HK1218755B - Biphenyl derivative and method for preparing same - Google Patents

Description

Biphenyl derivatives and preparation methods thereof

Technical Field

The present invention relates to novel muscarinic M3 receptor antagonists, and more particularly to novel biphenyl derivatives having muscarinic M3 receptor antagonistic activity, their isomers, their pharmaceutically acceptable salts or hydrates thereof, methods for preparing the same, and pharmaceutical compositions containing the same as active ingredients.

Background Art

Muscarinic receptors are found in all parts of the human body, including the brain and salivary glands. This class of receptors is a member of the G-protein coupled receptors and is further divided into 5 subtypes (M1 to M5). Of these subtypes, M1, M2, and M3 receptors are commonly found in tissues of animals and humans, and their pharmacological properties have been elucidated. The muscarinic M1 receptor is primarily expressed in the cerebral cortex and is involved in the regulation of higher cognitive functions. The M2 receptor is primarily found in the smooth muscle of the heart and bladder and is involved in the regulation of heart rhythm. It is known that the M3 receptor is commonly expressed in many peripheral tissues and is involved in stimulation of the gastrointestinal tract and urinary tract, as well as saliva secretion. The M4 and M5 receptors are found in the brain, and the M4 receptor is primarily involved in movement, but the role of the M5 receptor remains unclear.

In general, muscarinic receptor antagonists have been found to be useful in treating a variety of diseases, such as chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spastic colitis, chronic cystitis, Alzheimer's disease, senile dementia, glaucoma, schizophrenia, gastroesophageal reflux disease, arrhythmias and hypersalivation syndrome (Invest. Drugs, 1997, 6(10), 1395-1411, Drugs Future, 1997, 22(2): 135-137, Drugs Future, 1996, 21(11), 1105-1108, Drugs Future, 1997, 22(7), 733-737).

Meanwhile, it is known that among muscarinic receptors, M2 and M3 receptors are predominant in the human bladder and play a role in regulating bladder contraction. M2 receptors are present in the bladder at least three times more abundantly than M3 receptors, and they inhibit bladder relaxation through β-receptors rather than directly participating in bladder contraction. Therefore, M3 receptors appear to play the most important role in bladder contraction. Therefore, selective antagonists for M3 receptors exhibit excellent inhibitory effects on muscarinic bladder contraction, but they inhibit saliva secretion and cause dry mouth.

Therefore, the present inventors have prepared novel derivatives that can exhibit functional activity through their selective binding to the muscarinic M3 receptor and have minimal side effects, thereby completing the present invention.

Summary of the Invention

Technical issues

One object of the present invention is to provide novel biphenyl derivatives or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a method for preparing novel biphenyl derivatives or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a muscarinic M3 receptor antagonist comprising a novel biphenyl derivative, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.

Technical Solution

The present invention provides novel biphenyl derivatives or pharmaceutically acceptable salts thereof.

The present invention also provides a method for preparing the novel biphenyl derivative or a pharmaceutically acceptable salt thereof.

The present invention also provides a muscarinic M3 receptor antagonist comprising a novel biphenyl derivative, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.

As used herein, the term "alkyl" refers to a straight or branched hydrocarbon group. For example, a _C1 - _C6 alkyl group is an aliphatic hydrocarbon group having 1 to 6 carbon atoms and is intended to include all methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and the like.

As used herein, the term "alkoxy" refers to a group in which the hydrogen atom of a hydroxy group is replaced by an alkyl group. For example, _C1 - _C6 alkoxy is intended to include all methoxy, ethoxy, propoxy, n-butoxy, n-pentoxy, isopropoxy, sec-butoxy, tert-butoxy, neopentoxy, isopentoxy, etc.

New biphenyl derivatives

The present invention provides a novel biphenyl derivative represented by the following formula 1 or a pharmaceutically acceptable salt thereof:

[Formula 1]

in

R ₁ is hydrogen, halogen, hydroxy, substituted or unsubstituted C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy;

R ₂ , R ₃ and R ₄ are each independently hydrogen, halogen, substituted or unsubstituted amino, nitro, cyano, hydroxy, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, or -C(O)R ₆ ;

R ₅ is hydrogen or C ₁ -C ₆ alkyl;

n is 0 or 1; and

_R6 is hydrogen or amino.

In a preferred embodiment of the present invention, R ₁ in Formula 1 may be hydrogen or halogen; R ₂ , R ₃ and R ₄ may each independently be hydrogen, halogen or C ₁ -C ₆ alkyl; and R ₅ may be C ₁ -C ₆ alkyl.

In another preferred embodiment of the present invention, R ₁ in Formula 1 may be hydrogen; R ₂ , R ₃ and R ₄ may each independently be hydrogen or halogen; R ₅ may be a C ₁ -C ₆ alkyl group; and n may be 0 or 1.

In the present invention, the pharmaceutically acceptable salt is preferably an acid addition salt formed with a pharmaceutically acceptable free acid. The free acid that can be used in the present invention includes organic acids and inorganic acids. The inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., and the organic acid includes citric acid, acetic acid, lactic acid, maleic acid, coumaric acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, trifluoroacetic acid, galacturonic acid, pamoic acid, glutamic acid, aspartic acid, etc.

In addition, the compound of Formula 1 or its pharmaceutically acceptable salt may exhibit polymorphism and may also exist in the form of solvates (eg, hydrates, etc.) In addition, the compound of the present invention may also exist in the form of individual stereoisomers or mixtures of stereoisomers.

The present invention also relates to novel biphenyl derivatives selected from the group consisting of:

1) 2-(1-methylpyrrolidin-2-yl)ethyl(4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

2) 2-(1-methylpyrrolidin-2-yl)ethyl(3',5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

3) 2-(1-methylpyrrolidin-2-yl)ethyl(3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamate;

4) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

5) 2-(1-methylpyrrolidin-2-yl)ethyl(4'-methoxy-[1,1'-biphenyl]-2-yl)carbamate;

6) 2-(1-methylpyrrolidin-2-yl)ethyl[1,1'-biphenyl]-2-ylcarbamate;

7) 2-(1-methylpyrrolidin-2-yl)ethyl(4'-chloro-[1,1'-biphenyl]-2-yl)carbamate;

8) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-chloro-[1,1'-biphenyl]-2-yl)carbamate;

9) 2-(1-methylpyrrolidin-2-yl)ethyl(3',5'-dichloro-[1,1'-biphenyl]-2-yl)carbamate;

10) 2-(1-methylpyrrolidin-2-yl)ethyl(4'-trifluoromethoxy-[1,1'-biphenyl]-2-yl)carbamate;

11) 2-(1-methylpyrrolidin-2-yl)ethyl(4'-nitro-[1,1'-biphenyl]-2-yl)carbamate;

12) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-trifluoromethyl-[1,1'-biphenyl]-2-yl)carbamate;

13) 2-(1-methylpyrrolidin-2-yl)ethyl(4'-trifluoromethyl-[1,1'-biphenyl]-2-yl)carbamate;

14) 2-(1-methylpyrrolidin-2-yl)ethyl((3'-fluoro-4'-methyl)-[1,1'-biphenyl]-2-yl)carbamate;

15) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate;

16) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-ethoxy-[1,1'-biphenyl]-2-yl)carbamate;

17) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-chloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

18) 2-(1-methylpyrrolidin-2-yl)ethyl(3',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

19) 2-(1-methylpyrrolidin-2-yl)ethyl(4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

20) 2-(1-methylpyrrolidin-2-yl)ethyl(3',5,5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamate;

21) 2-(1-methylpyrrolidin-2-yl)ethyl(5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

22) 2-(1-methylpyrrolidin-2-yl)ethyl(5-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl)carbamate;

23) 2-(1-methylpyrrolidin-2-yl)ethyl(4-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

24) 2-(1-methylpyrrolidin-2-yl)ethyl(3',4-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

25) 2-(1-methylpyrrolidin-2-yl)ethyl(4-methoxy-[1,1'-biphenyl]-2-yl)carbamate;

26) 2-(1-methylpyrrolidin-2-yl)ethyl(5-methyl-[1,1'-biphenyl]-2-yl)carbamate;

27) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-fluoro-5-methyl-[1,1'-biphenyl]-2-yl)carbamate;

28) 2-(1-methylpyrrolidin-2-yl)ethyl(4'-cyano-[1,1'-biphenyl]-2-yl)carbamate;

29) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-(3-hydroxypropyl)-[1,1'-biphenyl]-2-yl)carbamate;

30) 2-(1-methylpyrrolidin-2-yl)ethyl (4'-(dimethylamino)-[1,1'-biphenyl]-2-yl)carbamate;

31) 2-(1-methylpyrrolidin-2-yl)ethyl(4'-(tert-butyl)-[1,1'-biphenyl]-2-yl)carbamate;

32) 2-(1-methylpyrrolidin-2-yl)ethyl(2'-amino-[1,1'-biphenyl]-2-yl)carbamate;

33) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-amino-[1,1'-biphenyl]-2-yl)carbamate;

34) 2-(1-methylpyrrolidin-2-yl)ethyl(2'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

35) 2-(1-methylpyrrolidin-2-yl)ethyl(2'-chloro-[1,1'-biphenyl]-2-yl)carbamate;

36) 2-(1-methylpyrrolidin-2-yl)ethyl(2'-hydroxy-[1,1'-biphenyl]-2-yl)carbamate;

37) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-tert-butyl-5'-methyl-[1,1'-biphenyl]-2-yl)carbamate;

38) 2-(1-methylpyrrolidin-2-yl)ethyl(4'-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate;

39) 2-(1-methylpyrrolidin-2-yl)ethyl(4'-amino-3'-chloro-[1,1'-biphenyl]-2-yl)carbamate;

40) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-hydroxy-[1,1'-biphenyl]-2-yl)carbamate;

41) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

42) 2-(1-methylpyrrolidin-2-yl)ethyl(3',4',5-trifluoro-[1,1'-biphenyl]-2-yl)carbamate;

43) 2-(1-methylpyrrolidin-2-yl)ethyl(3',4'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

44) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

45) 2-(1-methylpyrrolidin-2-yl)ethyl(5-fluoro-3',5'-dimethyl-[1,1'-biphenyl]-2-yl)carbamate;

46) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-amino-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

47) 2-(1-methylpyrrolidin-2-yl)ethyl(5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate;

48) 2-(1-methylpyrrolidin-2-yl)ethyl(4'-fluoro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate;

49) 2-(1-methylpyrrolidin-2-yl)ethyl (3'-fluoro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate;

50) 2-(1-methylpyrrolidin-2-yl)ethyl(3',5'-difluoro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate;

51) 2-(1-methylpyrrolidin-2-yl)ethyl (3'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate;

52) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-chloro-5,5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

53) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-chloro-4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

54) 2-(1-methylpyrrolidin-2-yl)ethyl(4'-chloro-3',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

55) 2-(1-methylpyrrolidin-2-yl)ethyl(3',5'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

56) 2-(1-methylpyrrolidin-2-yl)ethyl(3',5'-dichloro-4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

57) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-chloro-5-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)carbamate;

58) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-chloro-5-fluoro-4'-hydroxy-[1,1'-biphenyl]-2-yl)carbamate;

59) 2-(1-methylpyrrolidin-2-yl)ethyl(5-fluoro-3',4'-dimethyl-[1,1'-biphenyl]-2-yl)carbamate;

60) 2-(1-methylpyrrolidin-2-yl)ethyl(5-methoxy-[1,1'-biphenyl]-2-yl)carbamate;

61) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-fluoro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate;

62) 2-(1-methylpyrrolidin-2-yl)ethyl(3',5'-difluoro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate;

63) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate;

64) 2-(1-methylpyrrolidin-2-yl)ethyl(3',5'-dichloro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate;

65) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-chloro-4'-fluoro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate;

66) 2-(1-methylpyrrolidin-2-yl)ethyl(5-chloro-[1,1'-biphenyl]-2-yl)carbamate;

67) 2-(1-methylpyrrolidin-2-yl)ethyl(5-chloro-3'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

68) 2-(1-methylpyrrolidin-2-yl)ethyl(5-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

69) 2-(1-methylpyrrolidin-2-yl)ethyl(5-chloro-3',5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

70) 2-(1-methylpyrrolidin-2-yl)ethyl(3',5-dichloro-[1,1'-biphenyl]-2-yl)carbamate;

71) 2-(1-methylpyrrolidin-2-yl)ethyl(3',5,5'-trichloro-[1,1'-biphenyl]-2-yl)carbamate;

72) 2-(1-methylpyrrolidin-2-yl)ethyl(3',5-dichloro-5'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

73) 2-(1-methylpyrrolidin-2-yl)ethyl(3',5-dichloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

74) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-fluoro-4'-formyl-[1,1'-biphenyl]-2-yl)carbamate;

75) 2-(1-methylpyrrolidin-2-yl)ethyl(3',5'-difluoro-5-hydroxy-[1,1'-biphenyl]-2-yl)carbamate;

76) 2-(1-methylpyrrolidin-2-yl)ethyl(3',5'-dichloro-5-hydroxy-[1,1'-biphenyl]-2-yl)carbamate;

77) 2-(1-methylpyrrolidin-2-yl)ethyl(3'-chloro-4'-fluoro-5-hydroxy-[1,1'-biphenyl]-2-yl)carbamate;

78) (R)-Pyrrolidin-3-ylmethyl[1,1′-biphenyl]-2-ylcarbamate;

79)(S)-Pyrrolidin-3-ylmethyl[1,1′-biphenyl]-2-ylcarbamate;

80)(R)-Pyrrolidin-3-ylmethyl(3',5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

81)(S)-Pyrrolidin-3-ylmethyl(3',5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

82)(S)-Pyrrolidin-3-ylmethyl(5-fluoro-[1,1′-biphenyl]-2-yl)carbamate;

83)(S)-Pyrrolidin-3-ylmethyl(5-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl)carbamate;

84) (R)-Pyrrolidin-3-ylmethyl (3',5,5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamate;

85)(S)-Pyrrolidin-3-ylmethyl(3',5,5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamate;

86) (R)-Pyrrolidin-3-ylmethyl (5-methyl-[1,1′-biphenyl]-2-yl)carbamate;

87) (R)-Pyrrolidin-3-ylmethyl (3'-fluoro-5-methyl-[1,1'-biphenyl]-2-yl)carbamate;

88)(S)-Pyrrolidin-2-ylmethyl(4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

89) (R)-(1-methylpyrrolidin-3-yl)methyl[1,1′-biphenyl]-2-ylcarbamate;

90)(S)-(1-Methylpyrrolidin-3-yl)methyl[1,1′-biphenyl]-2-ylcarbamate;

91)(R)-(1-methylpyrrolidin-3-yl)methyl(3',5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

92)(S)-(1-Methylpyrrolidin-3-yl)methyl(3',5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

93) (S)-(1-methylpyrrolidin-3-yl)methyl(5-fluoro-[1,1′-biphenyl]-2-yl)carbamate;

94) (S)-(1-methylpyrrolidin-3-yl)methyl(5-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl)carbamate;

95) (R)-(1-methylpyrrolidin-3-yl)methyl(3',5,5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamate;

96) (S)-(1-methylpyrrolidin-3-yl)methyl(3',5,5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamate;

97) (R)-(1-methylpyrrolidin-3-yl)methyl(5-methyl-[1,1′-biphenyl]-2-yl)carbamate;

98) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-fluoro-5-methyl-[1,1'-biphenyl]-2-yl)carbamate;

99)(S)-(1-Methylpyrrolidin-2-yl)methyl(4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

100)(R)-(1-methylpyrrolidin-3-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate;

101)(S)-(1-methylpyrrolidin-3-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate;

102) (R)-(1-ethylpyrrolidin-3-yl)methyl[1,1′-biphenyl]-2-ylcarbamate;

103) (S)-(1-ethylpyrrolidin-3-yl)methyl[1,1'-biphenyl]-2-ylcarbamate;

104) (R)-(1-ethylpyrrolidin-3-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate;

105) (S)-(1-ethylpyrrolidin-3-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate;

106) (S)-(1-ethylpyrrolidin-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate;

107)(S)-(1-isobutylpyrrolidin-2-yl)methyl[1,1′-biphenyl]-2-ylcarbamate;

108) (S)-(1-methylpyrrolidin-3-yl)methyl(3',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

109) (R)-(1-methylpyrrolidin-2-yl)methyl[1,1′-biphenyl]-2-ylcarbamate;

110) (R)-(1-methylpyrrolidin-2-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate;

111)(R)-(1-methylpyrrolidin-2-yl)methyl(5-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl)carbamate;

112)(S)-(1-Isopropylpyrrolidin-2-yl)methyl[1,1′-biphenyl]-2-ylcarbamate;

113) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

114) (R)-(1-methylpyrrolidin-3-yl)methyl(4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

115) (R)-(1-methylpyrrolidin-3-yl)methyl(3',4'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

116) (S)-(1-methylpyrrolidin-3-yl)methyl(3'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

117) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-[1,1'-biphenyl]-2-yl)carbamate;

118) (S)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-[1,1'-biphenyl]-2-yl)carbamate;

119) (S)-(1-methylpyrrolidin-3-yl)methyl(3',5'-dichloro-[1,1'-biphenyl]-2-yl)carbamate;

120) (S)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-5'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

121)(S)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

122)(S)-(1-methylpyrrolidin-3-yl)methyl(5-fluoro-3',5'-dimethyl-[1,1'-biphenyl]-2-yl)carbamate;

123) (S)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-5-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)carbamate;

124) (S)-(1-methylpyrrolidin-3-yl)methyl(4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

125)(S)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

126) (S)-(1-methylpyrrolidin-3-yl)methyl(3',5'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

127) (S)-(1-methylpyrrolidin-3-yl)methyl(4'-chloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

128) (S)-(1-methylpyrrolidin-3-yl)methyl(3',4'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

129) (S)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-5,5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

130) (R)-(1-methylpyrrolidin-3-yl)methyl(3',4'-dichloro-[1,1'-biphenyl]-2-yl)carbamate;

131)(R)-(1-methylpyrrolidin-3-yl)methyl(3',5'-dichloro-[1,1'-biphenyl]-2-yl)carbamate;

132) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-5'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

133) (R)-(1-methylpyrrolidin-3-yl)methyl(5-fluoro-3'-amino-[1,1'-biphenyl]-2-yl)carbamate;

134) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-5-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)carbamate;

135) (R)-(1-methylpyrrolidin-3-yl)methyl(3',5'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

136) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

137) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-hydroxy-[1,1'-biphenyl]-2-yl)carbamate;

138) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-5'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate;

139) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-5-fluoro-5'-methoxy-[1,1'-biphenyl]-2-yl)carbamate;

140) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-5-fluoro-5'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate;

141)(R)-(1-methylpyrrolidin-3-yl)methyl(4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

142) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-5,5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

143) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

144) (R)-(1-methylpyrrolidin-3-yl)methyl(2',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

145) (R)-(1-methylpyrrolidin-3-yl)methyl(3',5-dichloro-[1,1'-biphenyl]-2-yl)carbamate;

