-4- (2- (3-methyl-3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide

Methylation was carried out for 5 hours in the same manner as in step 2 of Example 100, using the compound of Example 101 instead of N- (4-sulfamoylphenethyl) acetamide in Step 2 of Example 100 to obtain the title compound ≪ / RTI >

Example 103. 7- (N, N-dimethylsulfamoyl) -N-methyl-N- (3-phenylpropyl) -1,2,3,4-tetrahydroisoquinolin-

The compound of Example 97 was methylated to give the title compound.

Example 104. N- (3-phenylpropyl) -1,2,3,4-tetrahydroquinoline-1 (2H) -carboxamide

A THF solution (20 ml) of 3-phenyl-1-propylamine (14.81 mmol) and DIPEA (29.62 mmol) was slowly added to a THF solution (20 ml) of triphosgene (5.90 mmol) Followed by stirring for 30-45 minutes. When a white precipitate was formed, an additional THF solution (20 ml) was added. A THF solution (20 ml) of tetrahydroquinoline (14.61 mmol) was then added and stirred at 40-45 [deg.] C overnight. The reaction mixture was added to 250 ml of a saturated NaHCO ₃ solution and the 200 ml of ethyl acetate. The organic layer was washed successively with 1N HCl, water, and brine. The organic layer was concentrated and purified by column chromatography (EA: hexane) to give the title compound (1.20 g).

Example 105. N- (4-phenylbutyl) -1,2,3,4-tetrahydroquinoline-1 (2H) -carboxamide

4-phenyl-1-butylamine (4.02 mmol) and a THF solution (20 ml) of DIPEA (8.04 mmol) were slowly added to a THF solution (20 ml) of triphosgene (1.61 mmol) Followed by stirring for 30-45 minutes. When a white precipitate was formed, an additional THF solution (20 ml) was added. A THF solution (20 ml) of tetrahydroquinoline (4.02 mmol) was then added and stirred overnight at 40-45 ° C. The reaction mixture was added to 250 ml of a saturated NaHCO ₃ solution and the 200 ml of ethyl acetate. The organic layer was washed successively with 1N HCl, water, and brine. The organic layer was concentrated and purified by column chromatography (EA: hexane) to obtain the title compound.

Example 106. N- (4-phenylbutyl) -1,2,3,4-tetrahydroquinoline-2 (1H) -carboxamide

4-phenyl-1-butylamine (4.02 mmol) and a THF solution (20 ml) of DIPEA (8.04 mmol) were slowly added to a THF solution (20 ml) of triphosgene (1.61 mmol) Followed by stirring for 30-45 minutes. When a white precipitate was formed, an additional THF solution (20 ml) was added. Then THF solution (20 ml) of tetrahydroisoquinoline (4.02 mmol) was added and stirred overnight at 40-45 ° C. The reaction mixture was added to 250 ml of a saturated NaHCO ₃ solution and the 200 ml of ethyl acetate. The organic layer was washed successively with 1N HCl, water, and brine. The organic layer was concentrated and purified by column chromatography (EA: hexane) to obtain the title compound.

Example 107. N- (4-phenylbutyl) indoline-1-carboxamide

4-phenyl-1-butylamine (4.02 mmol) and a THF solution (20 ml) of DIPEA (8.04 mmol) were slowly added to a THF solution (20 ml) of triphosgene (1.61 mmol) Followed by stirring for 30-45 minutes. When a white precipitate was formed, an additional THF solution (20 ml) was added. Then a solution of indolin (4.02 mmol) in THF (20 ml) was added and stirred overnight at 40-45 ° C. The reaction mixture was added to 250 ml of a saturated NaHCO ₃ solution and the 200 ml of ethyl acetate. The organic layer was washed successively with 1N HCl, water, and brine. The organic layer was concentrated and purified by column chromatography (EA: hexane) to obtain the title compound.

Example 108. N-methyl-N- (4-phenylbutyl) indoline-1-carboxamide

The compound of Example 107 (1.68 mmol) was dissolved in DMF (20 ml) and sodium hydride (5.03 mmol) was added at room temperature. After stirring for 30-45 minutes until sodium salt was formed, methyl iodide (5.03 mmol) was added thereto, and the mixture was stirred at 40-45 ° C. until the reaction was terminated. After the reaction was completed, the ammonium chloride solution was added to the reaction mixture to remove the reaction, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated and purified by column chromatography (EA: hexane).

Example 109. N-methyl-N- (3-phenylpropyl) indoline-1-carboxamide

The compound of Example 10 (1.96 mmol) was dissolved in DMF (20 ml) and sodium hydride (5.90 mmol) was added at room temperature. After stirring for 30-45 minutes until sodium salt was formed, methyl iodide (5.90 mmol) was added thereto and stirred at 40-45 ° C until the reaction was terminated. After the reaction was completed, the ammonium chloride solution was added to the reaction mixture to remove the reaction, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated and purified by column chromatography (EA: hexane).

Example 110. N- (3-phenylpropyl) isoindoline-2-carboxamide

A THF solution (20 ml) of 3-phenyl-1-propylamine (3.70 mmol) and DIPEA (7.4 mmol) was slowly added to a THF solution (20 ml) of triphosgene (1.48 mmol) under dry conditions at room temperature Followed by stirring for 30-45 minutes. A further THF solution (20 ml) was added in the event of a white precipitate. Then a solution of isoindoline (3.70 mmol) in THF (20 ml) was added and stirred overnight at 40-45 ° C. The reaction mixture was added to 250 ml of a saturated NaHCO ₃ solution and the 200 ml of ethyl acetate. The organic layer was washed successively with 1N HCl, water, and brine. The organic layer was concentrated and purified by column chromatography (EA: hexane) to obtain the title compound.

Example 111. N-methyl-N- (3-phenylpropyl) isoindoline-2-carboxamide

The compound of Example 110 (0.89 mmol) was dissolved in DMF (20 ml), and sodium hydride (2.67 mmol) was slowly added to the reaction flask at room temperature. After stirring for 30-45 minutes until sodium salt was formed, methyl iodide (2.67 mmol) was added thereto and stirred at 40-45 ° C. until the reaction was terminated. After the reaction was completed, the ammonium chloride solution was added to the reaction mixture to remove the reaction, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated and purified by column chromatography (EA: hexane).

Example 112. Diindolin-1-ylmethanone

The title compound (250 mg) as a bis-indolinecarbonyl compound was isolated in addition to the compound of Example 107 in the process of synthesizing the compound of Example 107 and separating by column chromatography.

Example 113. l- (4-methoxyphenethyl) -3- (3-phenylpropyl) urea

A THF solution (20 ml) of 4-methoxyphenethylamine (1.98 mmol) and 3-phenylisocyanate (1.78 mmol) was stirred at 40-45 째 C until the reaction was terminated. The reaction mixture was then partitioned between 1N HCl solution and water and extracted with ethyl acetate. The solvent was evaporated and purified by column chromatography (EA: hexane).

Example 114. N- (4-phenylbutyl) isoindolin-2-carboxamide

A THF solution (20 ml) of 3-phenyl-1-butylamine (3.36 mmol) and DIPEA (6.72 mmol) was slowly added to a THF solution (20 ml) of triphosgene (1.34 mmol) Followed by stirring for 30-45 minutes. A further THF solution (20 ml) was added in the event of a white precipitate. Then a solution of isoindoline (3.36 mmol) in THF (20 ml) was added and stirred overnight at 40-45 ° C. The reaction mixture was added to 250 ml of a saturated NaHCO ₃ solution and the 200 ml of ethyl acetate. The organic layer was washed successively with 1N HCl, water, and brine. The organic layer was concentrated and purified by column chromatography (EA: hexane) to obtain the title compound.

Example 115. l- (4-fluorophenethyl) -3- (3-phenylpropyl) urea

A THF solution (20 ml) of 4-fluorophenethylamine (2.15 mmol) and 3-phenylisocyanate (1.94 mmol) was stirred at 40-45 째 C until the reaction was terminated. The reaction mixture was then partitioned between 1N HCl solution and water and extracted with ethyl acetate. The solvent was evaporated and purified by column chromatography (EA: hexane).

Example 116. N-methyl-N- (4-phenylbutyl) isoindolin-2-carboxamide

The compound of Example 114 (1.35 mmol) was dissolved in DMF (20 ml), and sodium hydride (5.44 mmol) was slowly added to the reaction flask at room temperature. After stirring for 30-45 minutes until sodium salt was formed, methyl iodide (5.44 mmol) was added thereto, and the mixture was stirred at 40-45 ° C. until the reaction was terminated. After the reaction was completed, the ammonium chloride solution was added to the reaction mixture to remove the reaction, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated and purified by column chromatography (EA: hexane).

Example 117. l- (4-isopropylphenethyl) -3- (3-phenylpropyl) urea

In the same manner as in Example 1, except that 4-isopropylphenethylamine was used instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 118. 1- (2-morpholinethyl) -3- (3-phenylpropyl) urea

In the same manner as in Example 1, except that 2-morpholinethylamine was used instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 119. l- (2,4-dichlorophenethyl) -3- (3-phenylpropyl) urea

In the same manner as in Example 1, except that 2,4-dichlorophenethylamine was used instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 120. 4- (2- (3- (3-phenylpropyl) ureido) ethyl) benzoic acid

In the same manner as in Example 1, except that 4- (2-aminoethyl) benzoic acid was used instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 121. N-methyl-N- (3-phenylpropyl) -1,2,3,4-tetrahydroquinoline- 1 (2H) -carboxamide

The compound of Example 104 (1.67 mmol) was dissolved in DMF (20 ml), and sodium hydride (5.00 mmol) was slowly added to the reaction flask at room temperature. After stirring for 30-45 minutes until sodium salt was formed, methyl iodide (1.69 mmol) was added thereto, and the mixture was stirred at 40-45 ° C. until the reaction was terminated. After the reaction was completed, the ammonium chloride solution was added to the reaction mixture to remove the reaction, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated and purified by column chromatography (EA: hexane).

Example 122. N-methyl-N- (4-phenylbutyl) -1,2,3,4-tetrahydroquinoline-2 (1H) -carboxamide

The compound of Example 106 (1.29 mmol) was dissolved in DMF (20 ml), and sodium hydride (1.56 mmol) was slowly added to the reaction flask at room temperature. After stirring for 30-45 min until sodium salt was formed, methyl iodide (1.56 mmol) was added thereto, and the mixture was stirred at 40-45 캜 until the reaction was terminated. After the reaction was completed, the ammonium chloride solution was added to the reaction mixture to remove the reaction, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated and purified by column chromatography (EA: hexane).

Example 123 N ^One - (3-phenylpropyl) piperidine-l, 4-dicarboxamide

Piperidine-4-carboxamide (2.34 mmol) and 3-phenylisocyanate (2.10 mmol) in DMF (20 ml) was stirred at 40-45 ° C until the reaction was terminated. The reaction mixture was then partitioned between 1N HCl solution and water and extracted with ethyl acetate. The solvent was evaporated and purified by column chromatography (EA: hexane).

Example 124. N-methyl-N- (3-phenylpropyl) -1,2,3,4-tetrahydroquinoline-2 (1H)

The compound (0.85 mmol) of Example 37 was dissolved in DMF (20 ml), and sodium hydride (1.69 mmol) was slowly added to the reaction flask at room temperature. After stirring for 30-45 minutes until sodium salt was formed, methyl iodide (1.69 mmol) was added thereto and stirred at 40-45 ° C. until the reaction was terminated. After the reaction was completed, the ammonium chloride solution was added to the reaction mixture to remove the reaction, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated and purified by column chromatography (EA: hexane).

Example 125. l-Cyclohexyl-3- (3-phenylpropyl) urea

In the same manner as in Example 1, except that 2-phenyl aziridine was replaced by cyclohexylamine, the title compound was obtained.

Example 126. N- (3-phenylpropyl) piperidine-1-carboxamide

3-phenylpropan-l-amine (3.52 mmol) and DIPEA (7.04 mmol) were slowly added to a cold THF solution (20 ml) of triphosgene (1.41 mmol) at 0 ° C. After stirring for 30 minutes, piperidine (3.52 mmol) was added, the mixture was allowed to slowly warm to room temperature, and the mixture was stirred for 8 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was concentrated and purified by column chromatography (EA: hexane) to obtain the title compound.

Example 127. l- (3,4-dimethoxybenzyl) -3- (3-phenylpropyl) urea

In the same manner as in Example 1, except that 3,4-dimethoxybenzylamine was used instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 128. N- (4- (N, N-dimethylsulfamoyl) phenethyl) -4-phenylpiperidine-1-carboxamide

In the same manner as in Example 126, except for using 2- (4-sulfamoylphenyl) ethylamine instead of 3-phenylpropan-1-amine and 4-phenylpiperidine instead of piperidine in the preparation method of Example 126, To obtain N- (4- (sulfamoyl) phenethyl) -4-phenylpiperidine-1-carboxamide.

Methylation reaction was carried out on the carboxamide compound obtained in the same manner as in the methylation reaction of Example 124 to obtain the title compound.

Example 129. 4- (4- (N, N-dimethylsulfamoyl) phenyl) -N- (3-phenylpropyl) piperidine-

1. Preparation of 1- (4-phenylpiperidin-1-yl) ethanone

To a cold methylene chloride solution (10 ml) of 4-phenylpiperidine (6.20 mmol) was added triethylamine (9.30 mmol) at 0 ° C. After 5 minutes, acetyl chloride (9.30 mmol) was added at the same temperature, followed by stirring at room temperature for 3 hours. The reaction was monitored by TLC. After the reaction was terminated, the reaction mixture was poured into water to remove the reaction and the reaction was quenched with methylene chloride. The organic layer was washed twice with water and then concentrated to obtain a crude product. The product was used in the next step without purification. Yield 80%.

2. Preparation of 4- (1-acetylpiperidin-4-yl) benzene-1 -sulfonyl chloride

(2 ml) of the above prepared 1- (4-phenylpiperidin-1-yl) ethanone (3.33 mmol) was slowly added to a cold solution (2 ml) of chlorosulfuric acid at 0 ° C And the mixture was stirred for 3 hours while keeping the temperature at room temperature. The reaction was monitored by TLC. After the reaction was terminated, the reaction mixture was slowly poured into crushed ice with vigorous stirring. After all the ice had melted, the reaction was extracted with methylene chloride and concentrated. The crude product was used in the next step.

3. Preparation of 4- (1-acetylpiperidin-4-yl) -N, N-dimethylbenzenesulfonamide

To the cold THF solution (10 ml) of N, N-dimethylbenzenesulfonamide (2.66 mmol) was added NaHCO ₃ (1.99 mmol) at 0 ° C to give the free amine. To the reaction mixture was added a THF solution of 4- (1-acetylpiperidin-4-yl) benzene-1-sulfonyl chloride (1.33 mmol). The reaction mixture was stirred for 5 hours while gradually warming to room temperature. After the reaction was terminated, water was added and the reaction mixture was extracted with ethyl acetate. The product was purified by column chromatography.

4. Preparation of N, N-dimethyl-4- (piperidin-4-yl) benzenesulfonamide

3N HCl (100 ml) was added to an n-butanol solution (2 ml) of 4- (1-acetylpiperidin-4-yl) -N, N-dimethylbenzenesulfonamide (0.10 mmol) Lt; / RTI > After the reaction was completed, the reaction mixture was extracted with diethyl ether. The aqueous layer was neutralized using potassium carbonate solids and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. A white solid product was obtained, which was used in the next step. Total yield 30%.

Preparation of 4- (4- (N, N-dimethylsulfamoyl) phenyl) -N- (3-phenylpropyl) piperidine-1-carboxamide

In the same manner as in Example 1, except that N, N-dimethyl-4- (piperidin-4-yl) benzenesulfonamide obtained above was used instead of 2-phenyl aziridine in the production method of Example 1, The title compound was obtained.

Example 130. 2 - ((lR, 4R) -4-hydroxycyclohexylamino) -N- (3-phenylpropyl) acetamide

3-phenylisocyanate (4.34 mmol) was slowly added to the THF solution (20 ml) of trans-4-aminocyclohexanol (4.34 mmol) at room temperature for 10-15 minutes and then TEA (6.51 mmol) was added. The reaction mixture was stirred at 40-45 [deg.] C for 24 hours. The termination of the reaction was confirmed by TLC. THF (50 ml) was added to the reaction flask, and the mixture was stirred for 30 minutes, and then the solvent was distilled to obtain a solid. To the solid was added water and 3N HCl solution (150 + 50 ml), and the mixture was stirred for 30-40 minutes. The solids were filtered and washed with dichloromethane and ether (50 ml each). The solids were dried in an oven and vacuum pump for 6-8 hours.

Example 131. Methyl 2- (3-cyclohexylureido) -3- (1H-indol-3-yl) propanoate

Cyclohexane isocyanate (0.86 mmol) was slowly added to the THF solution (20 ml) of D-tryptophan methyl ester hydrochloride (0.78 mmol) at room temperature for 10-15 minutes and then TEA (6.51 mmol) was added. The reaction mixture was stirred at 40-45 [deg.] C for 24 hours. The termination of the reaction was confirmed by TLC. The next day the solvent was distilled off and water (100 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was washed with brine and dried over sodium sulfate. The solvent was distilled off and adsorbed onto silica gel using methylene chloride. Chromatographic separation with 5-10% ethyl acetate in hexanes gave the title compound.

Example 132. N- (3-phenylpropyl) -5-sulfamoylindoline-1-carboxamide

1. Preparation of indolin-5-sulfonamide

Ammonium acetate (12.97 mmol) was added to a THF solution (20 ml) of 1- (2,2,2-trifluoroacetyl) indoline-5-sulfonyl chloride (0.95 mmol) in a 1-necked round bottom flask at room temperature, And TEA (14.34 mmol) were added and the flask was immediately stopped with a stopper, followed by stirring at room temperature for 6-8 hours. The reaction was quenched with water and extracted with ethyl acetate (100 ml). The solvent was distilled to obtain a residue. The residue was dissolved again in THF solution (20 ml), and a minimal amount of LiOH (20.88 mmol) dissolved in water was added thereto, followed by stirring at 45-50 ° C for 6-8 hours. After confirming that the reaction was terminated by TLC, work-up was carried out. Extra base was neutralized by adding 1N HCl to pH ~ 7. The reaction was extracted again with ethyl acetate (100 ml). The organics were washed with brine and dried with sodium sulfate. The solvent was distilled to give the crude (0.172 g) which was used in the next step without further purification.