146) (R)-(1-methylpyrrolidin-3-yl)methyl(3',5-dichloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

147) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-4'-fluoro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate;

148) (S)-(1-methylpyrrolidin-2-yl)methyl(3'-chloro-5'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

149)(S)-(1-Methylpyrrolidin-2-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

150) (R)-(1-ethylpyrrolidin-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

151) (R)-(1-isopropylpyrrolidin-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

152) (R)-(1-methylpyrrolidin-3-yl)methyl (3'-(hydroxymethyl)-[1,1'-biphenyl]-2-yl)carbamate;

153) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-carbamoyl-[1,1'-biphenyl]-2-yl)carbamate;

154) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-amino-[1,1'-biphenyl]-2-yl)carbamate;

155) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-cyano-[1,1'-biphenyl]-2-yl)carbamate;

156) (R)-(1-methylpyrrolidin-3-yl)methyl(2'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

157) (R)-(1-methylpyrrolidin-3-yl)methyl(2',4'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

158) (R)-(1-methylpyrrolidin-3-yl)methyl(2',3'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

159) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-6'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

160) (S)-(1-methylpyrrolidin-2-yl)methyl(3'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

161)(S)-(1-methylpyrrolidin-2-yl)methyl(3',5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

162) (S)-(1-methylpyrrolidin-2-yl)methyl(3',4'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

163) (S)-(1-methylpyrrolidin-2-yl)methyl(2',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamate;

164) (S)-(1-methylpyrrolidin-2-yl)methyl(4'-chloro-[1,1'-biphenyl]-2-yl)carbamate;

165)(S)-(1-methylpyrrolidin-2-yl)methyl(3'-chloro-[1,1'-biphenyl]-2-yl)carbamate;

166) (S)-(1-methylpyrrolidin-2-yl)methyl(3',4'-dichloro-[1,1'-biphenyl]-2-yl)carbamate;

167) (S)-(1-methylpyrrolidin-2-yl)methyl(2',4'-dichloro-[1,1'-biphenyl]-2-yl)carbamate;

168) (S)-(1-methylpyrrolidin-2-yl)methyl(3'-hydroxy-[1,1'-biphenyl]-2-yl)carbamate;

169)(S)-(1-methylpyrrolidin-2-yl)methyl(3'-cyano-[1,1'-biphenyl]-2-yl)carbamate;

170) (S)-(1-methylpyrrolidin-2-yl)methyl(3'-amino-[1,1'-biphenyl]-2-yl)carbamate;

171)(S)-(1-methylpyrrolidin-2-yl)methyl(3',4',5-trifluoro-[1,1'-biphenyl]-2-yl)carbamate;

172) (S)-(1-methylpyrrolidin-2-yl)methyl(3',5,5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamate;

173) (S)-(1-methylpyrrolidin-2-yl)methyl(2',4',5,5'-tetrafluoro-[1,1'-biphenyl]-2-yl)carbamate;

174)(S)-(1-Methylpyrrolidin-2-yl)methyl(3'-chloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

175)(S)-(1-Methylpyrrolidin-2-yl)methyl(4'-chloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

176) (S)-(1-methylpyrrolidin-2-yl)methyl(2',4'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

177)(S)-(1-Methylpyrrolidin-2-yl)methyl(3',4'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

178) (S)-(1-methylpyrrolidin-2-yl)methyl(3'-cyano-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

179)(S)-(1-methylpyrrolidin-2-yl)methyl(3'-hydroxy-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

180) (S)-(1-methylpyrrolidin-2-yl)methyl(5-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate;

181)(S)-(1-methylpyrrolidin-2-yl)methyl(3'-chloro-4,4',5-trifluoro-[1,1'-biphenyl]-2-yl)carbamate;

182) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-4,5-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

183) 2-(1-methylpyrrolidin-2-yl)ethyl(2',4'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

184) 2-(1-methylpyrrolidin-2-yl)ethyl(2',3'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

185) 2-(1-methylpyrrolidin-2-yl)ethyl(2',6'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

186) 2-(1-methylpyrrolidin-2-yl)ethyl(5'-chloro-2'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

187) (S)-(1-methylpyrrolidin-2-yl)methyl(2'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

188) (S)-(1-methylpyrrolidin-2-yl)methyl(2',4'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

189) (S)-(1-methylpyrrolidin-2-yl)methyl(2',3'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

190) (S)-(1-methylpyrrolidin-2-yl)methyl(3'-chloro-6'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

191)(R)-(1-methylpyrrolidin-3-yl)methyl(3',5'-dimethyl-[1,1'-biphenyl]-2-yl)carbamate;

192) (R)-(1-methylpyrrolidin-3-yl)methyl(5-fluoro-3′-methyl-[1,1′-biphenyl]-2-yl)carbamate;

193) (R)-(1-methylpyrrolidin-3-yl)methyl(5-fluoro-3',5'-dimethyl-[1,1'-biphenyl]-2-yl)carbamate;

194) (R)-(1-methylpyrrolidin-3-yl)methyl(3',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

195) (R)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

196) (R)-(1-ethylpyrrolidin-3-yl)methyl(3'-chloro-4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

197)(S)-(1-Methylpyrrolidin-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate;

198) (S)-(1-methylpyrrolidin-2-yl)methyl(4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

199)(S)-(1-methylpyrrolidin-2-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate;

200)(S)-(1-methylpyrrolidin-2-yl)methyl(5-fluoro-[1,1′-biphenyl]-2-yl)carbamate;

201)(S)-(1-methylpyrrolidin-2-yl)methyl(5-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl)carbamate;

202)(S)-(1-methylpyrrolidin-2-yl)methyl(3',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

203) (S)-(1-methylpyrrolidin-2-yl)methyl(4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

204)(S)-(1-methylpyrrolidin-2-yl)methyl(4-fluoro-[1,1′-biphenyl]-2-yl)carbamate;

205)(S)-(1-methylpyrrolidin-2-yl)methyl(3',4-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

206) (S)-(1-methylpyrrolidin-2-yl)methyl(5-methyl-[1,1′-biphenyl]-2-yl)carbamate;

207)(S)-(1-methylpyrrolidin-2-yl)methyl(3'-fluoro-5-methyl-[1,1'-biphenyl]-2-yl)carbamate;

208) (S)-(1-methylpyrrolidin-2-yl)methyl(5-fluoro-3',5'-dimethyl-[1,1'-biphenyl]-2-yl)carbamate;

209) (S)-(1-methylpyrrolidin-2-yl)methyl(4'-(tert-butyl)-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

210) (S)-(1-methylpyrrolidin-2-yl)methyl(3'-chloro-5,5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

211)(S)-(1-methylpyrrolidin-2-yl)methyl(3'-chloro-4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

212) (S)-(1-methylpyrrolidin-2-yl)methyl(4'-chloro-3',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate;

213) (S)-(1-methylpyrrolidin-2-yl)methyl(3'-amino-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

214)(S)-(1-methylpyrrolidin-2-yl)methyl(2',5-difluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate;

215) (S)-(1-methylpyrrolidin-2-yl)methyl(3'-chloro-5-fluoro-5'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate;

216)(S)-(1-methylpyrrolidin-2-yl)methyl(3'-chloro-5-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)carbamate;

217)(S)-(1-methylpyrrolidin-2-yl)methyl(3'-chloro-5-fluoro-5'-methoxy-[1,1'-biphenyl]-2-yl)carbamate;

218) (S)-(1-methylpyrrolidin-2-yl)methyl(5-fluoro-2',4'-bis(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate;

219)(S)-(1-methylpyrrolidin-2-yl)methyl(3'-ethoxy-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate;

220) (S)-(1-methylpyrrolidin-2-yl)methyl(5-fluoro-3',4'-dimethoxy-[1,1'-biphenyl]-2-yl)carbamate;

221)(S)-(1-methylpyrrolidin-2-yl)methyl(5-fluoro-3',5'-dimethoxy-[1,1'-biphenyl]-2-yl)carbamate;

222)(S)-(1-methylpyrrolidin-2-yl)methyl(5-methoxy-[1,1′-biphenyl]-2-yl)carbamate;

223)(S)-(1-methylpyrrolidin-2-yl)methyl(3'-fluoro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate;

224)(S)-(1-methylpyrrolidin-2-yl)methyl(3'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate;

225)(S)-(1-methylpyrrolidin-2-yl)methyl(3',4'-dichloro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate; and

226) (S)-(1-Methylpyrrolidin-2-yl)methyl(3',5'-dichloro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate.

Method for preparing new biphenyl derivatives

The present invention provides methods for preparing the compound of Formula 1 or a pharmaceutically acceptable salt thereof (Preparation Methods 1 to 4).

Preparation method 1

The method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof of the present invention may include reacting a compound of Formula 2 below with a compound of Formula 3 below in the presence of a carbamate synthesis reagent:

[Formula 2]

[Formula 3]

wherein _R1 to _R5 and n are the same as defined in Formula 1.

The carbamate synthesis reagent preferably includes an azide compound. In particular, the carbamate synthesis reagent used in the present invention can be a mixture of diphenylphosphoryl azide (DPPA) and triethylamine, a mixture of propylphosphonic anhydride (T3P), trimethylsilyl azide (TMSN ₃ ) and triethylamine, a mixture of sodium azide (NaN ₃ ), tetrabutylammonium bromide and zinc (II) trifluoromethanesulfonate, etc.

In addition, the carbamate synthesis reaction may be performed at a temperature of 100° C. to 120° C. for 4 to 12 hours.

Preparation method 2

In addition, the method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof of the present invention may include the following steps: reacting a compound of Formula 2 below with a compound of Formula 3a below in the presence of a carbamate synthesis reagent to prepare a compound of Formula 4 below; removing an amine protecting group from the compound of Formula 4 to prepare a compound of Formula 1a below; and introducing an _R5 substituent into the compound of Formula 1a:

[Formula 2]

[Formula 3a]

[Formula 4]

[Formula 1a]

wherein R ₁ to R ₄ and n are the same as defined in Formula 1; and PG ₁ is an amine protecting group, which can be selected from Boc (tert-butyloxycarbonyl), benzyl, tert-butyl, PMB (4-methoxybenzyl), Fmoc (fluorenylmethoxycarbonyl), Ts (toluenesulfonyl), MOM (methoxymethyl), THP (tetrahydropyranyl), TBDMS (tert-butyldimethylsilyl) and TBDPS (tert-butyldiphenylsilyl).

The carbamate synthesis reagents and reaction conditions are the same as described above for Preparation Method 1.

In addition, palladium-carbon (Pd-C); strong acids such as trifluoroacetic acid, sulfuric acid, hydrobromic acid, etc.; or bases such as piperidine; cerium (IV) ammonium nitrate; tetra-n-butylammonium fluoride, etc. can be used in the reaction of removing the amine protecting group. The reaction can be carried out at room temperature for 3 to 12 hours.

In addition, the reaction of introducing the _R5 substituent can be carried out using formaldehyde solution, acetic acid and zinc, or can be carried out using an alkyl halide, potassium carbonate, potassium iodide or triethylamine. Water or dimethylformamide can be used as a solvent. The reaction can be carried out at room temperature to 120°C for 5 to 12 hours.

Meanwhile, the compound of Formula 2 can be prepared by a method comprising the following steps: reacting a compound of the following Formula 5 in the presence of an acid to prepare a compound of the following Formula 6, the compound of Formula 6 having a carboxylic acid protecting group introduced therein; coupling the compound of Formula 6 with a compound of the following Formula 7 to prepare a compound of the following Formula 8; and deesterifying the compound of Formula 8 in the presence of a base:

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

wherein R ₁ to R ₅ and n are the same as defined in Formula 1; X is a halogen; and PG ₂ is a protecting group which may be selected from C ₁ -C ₄ alkyl, benzyl, PMB (4-methoxybenzyl), THP (tetrahydropyranyl), TBDMS (tert-butyldimethylsilyl) and TBDPS (tert-butyldiphenylsilyl).

In the reaction of introducing the carboxylic acid protecting group, thionyl chloride or sulfuric acid is preferably used as the acid, and ethanol or methanol can be used as the solvent. The reaction can be carried out at a temperature of 80°C to 100°C for 4 to 24 hours.

In addition, the base for the coupling reaction is preferably selected from potassium carbonate and sodium carbonate. The catalyst for the coupling reaction can be tetrakis(triphenylphosphine)palladium or dichlorobis(triphenylphosphine)palladium, and the solvent for the coupling reaction can be toluene, a mixture of toluene and ethanol, a mixture of ethanol and water, a mixture of acetonitrile and water, etc. In addition, the coupling reaction can be carried out at a temperature of 100°C to 120°C for 10 minutes to 12 hours.

In addition, the base used in the deesterification reaction is preferably selected from sodium hydroxide and potassium hydroxide, and the solvent used in the deesterification reaction can be ethanol or a mixture of ethanol and water. The deesterification reaction can be carried out at a temperature of 100° C. to 120° C. for 2 to 12 hours.

Preparation method 3

In addition, the method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof of the present invention may include the following steps: reacting a compound of Formula 5 below with a compound of Formula 3 below in the presence of a carbamate synthesis reagent to prepare a compound of Formula 9 below; and coupling a compound of Formula 7 below with a compound of Formula 9:

[Formula 5]

[Formula 3]

[Formula 9]

[Formula 7]

wherein R ₁ to R ₅ and n are the same as defined in Formula 1; and X is a halogen.

The carbamate synthesis reagents and reaction conditions are the same as described above for Preparation Method 1.

Otherwise, the coupling reaction reagents and reaction conditions are the same as those described above for Preparation Method 2.

Preparation method 4

In addition, the method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof of the present invention may include the following steps: reacting a compound of Formula 5 below with a compound of Formula 3a below in the presence of a carbamate synthesis agent to prepare a compound of Formula 9a below; deprotecting the compound of Formula 9a to obtain a compound of Formula 9b below; introducing an _R5 substituent into the compound of Formula 9b to prepare a compound of Formula 9 below; and coupling a compound of Formula 7 below with a compound of Formula 9:

[Formula 5]

[Formula 3a]

[Formula 9a]

[Formula 9b]

[Formula 9]

[Formula 7]

wherein R ₁ to R ₅ and n are the same as defined in Formula 1; X is a halogen; and PG ₁ is the same as defined in Preparation Method 2.

The carbamate synthesis reagents and reaction conditions are the same as described above for Preparation Method 1.

In addition, the deprotection reaction, the reaction for introducing the R ₅ substituent and the coupling reaction are as described above for Preparation Method 2.

Pharmaceutical compositions containing novel biphenyl derivatives

The present invention provides a muscarinic M3 receptor antagonist comprising a compound of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.

In the present invention, the muscarinic M3 receptor antagonist can be a composition for preventing or treating a disease selected from chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spastic colitis, chronic cystitis, Alzheimer's disease, senile dementia, glaucoma, schizophrenia, gastroesophageal reflux disease, arrhythmia and hypersalivation syndrome.

In the present invention, in addition to the compound of Formula 1 or a pharmaceutically acceptable salt thereof, the muscarinic M3 receptor antagonist may further comprise one or more active ingredients that exhibit the same or similar functions as the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

For administration, the composition of the present invention can also include at least one pharmaceutically acceptable carrier.The pharmaceutically acceptable carrier for the composition of the present invention can be physiological saline, sterile water, Ringer's solution, buffered saline, glucose solution, maltodextrin solution, glycerol, ethanol, or one or more mixtures thereof. If necessary, other conventional additives, such as antioxidants, buffers or antibacterial agents, can be added to the composition of the present invention. In addition, diluents, dispersants, surfactants, adhesives and lubricants can be further added to the composition to prepare injectable formulations (such as aqueous solutions, suspensions or emulsions), pills, capsules, granules or tablets. In addition, the composition of the present invention can be preferably prepared according to the component of specific disease or composition using appropriate methods known in the art or Remington ' s Pharmaceutical Science, Merck Publishing Company, the method described in Easton PA.

Furthermore, when the muscarinic M3 receptor antagonist of the present invention is used for oral administration, the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be contained in an amount of 1 to 95 wt %, preferably 1 to 70 wt %, based on the total weight of the M3 receptor antagonist.

The pharmaceutical composition of the present invention may be administered orally, or may be administered parenterally in the form of an injectable solution, a suppository, a transdermal preparation, an inhalation preparation, or an intravesical preparation.

The present invention also provides a method for treating or alleviating diseases associated with activity on muscarinic M3 receptors, comprising administering a muscarinic M3 receptor antagonist comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient to animals including humans in need of muscarinic M3 receptor antagonism.

The muscarinic M3 receptor antagonists of the present invention can be used alone or in combination with surgery, hormone therapy, drug therapy and biological response modifiers to prevent or treat diseases associated with activity at the muscarinic M3 receptor.

Methods for preventing or treating muscarinic M3 receptor-related diseases

The present invention also provides a method for preventing or treating muscarinic M3 receptor-related diseases, such as diseases selected from chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spastic colitis, chronic cystitis, Alzheimer's disease, senile dementia, glaucoma, schizophrenia, gastroesophageal reflux disease, arrhythmia and hypersalivation syndrome, comprising administering to a subject in need thereof a composition comprising as an active ingredient a compound of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

Compositions used in the prophylactic or therapeutic methods of the present invention include the pharmaceutical compositions described herein.

Furthermore, individuals in need of the preventive or therapeutic methods of the present invention include mammals, particularly humans.

Beneficial effects

The biphenyl derivatives of the present invention have affinity and selectivity for muscarinic M3 receptors, as well as low toxicity. Therefore, these biphenyl derivatives can be used as agents for preventing or treating various diseases involving muscarinic M3 receptors, particularly urinary system diseases such as enuresis, neurogenic urinary frequency, neurogenic bladder, unstable bladder, chronic cystitis, bladder spasm, urinary incontinence or urinary frequency; respiratory system diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma or rhinitis; and digestive tract diseases such as irritable bowel syndrome, spastic colitis or diverticulitis.

In particular, because the biphenyl derivatives of the present invention have high selectivity for muscarinic M2 receptors and muscarinic M3 receptors present in smooth muscle, glandular tissue, etc., these biphenyl derivatives are M3 receptor antagonists with fewer side effects and are therefore very useful as agents for preventing or treating urinary incontinence, frequent urination, chronic bronchitis, chronic obstructive pulmonary disease, asthma, rhinitis, etc.

Example

With reference to the accompanying synthesis example, embodiment and experimental example, the present invention will be described more completely below. However, embodiments of the present invention can be changed in various forms, and the scope of the present invention should not be construed as being limited to the following examples. Embodiments of the present invention are provided so that those skilled in the art can fully understand the present invention.

In addition, unless otherwise specified, the reagents specified below were purchased from Aldrich Korea, Acros, Lancaster, and TCI. ^{The 1} H NMR used herein was a Varian 400 MHz, and the microwave oven used herein was a Monowave 300 from Anton Paar.

[Synthesis Example 1] Synthesis of 4'-fluoro-[1,1'-biphenyl]-2-carboxylic acid

[Step 1] Synthesis of ethyl 2-bromobenzoate

2-Bromobenzoic acid (5 g, 24.87 mmol) was dissolved in ethanol (100 mL). Sulfuric acid (5 mL) was added and stirred at reflux for 24 hours. After terminating the reaction, the reactant was cooled to room temperature. The solvent was removed by concentrating the reactant under reduced pressure and extracted with water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (4.9 g, 86%).