2. Preparation of N- (3-phenylpropyl) -5-sulfamoylindoline-1-carboxamide

3-phenylpropyl isocyanate (0.85 mmol) was slowly added to the THF solution (20 ml) of the above-prepared indolin-5-sulfonamide (0.85 mmol) at room temperature. The reaction mixture was stirred at 40-45 [deg.] C for 24 hours. The termination of the reaction was confirmed by TLC. 1N HCl solution (100 ml) was added to the reaction mixture and stirred for 20 minutes. The residue was then separated by removal of the HCl solution. The residue was dissolved in ethyl acetate (100 ml), washed with water and brine, and dried over sodium sulfate. The solvent was distilled off and treated with ether to give a solid. The solid was filtered and washed with ether. The cream-colored solid was dried in an oven at 60 < 0 > C for 12 hours and then dried with a vacuum pump to give the title compound.

Example 133. 5- (N, N-dimethylsulfamoyl) -N-methyl-N- (3-phenylpropyl) indoline-

1. Preparation of 5- (N, N-dimethylsulfamoyl) -N-methyl-N- (3-phenylpropyl) indoline-1-carboxamide

Sodium hydride (2.07 mmol) was added to a DMF solution (10 ml) of the compound of Example 132 (0.62 mmol) at room temperature and the mixture was stirred for 30-45 minutes. Methyl iodide (2.07 mmol) was added to the reaction mixture and stirred at 40-45 ° C for 24 hours. The next day, TLC was used to confirm the termination of the reaction. The reaction was quenched with NH ₄ Cl + 1N HCl solution (100 ml each) and stirred for 30 min. Ethyl acetate (200 ml) was added and the organic layer was washed with water (100 ml) and brine (100 ml), and dried over sodium sulfate. The solvent was distilled off and the residue was adsorbed onto silica gel using methylene chloride. The title compound was then separated and purified by column chromatography using ethyl acetate and hexane.

Example 134. l- (6-methylpyridin-3-yl) -3- (3-phenylpropyl) urea

A round bottom flask was charged with 5-amino-2-picoline (2.77 mmol) at room temperature with THF solution (20 ml). 3-Phenyl-1-propyl isocyanate (2.77 mmol) was slowly added to the reaction flask and stirred at 40-45 ° C. until the reaction was complete. The reaction mixture was then adsorbed onto silica gel and purified by column chromatography (EA: hexane) to obtain the title compound.

Example 135. l- (3-phenylpropyl) -3 - ((tetrahydro-2H-pyran-4- yl) methyl) urea

In the same manner as in Example 1, except for using 4- (aminomethyl) tetrahydro-2H-pyran instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained.

Example 136. Methyl 3- (1H-indol-3-yl) -2- (3-phenethylethylureido) propanoate

Phenethyl isocyanate (0.86 mmol) was slowly added to the THF solution (20 ml) of D-tryptophan methyl ester hydrochloride (0.78 mmol) at room temperature for 10-15 minutes and then TEA (0.94 mmol) was added. The reaction mixture was stirred at 40-45 [deg.] C for 24 hours. The next day, TLC was used to confirm the termination of the reaction. After the solvent was distilled off, ammonium chloride (100 ml) and ethyl acetate (100 ml) were added to the residue. The organic layer was washed with brine and then dried with sodium sulfate. The solvent was distilled off and the residue was adsorbed onto silica gel using methylene chloride. The title compound was then separated and purified by column chromatography using ethyl acetate and hexane.

Example 137. 4- (2- (3- (3- (4-Methoxyphenyl) propyl) ureido) ethyl) benzenesulfonamide

1. Preparation of 1- (3-isocyanatopropyl) -4-methoxybenzene

To the acetone solution (60 ml) of 4- (4-methoxyphenyl) butanoic acid (15.5 mmol) was slowly added triethylamine (18.6 mmol) at room temperature for 5 minutes. Then, the reaction mixture was cooled to -10 ° C, and a solution of methyl chloroformate (18.6 mmol) in acetone (10 ml) was added thereto for 20-30 minutes and further stirred for 20 minutes. An aqueous solution (6 ml) of sodium azide (31.1 mmol) was then added for 20-30 minutes and then further stirred for 30-45 minutes. The reaction was quenched with ice + water (300 ml), stirred for 5-10 minutes, toluene (250 ml) was added, and the mixture was further stirred for 20-30 minutes. The toluene layer was collected and the aqueous layer was extracted again with toluene (100 ml). The toluene layer was dried with sodium sulfate, concentrated to about 100 ml, and refluxed at 100-110 ° C for 2-3 hours. The solvent was distilled off and the residue was used in the next step without further purification.

2. Preparation of 4- (2- (3- (3- (4-methoxyphenyl) propyl) ureido) ethyl) benzenesulfonamide

4- (2-aminoethyl) benzenesulfonamide (0.86 mmol) was added to a THF solution (20 ml) of 1- (3-isocyanatopropyl) -4-methoxybenzene Gt; min. ≪ / RTI > The reaction mixture was stirred at 40-45 [deg.] C for 24 hours. The next day, TLC was used to confirm the termination of the reaction. The solvent was distilled off and ammonium chloride (100 ml), 1N HCl solution (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was washed with brine and then dried with sodium sulfate. The solvent was distilled off and the residue was adsorbed onto silica gel using methylene chloride. The title compound was then separated and purified by column chromatography using ethyl acetate and hexane.

Example 138. Synthesis of 4-hydroxy-N- (3- (4-methoxyphenyl) propyl) piperidine-1-carboxamide

4-hydroxypiperidine (0.86 mmol) was slowly added to a THF solution (20 ml) of 1- (3-isocyanatopropyl) -4-methoxybenzene (0.78 mmol) at room temperature over 10-15 minutes . The reaction mixture was stirred at 40-45 [deg.] C for 24 hours. The next day, TLC was used to confirm the termination of the reaction. The solvent was distilled off and ammonium chloride (100 ml), 1N HCl solution (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was washed with brine and then dried with sodium sulfate. The solvent was distilled off and the residue was adsorbed onto silica gel using methylene chloride. The title compound was then separated and purified by column chromatography using ethyl acetate and hexane.

Example 139. 4- (4- (N, N-dimethylsulfamoyl) phenyl) piperidine-N-phenethyl-

In the same manner as in Example 1, except for using 4- (4- (N, N-dimethylsulfamoyl) phenyl) piperidine instead of 2-phenyl aziridine in the production method of Example 1, the title compound was obtained .

Example 140. N-benzyl-4- (4- (N, N-dimethylsulfamoyl) phenylpiperidine-1-carboxamide

The procedure of Example 1 was repeated using 4- (4- (N, N-dimethylsulfamoyl) phenyl) piperidine instead of 2-phenyl aziridine and benzyl isocyanate in place of 3-phenylpropyl isocyanate. The title compound was obtained.

Example 141. Methyl 3- (1H-indol-3-yl) -2- (3- (3-phenylpropyl) ureido) propanoate

Triethylamine (0.88 mmol) was added to a THF solution (20 ml) of 3- (isocyanatopropyl) benzene (0.58 mmol) and D-tryptophan methyl ester hydrochloride (0.58 mmol) at room temperature for 10-15 minutes Lt; / RTI > The reaction mixture was stirred at 40-45 [deg.] C for 24 hours. The next day, TLC was used to confirm the termination of the reaction. The reaction was diluted with ethyl acetate (50 ml) and water (100 ml). The organic layer and the aqueous layer were separated. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 142. 4- (hydroxymethyl) -N- (3- (4-methoxyphenyl) propyl) piperidine-1-carboxamide

1. Preparation of 1- (3-isocyanatopropyl) -4-methoxybenzene

To the acetone solution (60 ml) of 4- (4-methoxyphenyl) butanoic acid (15.5 mmol) was slowly added triethylamine (18.6 mmol) at room temperature for 5 minutes. Then, the mixture was cooled to -10 ° C., and a solution of methyl chloroformate (18.6 mmol) in acetone (10 ml) was added thereto for 20-30 minutes, followed by further stirring for 20 minutes. A solution of sodium azide (31.1 mmol) in water (6 ml) was then added for 20-30 minutes and then for an additional 30-45 minutes. The reaction was quenched with ice + water (300 ml), stirred for 5-10 minutes, toluene (250 ml) was added, and the mixture was further stirred for 20-30 minutes. The toluene layer was treated with sodium sulfate, concentrated to about 100 ml, and refluxed at 100-110 [deg.] C for 2-3 hours to remove nitrogen and form an isocyanate. The solvent was distilled off and the residue was used in the next step without further purification.

2. 4- (Hydroxymethyl) -N- (3- (4-methoxyphenyl) propyl) piperidine-1-carboxamide

Piperidin-4-yl-methanol (1.04 mmol) was slowly added to a THF solution (20 ml) of 1- (3-isocyanatopropyl) -4-methoxybenzene . The reaction mixture was stirred at 40-45 [deg.] C for 24 hours. The next day, TLC was used to confirm the termination of the reaction. The solvent was evaporated and ammonium chloride (100 ml), 1 N HCl solution (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was evaporated and the residue was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 143. l- (3- (4-Methoxyphenyl) propyl) -3- (tetrahydro-2H-pyran-

A THF solution (20 ml) of 1- (3-isocyanatopropyl) -4-methoxybenzene (1.05 mmol) and tetrahydro-2H-pyran- Lt; / RTI > The next day, TLC was used to confirm the termination of the reaction. The solvent was distilled off and ammonium chloride (100 ml), 1N HCl solution (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 144. l- (3- (4-methoxyphenyl) propyl) -3- (2-morpholinoethyl) urea

A THF solution (20 ml) of 1- (3-isocyanatopropyl) -4-methoxybenzene (1.05 mmol) and 2-morpholinoethanamine (1.05 mmol) was stirred at 40-45 ° C for 24 hours . The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 145. N- (3- (4-methoxyphenyl) propyl) piperidine-1-carboxamide

A THF solution (20 ml) of 1- (3-isocyanatopropyl) -4-methoxybenzene (1.05 mmol) and piperidine (1.05 mmol) was stirred at 40-45 ° C for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 146. N- (3- (4-methoxyphenyl) propyl) morpholine-4-carboxamide

A THF solution (20 ml) of 1- (3-isocyanatopropyl) -4-methoxybenzene (1.05 mmol) and morpholine (1.05 mmol) was stirred at 40-45 ° C for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 147. N- (3- (4-methoxyphenyl) propyl) -4-phenylpiperidine-1-carboxamide

A THF solution (20 ml) of 1- (3-isocyanatopropyl) -4-methoxybenzene (1.05 mmol) and 4-phenylpiperidine (1.05 mmol) was stirred at 40-45 ° C for 24 hours . The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 148. 2- (3-cyclohexylureido) -3- (lH-indol-3-yl) propanoic acid

A THF solution (20 ml) of cyclohexyl isocyanate (1.22 mmol) and D-tryptophan (1.22 mmol) was stirred at 40-45 ° C for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 149. l-benzyl-3- (3- (4-methoxyphenyl) propyl) urea

A THF solution (20 ml) of 1- (3-isocyanatopropyl) -4-methoxybenzene (1.05 mmol) and benzylamine (1.05 mmol) was stirred at 40-45 ° C for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 150. Synthesis of 4- (4- (N, N-dimethylsulfamoyl) phenyl) -N- (3- (4- methoxyphenyl) propyl) piperidine-

A THF solution of (1- (3-isocyanatopropyl) -4-methoxybenzene (0.58 mmol) and N, N-dimethyl-4- (piperidin- 4- yl) benzenesulfonamide 20 ml) was stirred at 40-45 [deg.] C for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 151. 4- (2- (3- (3- (4-Chlorophenyl) propyl) ureido) ethyl) benzenesulfonamide

1. Synthesis of 1- (3-isocyanatopropyl) -4-chlorobenzene

Triethylamine (7.8 mmol) was slowly added to the acetone solution (60 ml) of 4- (4-chlorophenyl) butanoic acid (6.5 mmol) at room temperature for 5 minutes at room temperature. Then, the reaction mixture was cooled to -10 ° C, and a solution of methyl chloroformate (7.8 mmol) in acetone (10 ml) was added thereto for 20-30 minutes, followed by stirring for an additional 20 minutes. A solution of sodium azide (13.1 mmol) in water (6 ml) was then added for 20-30 minutes and then for another 30-45 minutes. The reaction was quenched with ice + water (300 ml), stirred for 5-10 minutes, toluene (250 ml) was added, and the mixture was further stirred for 20-30 minutes. The toluene layer was collected, treated with sodium sulfate, concentrated to about 100 ml, and then refluxed at 100-110 ° C for 2-3 hours to remove nitrogen and form an isocyanate. The solvent was distilled off and the residue was used in the next step without further purification.

2. Synthesis of 4- (2- (3- (3- (4-chlorophenyl) propyl) ureido) ethyl) benzenesulfonamide

4- (2-aminoethyl) benzenesulfonamide (1.02 mmol) was added to a THF solution (20 ml) of 1- (3-isocyanatopropyl) -4-chlorobenzene Lt; / RTI > The reaction mixture was stirred at 40-45 [deg.] C for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), 1N HCl solution (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 152. l- (3- (4-chlorophenyl) propyl) -3- (tetrahydro-2H-pyran-

2H-pyran-4-amine (1.02 mmol) was slowly added to a THF solution (20 ml) of 1- (3-isocyanatopropyl) -4-chlorobenzene (1.02 mmol) . The reaction mixture was stirred at 40-45 [deg.] C for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), 1N HCl solution (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 153. l- (3,4-dimethoxyphenethyl) -3- (3- (4-methoxyphenyl) propyl) urea

A THF solution (20 ml) of 1- (3-isocyanatopropyl) -4-methoxybenzene (1.05 mmol) and 2- (3,4- dimethoxyphenyl) ethanamine 0.0 > C < / RTI > for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 154. N- (3- (4-chlorophenyl) propyl) -4-hydroxypiperidine-1-carboxamide

A THF solution (20 ml) of 1- (3-isocyanatopropyl) -4-chlorobenzene (1.02 mmol) and piperidin-4-ol (1.02 mmol) was stirred at 40-45 ° C for 24 hours . The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 155. 4-hydroxy-N- (4-phenylbutyl) piperidine-1-carboxamide

1. Synthesis of (4-isocyanatobutyl) benzene

To an acetone solution (150 ml) of 5-phenylpentanoic acid (33.08 mmol) at room temperature, triethylamine (40.0 mmol) was slowly added at room temperature for 5 minutes. Then, the reaction mixture was cooled to -10 ° C, and a solution of methyl chloroformate (40.4 mmol) in acetone (10 ml) was added thereto for 20-30 minutes, followed by stirring for an additional 20 minutes. A solution of sodium azide (67.4 mmol) in water (6 ml) was then added for 20-30 minutes and then for another 30-45 minutes. The reaction was quenched with ice + water (300 ml), stirred for 5-10 minutes, toluene (250 ml) was added, and the mixture was further stirred for 20-30 minutes. The toluene layer was collected and the aqueous layer was extracted again with toluene (100 ml). The toluene layer was treated with sodium sulfate, concentrated to about 100 ml, and then refluxed at 100-110 ° C for 2-3 hours to remove nitrogen and form an isocyanate. The solvent was distilled off and the residue was used in the next step without further purification.