[Step 2] Synthesis of ethyl 4'-fluoro-[1,1'-biphenyl]-2-carboxylate

Ethyl 2-bromobenzoate (1 g, 4.37 mmol) prepared in step 1 was dissolved in a mixed solution of toluene (20 mL) and ethanol (4 mL), and then 4-fluorophenylboric acid (672 mg, 4.80 mmol), potassium carbonate (1.21 g, 8.73 mmol), and tetrakis(triphenylphosphine)palladium (504 mg, 0.44 mmol) were added. The reaction was stirred at 100°C for 6 hours, cooled to room temperature, and filtered through celite. The solvent was removed by concentrating the reaction under reduced pressure. It was extracted with water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (948 mg, 89%).

[Step 3] Synthesis of 4'-fluoro-[1,1'-biphenyl]-2-carboxylic acid

The 4'-fluoro-[1,1'-biphenyl]-2-carboxylic acid ethyl ester (948 mg, 3.33 mmol) prepared in step 2 was dissolved in ethanol (20 mL). 2N-sodium hydroxide solution (5.82 mL, 11.64 mmol) was added thereto and stirred at reflux for 12 hours. The reactant was cooled to room temperature. The solvent was removed by concentrating the reactant under reduced pressure. It was extracted with 1N-hydrochloric acid and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to prepare the title compound (747 mg, 89%).

[Synthesis Examples 2 to 15]

Using 2-bromobenzoic acid as a raw material and the reaction materials in Table 1, the compounds of Synthesis Examples 2 to 15 were prepared in the same manner as in Synthesis Example 1.

[Table 1] Synthesis Examples 1 to 15

Synthesis example Chemical name Reaction substances 1 4'-Fluoro-[1,1'-biphenyl]-2-carboxylic acid 4-Fluorophenylboronic acid 2 3',5'-Difluoro-[1,1'-biphenyl]-2-carboxylic acid 3,5-Difluorophenylboronic acid 3 3',4',5'-Trifluoro-[1,1'-biphenyl]-2-carboxylic acid 3,4,5-Trifluorophenylboronic acid 4 3'-Fluoro-[1,1'-biphenyl]-2-carboxylic acid 3-Fluorophenylboronic acid 5 4'-Methoxy-[1,1'-biphenyl]-2-carboxylic acid 4-Methoxyphenylboronic acid 6 4'-Chloro-[1,1'-biphenyl]-2-carboxylic acid 4-Chlorophenylboronic acid 7 3'-Chloro-[1,1'-biphenyl]-2-carboxylic acid 3-Chlorophenylboronic acid 8 3',5'-Dichloro-[1,1'-biphenyl]-2-carboxylic acid 3,5-Dichlorophenylboronic acid 9 4'-Trifluoromethoxy-[1,1'-biphenyl]-2-carboxylic acid 4-Trifluoromethoxyphenylboronic acid 10 4'-Nitro-[1,1'-biphenyl]-2-carboxylic acid 4-Nitrophenylboronic acid 11 3'-Trifluoromethyl-[1,1'-biphenyl]-2-carboxylic acid 3-Trifluoromethylphenylboronic acid 12 4'-Trifluoromethyl-[1,1'-biphenyl]-2-carboxylic acid 4-Trifluoromethylphenylboronic acid 13 3'-Fluoro-4'-methyl-[1,1'-biphenyl]-2-carboxylic acid 3-Fluoro-4-methylphenylboronic acid 14 3'-Methyl-[1,1'-biphenyl]-2-carboxylic acid 3-Methylphenylboronic acid 15 3'-Ethoxy-[1,1'-biphenyl]-2-carboxylic acid 3-Ethoxyphenylboronic acid

[Synthesis Example 16] Synthesis of 3'-chloro-5-fluoro-[1,1'-biphenyl]-2-carboxylic acid

[Step 1] Ethyl 2-bromo-4-fluorobenzoate

2-Bromo-4-fluorobenzoic acid (2.37 g, 10.82 mmol) was dissolved in ethanol (100 mL). Thionyl chloride (1.57 mL, 21.64 mmol) was added and stirred at reflux for 24 hours. After terminating the reaction, the reactant was cooled to room temperature. The solvent was removed by concentrating the reactant under reduced pressure. It was extracted with water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (2.29 g, 87%).

[Step 2] Synthesis of ethyl 3'-chloro-5-fluoro-[1,1'-biphenyl]-2-carboxylate

Ethyl 2-bromo-4-fluorobenzoate (1.1 g, 4.47 mmol) prepared in Step 1 was dissolved in toluene (20 mL). 3-Chlorophenylboronic acid (766 mg, 4.90 mmol), potassium carbonate (1.23 g, 8.90 mmol), and tetrakis(triphenylphosphine)palladium (520 mg, 0.44 mmol) were added. The reaction was stirred at 100°C for 6 hours and cooled to room temperature. It was filtered through celite and the solvent was removed by concentrating the reaction under reduced pressure. It was extracted with water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (850 mg, 69%).

[Step 3] 3'-Chloro-5-fluoro-[1,1'-biphenyl]-2-carboxylic acid

The 3'-chloro-5-fluoro-[1,1'-biphenyl]-2-carboxylic acid ethyl ester (850mg, 3.05mmol) prepared in step 2 was dissolved in ethanol (20mL). 2N-sodium hydroxide solution (4.57mL, 9.15mmol) was added thereto and stirred at reflux for 12 hours. The reactant was cooled to room temperature. The solvent was removed by concentrating the reactant under reduced pressure and extracted with 1N-hydrochloric acid and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to prepare the title compound (650mg, 85%).

[Synthesis Examples 17 to 26]

The compounds of Synthesis Examples 17 to 26 were prepared in the same manner as in Synthesis Example 16 using the starting materials and reaction materials in Table 2.

[Table 2] Synthesis Examples 16 to 26

[Synthesis Example A] Synthesis of 2-(1-methylpyrrolidin-2-yl)ethyl(2-iodophenyl)carbamate

2-Iodobenzoic acid (1 g, 4.03 mmol) was dissolved in toluene (50 mL). Biphenylphosphoryl azide (1.04 mL, 4.84 mmol) and triethylamine (566 uL, 4.03 mmol) were added thereto. It was stirred at room temperature for 30 minutes and then stirred at reflux for 1 hour. The reactant was cooled to room temperature. 2-(2-hydroxyethyl)-1-methylpyrrolidine (651 uL, 4.84 mmol) was added thereto and stirred at reflux for 12 hours. The reactant was cooled to room temperature. The solvent was removed by concentrating the reactant under reduced pressure and extracted with water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (1.16 g, 77%).

[Synthesis Examples B to E]

The compounds of Synthesis Examples B to E were prepared in the same manner as Synthesis Example A using the starting materials in Table 3 instead of 2-iodobenzoic acid.

[Table 3] Synthesis Examples A to E

[Synthesis Example F] Synthesis of (R)-(1-methylpyrrolidin-3-yl)methyl(2-bromophenyl)carbamate

[Step 1] Preparation of tert-butyl (R)-3-((((2-bromophenyl)carbamoyl)oxy)methyl)pyrrolidine-1-carboxylate synthesis

2-Bromobenzoic acid (4.5 g, 22.4 mmol) was dissolved in toluene (100 mL), and diphenylphosphoryl azide (5.8 mL, 26.9 mmol) and triethylamine (3.15 mL, 22.4 mmol) were added thereto. It was stirred at room temperature for 30 minutes and then stirred at reflux for 1 hour. The reactant was cooled to room temperature, (R)-3-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (5.41 g, 26.9 mmol) was added thereto, and stirred at reflux for 12 hours. The reactant was cooled to room temperature. The solvent was removed by concentrating the reactant under reduced pressure. It was extracted with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (8.1 g, 91%).

[Step 2] Synthesis of ((R)-pyrrolidin-3-ylmethyl (2-bromophenyl)carbamate

(R)-tert-Butyl 3-((((2-bromophenyl)carbamoyl)oxy)methyl)pyrrolidine-1-carboxylate (8.1 g, 20.29 mmol) prepared in Step 1 was dissolved in dichloromethane (100 mL). Trifluoroacetic acid (50 mL) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was removed by concentrating the reactant under reduced pressure, and the mixture was extracted with 2N sodium hydroxide solution and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (3.94 g, 65%).

[Step 3] Synthesis of (R)-(1-methylpyrrolidin-3-yl)methyl(2-bromophenyl)carbamate

(R)-pyrrolidin-3-ylmethyl(2-bromophenyl)carbamate (3.94 g, 13.13 mmol) prepared in Step 2 was dissolved in water (100 mL). Acetic acid (5 mL), formaldehyde solution (15 mL), and zinc powder (1.5 g) were added sequentially and stirred at room temperature for 12 hours. The reaction mixture was filtered, neutralized with 2N sodium hydroxide solution, and extracted with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography to produce the title compound (3.06 g, 75%).

[Synthesis Examples G to L]

The compounds of Synthesis Examples G to L were prepared in the same manner as Synthesis Example F using the starting materials and reaction materials in Table 4.

[Table 4] Synthesis Examples F to L

[Synthesis Example M] Synthesis of (S)-(1-methylpyrrolidin-2-yl)methyl(2-bromophenyl)carbamate

2-Bromobenzoic acid (2 g, 9.95 mmol) was dissolved in toluene (75 mL), and then biphenylphosphoryl azide (2.57 mL, 11.94 mmol) and triethylamine (1.4 mL, 9.95 mmol) were added. The mixture was stirred at room temperature for 30 minutes and then stirred at reflux for 1 hour. The reaction was cooled to room temperature. (S)-(1-methylpyrrolidin-2-yl)methanol (1.42 mL, 11.94 mmol) was added and stirred at reflux for 4 hours. The reaction was cooled to room temperature. The solvent was removed by concentrating the reaction under reduced pressure. The mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (1.4 g, 45%).

[Synthesis Examples N to P]

The compounds of Synthesis Examples N to P were prepared in the same manner as Synthesis Example M using the starting materials and reaction materials in Table 5.

[Table 5] Synthesis Examples M to P

Example

[Table 6] Example compounds

[Example 1] 2-(1-methylpyrrolidin-2-yl)ethyl(4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate Synthesis

4'-Fluoro-[1,1'-biphenyl]-2-carboxylic acid (747 mg, 3.46 mmol) (Synthesis Example 1) was dissolved in toluene (20 mL), and then biphenylphosphoryl azide (958 uL, 4.15 mmol) and triethylamine (486 uL, 3.46 mmol) were added thereto. It was stirred at room temperature for 30 minutes and then stirred under reflux for another hour. The reactant was cooled to room temperature. 2-(2-hydroxyethyl)-1-methylpyrrolidine (558 uL, 4.15 mmol) was added thereto and stirred under reflux for 12 hours. The reactant was cooled to room temperature. The solvent was removed by concentration under reduced pressure, and then it was extracted with water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (280 mg, 24%).

[Examples 2 to 16]

The compounds of Examples 2 to 16 were prepared in the same manner as in Example 1 using the starting materials in Table 7 instead of 4'-fluoro-[1,1'-biphenyl]-2-carboxylic acid (747 mg, 3.46 mmol) (Synthesis Example 1).

[Table 7] Examples 2 to 16

[Example 17] 2-(1-methylpyrrolidin-2-yl)ethyl(3'-chloro-5-fluoro-[1,1'-biphenyl]-2-yl)amino Synthesis of formate

3'-Chloro-5-fluoro-[1,1'-biphenyl]-2-carboxylic acid (300 mg, 1.20 mmol) (Synthesis Example 16) was dissolved in toluene (20 mL), and then biphenylphosphoryl azide (310 uL, 1.44 mmol) and triethylamine (202 uL, 1.44 mmol) were added thereto. It was stirred at room temperature for 30 minutes, and then stirred under reflux for another hour. The reactant was cooled to room temperature. 2-(2-hydroxyethyl)-1-methylpyrrolidine (194 uL, 1.44 mmol) was added thereto, and then stirred under reflux for 12 hours. The reactant was cooled to room temperature. The solvent was removed by concentration under reduced pressure, and then it was extracted with water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (93 mg, 21%).

[Examples 18 to 27]

The compounds of Examples 18 to 27 were prepared in the same manner as in Example 17 using the starting materials in Table 8 instead of 3'-chloro-5-fluoro-[1,1'-biphenyl]-2-carboxylic acid (300 mg, 1.20 mmol) (Synthesis Example 16).

[Table 8] Examples 18 to 27

[Example 28] 2-(1-methylpyrrolidin-2-yl)ethyl(4'-cyano-[1,1'-biphenyl]-2-yl)carbamic acid Synthesis of esters

2-(1-methylpyrrolidin-2-yl)ethyl(2-iodophenyl)carbamate (600mg, 1.6mmol) (Synthesis Example A) was dissolved in a mixed solution of toluene (20mL) and ethanol (4mL). 4-Cyanophenylboronic acid (259mg, 1.76mmol), potassium carbonate (442mg, 3.2mmol) and tetrakis(triphenylphosphine)palladium (370mg, 0.32mmol) were added thereto. The reactants were stirred at 110°C for 12 hours and cooled to room temperature. They were filtered through celite and the solvent was removed by concentrating under reduced pressure. They were extracted with water and ethyl acetate, and the organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (193mg, 35%).

[Examples 29 to 32]

The compounds of Examples 29 to 32 were prepared in the same manner as in Example 28 using 2-(1-methylpyrrolidin-2-yl)ethyl(2-iodophenyl)carbamate of Synthesis Example A and the reactants in Table 9 as a starting material.

[Table 9] Examples 29 to 32

[Example 33] 2-(1-methylpyrrolidin-2-yl)ethyl(3'-amino-[1,1'-biphenyl]-2-yl)carbamic acid Synthesis of esters

2-(1-Methylpyrrolidin-2-yl)ethyl(2-iodophenyl)carbamate (1.36 g, 3.63 mmol) (Synthesis Example A) was dissolved in a mixed solution of acetonitrile (15 mL) and water (15 mL). 3-Aminophenylboronic acid (995 mg, 7.26 mmol), sodium carbonate (772 mg, 7.26 mmol) and dichlorobis(triphenylphosphine)palladium (127 mg, 0.18 mmol) were added thereto. The reactants were stirred at 110°C in a microwave oven for 10 minutes and cooled to room temperature. They were filtered through celite and the solvent was removed by concentration under reduced pressure. They were extracted with water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (192 mg, 16%).

[Examples 34 to 41]

The compounds of Examples 34 to 41 were prepared in the same manner as in Example 33 using 2-(1-methylpyrrolidin-2-yl)ethyl(2-iodophenyl)carbamate of Synthesis Example A as a raw material and the reaction materials in Table 10.

[Table 10] Examples 34 to 41

[Example 42] 2-(1-methylpyrrolidin-2-yl)ethyl(3',4',5-trifluoro-[1,1'-biphenyl]-2-yl)amino Synthesis of methyl formate

2-(1-Methylpyrrolidin-2-yl)ethyl(2-bromo-4-fluorophenyl)carbamate (400mg, 1.16mmol) (Synthesis Example B) was dissolved in toluene (20mL). 3,4-Fluorophenyldiboronic acid (280mg, 1.74mmol), potassium carbonate (321mg, 2.32mmol) and tetrakis(triphenylphosphine)palladium (140mg, 0.12mmol) were added thereto. The reactants were stirred at 120°C for 12 hours and cooled to room temperature. They were filtered through celite and the solvent was removed by concentrating under reduced pressure. They were extracted with water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (15mg, 3%).

[Examples 43 to 46]

The compounds of Examples 43 to 46 were prepared in the same manner as in Example 42 using 2-(1-methylpyrrolidin-2-yl)ethyl(2-bromo-4-fluorophenyl)carbamate of Synthesis Example B as a starting material and the reactants in Table 11.

[Table 11] Examples 43 to 46

[Examples 47 to 51]

Using 2-(1-methylpyrrolidin-2-yl)ethyl(2-bromo-4-(trifluoromethyl)phenyl)carbamate of Synthesis Example C as a raw material instead of 2-(1-methylpyrrolidin-2-yl)ethyl(2-bromo-4-fluorophenyl)carbamate of Synthesis Example B and using the reaction materials in Table 12, the compounds of Examples 47 to 51 were prepared in the same manner as in Example 42.

[Table 12] Examples 47 to 51

[Example 52] 2-(1-methylpyrrolidin-2-yl)ethyl(3'-chloro-5,5'-difluoro-[1,1'-biphenyl]-2-yl) Synthesis of carbamates

2-(1-Methylpyrrolidin-2-yl)ethyl(2-bromo-4-fluorophenyl)carbamate (300 mg, 0.87 mmol) (Synthesis Example B) was dissolved in a mixed solution of acetonitrile (10 mL) and water (10 mL). To this was added (3-chloro-5-fluorophenyl)boric acid (303 mg, 1.74 mmol), sodium carbonate (184 mg, 1.74 mmol) and dichlorobis(triphenylphosphine)palladium (31 mg, 0.04 mmol). The reactants were stirred in a microwave oven at 110°C for 10 minutes and cooled to room temperature. They were filtered through celite and the solvent was removed by concentration under reduced pressure. They were extracted with water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (51 mg, 15%).

[Examples 53 to 59]

The compounds of Examples 53 to 59 were prepared in the same manner as in Example 52 using 2-(1-methylpyrrolidin-2-yl)ethyl(2-bromo-4-fluorophenyl)carbamate of Synthesis Example B as a starting material and the reactants in Table 13.

[Table 13] Examples 53 to 59

[Examples 60 to 65]

Using 2-(1-methylpyrrolidin-2-yl)ethyl(2-bromo-4-methoxyphenyl)carbamate of Synthesis Example D instead of 2-(1-methylpyrrolidin-2-yl)ethyl(2-bromo-4-fluorophenyl)carbamate of Synthesis Example B and using the reaction materials in Table 14, the compounds of Examples 60 to 65 were prepared in the same manner as in Example 52.

[Table 14] Examples 60 to 65

[Examples 66 to 73]

Using 2-(1-methylpyrrolidin-2-yl)ethyl(2-bromo-4-chlorophenyl)carbamate of Synthesis Example E as a raw material instead of 2-(1-methylpyrrolidin-2-yl)ethyl(2-bromo-4-fluorophenyl)carbamate of Synthesis Example B and using the reaction materials in Table 15, the compounds of Examples 66 to 73 were prepared in the same manner as in Example 52.

[Table 15] Examples 66 to 73

[Example 74] (R)-(1-methylpyrrolidin-3-yl)methyl(3'-fluoro-4'-formyl)-[1,1'-biphenyl]-2- Synthesis of 2-amino-3-aminocarbamate

The title compound (124 mg, 50%) was prepared in the same manner as in Example 52 using (R)-(1-methylpyrrolidin-3-yl)methyl(2-bromophenyl)carbamate (220 mg, 0.70 mmol) (Synthesis Example F) and 3-fluoro-4-formylphenylboronic acid (237 mg, 1.41 mmol) as starting materials.