2. Synthesis of 4-hydroxy-N- (4-phenylbutyl) piperidine-1-carboxamide

A THF solution (20 ml) of 1- (3-isocyanatopropyl) -4-chlorobenzene (1.71 mmol) and piperidin-4-ol (1.71 mmol) was stirred at 40-45 ° C for 24 hours . The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 156. 4- (2- (3- (4-Phenylbutyl) ureido) ethyl) benzenesulfonamide

(20 ml) of (4-isocyanatobutyl) benzene (1.71 mmol) and 4- (2-aminoethyl) benzenesulfonamide (1.71 mmol) were stirred at 40-45 ° C for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 157. N- (4-phenylbutyl) morpholine-4-carboxamide

(1.42 mmol) and morpholine (1.42 mmol) in THF (20 ml) was stirred at 40-45 ° C for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 158. l- (4-phenylbutyl) -3- (tetrahydro-2H-pyran-4-yl) urea

(1.42 mmol) and tetrahydro-2H-pyran-4-amine (1.42 mmol) in THF (20 ml) was stirred at 40-45 ° C for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 159. 4- (4-chlorophenyl) -4-hydroxy-N- (3-phenylpropyl) piperidine-

(20 ml) of (3-isocyanatopropyl) benzene (2.01 mmol) and 4- (4-chlorophenyl) piperidin-4-ol (2.01 mmol) Lt; / RTI > The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 160. N- (3-phenylpropyl) -1,4-dioxa-8-azaspiro [4.5] decane-

(20 ml) of THF (3-isocyanatopropyl) benzene (1.64 mmol) and 1,4-dioxa-8-azaspiro [4.5] decane Lt; / RTI > The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 161. l- (4-fluorobenzyl) -3- (4-phenylbutyl) urea

Benzene (1.48 mmol) and 4-fluorobenzylamine (1.48 mmol) in THF (20 ml) was stirred at 40-45 ° C for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 162. 4- (2- (3- (4-Methoxyphenyl) ureido) ethyl) benzenesulfonamide

A THF solution (20 ml) of 1- (2-isocyanatoethyl) -4-methoxybenzene (1.41 mmol) and 4- (2- aminoethyl) benzenesulfonamide Stir for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 163. 1- (2-morpholinoethyl) -3- (4-phenylbutyl) urea

(20 ml) of (4-isocyanatobutyl) benzene (1.48 mmol) and 2- (3,4-dimethoxyphenyl) ethanamine (1.48 mmol) were stirred at 40-45 ° C for 24 hours . The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 164. 4- (hydroxymethyl) -N- (4-phenylbutyl) piperidine-1-carboxamide

Benzene (1.48 mmol) and piperidin-4-ylmethanol (1.48 mmol) in THF (20 ml) was stirred at 40-45 ° C for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 165. l- (3,4-Dimethoxyphenethyl) -3- (4-phenylbutyl) urea

(20 ml) of (4-isocyanatobutyl) benzene (1.42 mmol) and 2- (3,4-dimethoxyphenyl) ethanamine (1.42 mmol) were stirred at 40-45 ° C for 24 hours . The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 166. N- (4-phenylbutyl) piperidine-1-carboxamide

Benzene (1.42 mmol) and piperidine (1.42 mmol) in THF (20 ml) was stirred at 40-45 ° C for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 167. 4- (4-chlorophenyl) -4-hydroxy-N- (4-phenylbutyl) piperidine-

(20 ml) of 4- (4-isocyanatobutyl) benzene (1.42 mmol) and 4- (4-chlorophenyl) piperidin-4-ol (1.42 mmol) was stirred at 40-45 ° C for 24 hours Lt; / RTI > The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 168. 4-hydroxy-N- (4-methoxyphenethyl) piperidine-1-carboxamide

A THF solution (20 ml) of 1- (2-isocyanatoethyl) -4-methoxybenzene (1.41 mmol) and 2-piperidin- Lt; / RTI > The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 169. 4- (2- (3- (4-fluorophenethyl) ureido) ethyl) benzenesulfonamide

A THF solution (20 ml) of 1- (2-isocyanatoethyl) -4-fluorobenzene (1.51 mmol) and 2- (3,4-dimethoxyphenyl) 0.0 > C < / RTI > for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 170. N- (4-fluorophenethyl) -4-hydroxypiperidine-1-carboxamide

A THF solution (20 ml) of 1- (2-isocyanatoethyl) -4-fluorobenzene (1.51 mmol) and 4- (2- aminoethyl) benzenesulfonamide (1.51 mmol) Stir for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 171. l- (3-fluoro-4-morpholinophenyl) -3- (4-fluorophenethyl) urea

A THF solution (20 ml) of 1- (2-isocyanatoethyl) -4-fluorobenzene (1.51 mmol) and 3-fluoro-4-morpholinoaniline (20 ml) Lt; / RTI > The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 172. 3- (3-fluoro-4-morpholinophenyl) -1-methyl-1-phenethyl urea

A solution of N-methyl-2-phenylethanamine (10.19 mmol) and DIPEA (10.19 mmol) in THF (20 ml) was added to a solution of triphosgene (3.56 mmol) in THF (20 ml) After the slow addition, additional THF solution (20 ml) was added. The reaction mixture was stirred for an additional hour. Then, a solution of 3-fluoro-4-morpholinoaniline (10.19 mmol) and DIPEA in THF (10 ml) was added and stirred for 24 hours. The next day, the completion of the reaction was confirmed by TLC. Water (150 ml) and ethyl acetate (100 ml) were added. The organic layer was treated with brine and dried over sodium sulfate. The solvent was evaporated and the concentrate was adsorbed onto silica gel using methylene chloride. This was separated by column chromatography using ethyl acetate in hexane to give the title compound.

Example 173. 1- (3-methoxyphenethyl) -3- (3-phenylpropyl) urea

A THF solution (20 ml) of 1- (3-isocyanatopropyl) benzene (1.65 mmol) and 2- (3-methoxyphenyl) ethanamine (1.65 mmol) was stirred at 40-45 ° C for 24 hours . The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 174. l- (3-Fluoro-4-morpholinophenyl) -3- (3-phenylpropyl) urea

(20 ml) of (3-isocyanatopropyl) benzene (1.55 mmol) and 3-fluoro-4-morpholinoaniline (1.55 mmol) were stirred at 40-45 ° C for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Example 175. 4- (2- (3- (3-Fluoro-4-morpholinophenyl) -l-methylureido) ethyl) -N, N-dimethylbenzenesulfonamide

Chlorosulfonic acid (29.1 mmol) was added to a methylene chloride solution (20 ml) of the compound of Example 172 (7.27 mmol) at room temperature, and the mixture was stirred at 40-45 ° C for 24 hours. After the reaction was completed the next day, the reaction was quenched with ice water, extracted with methylene chloride, dried over sodium sulfate, and the solvent was evaporated to obtain a pink residue. Dimethylamine hydrochloride (5.5 mmol) and TEA (5.73 mmol) were added to a THF (30 ml) solution of the above residue (1.01 mmol) and the mixture was heated to 50-60 캜 and stirred for 2 hours. The solvent was evaporated and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was evaporated and the concentrate was adsorbed onto silica gel using methylene chloride. Column chromatography was performed using ethyl acetate in hexane to obtain the title compound.

Example 176. N- (4- (N, N-dimethylsulfamoyl) benzyl) -4-phenylpiperidine-1-carboxamide

1. Synthesis of 4-phenyl-N- (4-sulfamoylbenzyl) piperidine-1-carboxamide (I)

4- (aminomethyl) benzenesulfonamide (2.00 mmol) and DIPEA (4.00 mmol) were added to a THF solution (10 ml) of triphosgene (0.80 mmol) at 0-5 ° C and the mixture was stirred for 45 minutes. A solution of 4-phenylpiperidine (2.00 mmol) in THF (5 ml) was then added. The whole reaction mixture was stirred at ambient temperature for 10 hours. The termination of the reaction was confirmed by TLC. After the reaction was completed, followed by the addition of NaHCO ₃ solution was added to the reaction mixture and extracted with ethyl acetate. The aqueous layer was extracted once more with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate to evaporate the solvent. The crude material was purified by column chromatography.

2. Preparation of N- (4- (N, N-dimethylsulfamoyl) benzyl) -4-phenylpiperidine-1-carboxamide

4-Phenyl-N- (4-sulfamoylbenzyl) piperidine-1-carboxamide (I) (1.00 mmol) prepared above was suspended in DMF (5 ml) suspension of NaH (2.20 mmol) ≪ / RTI > and stirred at ambient temperature for 45 minutes. The solution was cooled again and then methyl iodide (2.20 mmol) was added and the whole reaction mixture was stirred at room temperature for 3 hours. After the reaction was terminated, saturated NH ₄ Cl was added and the reaction mixture was extracted with ethyl acetate. The extract was concentrated and purified by column chromatography to give the title compound.

Example 177. 4- (4- (N, N-dimethylsulfamoyl) phenyl) -N- (tetrahydro-2H-pyran-4-yl) piperidine-

(Tetrahydro-2H-pyranyl) amine was used instead of 3-phenylpropan-1-amine and 4- (4-dimethylsulfamoylphenyl) piperidine instead of piperidine in the preparation method of Example 126 The title compound was obtained by following the same procedure as in Example 126.

Example 178. N- (3- (4- (N, N-dimethylsulfamoyl) phenyl) propyl-4-hydroxypiperidine-

Compounds I to IV of the above synthesis method were obtained by a similar method to that of compounds I to IV in Example 129.

In the same manner as in Example 126, except for using 3-phenylpropane-1-amine instead of 3-phenylpropane-1-amine (Compound IV obtained above and using 4-hydroxypiperidine instead of piperidine, Compound.

Example 179. 4-methoxy-2- (2- (3- (3-phenylpropyl) ureido) ethyl) benzenesulfonamide

The N-acylation reaction and the chlorosulfonation reaction of the amine were carried out in a similar manner to the previous reaction method. To prepare the sulfonamide derivatives, the sulfonyl chloride intermediate (1 mmol) was added to THF and excess ammonium acetate (5 mmol) was added and refluxed for 5 hours. The solvent was evaporated, water was added and extracted with ethyl acetate to give a pale white solid which was used in the next step without purification.

Example 180. 4- (3- (3-benzylureido) propyl) -N, N-dimethylbenzenesulfonamide

In the same manner as in Example 126, except for using benzylamine instead of 3-phenylpropan-1-amine and 3- (4-dimethylsulfamoylphenyl) propylamine instead of piperidine, the title compound The title compound was obtained.

≪ * >

Example 181. N- (3- (4-sulfamoylphenyl) propyl) morpholine-4-carboxamide

The compound of Example 47 was subjected to chlorosulfonation in a similar manner to that described above, and then reacted with ammonium acetate analogously to Example 179 to obtain the compound.

Example 182. N- (3- (4-N, N-dimethylsulfamoyl) phenyl) propyl) morpholine-

Also, after performing chlorosulfonation as in Example 181, the compound was obtained by amination reaction.

Example 183. N, N-Dimethyl-4- (3- (3- (tetrahydro-2H-pyran-4-yl) ureido) propyl) benzenesulfonamide

The compound of Example 46 was subjected to chlorosulfonation and amination reactions in a similar manner as before to give the title compound.

Example 184. Synthesis of 1-oxo-N- (3-phenylpropyl) -3,4-dihydroisoquinolin-2- (1H)

The compound of Example 37 was slowly oxidized in the atmosphere to give the compound of Example 184. The title compound

Example 185. l- (l-methylpiperidin-4-yl) -3- (3-phenylpropyl) urea

The title compound was synthesized by following the procedure of Example 1 while using 1-methylpiperidin-4-amine instead of 2-phenyl aziridine in the same manner as in Example 1.

The reaction scheme of Examples 186 and 187

Example 186. 2-phenyl-N- (3-phenylpropyl) cyclopropanecarboxamide

2-phenyl-1-cyclopropanecarboxylic acid (0.30 mol) was added to a 100 ml round bottom flask at 0 ° C along with methylene chloride. About 2 ml of thionyl chloride was added to the flask and refluxed for 3 hours. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the mixture was dissolved in methylene chloride (50 ml) and then cooled to 0 ° C. Triethylamine (0.60 mol) was added to the solution, 3-phenylpropylamine was added thereto, and the mixture was stirred for 3 hours. Then the mixture was washed with water and brine and concentrated under reduced pressure after drying with Na ₂ SO _4. The crude product was purified by flash column chromatography to give the title compound.

Example 187. 2-phenyl-N- (4-phenylbutyl) cyclopropanecarboxamide

Following the procedure of Example 186 while using 4-phenylbutylamine instead of 3-phenylpropylamine in the preparation method of Example 186, the title compound was obtained.

Example 188. N-phenethyl-5-phenylpentanamide

5-phenylpentanecarboxylic acid (0.30 mol) was added to a 100 ml round-bottomed flask at 0 ° C along with methylene chloride. About 2 ml of thionyl chloride was added to the flask and refluxed for 2 hours. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the mixture was dissolved in methylene chloride (50 ml) and then cooled to 0 ° C. Triethylamine (0.60 mol) was added to the solution, 2-phenylethylamine was added thereto, and the mixture was stirred for 3 hours. Then the mixture was washed with water and brine and concentrated under reduced pressure after drying with Na ₂ SO _4. The crude product was purified by flash column chromatography to give the title compound.

Example 189. 4-phenyl-N- (3-phenylpropyl) butanamide

In the same manner as in Example 188, except for using 4-phenylbutanecarboxylic acid instead of 5-phenylpentanecarboxylic acid and 3-phenylpropylamine instead of 2-phenylethylamine in the same manner as in Example 188, the title Compound.

Example 190. 5-phenyl-N- (tetrahydro-2H-pyran-4-yl) pentanamide

In the same manner as in Example 188, the title compound was obtained using 4-amino-tetrahydro-2H-pyrane instead of 2-phenylethylamine in the same manner as in Example 188.

Example 191. l-morpholino-5-phenylpentan-l-one

In the same manner as in Example 188, the title compound was obtained by carrying out the same processes as in Example 188 with the exception that 2-phenylethylamine and morpholine were used.

Example 192. 5-Phenyl-N- (4-sulfamoylphenethyl) pentanamide

The procedure of Example 188 was repeated except for using 4-sulfamoylphenethylamine in place of 2-phenylethylamine in the preparation method of Example 188 to obtain the title compound.

Example 193. l- (4-hydroxypiperidin-l-yl) -5-phenylpentan-l-one

Following the procedure of Example 188 while using 4-hydroxypiperidine instead of 2-phenylethylamine in the preparation method of Example 188, the title compound was obtained.

Example 194. N- (3,4-dimethoxyphenethyl) -5-phenylpentanamide

Following the procedure of Example 188 while using 3,4-dimethoxyphenethylamine in place of 2-phenylethylamine in the preparation method of Example 188, the title compound was obtained.

Example 195. N- (2-methoxyphenethyl) -5-phenylpentanamide

In the same manner as in Example 188, the title compound was obtained by using 2-methoxyphenethylamine instead of 2-phenylethylamine.

Example 196. N- (4-methylphenethyl) -5-phenylpentanamide

In the same manner as in Example 188, except for using 4-methylphenethylamine instead of 2-phenylethylamine, the title compound was obtained.

Example 197. N- (2-fluorophenethyl) -5-phenylpentanamide

In the same manner as in Example 188, except for using 2-fluorophenethylamine instead of 2-phenylethylamine, the titled compound was obtained.

Example 198. N- (4- (N, N-dimethylsulfamoyl) phenethyl-N-methyl-5-phenylpentanamide

In the same manner as in Example 133, except for using the compound of Example 192 instead of the compound of Example 132, the title compound was obtained.

Example 199. N-methyl-N-phenethyl-5-phenylpentanamide

Of the preparation method of Example 19, the same procedure as in Example 19 was conducted using the compound of Example 188 instead of the compound of Example 18 to obtain the title compound.

Example 200. N- (3-phenylpropyl) tetrahydro-2H-pyran-4-carboxamide

In the same manner as in Example 188, except for using 5-phenylpentanecarboxylic acid instead of tetrahydro-2H-pyran-4-carboxylic acid and using 3-phenylpropylamine instead of 2- To give the title compound.

The starting material tetrahydro-2H-pyran-4-carboxylic acid is commercially available or can be obtained by hydrolysis of tetrahydro-2H-pyran-4-carboxylic acid methyl ester with 6N HCl.

Example 201. N- (2,3-dihydro-1H-inden-2-yl) -5-phenylpentanamide

In the same manner as in Example 188, the title compound was obtained by using 2,3-dihydro-1H-inden-2-amine instead of 2-phenylethylamine in the same manner as in Example 188.

Example 202. N-benzyl-5-phenylpentanamide

In the same manner as in Example 188, the title compound was obtained by carrying out the same processes as in Example 188 with the exception that benzylamine was used instead of 2-phenylethylamine.

Example 203. 3-cyclohexyl-N- (3-phenyl) propanamide

In the same manner as in Example 188, except for using 3-cyclohexylpropane-1-carboxylic acid instead of 5-phenylpentanecarboxylic acid and 3-phenylpropylamine instead of 2-phenylethylamine in the preparation method of Example 188 To give the title compound.

Example 204. N- (3-phenylpropyl) -1H-indole-3-carboxamide

In the same manner as in Example 188, except that 1H-indole-3-carboxylic acid was used instead of 5-phenylpentanecarboxylic acid and 3-phenylpropylamine was used instead of 2-phenylethylamine in the preparation method of Example 188 The title compound was obtained.

Example 205. 6-methoxy-N- (3-phenylpropyl) -lH-indole-2-carboxamide

In the same manner as in Example 188, except for using 6-methoxy-1H-indole-3-carboxylic acid instead of 5-phenylpentanecarboxylic acid and 3-phenylpropylamine instead of 2- The title compound was obtained.

Example 206. 4-benzylpiperazin-l-yl- (6-methoxy-lH-indol-2-yl)

In the same manner as in Example 188, except for using 6-methoxy-1H-indole-3-carboxylic acid instead of 5-phenylpentanecarboxylic acid and benzylpiperazine instead of 2-phenylethylamine in the preparation method of Example 188 To give the title compound.

Example 207. N- (4- (N, N-dimethylsulfamoyl) phenethyl) -5-phenylpentanamide

Using the compound of Example 192, methylation reaction was carried out using 2 equivalents of NaH and CH ₃ I in the same manner as in Example 36-2 to obtain the title compound.

Example 208. N-phenethyl-2- (phenethylamino) acetamide

1. Preparation of 2-chloro-N-phenylacetamide

To a solution of phenethylamine (39.70 mmol) in methylene chloride (15 ml) at 0 C was added triethylamine (47.60 mmol) followed by chloroacetyl chloride (47.60 mmol). The reaction mixture was stirred at 0 < 0 > C for 1 hour. After the reaction was completed, water was added and extracted with ethyl acetate. The extract was purified by column chromatography to give the title compound.

2. Preparation of N-phenethyl-2- (phenethylamino) acetamide

KI (1.85 mmol) was added to a DMF (5 ml) solution of 2-chloro-N-phenylacetamide (3.70 mmol) and the mixture was stirred at room temperature for 5 minutes. Then phenethylamine (3.70 mmol) and K ₂ CO ₃ (4.07 mmol) were added to the mixture and stirred at 40 ° C for 5 hours. After the reaction was completed, water was added and extracted with ethyl acetate. The extract was purified by column chromatography to give the title compound.

Example 209. 2-methyl (phenethylamino) -N-phenylacetamide

In the same manner as in Example 208, Step 2, except for using N-methyl-N-phenylethylamine instead of phenethylamine, the title compound was obtained.

Example 210. 2- (phenylamino) -N- (3-phenylpropyl) acetamide

1. Preparation of 2-chloro-N- (3-phenylpropyl) acetamide

Chloroacetyl chloride (44.37 mmol) was slowly added to a dichloromethane (60 ml) solution of TEA (57.68 mmol) and 3-phenyl-1-propylamine (44.37 mmol) at 10-20 ° C for 30-40 minutes. The reaction mixture was stirred overnight. The next day, TLC was used to confirm the termination of the reaction. Water and 1N HCl were added and stirred for 30 minutes. The organic layer was washed with water and brine, and dried over sodium sulfate. The solvent was distilled to obtain a crude residue which was purified by column chromatography. The title compound was obtained as a liquid, which was allowed to stand for several days to give a solid (7.60 g).