[Example 75] 2-(1-methylpyrrolidin-2-yl)ethyl (3',5'-difluoro-5-hydroxy-[1,1'-biphenyl]-2- Synthesis of 2-amino-3-aminocarbamate

2-(1-Methylpyrrolidin-2-yl)ethyl(3',5'-difluoro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate (130 mg, 0.33 mmol) (Example 62) was dissolved in dichloromethane (10 mL). Boron trichloride solution (1.0 M dichloromethane, 0.99 ml, 0.99 mmol) was added thereto and stirred at room temperature for 2 hours. After terminating the reaction, the reactant was extracted with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (68 mg, 55%).

[Example 76] 2-(1-methylpyrrolidin-2-yl)ethyl (3',5'-dichloro-5-hydroxy-[1,1'-biphenyl]-2- Synthesis of 2-amino-3-aminocarbamate

The title compound (10 mg, 12%) was prepared in the same manner as in Example 75 using 2-(1-methylpyrrolidin-2-yl)ethyl(3′,5′-dichloro-5-methoxy-[1,1′-biphenyl]-2-yl)carbamate (90 mg, 0.21 mmol) (Example 64) instead of Example 62.

[Example 77] 2-(1-methylpyrrolidin-2-yl)ethyl (3'-chloro-4'-fluoro-5-hydroxy-[1,1'-biphenyl]-2- Synthesis of 2-amino-3-aminocarbamate

The title compound (130 mg, 96%) was prepared in the same manner as in Example 75 using 2-(1-methylpyrrolidin-2-yl)ethyl(3'-chloro-4'-fluoro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate (140 mg, 0.34 mmol) (Example 65) instead of Example 62.

[Example 78] Synthesis of (R)-pyrrolidin-3-ylmethyl[1,1'-biphenyl]-2-ylcarbamate

[Step 1] (R)-3-((([1,1'-biphenyl]-2-ylcarbamoyl)oxy)methyl)pyrrolidine-1-carboxylic acid tert- Butyl ester

[1,1'-Biphenyl]-2-carboxylic acid (2 g, 10.09 mmol) was dissolved in toluene (50 mL), and then biphenylphosphoryl azide (2.61 mL, 12.11 mmol) and triethylamine (1.42 mL, 10.09 mmol) were added thereto. It was stirred at room temperature for 30 minutes and then stirred at reflux for another hour. The reactant was cooled to room temperature. (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (2.44 g, 12.11 mmol) was added thereto and stirred at reflux for 12 hours. The reactant was cooled to room temperature. The solvent was removed by concentration under reduced pressure, and then it was extracted with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (3 g, 75%).

¹ H NMR (CDCl ₃ ): δ8.15-7.97(bs,1H),7.55-7.26(m,6H),7.26-7.05(m,2H), 6.67-6.52(bs,1H),4.19-3.90(m,2H),3.57-3.18(m,2H),3.13-2.73(bs,1H), 2.57-2.38(m,1H),2.00-1.83(m,1H),1.70-1.53(m,2H)1.43(s,9H)

[Step 2] Synthesis of (R)-pyrrolidin-3-ylmethyl[1,1'-biphenyl]-2-ylcarbamate

Tert-butyl (R)-3-((([1,1'-biphenyl]-2-ylcarbamoyl)oxy)methyl)pyrrolidine-1-carboxylate (3 g, 7.57 mmol) was dissolved in dichloromethane (80 mL). Trifluoroacetic acid (40 mL) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was removed by concentrating the reaction under reduced pressure, and the mixture was extracted with 2N sodium hydroxide solution and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (1.73 g, 77%).

[Examples 79 to 88]

The compounds of Examples 79 to 88 were prepared in the same manner as in Example 78 using the starting materials and reaction materials in Table 16.

[Table 16] Examples 79 to 88

[Example 89] Synthesis of (R)-(1-methylpyrrolidin-3-yl)methyl[1,1'-biphenyl]-2-ylcarbamate

(R)-pyrrolidin-3-ylmethyl[1,1'-biphenyl]-2-ylcarbamate (727 mg, 2.45 mmol) (Example 78) was dissolved in water (50 mL). Acetic acid (1 mL), formaldehyde solution (3 mL) and zinc powder (300 mg) were added sequentially and stirred at room temperature for 12 hours. The reactant was filtered, neutralized with 2N-sodium hydroxide, and extracted with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (209 mg, 28%).

[Examples 90 to 99]

The compounds of Examples 90 to 99 were prepared in the same manner as in Example 89 using the starting materials in Table 17 instead of (R)-pyrrolidin-3-ylmethyl[1,1′-biphenyl]-2-ylcarbamate.

[Table 17] Examples 90 to 99

[Example 100] (R)-(1-methylpyrrolidin-3-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)amino Synthesis of formate

[Step 1] Synthesis of (R)-pyrrolidin-3-ylmethyl (3'-methyl-[1,1'-biphenyl]-2-yl)carbamate

The title compound was prepared in the same manner as in Example 78 using 3'-methyl-[1,1'-biphenyl]-2-carboxylic acid (Synthesis Example 14) and (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate as starting materials.

¹ H NMR (CDCl ₃ ): δ8.13-7.97(bs,1H),7.41-7.28(m,2H),7.26-7.02(m,5H), 6.77-6.62(bs,1H),4.13-3.92(m,2H),3.09-2.82(m,3H),2.72-2.49(m,2H), 2.47-2.30(m,4H),1.97-1.81(m,1H),1.50-1.36(m,1H)

[Step 2] (R)-(1-methylpyrrolidin-3-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamic acid Synthesis of esters

The title compound (30 mg, 5%) was prepared in the same manner as in Example 89 using (R)-pyrrolidin-3-ylmethyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate (600 mg, 1.93 mmol) prepared in Step 1.

[Example 101] (S)-(1-methylpyrrolidin-3-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)amino Synthesis of formate

[Step 1] Synthesis of (S)-pyrrolidin-3-ylmethyl (3'-methyl-[1,1'-biphenyl]-2-yl)carbamate

The title compound was prepared in the same manner as in Example 78 using 3'-methyl-[1,1'-biphenyl]-2-carboxylic acid (Synthesis Example 14) and (S)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate as starting materials.

¹ H NMR (CDCl ₃ ): δ8.15-7.99(bs,1H),7.45-7.29(m,2H),7,27-7.06(m,5H), 6.74-6.59(bs,1H),4.15-3.92(m,2H),3.07-2.79(m,4H),2.69-2.57(m,1H), 2.39(s,3H),2.07-1.92(bs,1H)1.92-1.79(m,1H),1.48-1.33(m,1H)

[Step 2] (S)-(1-methylpyrrolidin-3-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamic acid Synthesis of esters

The title compound (208 mg, 22%) was prepared in the same manner as in Example 89 using (S)-pyrrolidin-3-ylmethyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate (900 mg, 2.90 mmol) prepared in Step 1.

[Example 102] Synthesis of (R)-(1-ethylpyrrolidin-3-yl)methyl[1,1'-biphenyl]-2-ylcarbamate become

(R)-pyrrolidin-3-ylmethyl[1,1'-biphenyl]-2-ylcarbamate (1 g, 3.37 mmol) (Example 78) was dissolved in dimethylformamide (20 mL). Potassium carbamate (652 mg, 4.72 mmol), potassium iodide (112 mg, 0.67 mmol), triethylamine (1.42 mL, 10.11 mmol) and iodoethane (323 uL, 4.04 mmol) were added thereto in sequence and stirred at 120 ° C for 12 hours. The reactant was cooled to room temperature and extracted with water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (142 mg, 13%).

[Examples 103 to 105]

The compounds of Examples 103 to 105 were prepared in the same manner as in Example 102 using the starting materials in Table 18 instead of (R)-pyrrolidin-3-ylmethyl[1,1′-biphenyl]-2-ylcarbamate.

[Table 18] Examples 103 to 105

[Example 106] Synthesis of (S)-(1-ethylpyrrolidin-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate become

The title compound (385 mg, 35%) was prepared in the same manner as in Example 102 using (S)-pyrrolidin-2-ylmethyl[1,1′-biphenyl]-2-ylcarbamate (1 g, 3.37 mmol) and 2-iodoethane (323 uL, 4.04 mmol) as starting materials.

[Example 107] Preparation of (S)-(1-isobutylpyrrolidin-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate synthesis

The title compound (47 mg, 4%) was prepared in the same manner as in Example 102 using (S)-pyrrolidin-2-ylmethyl[1,1′-biphenyl]-2-ylcarbamate (940 mg, 3.17 mmol) and 1-iodo-2-methylpropane (438 uL, 3.08 mmol) as starting materials.

[Example 108] (S)-(1-methylpyrrolidin-3-yl)methyl(3',5-difluoro-[1,1'-biphenyl]-2-yl)amino Synthesis of methyl formate

Using 3',5-difluoro-[1,1'-biphenyl]-2-carboxylic acid (800 mg, 3.42 mmol) (Synthesis Example 17) and (S)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (825 mg, 4.10 mmol) as raw materials, the title compound (50 mg, 5%) was prepared in the same manner as in Example 78 and Example 89.

[Example 109] Synthesis of (R)-(1-methylpyrrolidin-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate become

[Step 1] Synthesis of (R)-pyrrolidin-2-ylmethyl[1,1'-biphenyl]-2-ylcarbamate

Using [1,1'-biphenyl]-2-carboxylic acid (821 mg, 4.14 mmol) and (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (1 g, 4.97 mmol) as starting materials, the title compound (730 mg, 60%) was prepared in the same manner as in Example 78.