2. Preparation of 2- (phenylamino) -N- (3-phenylpropyl) acetamide

₂ -chloro-N- (3-phenylpropyl) acetamide (2.36 mmol) was slowly added to the DMF solution (20 ml) of K ₂ CO ₃ (3.54 mmol) and aniline Followed by KI (1.18 mmol). The reaction mixture was stirred at 40-45 [deg.] C for 26 hours. The next day, TLC was used to confirm the termination of the reaction. Water, NH ₄ Cl solution and ethyl acetate (200 ml) were added to the reaction mixture and stirred for 30 minutes. After separating the layers, the organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated to obtain a crude residue, which was purified by column chromatography (EA: hexane) to give the title compound.

Example 211. N-phenethyl-2- (phenethylthio) acetamide

In the same manner as in Example 208, Step 2, except for using 2-phenylethylthiol instead of phenethylamine, the title compound was obtained.

Example 212. 2- (methyl (phenyl) amino) -N- (3-phenylpropyl) acetamide

₂ -chloro-N- (3-phenylpropyl) acetamide (2.36 mmol) was added to a DMF solution (20 ml) of K ₂ CO ₃ (3.54 mmol) and N-methylaniline , And then KI (1.18 mmol) was added thereto. The reaction mixture was stirred at 40-45 [deg.] C for 26 hours. The next day, TLC was used to confirm the termination of the reaction. Water, NH ₄ Cl solution and ethyl acetate (200 ml) were added and stirred for 30 minutes. After separating the aqueous layer and the organic layer, the organic layer was washed with water and brine and dried over sodium sulfate. The solvent was distilled off and the resulting crude residue was purified by column chromatography (EA: hexane) to give the title compound.

Example 213. 2- (benzyl (methyl) amino) -N- (3-phenylpropyl) acetamide

1. Preparation of 2- (benzylamino) -N- (3-phenylpropyl) acetamide

To the THF solution (20 ml) of 3-phenyl-1-propylamine (2.07 mmol) was added NaH (2.07 mmol) at room temperature and the reaction mixture was stirred for 40-45 minutes. A THF solution (20 ml) of N-benzylglycine ethyl ester (2.07 mmol) was then slowly added over 30-40 minutes. The reaction mixture was stirred at 40-45 [deg.] C overnight. The next day, TLC was used to confirm the termination of the reaction. The reaction mixture was adsorbed onto silica gel and purified by column chromatography.

2. Preparation of 2- (benzyl (methyl) amino) -N- (3-phenylpropyl) acetamide

After dissolving the above prepared 2- (benzylamino) -N- (3-phenylpropyl) acetamide compound (1.60 mmol) in THF solution (20 ml), sodium hydride (1.60 mmol) Lt; / RTI > The reaction was continued stirring for 30-45 min until sodium salt was formed. Methyl iodide (1.60 mmol) was then added to the reaction mixture and stirred at 40-45 ° C until the reaction was complete. After the reaction was completed, the organic layer was concentrated, adsorbed onto silica gel, and then subjected to column chromatography (EA: hexane) to obtain the title compound.

Example 214. 2- (benzyloxy) -N- (3-phenylpropyl) acetamide

Sodium hydride (5.55 mmol) was added to a DMF solution (10 ml) of benzyl alcohol (4.62 mmol) and stirred at room temperature for 45-60 minutes. 2-Chloro-N- (3-phenylpropyl) acetamide (2.30 mmol) was then slowly added followed by KI (1.15 mmol). The reaction mixture was stirred at 40-45 [deg.] C for 26 hours. The next day, TLC was used to confirm the termination of the reaction. Water, NH ₄ Cl solution and ethyl acetate (200 ml) were added and stirred for 30 minutes. After separating the aqueous layer and the organic layer, the organic layer was washed with water and brine and dried over sodium sulfate. The solvent was distilled off and the resulting crude residue was purified by column chromatography (EA: hexane) to give the title compound.

Example 215. 2-phenoxy-N- (3-phenylpropyl) acetamide

To a solution of phenol (1.18 mmol) in THF (20 ml) was added sodium hydride (1.41 mmol) and the mixture was stirred at room temperature for 45-60 minutes. 2-Chloro-N- (3-phenylpropyl) acetamide (1.18 mmol) was then slowly added followed by KI (0.59 mmol). The reaction mixture was stirred at 40-45 [deg.] C for 26 hours. The reaction mixture was adsorbed onto silica gel and purified by column chromatography (EA: hexane) to obtain the title compound.

Example 216. 2- (benzylthio) -N- (3-phenylpropyl) acetamide

Potassium carbonate (2.12 mmol) was added to a DMF (10 ml) solution of phenylmethanethiol (1.41 mmol) and the mixture was stirred at room temperature for 45-60 minutes. 2-Chloro-N- (3-phenylpropyl) acetamide (1.41 mmol) was then added followed by KI (0.70 mmol). The reaction mixture was stirred at 40-45 [deg.] C for 26 hours. The next day, TLC was used to confirm the termination of the reaction. Water, NH ₄ Cl solution and ethyl acetate (200 ml) were added and stirred for 30 minutes. After separating the aqueous layer and the organic layer, the organic layer was washed with water and brine and dried over sodium sulfate. The solvent was distilled off and the resulting crude residue was purified by column chromatography (EA: hexane) to give the title compound.

Example 217. N- (4-phenylbutyl) cinnamamide

In the same manner as in Example 188, except for using cinnamic acid instead of 5-phenylpentanecarboxylic acid and 4-phenylbutylamine instead of 2-phenylethylamine, the title compound ≪ / RTI >

Example 218. 2-phenethoxy-N-phenylacetamide

In the same manner as in Example 208, Step 2, except for using 2-phenylethanol instead of phenethylamine, the title compound was obtained.

The reaction schemes of Examples 219 to 221

Example 219. 3- (benzylamino) -N-phenethylpropanamide

In the same manner as in Example 208, except for using 3-bromopropionyl chloride in place of chloroacetyl chloride in Example 208, 3-bromo-N-phenethylpropanamide was obtained .

In the process of Example 208-2, 3-bromo-N-phenethylpropanamide prepared above was used instead of 2-chloro-N-phenylacetamide and benzylamine was used in place of phenethylamine to give the title compound Of the title compound.

Example 220. 3- (benzyl (methyl) amino) -N-phenethylpropanamide

In the same manner as in Example 208-2, 3-bromo-N-phenethylpropanamide prepared in Example 219 was used instead of 2-chloro-N-phenylacetamide, and benzyl (methyl) amine , The titled compound was obtained.

Example 221. 3- (benzylthio) -N-phenethylpropanamide

In the process of Example 208-2, 3-bromo-N-phenethylpropanamide prepared in Example 219 was used instead of 2-chloro-N-phenylacetamide using benzylthiol instead of phenethylamine In the same manner as in Example 208-2, the title compound was obtained.

Examples 222, 223 and 237:

Example 222. N-phenethyl-4- (phenylamino) butanamide

1. Preparation of 4-chloro-N-phenethylbutanamide

To the cold methylene chloride solution (15 ml) of phenethylamine (39.70 mmol) at 0 C was added triethylamine (47.60 mmol) followed by 4-chlorobutyryl chloride (47.60 mmol). The reaction mixture was stirred at 0 < 0 > C for 1 hour. After the reaction was completed, water was added and extracted with ethyl acetate. The product was purified by column chromatography to give the title compound. Yield 70%

2. Preparation of N-phenethyl-4- (phenylamino) butanamide

To the suspension of NaH (3.70 mmol) in DMF (5 ml) was added phenylamine (3.70 mmol) at 0 < 0 > C and stirred for 15 min. 4-Chloro-N-phenethylbutanamide (3.70 mmol) and KI (1.85 mmol) were added to the reaction mixture, and the mixture was stirred at 60 ° C for 8 hours. After the reaction was completed, water was added and extracted with ethyl acetate. The product was purified by column chromatography to give the title compound.

Example 223. 4- (methyl (phenyl) amino) -N-phenethylbutanamide

In the same manner as in Example 222-2, using methyl (phenyl) amine instead of phenylamine, in the preparation method of Example 222-2, the title compound was obtained.

≪ tb > * Examples 224 and 225 <

Example 224. Synthesis of 3- (phenylamino) -N- (3-phenylpropyl) propanamide

In the process of Example 208-1, 3-phenylpropan-1-amine was used instead of phenethylamine and 3-bromopropionyl chloride was used instead of chloroacetyl chloride in the same manner as in Example 208, To obtain 3-bromo-N- (3-phenylpropyl) propanamide.

In the process of Example 208-2, 3-bromo-N- (3-phenylpropyl) propanamide prepared above was used instead of 2-chloro-N-phenylacetamide, phenylamine , To thereby obtain the title compound.

Example 225. 3- (methyl (phenyl) amino) -N- (3-phenylpropyl) propanamide

In the process of Example 208-1, 3-phenylpropan-1-amine was used instead of phenethylamine and 3-bromopropionyl chloride was used instead of chloroacetyl chloride in the same manner as in Example 208, To obtain 3-bromo-N- (3-phenylpropyl) propanamide.

Bromo-N- (3-phenylpropyl) propanamide prepared above instead of 2-chloro-N-phenylacetamide was obtained in the same manner as in Example 208-2, except that methyl (phenyl) Amine in the same manner as in the step 2 of Example 208, the titled compound was obtained.

Example 226. 2- (phenylamino) -N- (4-phenylbutyl) acetamide

1. Preparation of 2-chloro-N- (4-phenylbutyl) acetamide

Chloroacetyl chloride (24.45 mmol) was slowly added to the dichloromethane (60 ml) solution of TEA (31.79 mmol) and 4-phenyl-1-butylamine (24.45 mmol) at 10-20 ° C for 30-40 minutes. The reaction mixture was stirred overnight. The next day, the completion of the reaction was confirmed by TLC. Water and 1N HCl were added and stirred for 30 minutes. After partitioning into an aqueous layer and an organic layer, the organic layer was washed with water and brine and dried over sodium sulfate. The organic material was distilled to obtain a crude residue, which was purified by column chromatography to obtain a pure liquid compound. The liquid compound was left standing for several days to give the title compound (2.5 g) as a semisolid.

2. Preparation of 2- (phenylamino) -N- (4-phenylbutyl) acetamide

₂ -chloro-N- (4-phenylbutyl) acetamide (1.33 mmol) was slowly added to the DMF solution (20 ml) of K ₂ CO ₃ (5.33 mmol) and aniline Followed by KI (1.33 mmol). The reaction mixture was stirred at 40-45 [deg.] C for 26 hours. The next day, TLC was used to confirm the termination of the reaction. Water, NH ₄ Cl solution and ethyl acetate (200 ml) were added and stirred for 30 minutes. After partitioning into an aqueous layer and an organic layer, the organic layer was washed with water and brine and dried over sodium sulfate. The organic material was distilled to obtain a crude residue, which was purified by column chromatography (EA: hexane) to obtain a pure compound.

Example 227. 2- (methyl (phenyl) amino) -N- (4-phenylbutyl) acetamide

₂ -chloro-N- (4-phenylbutyl) acetamide (1.33 mmol) was added to a DMF solution (20 ml) of K ₂ CO ₃ (5.33 mmol) and N-methylaniline Lt; / RTI > and KI (1.33 mmol) was added. The reaction mixture was stirred at 40-45 [deg.] C for 26 hours. The next day, TLC was used to confirm the termination of the reaction. Water, NH ₄ Cl solution and ethyl acetate (200 ml) were added and stirred for 30 minutes. After partitioning into an aqueous layer and an organic layer, the organic layer was washed with water and brine and dried over sodium sulfate. The organic material was distilled to obtain a crude residue, which was purified by column chromatography (EA: hexane) to obtain a pure compound.

Example 228. 2-phenoxy-N- (4-phenylbutyl) acetamide

Sodium hydride (1.91 mmol) was added to a THF solution (10 ml) of phenol (1.59 mmol) and the mixture was stirred at room temperature for 30-45 minutes. 2-Chloro-N- (4-phenylbutyl) acetamide (1.50 mmol) was added to the reaction flask for 10-15 minutes and KI (0.80 mmol) was added. The reaction mixture was stirred at 40-45 [deg.] C for 26 hours. The next day, TLC was used to confirm the termination of the reaction. The reaction mixture was adsorbed onto silica gel and then purified by column chromatography (EA: hexane) to obtain the title compound.

Example 229. 2- (benzylamino) -N- (3-phenylpropyl) acetamide

To a solution of 3-phenyl-1-propylamine (2.07 mmol) in THF (20 ml) was added NaH (2.07 mmol) at room temperature and the reaction mixture was stirred for 40-45 minutes. A THF solution (20 ml) of N-benzylglycine ethyl ester (2.07 mmol) was then slowly added over 30-40 minutes. The reaction mixture was stirred at 40-45 [deg.] C overnight. The next day, TLC was used to confirm the termination of the reaction. The reaction mixture was adsorbed onto silica gel and then purified by column chromatography (EA: hexane) to obtain the title compound.

Example 230. 2- (benzyl (methyl) amino) -N- (4-phenylbutyl) acetamide

₂ -chloro-N- (4-phenylbutyl) acetamide (1.77 mmol) was added to a DMF (10 ml) solution of K ₂ CO ₃ (3.55 mmol) and N-methylbenzylamine 0.0 > (0.88 < / RTI > mmol). The reaction mixture was stirred at 40-45 [deg.] C for 26 hours. The next day, TLC was used to confirm the termination of the reaction. Water, NH ₄ Cl solution and ethyl acetate (200 ml) were added and stirred for 30 minutes. After partitioning into an aqueous layer and an organic layer, the organic layer was washed with water and brine and dried over sodium sulfate. The organic material was distilled to obtain a crude residue, which was purified by column chromatography (EA: hexane) to obtain a pure compound.

Example 231. 2- (benzylthio) -N- (4-phenylbutyl) acetamide

₂ -chloro-N- (4-phenylbutyl) acetamide (1.77 mmol) was added to a DMF (10 ml) solution of K ₂ CO ₃ (3.55 mmol) and phenylmethanethiol After the addition slowly, KI (0.88 mmol) was added. The reaction mixture was stirred at 40-45 [deg.] C for 26 hours. The next day, TLC was used to confirm the termination of the reaction. Water, NH ₄ Cl solution and ethyl acetate (200 ml) were added and stirred for 30 minutes. After partitioning into an aqueous layer and an organic layer, the organic layer was washed with water and brine and dried over sodium sulfate. The organic material was distilled to obtain a crude residue, which was purified by column chromatography (EA: hexane) to obtain a pure compound.

Example 232. 2- (benzyloxy) -N- (4-phenylbutyl) acetamide

To a solution of the benzyl alcohol (2.66 mmol) in THF (20 ml) was added NaH (3.19 mmol) at room temperature and the reaction mixture was stirred for 30-45 minutes. 2-Chloro-N- (4-phenylbutyl) acetamide (2.66 mmol) was then slowly added to the reaction flask for 10-15 minutes before KI (1.33 mmol) was added. The reaction mixture was stirred at 40-45 [deg.] C for 26 hours. The next day, TLC was used to confirm the termination of the reaction. The reaction mixture was adsorbed onto silica gel and then purified by column chromatography (EA: hexane) to obtain the title compound.

Example 233. 3- (benzyloxy) -N-phenethylpropanamide

NaH (2.46 mmol) was added to a solution of benzyl alcohol (1.89 mmol) in THF (20 ml), and the reaction mixture was stirred for 30-45 minutes. 3-Chloro-N- (4-phenethyl) propanamide (1.89 mmol) was then slowly added to the reaction flask for 10-15 minutes before KI (0.89 mmol) was added. The reaction mixture was stirred at 40-45 [deg.] C for 26 hours. The next day, TLC was used to confirm the termination of the reaction. The reaction mixture was adsorbed onto silica gel and then purified by column chromatography (EA: hexane) to obtain the title compound.

Example 234. 2- (benzylamino) -N- (4-phenylbutyl) acetamide

To a solution of 4-phenyl-1-butylamine (1.77 mmol) in THF (20 ml) was added NaH (2.13 mmol) at room temperature and the reaction mixture was stirred for 30-45 minutes. A solution of N-benzylglycine ethyl ester (1.77 mmol) in THF (10 ml) was then slowly added over 30-40 minutes. The reaction mixture was stirred at 40-45 [deg.] C overnight. The next day, TLC was used to confirm the termination of the reaction. The reaction mixture was adsorbed onto silica gel and then purified by column chromatography (EA: hexane) to obtain the title compound.

Example 235. (benzylthio) -N-phenylacetamide

₂ -Chloro-N-phenylacetamide (1.77 mmol) was slowly added to the DMF (10 ml) solution of K ₂ CO ₃ (3.55 mmol) and phenylmethanethiol (1.77 mmol) at room temperature for 10-15 minutes KI (0.88 mmol) was added. The reaction mixture was stirred at 40-45 [deg.] C for 24 hours. The next day, TLC was used to confirm the termination of the reaction. Water, NH ₄ Cl solution and ethyl acetate (200 ml) were added and stirred for 30 minutes. After partitioning into an aqueous layer and an organic layer, the organic layer was washed with water and brine and dried over sodium sulfate. The organic material was distilled to obtain a crude residue, which was purified by column chromatography (EA: hexane) to obtain a pure compound.

Example 236. 2- (benzylamino) -N-phenylacetamide

To a solution of 4-phenyl-1-butylamine (3.30 mmol) in THF (20 ml) was added NaH (3.96 mmol) at room temperature and the reaction mixture was stirred for 30-45 minutes. To the reaction mixture was then slowly added a solution of N-benzylglycine ethyl ester (3.30 mmol) in THF (10 ml) for 30-40 min. The reaction mixture was stirred at 40-45 [deg.] C overnight. The next day, TLC was used to confirm the termination of the reaction. The reaction mixture was adsorbed onto silica gel and then purified by column chromatography (EA: hexane) to obtain the title compound.

Example 237. N-phenethyl-4-phenoxybutanamide

In the same manner as in Example 222, except for using phenol instead of phenylamine in Example 222, the title compound was obtained.

Example 238. 2- (benzyloxy) -N-phenylacetamide

In the same manner as in Example 235, the title compound was obtained by carrying out the same processes as in Example 235 with the exception that benzyl alcohol was used instead of phenylmethanethiol.

Example 239. 2- (benzyl (methyl) amino) -N-phenylacetamide

₂ -chloro-N-phenylacetamide (1.77 mmol) was slowly added to the DMF (10 ml) solution of K ₂ CO ₃ (3.55 mmol) and N-methylbenzylamine (1.77 mmol) at room temperature for 10-15 minutes And KI (0.88 mmol) was added thereto. The reaction mixture was stirred at 40-45 [deg.] C for 24 hours. The next day, TLC was used to confirm the termination of the reaction. Water, NH ₄ Cl solution and ethyl acetate (200 ml) were added and stirred for 30 minutes. After partitioning into an aqueous layer and an organic layer, the organic layer was washed with water and brine and dried over sodium sulfate. The organic material was distilled to obtain a crude residue, which was purified by column chromatography (EA: hexane) to obtain a pure compound.

Example 240. N- (2- (benzyloxy) ethyl) -3-phenylpropanamide

1. Preparation of N- (2-hydroxyethyl) -3-phenylpropanamide

3-phenylpropanoic acid was added to an oven-dried flask, and thionyl chloride (2.5 ml) was added thereto at room temperature. The reaction mixture was refluxed for 3-4 hours until the reaction was complete. The thionyl chloride was distilled off and 20 ml of methylene chloride was added. Meanwhile, ethanolamine (3.96 mmol) and triethylamine (5.00 mmol) were added to the other flask, and the mixture was cooled to -30 ° C. To the flask, 3-phenylpropanoyl chloride prepared above was gradually added thereto and stirred overnight. The next day, TLC was used to confirm the termination of the reaction. Water, NH ₄ Cl solution and ethyl acetate (200 ml) were added and stirred for 30 minutes. After partitioning into an aqueous layer and an organic layer, the organic layer was washed with water and brine and dried over sodium sulfate. The organic material was distilled to obtain a crude residue, which was purified by column chromatography (EA: hexane) to obtain a pure compound.

2. Preparation of N- (2- (benzyloxy) ethyl) -3-phenylpropanamide

N- (2-hydroxyethyl) -3-phenylpropanamide (0.77 mmol) prepared above was dissolved in THF (15 ml) in an oven-dried flask. Sodium hydride (0.93 mmol) was added to the solution and the mixture was stirred for 30-45 minutes. Benzyl bromide (0.77 mmol) at room temperature. The reaction mixture was stirred at 30-40 < 0 > C overnight. The reaction mixture was then adsorbed onto silica gel and subjected to column chromatography (EA: hexane) to obtain the title compound.

Example 241. N-benzyl-4- (benzyloxy) butanamide

4- (Benzyloxy) butanoic acid (2.57 mmol) was dissolved in dichloromethane (30 ml) and triethylamine (3.34 mmol) was added to the oven-dried flask at room temperature. Triphosgene (0.90 mmol) was slowly added to the reaction mixture for 20-30 minutes and then stirred for 15-20 minutes. A solution of benzylamine (2.57 mmol) in methylene chloride (20 ml) was slowly added to the reaction mixture at room temperature, and the mixture was stirred for 1-3 hours. Saturated ammonium chloride solution (100 ml) was added thereto, and the organic layer was separated. The separated organic layer was washed with 5% sodium bicarbonate, water and brine (100 ml each), dried over sodium sulfate, adsorbed on silica gel and purified by column chromatography (EA: hexane) to obtain the title compound.

Example 242. N-benzyl-4- (benzyloxy) -N-methylbutanamide

4- (Benzyloxy) butanoic acid (2.57 mmol) was dissolved in dichloromethane (30 ml) and triethylamine (3.34 mmol) was added to the oven-dried flask at room temperature. Triphosgene (0.90 mmol) was slowly added to the reaction mixture for 20-30 minutes and then stirred for 15-20 minutes. A solution of N-methylbenzylamine (2.57 mmol) in methylene chloride (20 ml) was slowly added to the reaction mixture at room temperature, and the mixture was stirred for 1-3 hours. Saturated ammonium chloride solution (100 ml) was added thereto, and the organic layer was separated. The separated organic layer was washed with 5% sodium bicarbonate, water and brine (100 ml each), dried over sodium sulfate, adsorbed on silica gel and purified by column chromatography (EA: hexane) to obtain the title compound.

Example 243. 4- (benzyloxy) -N-phenethylbutanamide

4- (Benzyloxy) butanoic acid (5.14 mmol) was dissolved in dichloromethane (30 ml) and triethylamine (6.69 mmol) was added to the oven-dried flask at room temperature. Triphosgene (1.69 mmol) was slowly added to the reaction mixture for 20-30 minutes and then stirred for 15-20 minutes. A solution of phenethylamine (5.14 mmol) in methylene chloride (20 ml) was slowly added to the reaction mixture at room temperature, and the mixture was stirred for 1-3 hours. Saturated ammonium chloride solution (100 ml) was added thereto, and the organic layer was separated. The separated organic layer was washed with 5% sodium bicarbonate, water and brine (100 ml each), dried over sodium sulfate, adsorbed on silica gel and purified by column chromatography (EA: hexane) to obtain the title compound.

Example 244. 4- (benzyloxy) -N-methyl-N-phenethylbutanamide

4- (Benzyloxy) butanoic acid (3.08 mmol) was dissolved in dichloromethane (30 ml) and triethylamine (4.01 mmol) was added to the oven-dried flask at room temperature. Triphosgene (1.01 mmol) was slowly added to the reaction mixture for 20-30 minutes and then stirred for 15-20 minutes. A solution of N-methyl-N-phenethylamine (3.08 mmol) in methylene chloride (20 ml) was slowly added to the reaction mixture at room temperature, and the mixture was stirred for 1-3 hours. Saturated ammonium chloride solution (100 ml) was added thereto, and the organic layer was separated. The separated organic layer was washed with 5% sodium bicarbonate, water and brine (100 ml each), dried over sodium sulfate, adsorbed on silica gel and purified by column chromatography (EA: hexane) to obtain the title compound.

Example 245. 2- (4-methoxybenzylamino) -N- (3-phenylpropyl) acetamide

To a DMF (10 ml) solution of K ₂ CO ₃ (3.55 mmol) and 4-methoxybenzylamine (1.77 mmol) was added slowly 2-chloro-N-phenylpropylacetamide (1.77 mmol) After addition, KI (0.88 mmol) was added. The reaction mixture was stirred at 40-45 [deg.] C for 24 hours. The next day, TLC was used to confirm the termination of the reaction. Water, NH ₄ Cl solution and ethyl acetate (200 ml) were added and stirred for 30 minutes. After partitioning into an aqueous layer and an organic layer, the organic layer was washed with water and brine and dried over sodium sulfate. The organic material was distilled to obtain a crude residue, which was purified by column chromatography (EA: hexane) to obtain a pure compound.

Example 246. 2- (4-chlorobenzylamino) -N- (3-phenylpropyl) acetamide

₂ -Chloro-N-phenylpropylacetamide (1.41 mmol) was slowly added to the DMF (10 ml) solution of K ₂ CO ₃ (2.12 mmol) and 4-chlorobenzylamine And KI (0.70 mmol) was added. The reaction mixture was stirred at 40-45 [deg.] C for 24 hours. The next day, TLC was used to confirm the termination of the reaction. Water, NH ₄ Cl solution and ethyl acetate (200 ml) were added and stirred for 30 minutes. After partitioning into an aqueous layer and an organic layer, the organic layer was washed with water and brine and dried over sodium sulfate. The organic material was distilled to obtain a crude residue, which was purified by column chromatography (EA: hexane) to obtain a pure compound.

Example 247. 2- (4-tert-butylbenzylamino) -N- (3-phenylpropyl) acetamide

To a DMF (10 ml) solution of K ₂ CO ₃ (2.48 mmol) and 4-tert-butylbenzylamine (1.65 mmol) was added 2-chloro-N-phenylpropylacetamide (1.65 mmol) After the addition slowly, KI (0.82 mmol) was added. The reaction mixture was stirred at 40-45 [deg.] C for 24 hours. The next day, TLC was used to confirm the termination of the reaction. Water, NH ₄ Cl solution and ethyl acetate (200 ml) were added and stirred for 30 minutes. After partitioning into an aqueous layer and an organic layer, the organic layer was washed with water and brine and dried over sodium sulfate. The organic material was distilled to obtain a crude residue, which was purified by column chromatography (EA: hexane) to obtain a pure compound.

Example 248. 2- (cyclohexylmethylamino) -N- (3-phenylpropyl) acetamide

₂ -Chloro-N-phenylpropylacetamide (1.93 mmol) was slowly added to the DMF (10 ml) solution of K ₂ CO ₃ (2.91 mmol) and cyclohexylmethylamine (1.93 mmol) at room temperature for 10-15 minutes Followed by KI (0.97 mmol). The reaction mixture was stirred at 40-45 [deg.] C for 24 hours. The next day, TLC was used to confirm the termination of the reaction. Water, NH ₄ Cl solution and ethyl acetate (200 ml) were added and stirred for 30 minutes. After partitioning into an aqueous layer and an organic layer, the organic layer was washed with water and brine and dried over sodium sulfate. The organic material was distilled to obtain a crude residue, which was purified by column chromatography (EA: hexane) to obtain a pure compound.

Example 249. 2- (4-fluorobenzylamino) -N- (3-phenylpropyl) acetamide

₂ -chloro-N-phenylpropylacetamide (1.99 mmol) was slowly added to a DMF (10 ml) solution of K ₂ CO ₃ (2.99 mmol) and 4- fluorobenzylamine After addition KI (0.99 mmol) was added. The reaction mixture was stirred at 40-45 [deg.] C for 24 hours. The next day, TLC was used to confirm the termination of the reaction. Water, NH ₄ Cl solution and ethyl acetate (200 ml) were added and stirred for 30 minutes. After partitioning into an aqueous layer and an organic layer, the organic layer was washed with water and brine and dried over sodium sulfate. The organic material was distilled to obtain a crude residue, which was purified by column chromatography (EA: hexane) to obtain a pure compound.

 [Intermediate Production 1]

Preparation of (E) -3- (4-fluorophenyl) acrylamide:

TEA (54.16 mmol), EDC.HCl and ammonium chloride (36.11 mmol) were added to a dichloromethane solution (30 ml) of (E) -3- (4- fluorophenyl) acrylic acid (18.05 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. After confirming that the compounds used at the beginning of the reaction completely disappeared by TLC, it was diluted 10-fold with dichloromethane (100 ml) and washed with 1N HCl (2x50 ml). The organic solvent layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude extract (Yield 83%) containing brown sticky oil (E) -3- (4-fluorophenyl) acrylamide. This crude extract was used directly in the next step without purification.

Preparation of tert-butyl 3- (4-fluorophenyl) propyl carbamate:

To THF solution (30 ml) of the above intermediate (E) -3- (4-fluorophenyl) acrylamide (10.89 mmol) at 0 ° C was dropwise added THF (32.69 mmol) containing 2.0 M LAH solution for 20 minutes . The pale yellow suspension of the reaction mixture was warmed to 70 < 0 > C for 3 hours. After cooling to 0 ° C, 1N NaOH solution was added to the reaction mixture, and ice water (2 ml) was added. (Boc) ₂ O (16.34 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through a celite bed, washed with ethyl acetate (50 ml), transferred to a 250 ml separatory funnel, and extracted with ethyl acetate. Ethyl acetate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel flash column chromatography (eluting with hexane containing 5-10 [v / v]% ethyl acetate) to give tert-butyl 3- (4-fluoro Phenyl) propyl carbamate.

Preparation of 3- (4-fluorophenyl) propane-1-amine hydrochloride:

To a dichloromethane solution (10 ml) of the intermediate tert-butyl 3- (4-fluorophenyl) propyl carbamate (3.95 mmol) at 0 ° C was added 1, 4-dioxane (7.905 mmol ) Was added dropwise for 5 minutes. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed from the reaction mixture and concentrated under reduced pressure to give 3- (4-fluorophenyl) propan-1-amine hydrochloride (Yield 80%) in a light brown solid state, and no further purification was performed .

Example 301. 4- (2- (3- (3- (4-fluorophenyl) propyl) ureido) ethyl) benzenesulfonamide

DIPEA (6.32 mmol) and triphosgene (0.843 mmol) were added to a solution of 3- (4-fluorophenyl) propane-1-amine hydrochloride (2.11 mmol) in THF The reaction mixture was stirred at 0 < 0 > C for 30 min. Then, 4- (2-aminoethyl) benzenesulfonamide (2.11 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 16 hours. To the reaction mixture was added 10% [v / v] sodium hydrogencarbonate solution (20 ml) and extracted with ethyl acetate (3x50 ml). The ethyl acetate layer was collected and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The thus-obtained crude extract was subjected to silica gel flash column chromatography (eluting with hexane solution containing 50 to 80% [v / v] ethyl acetate) - (3- (3- (4-fluorophenyl) propyl) ureido) ethyl) benzenesulfonamide.

Example 302. 4- (2- (3- (3- (4-Fluorophenyl) propyl) ureido) ethyl) -N, N-dimethylbenzenesulfonamide

To a DMF (5 ml) solution of 4- (2- (3- (3- (4- fluorophenyl) propyl) ureido) ethyl) benzenesulfonamide (0.79 mmol) was added 60% [v / v] NaH (1.44 mmol) was added thereto, followed by stirring for 30 minutes. MeI (1.44 mmol) was then added, the reaction mixture was warmed to room temperature, and stirred for 3 hours in this state. Water (30 ml) was added to the reaction mixture, which was then extracted with ethyl acetate (3 x 50 ml). The ethyl acetate layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by flash column chromatography on silica gel eluting with a hexane solution containing 50-70% [v / v] ethyl acetate to give 4- (2- (3- (3- (4- fluorophenyl) ) Ethyl) -N, N-dimethylbenzenesulfonamide was obtained.

Example 303. N- (3- (4-fluorophenyl) propyl) -4-hydroxypiperidine-1-carboxamide

DIPEA (2.37 mmol) and triphosgene (0.32 mmol) were added to a THF solution (10 ml) of 3- (4-fluorophenyl) propane-1-amine hydrochloride (0.79 mmol) Lt; / RTI > for 30 minutes. Piperidin-4-ol (0.79 mmol) was added, the mixture was warmed to room temperature, and stirred for 16 hours. To the reaction mixture was added 10% [v / v] sodium hydrogencarbonate solution (20 ml) and extracted with ethyl acetate (3x50 ml). The ethyl acetate layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was subjected to silica gel flash column chromatography (eluting with a hexane solution containing 60 to 80% [v / v] ethyl acetate) to obtain N- (3- (4-fluorophenyl) 1-carboxamide. ≪ / RTI >

Example 304. l- (3- (4-fluorophenyl) propyl) -3- (tetrahydro-2H-furan-

DIPEA (2.37 mmol) and triphosgene (0.32 mmol) were added to a THF solution (10 ml) of 3- (4-fluorophenyl) propane-1-amine hydrochloride (0.79 mmol) Lt; / RTI > for 30 minutes. Tetrahydro-2H-furan-4-amine (0.79 mmol) was added, the mixture was warmed to room temperature, and stirred for 16 hours. To the reaction mixture was added 10% [v / v] sodium hydrogencarbonate solution (20 ml) and extracted with ethyl acetate (3x50 ml). The ethyl acetate layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by flash column chromatography on silica gel eluting with a hexane solution containing 60-80% [v / v] ethyl acetate to give 1- (3- (4-fluorophenyl) propyl) -3- (tetrahydro- 2H-furan-4-yl) urea.

Example 305. l-benzyl-3- (3- (4-fluorophenyl) propyl) urea

DIPEA (3.95 mmol) and triposidine (0.52 mmol) were added to a THF (10 ml) solution of 3- (4-fluorophenyl) propan- 1- amine hydrochloride Stir at 0 < 0 > C for 30 min. Benzylamine (1.32 mmol) was added, the mixture was warmed to room temperature and stirred for 16 hours. To the reaction mixture was added 10% [v / v] sodium hydrogencarbonate solution (20 ml) and extracted with ethyl acetate (3x50 ml). The ethyl acetate layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was subjected to silica gel flash column chromatography (elution with hexane solution containing 60 to 80% [v / v] ethyl acetate) to obtain 1-benzyl-3- (3- (4- fluorophenyl) propyl) urea .

Example 306. Synthesis of 4- (dimethylamino) -N- (3-phenylpropyl) piperidine-1-carboxamide

DIPEA (4.82 mmol) and (3-isocyanatopropyl) benzene (2.41 mmol) were added to a solution of N, N-dimethylpiperidin-4-amine (2.53 mmol) in THF (10 ml) Stir at temperature for 5 hours. The solvent was removed using an evaporator, diethyl ether (15 ml) was added, and the mixture was stirred for 10 minutes. The resulting solid compound was filtered through a sintered funnel, washed with diethyl ether (2 x 5 ml) and dried in vacuo to give 4- (dimethylamino) -N- (3-phenylpropyl) piperidine- 1-carboxamide.

[Preparation of intermediate 2]

Preparation of 1- (3,4-dihydroquinolin-1 (2H) -yl) -2,2,2-trifluoroethanone:

TEA (45.05 mmol) and 2,2,2-trifluoroacetic anhydride (30.03 mmol) were added to a solution of 1,2,3,4-tetrahydroquinoline (15.02 mmol) in Et ₂ O (20 ml) Was added, and the mixture was stirred at room temperature for 5 hours. After confirming that the starting material was exhausted by TLC monitoring, water (50 ml) was added and extracted with Et ₂ O (3 x 50 ml). The organic solvent layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1- (3,4-dihydroquinolin-1 (2H) -yl) -2,2,2-trifluoroethanone as a brown oil , Which was used in the next step without further purification (Yield 100%).

Preparation of 1- (2,2,2-trifluoroacetyl) -1,2,3,4-tetrahydroquinoline-6-sulfonyl chloride:

To a dichloromethane solution (10 ml) of the intermediate 1- (3,4-dihydroquinolin-1 (2H) -yl) -2,2,2-trifluoroethanone (15.0 mmol) (75.04 mmol) were added. The mixture was warmed to room temperature and then stirred for 5 hours. The reaction mixture was poured into ice-water while stirring, and extracted with ethyl acetate (2x50 ml). The organic solvent layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1- (2,2,2-trifluoroacetyl) -1,2,3,4-tetrahydroquinoline-6-sulfonyl chloride.

Preparation of N, N-dimethyl-1- (2,2,2-trifluoroacetyl) -1,2,3,4-tetrahydroquinoline-6-sulfonamide:

To a dichloromethane solution (10 ml) of the intermediate 1- (2,2,2-trifluoroacetyl) -1,2,3,4-tetrahydroquinoline-6-sulfonyl chloride (3.05 mmol) Was added TEA (9.15 mmol) and dimethylamine hydrochloride (6.10 mmol). The reaction mixture was warmed to room temperature and then stirred for 5 hours. The reaction mixture was diluted with dichloromethane (70 ml) and washed with 1.0 N hydrochloric acid (2 x 30 ml). The organic solvent layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain N, N-dimethyl-1- (2,2,2-trifluoroacetyl) -1,2,3,4-tetrahydroquinoline- -Sulfonamide was obtained, which was used immediately in the next step without further purification (Yield 60%).

Preparation of N, N-dimethyl-1,2,3,4-tetrahydroquinoline-6-sulfonamide:

To a solution of the intermediate N, N-dimethyl-1- (2,2,2-trifluoroacetyl) -1,2,3,4-tetrahydroquinoline-6-sulfonamide (1.83 mmol) in methanol: water 3: 1 [v: v]) was mixed with potassium carbonate (5.49 mmol) and stirred at the same temperature for 5 hours. The solvent was then removed and ethyl acetate (50 ml) was added and washed with water (2x30 ml). The organic solvent layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain N, N-dimethyl-1,2,3,4-tetrahydroquinoline-6-sulfonamide.

Example 307. 6- (N, N-dimethylsulfamoyl) -N- (3-phenylpropyl) -3,4- dihydroquinoline- 1 (2H)

DIPEA (2.50 mmol) and triphosgene (0.33 mmol) were added to a THF solution (10 ml) of N, N-dimethyl-1,2,3,4-tetrahydroquinoline-6-sulfonamide (0.83 mmol) And the mixture was stirred at 0 ° C for 30 minutes. 3-phenylpropan-1-amine (0.91 mmol) was added, the reaction mixture was warmed to room temperature, and stirred for 16 hours. After adding 10% (w / v) sodium hydrogen carbonate solution (20 ml) and extracting with ethyl acetate (3x50 ml), the ethyl acetate layer was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography (eluting with hexane solution containing 20 to 30% [v / v] ethyl acetate) to obtain 6- (N, N-dimethylsulfamoyl) , 4-dihydroquinoline-1 (2H) -carboxamide.

[Intermediate Production 3]

Preparation of N- (3-phenylpropyl) acetamide:

TEA (29.19 mmol) and acetyl chloride (17.51 mmol) were added to a dichloromethane solution (20 ml) of 3-phenylpropan-1-amine (14.59 mmol) at 0 ° C and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with ice water (50 ml) and dichloromethane (2x50 ml), and the organic solvent layer was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain N- (3-phenylpropyl) acetamide. This compound was used directly in the next reaction without further purification.

Preparation of N-methyl-N- (3-phenylpropyl) acetamide:

60% (w / v) NaH (41.48 mmol) was added to a DMF solution (15 ml) of the intermediate N- (3-phenylpropyl) acetamide (13.82 mmol) at 0 ° C and stirred for 30 minutes. MeI (41.48 mmol) was added and the mixture was warmed to room temperature and then stirred at 40 < 0 > C for 16 hours. The reaction mixture was mixed with ice water (100 ml) and extracted with ethyl acetate (3 x 50 ml). The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to silica gel flash column chromatography (elution with hexane solution containing 30 to 50% [v / v] ethyl acetate) to obtain N-methyl-N- (3-phenylpropyl) acetamide.

Preparation of N-methyl-3-phenylpropane-1-amine:

N-Butanol (0.5 ml) was added to 3N HCl (5 ml) of the intermediate N-methyl-N- (3-phenylpropyl) acetamide (7.84 mmol) and the mixture was stirred at 90 ° C for 16 hours. The reaction was cooled to room temperature, then basified with saturated sodium hydrogencarbonate (pH = 9) and extracted with ethyl acetate (3x50 ml). The ethyl acetate layer was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give N-methyl-3-phenylpropan-1-amine as a light brown oil (Yield: 65%).

Example 308. 3- (hydroxymethyl) -N-methyl-N- (3-phenylpropyl) piperidine-1-carboxamide

DIPEA (8.04 mmol) and triphosgene (1.61 mmol) were added to a THF solution (10 ml) of the intermediate N-methyl-3-phenylpropan-1- amine (4.02 mmol) at 0 ° C, Lt; 0 > C for 30 minutes. Piperidin-3-ylmethanol (4.02 mmol) was added thereto. The reaction mixture was warmed to room temperature and stirred for 16 hours. Then, 10% (w / v) sodium hydrogen carbonate solution (20 ml) was added and extracted with ethyl acetate (3x50 ml). The ethyl acetate layer was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was flash column chromatographed on silica gel eluting with a hexane solution containing 70-80% [v / v] ethyl acetate to give 3- (hydroxymethyl) -N-methyl-N- (3- Pyridine-1-carboxamide.

[Preparation of intermediate 4]

The reaction scheme for preparing this intermediate is as described above and was prepared by the same procedure as in [Preparation of intermediate 2].

Example 309. 6- (N, N-diethylsulfamoyl) -N- (3-phenylpropyl) -3,4- dihydroquinoline- 1 (2H)

The reaction scheme for preparing this compound is as described above, and the same procedure as in the preparation of the compound of Example 307 was conducted.

[Preparation of intermediate 5]

The reaction scheme for preparing this intermediate is as described above and was prepared by the same procedure as in [Preparation of intermediate 2].

Example 310. 5- (N, N-diethylsulfamoyl) -N- (3-phenylpropyl) indoline-1-carboxamide

The reaction scheme for the preparation of this compound (5- (N, N-diethylsulfamoyl) -N- (3-phenylpropyl) indoline-1-carboxamide) Process.

Example 311. 5- (N, N-diethylsulfamoyl) -N-methyl-N- (3-phenylpropyl) indoline-

To a DMF solution (10 ml) of 5- (N, N-diethylsulfamoyl) -N- (3-phenylpropyl) indoline-1-carboxamide (0.602 mmol) was added 60% (w / 1.805 mmol) at 0 ° C, and the mixture was stirred for 30 minutes. MeI (1.805 mmol) was added and the mixture was warmed to room temperature and then stirred at the same temperature for 16 hours. Ice water (50 ml) was added to the reaction mixture, which was then extracted with ethyl acetate (3 x 30 ml). Only the ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was subjected to silica gel flash column chromatography (elution with 30-40% [v / v] ethyl acetate mixed with hexane) to obtain 5- (N, N-diethylsulfamoyl) -N- (3-phenylpropyl) indoline-1-carboxamide.

Example 312. Synthesis of 5- (N, N-diethylsulfamoyl) -N-ethyl-N- (3-phenylpropyl) indoline-

The reaction scheme for the preparation of this compound (5- (N, N-diethylsulfamoyl) -N-ethyl-N- (3-phenylpropyl) indoline-1-carboxamide) The process was the same as the preparation of the compound.

Example 313. Methyl 4- (3-phenylpropylcarbamoyl) piperazine-1-carboxylate

This compound (methyl 4- (3-phenylpropylcarbamoyl) piperazine-1-carboxylate) was prepared in the same manner as in the preparation of the compound of Example 307 as described above.

Example 314. Methyl 4- (methyl (3-phenylpropyl) carbamoyl) piperazine-1-carboxylate

The reaction scheme for preparing this compound (methyl 4- (methyl (3-phenylpropyl) carbamoyl) piperazine-1-carboxylate) was as described above and was prepared by the same procedure as for the preparation of the compound of Example 311.

Example 315. Ethyl 4- (3- (3-phenylpropyl) ureido) piperidine-1-carboxylate

(3-isocyanatopropyl) benzene (3.11 mmol) was added at room temperature to a THF solution (10 ml) of ethyl 4-aminopiperidine-1-carboxylate (3.101 mmol) Lt; / RTI > The solvent was removed using an evaporator, diethyl ether (15 ml) was added, and the mixture was stirred for 10 minutes. The solid product was obtained by filtration through a vacuum filter, washing with diethyl ether (2 x 5 ml) and vacuum drying to obtain ethyl 4- (3- (3-phenylpropyl) ureido) piperidine-l-carboxylate.

Example 316. l- (3-phenylpropyl) -3- (piperidin-4-ylmethyl) urea

To a THF solution (10 ml) of ethyl tert-butyl 4- (aminomethyl) piperidine-1-carboxylate (3.101 mmol) at room temperature was added (3-isocyanatopropyl) benzene The reaction mixture was then stirred at the same room temperature for 5 hours. After the solvent was removed by an evaporator, diethyl ether (15 ml) was added and the mixture was stirred for 10 minutes, and then filtered with a vacuum filter to obtain a solid compound. This was washed with diethyl ether (2 x 5 ml) and vacuum dried to obtain tert-butyl 4 - ((3- (3-phenylpropyl) ureido) methyl) piperidine-1-carboxylate . To a solution of the tert-butyl 4 - ((3- (3-phenylpropyl) ureido) methyl) piperidine-1-carboxylate (10.6 g) in THF (10 ml) at 0 ° C was added 1 , 4-dioxane (5.32 mmol) was added and the reaction mixture was stirred for 5 hours at room temperature. The solvent was removed with an evaporator, diethyl ether (15 ml) was added, and the mixture was stirred for 10 minutes. After filtration through a vacuum filtration funnel, the solid was washed with diethyl ether (2 x 5 ml) and dried in vacuo to give 1- (3-phenylpropyl) -3- (piperidin- .

[Preparation of intermediate 6]

The reaction scheme for preparing this intermediate is as described above and was prepared by the same procedure as in [Preparation of intermediate 2].

Example 317. Methyl 4- (1- (3-phenylpropylcarbamoyl) indolin-5-ylsulfonyl) piperazine-1-carboxylate

The reaction scheme for the preparation of this compound (methyl 4- (1- (3-phenylpropylcarbamoyl) indolin-5-ylsulfonyl) piperazine-1-carboxylate) Process.

Example 318. Methyl 4- (1- (phenethylcarbamoyl) indolin-5-ylsulfonyl) piperazine-1-carboxylate

1-carboxylate) The reaction scheme is as described above, and by the same procedure as in the preparation of the compound of Example 307 .

 [Intermediate Production 7]

Methyl-4-phenylbutanoate: < RTI ID = 0.0 >

To methanol solution (20 ml) of 4-phenylbutyric acid (30.51 m) was added concentrated sulfuric acid (1 ml) and refluxed for 10 hours. The solvent was evaporated by vacuum drying, water was added, and the mixture was extracted with ethyl acetate to obtain methyl-4-phenylbutanoate.

Preparation of methyl-4- (4- (chlorosulfonyl) phenyl) butanoate:

A methylene chloride solution (4 ml) of the intermediate methyl-4-phenylbutanoate (28.10 mmol) was added slowly to chlorosulfuric acid (20 ml) at 0 ° C, and the mixture was stirred at room temperature for 3 hours. When it was confirmed by TLC that all of the reaction proceeded, the reaction mixture was added with stirring while stirring. When all the ice melted, it was extracted with methylene chloride and concentrated under reduced pressure to obtain (methyl-4- (4- (chlorosulfonyl) phenyl) butanoate, which was used in the next step.

Preparation of methyl-4- (4- (N, N-dimethylsulfamoyl) phenyl) butanoate:

Sodium bicarbonate (3.98 mmol) was added to a THF solution (10 ml) of N, N-dimethylamine hydrochloride (5.32 mmol) at 0 ° C to form free amine. To the reaction mixture was added a THF solution of the intermediate methyl-4- (4- (chlorosulfonyl) phenyl) butanoate (2.66 mmol) and the mixture was slowly stirred for 5 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting mixture was subjected to column chromatography to obtain methyl-4- (4- (N, N-dimethylsulfamoyl) phenyl) butanoate.

Preparation of 4- (4- (N, N-dimethylsulfamoyl) phenyl) butanoic acid:

To a THF: water mixed solution (5 ml: 5 ml) of lithium hydroxide (15.00 mmol) was added the intermediate methyl-4- (4- (N, N- dimethylsulfamoyl) phenyl) butanoate ) Was added and stirred for 2 hours. The reaction mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic solvent layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4- (4- (N, N-dimethylsulfamoyl) phenyl) butanoic acid as a white solid.

Example 319. 4- (4- (N, N-dimethylsulfamoyl) phenyl-N- (3-phenylpropyl) butanamide

HOBT (3.10 mmol) and EDC (concentration) were added to a THF solution (10 ml) of the intermediate 4- (4- (N, N-dimethylsulfamoyl) phenyl) butanoic acid (2.58 mmol) at room temperature. Next, DIPEA (3.10 mmol) was added, and hydrochloric acid (3.10 mmol) was added. The reaction mixture was stirred for 2 hours, 3-phenylpropylamine (2.58 mmol) was added, and the mixture was stirred at room temperature for 6 hours. After the completion of the reaction was monitored by TLC, water was added to the reaction mixture and extracted with ethyl acetate. The organic solvent layer was dried over anhydrous sodium sulfate and the resulting crude extract (dried) was subjected to column chromatography to obtain 4- (4- (N, N-dimethylsulfamoyl) phenyl-N- Amide.

Example 320. 4- (4- (N, N-dimethylsulfamoyl) phenyl-N-methyl-N- (3- phenylpropyl)

4- (4- (N, N-dimethylsulfamoyl) phenyl-N- (3-phenylpropyl) butanamide (1.29 mmol) of Example 319 was added to a suspension of DMF in cold NaH (1.42 mmol) The resulting reaction mixture was cooled, CH ₃ I (1.42 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Then, NaH was added to the saturated ammonium chloride solution, and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was neutralized further, extracted with ethyl acetate and subjected to column chromatography to obtain 4- (4- (N, N-dimethylsulfamoyl) phenyl-N-methyl-N- (3-phenylpropyl) .

Preparation of the compounds of Examples 321 to 323

The reaction schemes for the compounds of Examples 321 to 323 were as described above and were prepared in a similar manner to the preparation of the compounds of Examples 198 and 207.

Example 321. 5-phenyl-N- (4-sulfamoylbenzyl) pentanamide

Example 322. N- (4- (N, N-dimethylsulfamoyl) benzyl) -5-phenylpentanamide

Example 323. N- (4- (N, N-dimethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide

Example 324. N, N-Dimethyl-4- (4-oxo-4- (4-phenylpiperidin- 1 -yl) butyl) benzenesulfonamide

 The reaction scheme for preparing this compound was as described above, and was prepared by a procedure similar to that of Example 319.

Example 325. N, N-dimethyl-4- (4-oxo-4- (4-phenylpiperazin-1-yl) butyl) benzenesulfonamide

The reaction scheme for the preparation of this compound is as described above, and a process similar to that of N, N-dimethyl-4- (4-oxo-4- (4-phenylpiperidin- 1 -yl) butyl) benzenesulfonamide of Example 324 (Preparation process of substituted carboxylic acid). In addition, the acid is converted to the acid chloride by the action of thionyl chloride due to the reaction with 4-phenylpiperazine using a base such as triethylamine.

Example 326. N- (4- (N, N-dimethylsulfamoyl) benzyl) -N-ethyl-5-phenylpentanamide

The reaction scheme for the preparation of this compound (N- (4- (N, N-dimethylsulfamoyl) benzyl) -N-ethyl-5-phenylpentanamide) , N-dimethylsulfamoyl) phenyl-N-methyl-N- (3-phenylpropyl) butanamide.

Example 327. N- (4- (N, N-dimethylsulfamoyl) phenethyl) -N-ethyl-5- phenylpentanamide

The reaction scheme for the preparation of this compound (N- (4- (N, N-dimethylsulfamoyl) phenethyl) -N-ethyl-5-phenylpentanamide) N, N-dimethylsulfamoyl) phenyl-N-methyl-N- (3-phenylpropyl) butanamide.

[Intermediate Production 8]

Preparation of N-benzyl-N-methylacetamide:

To the methylene chloride solution (20 ml) of cold N-benzylmethylamine (77.60 mmol) was added acetyl chloride (155.00 mmol) and the mixture was stirred at room temperature for 1 hour. TLC was used to confirm the completion of the reaction. Water (10 ml) was added to the resulting reaction product and extracted with ethyl acetate (10 ml × 2). The organic solvent layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain N-benzyl-N-methylacetamide.

Preparation of 4 - ((N-methylacetamido) methyl) benzene-1-sulfonyl chloride:

At 0 ° C, chlorosulfuric acid (20 ml) was added to methylene chloride (4 ml) of the intermediate N-benzyl-N-methylacetamide (28.10 mmol) and stirred at room temperature for 3 hours. After the completion of the reaction was monitored by TLC, the reaction mixture was slowly added with ice and the ice was melted. Then, 4 - ((N-methylacetamido) methyl) benzene-1-sulfonyl chloride The lead was extracted and used in the next reaction.

Preparation of N-methyl-N- (4-morpholinosulfonyl) benzyl) acetamide:

Triethylamine (3.06 mmol) was added to a solution (5 ml) of THF (5 ml) of cold morpholine (3.06 mmol) at 0 占 폚 and the mixture was stirred for 5 minutes. A THF solution of the intermediate 4 - ((N-methylacetamido) methyl) benzene-1-sulfonyl chloride (3.06 mmol) was added and the reaction mixture was stirred slowly at room temperature for 5 hours. When the reaction was completed, water was added, and the mixture was extracted with ethyl acetate, and then subjected to column chromatography to obtain N-methyl-N- (4-morpholinosulfonyl) benzyl) acetamide.

N-methyl-1- (4-morpholinosulfonyl) phenyl) methanamide:

To the n-butanol solution (2 ml) of the intermediate N-methyl-N- (4-morpholinosulfonyl) benzyl) acetamide was added 3 N hydrochloric acid solution (100 ml) and the mixture was refluxed for 12 hours. The reaction was extracted with ethyl acetate to remove unreacted intermediate. The acid layer was neutralized with solid potassium carbonate and ethylamine was used to obtain N-methyl-1- (4-morpholinosulfonyl) phenyl) methanamide as a free amine compound.

※  (N-methyl-N- (4- (morpholinosulfonyl) benzyl) -5-phenylpentanamide and N-methyl-N- Preparation of phenylbutanamide

Thionyl chloride (2.22 mmol) was added to a solution of the respective carboxylic acid (1.48 mmol) in methylene chloride (5 ml) and refluxed for 2 hours. The refluxed reaction was dried under vacuum to remove methylene chloride, and thionyl chloride was added to obtain the respective acid salt mixture. To the methylene chloride solution of cold N-methyl-1- (4-morpholinosulfonyl) phenyl) methanamide at 0 ° C was added triethylamine (1.48 mmol), and the methylene chloride solution of each of the above acid chlorides And the reaction mixture was stirred for 3 hours at room temperature. The reaction was monitored by TLC to confirm completion of the reaction. Water was added to the reaction mixture, and ethyl acetate was mixed and extracted. The organic solvent layer was washed with saturated sodium bicarbonate solution to remove all of the carboxylic acid and then washed with brine solution. The organic solvent layer was dried over anhydrous sodium sulfate and the resulting residue was subjected to column chromatography to obtain N-methyl-N- (4- (morpholinosulfonyl) benzyl) -5-phenylpentanamide and N-methyl- Morpholinosulfonyl) benzyl) -4-phenylbutanamide.

Example 328. N-methyl-N- (4- (morpholinosulfonyl) benzyl) -5-phenylpentanamide

Example 329. N-methyl-N- (4- (morpholinosulfonyl) benzyl) -4-phenylbutanamide

Example 330. N- (4- (N, N-diethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide

The reaction scheme for preparing this compound is as described above and was prepared in a similar manner to the preparation of the compound of Example 329.

Example 331. N- (4- (N-ethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide

The reaction scheme for preparing this compound is as described above and was prepared in a similar manner to the preparation of the compound of Example 329.

Example 332. N-methyl-N- (4- (N-methylsulfamoyl) benzyl) -5-phenylpentanamide

The reaction scheme for preparing this compound is as described above, and a similar procedure to that of the compound of Example 329 was prepared.

Example 333. N-methyl-N- (4- (N-morpholinosulfonyl) phenethyl) -5-phenylpentanamide

The reaction scheme for preparing this compound is as described above and was prepared in a similar manner to the preparation of the compound of Example 329.

Example 334. N-methyl-N- (4- (N-methylsulfamoyl) phenethyl) -5-phenylpentanamide

  The reaction scheme for preparing this compound is as described above and is prepared in a similar manner to the preparation of the compound of Example 329.

Example 335. N- (4- (N, N-dimethylsulfamoyl) phenethyl) -N-methyl-5-phenylpentanamide

The reaction scheme for preparing this compound is as described above and was prepared in a similar manner to the preparation of the compound of Example 329.

Preparation of the compounds of Examples 336 to 352

To the anhydrous THF solution (10 ml) of 3-amino-9-methyl-9H-carbazole (1.098 mmol) was added the respective isocyanate compound (1.318 mmol) and the mixture was stirred at room temperature (25 ° C) for 24 hours. The stirred mixture was filtered, washed with ethyl acetate, and the powder on the filter paper was dissolved in acetone and subjected to column chromatography to obtain a pure compound.

Example 336. 1- (9H-carbazol-3-yl) -3-phenylpropylurea

Example 337. 1- (9H-carbazol-3-yl) -3-phenylbutyl urea

Example 338. l- (9H-carbazol-3-yl) -3-cyclohexylurea

Example 339. 1- (9H-carbazol-3-yl) -3-phenethyl urea

Example 340. l- (9H-carbazol-3-yl) -3-propylurea

Example 341. 1- (9H-carbazol-3-yl) -3-benzylurea

Example 342. 1- (9H-carbazol-3-yl) -3- (4-methoxyphenethyl) urea

Example 343. 1- (9H-Carbazol-3-yl) -3-furanylurea

Example 344. 1- (9H-Carbazol-3-yl) -3- (4-nitrophenyl) urea

Example 345. 1- (9H-carbazol-3-yl) -3-hexylurea

Example 346. 1- (9H-Carbazol-3-yl) -3-nonyl urea

Example 347. 1- (9H-carbazol-3-yl) -3- (3-nitrophenyl) urea

Example 348. 1- (9H-Carbazol-3-yl) -3- (4-chlorophenyl) urea

Example 349. 1- (9H-carbazol-3-yl) -3- (2-nitrophenyl) urea

Example 350. 1- (9H-carbazol-3-yl) -3- (4-ethylphenyl) urea

Example 351. 1- (9H-carbazol-3-yl) -3-phenylurea

Example 352. 1- (9H-carbazol-3-yl) -3- (4-acetoxyphenyl) urea

※ Preparation of the compounds of Examples 353 to 369

To the anhydrous THF solution (10 ml) of 3-amino-9-methyl-9H-carbazole (0.510 mmol) was added the respective isocyanate compound (0.612 mmol) and the mixture was stirred at room temperature (25 ° C) for 24 hours. The stirred mixture was filtered, washed with ethyl acetate, and the powder on the filter paper was dissolved in acetone and subjected to column chromatography to obtain a pure compound.

Example 353. l- (9-Methyl-9H-carbazol-3-yl) -3-phenylpropylurea

Example 354. l- (9-Methyl-9H-carbazol-3-yl) -3-phenylbutyramide

Example 355. 1- (9-Methyl-9H-carbazol-3-yl) -3-cyclohexylurea

Example 356. l- (9-Methyl-9H-carbazol-3-yl) -3-phenethyl urea

Example 357. l- (9-methyl-9H-carbazol-3-yl) -3-propylurea

Example 358. 1- (9-Methyl-9H-carbazol-3-yl) -3-benzylurea

Example 359. l- (9-Methyl-9H-carbazol-3-yl) -3- (4-methoxyphenethyl) urea

Example 360. l- (9-Methyl-9H-carbazol-3-yl) -3-furfurylurea

Example 361. 1- (9-methyl-9H-carbazol-3-yl) -3- (4- nitrophenyl) urea

Example 362. 1- (9-methyl-9H-carbazol-3-yl) -3-hexylurea

Example 363. l- (9-Methyl-9H-carbazol-3-yl) -3-nonyl urea

Example 364. l- (9-Methyl-9H-carbazol-3-yl) -3- (3-nitrophenyl) urea

Example 365. 1- (9-methyl-9H-carbazol-3-yl) -3- (4- chlorophenyl) urea

Example 366. 1- (9-methyl-9H-carbazol-3-yl) -3- (2-nitrophenyl) urea

Example 367. 1- (9H-carbazol-3-yl) -3- (4-ethylphenyl) urea

Example 368. l- (9-methyl-9H-carbazol-3-yl) -3-phenylurea

Example 369. l- (9-methyl-9H-carbazol-3-yl) -3- (4- acetoxyphenyl) urea

Example

Experimental Example 1. Measurement of ATPase (ATP hydrolysis) activity

Energy production in the sarcomere is directly related to ATP hydrolysis. By measuring the increase in myosin ATPase activity in myofascial segment analysis, we determined whether the compound could activate myofascial segments by reference to the following literature: Pollard, T.D. 1982. Methods in Cell Biology, 24, 333-371; Vahey, M. 1983. Journal Cell Biology, 96, 1761-1765; Straight, A.F. et al., 2002. Nature Cell Biology, 4, 83.

Actin-stimulated ATPase activity was determined by spectrophotometry, and the method described by Pollard (1982) (Vahey, 1983; Straight et al 2002) and Cytoskeleton Inc. was modified and measured. The standard reaction mixture contained: the substance to be measured (10 μM), 20 mM Tris HCl (pH 7.5), 15 mM KCl, 6 mM MgCl ₂ , 1 m MATP, 0.006 mg / ml S1 myosin (CS-MYS03, Cytoskeleton ) And 0.2 mg / ml actin thin filament complex (CS-TFC01, Cytoskeleton) and Ca ²⁺ (pCa ²⁺ = 6.5). The reaction solution was incubated for 10 minutes at 37 ° C and then stopped by addition of cytotoxic reagent (Cytoskeleton, BK054 kit). After incubation at room temperature for 10 minutes, the absorbance at 650 nm was measured from the sample using a spectrophotometer from TECAN Infinite to analyze the liberated inorganic phosphate.

To calculate the EC ₅₀ , the compounds were analyzed at three different concentrations (1 μM, 5 μM and 10 μM) and the results were evaluated using Graphpad Prism 5 software.

Preparation of protein solution

S1 Myosin: S1 Myosin was diluted to 1.0 mg / ml with ice-cold Milli Q (250 / / 250)) purified water. And stored at -70 ° C. After taking 2 쨉 l of the solution, cold milli-Q purified water was added to a final volume of 50 쨉 l to prepare a final concentration of 0.04 mg / ml. If 4.5 μl is used in the assay, the final concentration is 0.006 mg / ml.

TFC01: Simply centrifuged to collect the product on the bottom of the tube. (RT) milli-Q purified water (1 mg / 500 쨉 l milli-Q purified water) was added to give 2 mg / ml. At first, a white solution appeared. After leaving for 10 minutes, the solution was made transparent by centrifugation at 500 x g for 30 seconds to remove air bubbles. Centrifugation at high speed precipitates the filaments. Stabilized at room temperature for 20 minutes. 30 ㎕ each was dispensed and stored at -70 캜. When used, 25 ㎕ was diluted to 100 ((0.5 mg / ml). Therefore, when 12 μl is used in the analysis, the final concentration is 0.2 mg / ml.

The ATPase activities analyzed for the compounds of each Example are shown in Tables 1 and 2 below.

[Table 1-1]

[Table 1-2]

[Table 1-3]

[Table 1-4]

[Table 1-5]

[Table 1-6]

[Table 1-7]

[Table 1-8]

[Table 1-9]

[Table 1-10]

[Table 1-11]

[Table 1-12]

[Table 1-13]

[Table 1-14]

[Table 1-15]

[Table 1-16]

[Table 1-17]

[Table 1-18]

[Table 1-19]

[Table 1-20]

[Table 2-1]

[Table 2-2]

[Table 2-3]

[Table 2-4]

[Table 2-5]

[Table 2-6]

[Table 2-7]

Experimental Example 2 Measurement of Coronary Effect by Echocardiography in a White Paper Model

Among the compounds of Experimental Example 1, echocardiogrphic experiments were carried out in Experimental Example 2 below with respect to compounds having excellent ATPase activity. Echocardiography was performed by an ultrasound technician without knowing the type of drug, and the echocardiogram was also performed with a blind test to report the type of drug.

A schematic experimental method is described in FIG. Experimental animals were male Sprague Dawley (SD) normal rats (Orient Bio, Korea) at 7 weeks of age. Isoflurane (Isoflurane) was induced by anesthesia with anesthesia, and then placed on the bench where the heart rate and temperature were measured. The electrocardiogram was measured and stabilized, and the heart rate was 250 times per minute The experiment was started in a stable state. The test instrument was a Vevo 2100 ultrasonic device (VisualSonic) developed for animal experiments and was imaged using a 25 MHz probe. A polyethylene tube (PE 10) and an infusion pump were connected to the right jugular vein of the white paper and the baseline and drugs were administered at 2, 4, 8, and 16 μg / kg / min, respectively After 3 min injection, echocardiogram was obtained and echocardiogram was obtained. After the end of the experiment using the compound according to the present invention, dobutamine was injected as a positive control. On the same day, the compound of the present invention was administered to one experimental animal. At least three rats per compound were used to minimize the error between the animals that could occur in the pharmacodynamic validation experiment. In all three animals, comparative experiments were conducted under the same conditions on the same day, .

The baseline images were obtained from an animal having a stabilized heart rate, and the concentration of the compound (compound according to the present invention) was increased from a low concentration (2 μg / kg / min) to 16 μg / kg / And cardiac function changes were measured by echocardiography to verify the effect of the drug. There was a difference in the absolute value of the contraction according to the injection concentration. The drug effect was verified by subtracting the final concentration of 16 ㎍ / kg / min and the fractional shortening value of the baseline, Respectively.

The compartment shortening rate, thinning rate and percent increase rate were calculated as follows

Fractional shortening (FS: left ventricular internal shortening rate) = (LVDd LVDs) / LVDd. LVDd: inner diameter of left ventricular dilator, and LVDs: inner diameter of left ventricle contraction. The segment shortening rate is a normalized standard deviation of the left ventricular internal diameter by the left ventricular dilatation diameter and can be used as an index reflecting the left ventricular contraction ability.

Ejection Fraction (EF) = {(Diastolic Lateral Diameter ² Systolic Lateral Diameter ² ) / Diastolic Lateral Diameter ² } X 100. Assuming that the left ventricle lumen is ellopsodial and that all shrinkage is uniform , Calculated using the left ventricular internal diameter of the systolic and diastolic horses measured in the M-mode of the left ventricle.

The% increase was calculated as follows:

FS% increase rate = (high dose EF value - baseline EF value) / baseline FS value

EF% increase rate = (high dose EF value - baseline EF value) / baseline EF value

(* High dose: 16 μg / kg / min, baseline: before drug administration)

The omepactives were used as positive control drugs and echocardiograms were performed in 70 compounds (compounds according to the invention). The results are shown in Table 2. In addition, as shown in FIG. 2, it was confirmed that the compound according to the present invention continuously changes the ventricular contractile function and the relaxation function without changing the heart rate as the injection concentration of the drug increases through the M-mode echocardiogram And Table 3).

[Table 3-1]

[Table 3-2]

[Table 3-3]

As can be seen from the results of Tables 1 and 2, the compounds according to the present invention are excellent in ATPase activity. As shown in Table 3, the compound according to the present invention continuously changes the ventricular contractile function and relaxation function without changing the heart rate as the injection concentration increases. In particular, 18 compounds (compounds of Examples 20, 27, 30, 35, 36, 42, 90, 100, 102, 103, 104, 109, 118, 135, 188, 190, 198 and 223) In comparison, ATPase activity as well as ventricular contraction and relaxation functions were similar or superior. These results indicate that the compounds according to the present invention can be candidates for the development of useful new drugs.

Claims (11)

A compound represented by the following formula (2), or a pharmaceutically acceptable salt thereof:
(2)

In Formula 2,
R ₅ is -C ₃ -C ₈ cycloalkyl {wherein the cycloalkyl may be substituted with hydrogen or phenyl}; -C ₁ -C ₅ alkyl-C ₃ -C ₈ cycloalkyl; -C ₁ -C ₁₀ alkyl-phenyl; -C ₃ -C ₁₀ heterocycloalkyl; -C ₄ -C ₁₃ heteroaryl, which may be substituted with one or more of hydrogen or C ₁ -C ₅ alkoxy; -C ₁ -C ₅ alkyl, -NRaRb {in the above Ra is hydrogen or C ₁ -C ₅ alkyl; Rb is -C ₄ -C ₁₂ arylalkyl, phenyl {one or more hydrogen, halogen, -C ₁ -C ₅ alkyl or -C ₁ -C ₅ can be substituted with alkoxy}, or -C ₁ -C ₅ alkyl, -C ₃ - C ₈ is cycloalkyl}; -C ₄ -C ₁₂ arylalkenyl; -C ₁ -C ₅ alkyl-S-Rc; Or -C ₁ -C ₅ alkyl-O-R c {wherein R c is -C ₄ -C ₁₂ arylalkyl or phenyl};
R ₆ is hydrogen or C ₁ -C ₅ alkyl;
R ₇ is phenyl {wherein the phenyl is one or more hydrogen, halogen, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy or SO ₂ NR'R "(wherein R 'and R" are each hydrogen or C ₁ -C ₅ Alkyl); -C ₃ -C ₁₀ heterocycloalkyl, wherein said heterocycloalkyl may be substituted with hydroxy or arylalkyl; -C ₁ -C ₅ alkyl (wherein the alkyl can be substituted with -C ₄ -C ₁₂ arylalkyl); Or a partially hydrogenated bi-ring benzene ring. The method according to claim 1,
R < ₅ > is 2-phenyl-cyclopropyl; Cyclohexylmethyl or cyclohexylethyl; -C ₁ -C ₅ alkyl-phenyl; Tetrahydropyran substituted with hydroxy or benzyl, morpholine or piperidine; An indole substituted with one or more hydrogen or methoxy; -C ₁ -C ₅ alkyl, -NRaRb {in the above Ra is hydrogen or C ₁ -C ₅ alkyl; Rb is benzyl, phenylethyl, phenyl {at least one hydrogen, can be substituted by halogen, tert- butyl or methoxy}, or -C ₁ -C ₅ alkyl-cyclohexyl} a; -C ₄ -C ₁₂ arylalkenyl; -C ₁ -C ₅ alkyl-S-Rc; Or -C ₁ -C ₅ alkyl, -O-Rc {wherein Rc is a phenyl, benzyl or phenylethyl} gt;
R ₆ is hydrogen or C ₁ -C ₅ alkyl;
R ₇ is phenyl, said phenyl being optionally substituted with one or more of hydrogen, halogen, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, SO ₂ NH ₂ or SO ₂ N (CH ₃ ) ₂ ; Tetrahydropyran substituted with hydrogen, hydroxy or benzyl, morpholine or piperazine; -C ₁ -C ₅ alkyl substituted by benzyloxy; Or a dihydroindane, or a pharmaceutically acceptable salt thereof. 3. The method of claim 2,
The compound
190. 5-Phenyl-N- (tetrahydro-2H-pyran-4-yl) pentanamide;
193. 1- (4-Hydroxypiperidin-1-yl) -5-phenylpentan-1-one;
196. N- (4-methylphenethyl) -5-phenylpentanamide;
197. N- (2-fluorophenethyl) -5-phenylpentanamide;
198. N- (4- (N, N-dimethylsulfamoyl) phenethyl-N-methyl-5-phenylpentanamide;
199. N-methyl-N-phenethyl-5-phenylpentanamide;
201. N- (2,3-Dihydro-1H-inden-2-yl) -5-phenylpentanamide;
205. 6-Methoxy-N- (3-phenylpropyl) -1H-indole-2-carboxamide;
206. (4-Benzylpiperazin-1-yl) (6-methoxy-1H-indol-2-yl) methanone;
207. N- (4- (N, N-dimethylsulfamoyl) phenethyl) -5-phenylpentanamide;
212. 2- (Methyl (phenyl) amino) -N- (3-phenylpropyl) acetamide;
213. 2- (Benzyl (methyl) amino) -N- (3-phenylpropyl) acetamide;
214. 2- (Benzyloxy) -N- (3-phenylpropyl) acetamide;
218. 2-Phenethoxy-N-phenylacetamide;
219. 3- (Benzylamino) -N-phenethylpropanamide;
220. 3- (Benzyl (methyl) amino) -N-phenethylpropanamide;
222. N-phenethyl-4- (phenylamino) butanamide;
223. 4- (Methyl (phenyl) amino) -N-phenethylbutanamide;
224. 3- (Phenylamino) -N- (3-phenylpropyl) propanamide;
225. 3- (Methyl (phenyl) amino) -N- (3-phenylpropyl) propanamide;
226. 2- (Phenylamino) -N- (4-phenylbutyl) acetamide;
227. 2- (Methyl (phenyl) amino) -N- (4-phenylbutyl) acetamide;
229. 2- (Benzylamino) -N- (3-phenylpropyl) acetamide;
230. 2- (Benzyl (methyl) amino) -N- (4-phenylbutyl) acetamide;
231. 2- (Benzylthio) -N- (4-phenylbutyl) acetamide;
232. 2- (Benzyloxy) -N- (4-phenylbutyl) acetamide;
233. 3- (Benzyloxy) -N-phenethylpropanamide;
234. 2- (Benzylamino) -N- (4-phenylbutyl) acetamide;
238. 2- (Benzyloxy) -N-phenylacetamide;
239. 2- (Benzyl (methyl) amino) -N-phenylacetamide;
240. N- (2- (Benzyloxy) ethyl) -3-phenylpropanamide;
242. N-benzyl-4- (benzyloxy) -N-methylbutanamide;
243. 4- (Benzyloxy) -N-phenethylbutanamide;
244. 4- (Benzyloxy) -N-methyl-N-phenethylbutanamide;
245. 2- (4-Methoxybenzylamino) -N- (3-phenylpropyl) acetamide;
246. 2- (4-Chlorobenzylamino) -N- (3-phenylpropyl) acetamide;
247. 2- (4-tert-Butylbenzylamino) -N- (3-phenylpropyl) acetamide;
248. 2- (Cyclohexylmethylamino) -N- (3-phenylpropyl) acetamide;
249. 2- (4-Fluorobenzylamino) -N- (3-phenylpropyl) acetamide;
319. 4- (4- (N, N-Dimethylsulfamoyl) phenyl-N- (3-phenylpropyl) butanamide;
320. 4- (4- (N, N-dimethylsulfamoyl) phenyl-N-methyl-N- (3-phenylpropyl) butanamide;
321. 5-Phenyl-N- (4-sulfamoylbenzyl) pentanamide;
322. N- (4- (N, N-dimethylsulfamoyl) benzyl) -5-phenylpentanamide;
323. N- (4- (N, N-dimethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide;
324. N, N-Dimethyl-4- (4-oxo-4- (4-phenylpiperidin-1-yl) butyl) benzenesulfonamide;
325. N, N-Dimethyl-4- (4-oxo-4- (4-phenylpiperazin-1-yl) butyl) benzenesulfonamide;
326. N- (4- (N, N-dimethylsulfamoyl) benzyl) -N-ethyl-5-phenylpentanamide;
327. N- (4- (N, N-dimethylsulfamoyl) phenethyl) -N-ethyl-5-phenylpentanamide;
328. N-methyl-N- (4- (morpholinosulfonyl) benzyl) -5-phenylpentanamide;
329. N-methyl-N- (4- (morpholinosulfonyl) benzyl) -4-phenylbutanamide;
330. N- (4- (N, N-diethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide;
331. N- (4- (N-ethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide;
332. N-methyl-N- (4- (N-methylsulfamoyl) benzyl) -5-phenylpentanamide;
333. N-methyl-N- (4- (N-morpholinosulfonyl) phenethyl) -5-phenylpentanamide;
334. N-methyl-N- (4- (N-methylsulfamoyl) phenethyl) -5-phenylpentanamide; And
335. N- (4- (N, N-dimethylsulfamoyl) phenethyl) -N-methyl-5-phenylpentanamide;
≪ / RTI > or a pharmaceutically acceptable salt thereof. The method of claim 3,
The compound
190. 5-Phenyl-N- (tetrahydro-2H-pyran-4-yl) pentanamide;
198. N- (4- (N, N-dimethylsulfamoyl) phenethyl-N-methyl-5-phenylpentanamide;
223. 4- (Methyl (phenyl) amino) -N-phenethylbutanamide;
319. 4- (4- (N, N-Dimethylsulfamoyl) phenyl-N- (3-phenylpropyl) butanamide;
320. 4- (4- (N, N-dimethylsulfamoyl) phenyl-N-methyl-N- (3-phenylpropyl) butanamide;
321. 5-Phenyl-N- (4-sulfamoylbenzyl) pentanamide;
322. N- (4- (N, N-dimethylsulfamoyl) benzyl) -5-phenylpentanamide;
323. N- (4- (N, N-dimethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide;
324. N, N-Dimethyl-4- (4-oxo-4- (4-phenylpiperidin-1-yl) butyl) benzenesulfonamide;
325. N, N-Dimethyl-4- (4-oxo-4- (4-phenylpiperazin-1-yl) butyl) benzenesulfonamide;
326. N- (4- (N, N-dimethylsulfamoyl) benzyl) -N-ethyl-5-phenylpentanamide;
327. N- (4- (N, N-dimethylsulfamoyl) phenethyl) -N-ethyl-5-phenylpentanamide;
328. N-methyl-N- (4- (morpholinosulfonyl) benzyl) -5-phenylpentanamide;
329. N-methyl-N- (4- (morpholinosulfonyl) benzyl) -4-phenylbutanamide;
330. N- (4- (N, N-diethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide;
331. N- (4- (N-ethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide;
332. N-methyl-N- (4- (N-methylsulfamoyl) benzyl) -5-phenylpentanamide;
333. N-methyl-N- (4- (N-morpholinosulfonyl) phenethyl) -5-phenylpentanamide;
334. N-methyl-N- (4- (N-methylsulfamoyl) phenethyl) -5-phenylpentanamide; And
335. N- (4- (N, N-dimethylsulfamoyl) phenethyl) -N-methyl-5-phenylpentanamide;
≪ / RTI > or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for preventing or treating heart failure comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof. 6. The method of claim 5,
The compound
186. 2-Phenyl-N- (3-phenylpropyl) cyclopropanecarboxamide;
187. 2-Phenyl-N- (4-phenylbutyl) cyclopropanecarboxamide;
188. N-phenethyl-5-phenylpentanamide;
189. 4-Phenyl-N- (3-phenylpropyl) butanamide;
190. 5-Phenyl-N- (tetrahydro-2H-pyran-4-yl) pentanamide;
191. 1-Morpholino-5-phenylpentan-1-one;
192. 5-Phenyl-N- (4-sulfamoylphenethyl) pentanamide;
193. 1- (4-Hydroxypiperidin-1-yl) -5-phenylpentan-1-one;
194. N- (3,4-Dimethoxyphenethyl) -5-phenylpentanamide;
195. N- (2-methoxyphenethyl) -5-phenylpentanamide;
196. N- (4-methylphenethyl) -5-phenylpentanamide;
197. N- (2-fluorophenethyl) -5-phenylpentanamide;
198. N- (4- (N, N-dimethylsulfamoyl) phenethyl-N-methyl-5-phenylpentanamide;
199. N-methyl-N-phenethyl-5-phenylpentanamide;
200. N- (3-Phenylpropyl) tetrahydro-2H-pyran-4-carboxamide;
201. N- (2,3-Dihydro-1H-inden-2-yl) -5-phenylpentanamide;
202. N-benzyl-5-phenylpentanamide;
203. 3-Cyclohexyl-N- (3-phenyl) propanamide;
204. N- (3-Phenylpropyl) -1H-indole-3-carboxamide;
205. 6-Methoxy-N- (3-phenylpropyl) -1H-indole-2-carboxamide;
206. 4-Benzylpiperazin-1-yl- (6-methoxy-1H-indol-2-yl) methanone;
207. N- (4- (N, N-dimethylsulfamoyl) phenethyl) -5-phenylpentanamide;
208. N-phenethyl-2- (phenethylamino) acetamide;
209. 2-Methyl (phenethylamino) -N-phenylacetamide;
210. 2- (Phenylamino) -N- (3-phenylpropyl) acetamide;
211. N-phenethyl-2- (phenethylthio) acetamide;
212. 2- (Methyl (phenyl) amino) -N- (3-phenylpropyl) acetamide;
213. 2- (Benzyl (methyl) amino) -N- (3-phenylpropyl) acetamide;
214. 2- (Benzyloxy) -N- (3-phenylpropyl) acetamide;
215. 2-Phenoxy-N- (3-phenylpropyl) acetamide;
216. 2- (Benzylthio) -N- (3-phenylpropyl) acetamide;
217. N- (4-Phenylbutyl) cinnamamide;
218. 2-Phenethoxy-N-phenylacetamide;
219. 3- (Benzylamino) -N-phenethylpropanamide;
220. 3- (Benzyl (methyl) amino) -N-phenethylpropanamide;
221. 3- (Benzylthio) -N-phenethylpropanamide;
222. N-phenethyl-4- (phenylamino) butanamide;
223. 4- (Methyl (phenyl) amino) -N-phenethylbutanamide;
224. 3- (Phenylamino) -N- (3-phenylpropyl) propanamide;
225. 3- (Methyl (phenyl) amino) -N- (3-phenylpropyl) propanamide;
226. 2- (Phenylamino) -N- (4-phenylbutyl) acetamide;
227. 2- (Methyl (phenyl) amino) -N- (4-phenylbutyl) acetamide;
228. 2-Phenoxy-N- (4-phenylbutyl) acetamide;
229. 2- (Benzylamino) -N- (3-phenylpropyl) acetamide;
230. 2- (Benzyl (methyl) amino) -N- (4-phenylbutyl) acetamide;
231. 2- (Benzylthio) -N- (4-phenylbutyl) acetamide;
232. 2- (Benzyloxy) -N- (4-phenylbutyl) acetamide;
233. 3- (Benzyloxy) -N-phenethylpropanamide;
234. 2- (Benzylamino) -N- (4-phenylbutyl) acetamide;
235. (Benzylthio) -N-phenylacetamide;
236. 2- (Benzylamino) -N-phenylacetamide;
237. N-phenethyl-4-phenoxybutanamide;
238. 2- (Benzyloxy) -N-phenylacetamide;
239. 2- (Benzyl (methyl) amino) -N-phenylacetamide;
240. N- (2- (Benzyloxy) ethyl) -3-phenylpropanamide;
241. N-Benzyl-4- (benzyloxy) butanamide;
242. N-benzyl-4- (benzyloxy) -N-methylbutanamide;
243. 4- (Benzyloxy) -N-phenethylbutanamide;
244. 4- (Benzyloxy) -N-methyl-N-phenethylbutanamide;
245. 2- (4-Methoxybenzylamino) -N- (3-phenylpropyl) acetamide;
246. 2- (4-Chlorobenzylamino) -N- (3-phenylpropyl) acetamide;
247. 2- (4-tert-Butylbenzylamino) -N- (3-phenylpropyl) acetamide;
248. 2- (Cyclohexylmethylamino) -N- (3-phenylpropyl) acetamide;
249. 2- (4-Fluorobenzylamino) -N- (3-phenylpropyl) acetamide;
319. 4- (4- (N, N-Dimethylsulfamoyl) phenyl-N- (3-phenylpropyl) butanamide;
320. 4- (4- (N, N-dimethylsulfamoyl) phenyl-N-methyl-N- (3-phenylpropyl) butanamide;
321. 5-Phenyl-N- (4-sulfamoylbenzyl) pentanamide;
322. N- (4- (N, N-dimethylsulfamoyl) benzyl) -5-phenylpentanamide;
323. N- (4- (N, N-dimethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide;
324. N, N-Dimethyl-4- (4-oxo-4- (4-phenylpiperidin-1-yl) butyl) benzenesulfonamide;
325. N, N-Dimethyl-4- (4-oxo-4- (4-phenylpiperazin-1-yl) butyl) benzenesulfonamide;
326. N- (4- (N, N-dimethylsulfamoyl) benzyl) -N-ethyl-5-phenylpentanamide;
327. N- (4- (N, N-dimethylsulfamoyl) phenethyl) -N-ethyl-5-phenylpentanamide;
328. N-methyl-N- (4- (morpholinosulfonyl) benzyl) -5-phenylpentanamide;
329. N-methyl-N- (4- (morpholinosulfonyl) benzyl) -4-phenylbutanamide;
330. N- (4- (N, N-diethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide;
331. N- (4- (N-ethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide;
332. N-methyl-N- (4- (N-methylsulfamoyl) benzyl) -5-phenylpentanamide;
333. N-methyl-N- (4- (N-morpholinosulfonyl) phenethyl) -5-phenylpentanamide;
334. N-methyl-N- (4- (N-methylsulfamoyl) phenethyl) -5-phenylpentanamide; And
335. N- (4- (N, N-dimethylsulfamoyl) phenethyl) -N-methyl-5-phenylpentanamide;
Wherein the compound is at least one compound selected from the group consisting of < RTI ID = 0.0 > 6. The method of claim 5,
Wherein the heart failure is acute or chronic heart failure. 6. The method of claim 5,
Wherein said heart failure is cardiac contractile heart failure, diastolic heart failure or congestive heart failure, for the prevention or treatment of heart failure. 6. The method of claim 5,
Wherein the prevention or treatment of heart failure is by modulating cardiac muscle myosin activity. A pharmaceutical composition for the prevention or treatment of heart failure comprising at least one compound selected from the group consisting of or a pharmaceutically acceptable salt thereof:
188. N-phenethyl-5-phenylpentanamide;
190. 5-Phenyl-N- (tetrahydro-2H-pyran-4-yl) pentanamide;
198. N- (4- (N, N-dimethylsulfamoyl) phenethyl-N-methyl-5-phenylpentanamide;
223. 4- (Methyl (phenyl) amino) -N-phenethylbutanamide;
319. 4- (4- (N, N-Dimethylsulfamoyl) phenyl-N- (3-phenylpropyl) butanamide;
320. 4- (4- (N, N-dimethylsulfamoyl) phenyl-N-methyl-N- (3-phenylpropyl) butanamide;
321. 5-Phenyl-N- (4-sulfamoylbenzyl) pentanamide;
322. N- (4- (N, N-dimethylsulfamoyl) benzyl) -5-phenylpentanamide;
323. N- (4- (N, N-dimethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide;
324. N, N-Dimethyl-4- (4-oxo-4- (4-phenylpiperidin-1-yl) butyl) benzenesulfonamide;
325. N, N-Dimethyl-4- (4-oxo-4- (4-phenylpiperazin-1-yl) butyl) benzenesulfonamide;
326. N- (4- (N, N-dimethylsulfamoyl) benzyl) -N-ethyl-5-phenylpentanamide;
327. N- (4- (N, N-dimethylsulfamoyl) phenethyl) -N-ethyl-5-phenylpentanamide;
328. N-methyl-N- (4- (morpholinosulfonyl) benzyl) -5-phenylpentanamide;
329. N-methyl-N- (4- (morpholinosulfonyl) benzyl) -4-phenylbutanamide;
330. N- (4- (N, N-diethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide;
331. N- (4- (N-ethylsulfamoyl) benzyl) -N-methyl-5-phenylpentanamide;
332. N-methyl-N- (4- (N-methylsulfamoyl) benzyl) -5-phenylpentanamide;
333. N-methyl-N- (4- (N-morpholinosulfonyl) phenethyl) -5-phenylpentanamide;
334. N-methyl-N- (4- (N-methylsulfamoyl) phenethyl) -5-phenylpentanamide; And
335. N- (4- (N, N-dimethylsulfamoyl) phenethyl) -N-methyl-5-phenylpentanamide. 11. The method of claim 10,
Wherein said heart failure is cardiac contractile heart failure, diastolic heart failure or congestive heart failure.

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