¹ H NMR (CDCl ₃ ): δ8.09-8.08(m,1H),7.49-7.47(m,1H),7.29-7.26(m,1H), 7.17(m,1H),6.92-6.89(m,1H),4.15-4.04(m,2H),3.12-3.08(m,1H), 2.99-2.94(m,2H),2.74-2.72(m,1H),2.51-2.44(m,1H),1.98-1.89(m,1H), 1.51-1.44(m,1H)

[Step 2] Synthesis of (R)-(1-methylpyrrolidin-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate

The title compound (183 mg, 24%) was prepared in the same manner as in Example 89 using (R)-pyrrolidin-2-ylmethyl[1,1′-biphenyl]-2-ylcarbamate (730 mg, 2.46 mmol) as a starting material.

[Example 110] (R)-(1-methylpyrrolidin-2-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)amino Synthesis of formate

Using 3'-methyl-[1,1'-biphenyl]-2-carboxylic acid (700 mg, 3.3 mmol) (Synthesis Example 14) and (R)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (797 mg, 3.96 mmol) as raw materials, the title compound (258 mg, 24%) was prepared in the same manner as in Example 78 and Example 89.

[Example 111] (R)-(1-methylpyrrolidin-2-yl)methyl(5-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl) Synthesis of carbamates

Using 5-fluoro-3'-methyl-[1,1'-biphenyl]-2-carboxylic acid (1 g, 4.34 mmol) (Synthesis Example 21) and (R)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.05 g, 5.21 mmol) as starting materials, the title compound (52 mg, 4%) was prepared in the same manner as in Example 78 and Example 89.

[Example 112] Preparation of (S)-(1-isopropylpyrrolidin-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate synthesis

[Step 1] Synthesis of (S)-pyrrolidin-2-ylmethyl[1,1'-biphenyl]-2-ylcarbamate

Using [1,1'-biphenyl]-2-carboxylic acid (2.5 g, 12.61 mmol) and (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (3.05 g, 15.14 mmol) as starting materials, the title compound (3.06 g, 82%) was prepared in the same manner as in Example 78.

¹ H NMR(CDCl ₃ )δ7.88(m,1H),7.48-7.42(m,1H),7.15-7.05(m,4H), 7.04-6.92(m,1H),6.40(s,1H),4.78-4.76(m,1H),3.23-3.21(m,1H), 2.87-2.73(m,4H),2.06-2.05(m,3H),2.04-1.67(m,1H),1.66-1.54(m,1H), 1.53-1.35(m,1H)

[Step 2] Synthesis of (S)-(1-isopropylpyrrolidin-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate

The title compound (78 mg, 7%) was prepared in the same manner as in Example 102 using (S)-pyrrolidin-2-ylmethyl[1,1′-biphenyl]-2-ylcarbamate (1 g, 3.37 mmol) and 2-iodopropyl (404 uL, 4.04 mmol) as starting materials.

[Example 113] (R)-(1-methylpyrrolidin-3-yl)methyl(3'-fluoro-[1,1'-biphenyl]-2-yl)aminomethane Synthesis of acid esters

(R)-(1-methylpyrrolidin-3-yl)methyl(2-bromophenyl)carbamate (230 mg, 0.73 mmol) (Synthesis Example F) was dissolved in a mixed solution of ethanol (5 mL) and water (5 mL). 3-Fluorophenylboronic acid (123 mg, 0.88 mmol), potassium carbonate (203 mg, 1.47 mmol), di(acetate)dicyclohexylphenylphosphine palladium(II) and polymer-supported FibreCat ^™ (30 mg) were added thereto. The reactants were stirred at 110° C. for 12 hours and then cooled to room temperature. They were filtered through celite and the solvent was removed by concentration under reduced pressure. They were extracted with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (60 mg, 25%).

[Examples 114 to 115]

The compounds of Examples 114 to 115 were prepared using the reactants in Table 19 in place of 3-fluorophenylboronic acid.

[Table 19] Examples 114 to 115

[Example 116] (S)-(1-methylpyrrolidin-3-yl)methyl(3'-fluoro-[1,1'-biphenyl]-2-yl)aminomethane Synthesis of acid esters

(S)-(1-methylpyrrolidin-3-yl)methyl(2-bromophenyl)carbamate (200 mg, 0.64 mmol) (Synthesis Example G) was dissolved in toluene (10 mL). 3-Fluorophenylboric acid (179 mg, 1.28 mmol), potassium carbonate (177 mg, 1.28 mmol) and tetrakis(triphenylphosphine)palladium (74 mg, 0.064 mmol) were added thereto. The reactants were stirred at 110° C. for 12 hours and cooled to room temperature. The mixture was filtered through celite and the solvent was removed by concentrating under reduced pressure. The mixture was extracted with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (102 mg, 49%).

[Examples 117 to 129]

The compounds of Examples 117 to 129 were prepared in the same manner as in Example 116 using the starting materials and reaction materials in Table 20.

[Table 20] Examples 117 to 129

[Example 130] (R)-(1-methylpyrrolidin-3-yl)methyl(3',4'-dichloro-[1,1'-biphenyl]-2-yl)amino Synthesis of methyl formate

(R)-(1-methylpyrrolidin-3-yl)methyl(2-bromophenyl)carbamate (225 mg, 0.72 mmol) (Synthesis Example F) was dissolved in a mixed solution of ethanol (5 mL) and water (5 mL). 3,4-dichlorophenylboronic acid (274 mg, 1.44 mmol), potassium carbonate (199 mg, 1.44 mmol) and tetrakis(triphenylphosphine)palladium (83 mg, 0.072 mmol) were added thereto. The reactants were stirred at 110° C. for 6 hours and cooled to room temperature. They were filtered through celite and the solvent was removed by concentrating under reduced pressure. They were extracted with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (151 mg, 56%).

[Examples 131 to 135]

The compounds of Examples 131 to 135 were prepared in the same manner as in Example 130 using the starting materials and reaction materials in Table 21.

[Table 21] Examples 131 to 135

[Example 136] (R)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl) Synthesis of carbamates

(R)-(1-Methylpyrrolidin-3-yl)methyl(2-bromophenyl)carbamate (250 mg, 0.80 mmol) (Synthesis Example F) was dissolved in a mixed solution of acetonitrile (6 mL) and water (6 mL). (3-Chloro-4-fluorophenyl)boric acid (279 mg, 1.60 mmol), sodium carbonate (170 mg, 1.60 mmol), and dichlorobis(triphenylphosphine)palladium (28 mg, 0.04 mmol) were added. The reaction was stirred at 110°C in a microwave oven for 30 minutes and cooled to room temperature. It was filtered through celite and the solvent was removed by concentration under reduced pressure. It was extracted with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (23 mg, 70%).

[Examples 137 to 149]

The compounds of Examples 137 to 149 were prepared in the same manner as in Example 136 using the starting materials and reaction materials in Table 22.

[Table 22] Examples 137 to 149

[Example 150] (R)-(1-ethylpyrrolidin-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl) Synthesis of carbamates

[Step 1] (R)-3-((((3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamoyl)oxy)methyl)pyrrolidone Synthesis of tert-Butyl Pyrrolidine-1-carboxylate

The title compound (3.4 g, 76%) was prepared in the same manner as in Example 42 using (R)-tert-butyl 3-((((2-bromophenyl)carbamoyl)oxy)methyl)pyrrolidine-1-carboxylate (4 g, 10.02 mmol) (Synthesis Example F, Step 1) and (3-chloro-4-fluoro)phenylboronic acid (3.5 g, 20.04 mmol) as starting materials.

¹ H NMR (CDCl ₃ ): δ8.01(s,1H),7.41-7.35(m,2H),7.31-7.22(m,2H), 7.20-7.13(m,2H),6.34(s,1H),4.15-4.07(m,2H),3.48-3.29(m,3H),3.15-2.99(s, 1H),2.51-2.48(m,1H),1.98-1.94(m,1H),1.44-1.38(m,10H)

[Step 2] Preparation of (R)-pyrrolidin-3-ylmethyl (3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate synthesis

The title compound (2.3 g, 87%) was prepared in the same manner as in Example 78 using (R)-tert-butyl 3-((((3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamoyl)oxy)methyl)pyrrolidine-1-carboxylate (3.4 g, 7.57 mmol) prepared in Step 1 as a starting material.

¹ H NMR (CDCl ₃ ): δ7.98(s,1H),7.41-7.34(m,2H),7.23-7.17(m,2H), 7.16-7.11(m,2H),6.55(s,1H),4.10-4.01(m,2H),3.99-2.86(m,3H),2.70-2.66(s, 1H),2.45-2.39(m,1H),1.95-1.86(m,1H),1.47-1.41(m,1H)

[Step 3] Preparation of (R)-pyrrolidin-3-ylmethyl (3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate synthesis

(R)-pyrrolidin-3-ylmethyl (3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate (345 mg, 0.99 mmol) prepared in Step 2 was dissolved in tetrahydrofuran (20 mL). Triethylamine (150 uL, 1.09 mmol) and bromoethane (118 uL, 1.58 mmol) were added sequentially, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and extracted with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography to produce the title compound (74 mg, 20%).

[Example 151] (R)-(1-isopropylpyrrolidin-3-yl)methyl (3'-chloro-4'-fluoro-[1,1'-biphenyl]-2- Synthesis of 2-amino-3-amino-4-amino-2-aminocarbamate

(R)-Pyrrolidin-3-ylmethyl (3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate (347 mg, 1.00 mmol) (Example 150, Step 2) was dissolved in tetrahydrofuran (20 mL). Triethylamine (150 uL, 1.10 mmol) and 2-bromopropane (100 uL, 1.10 mmol) were added sequentially and stirred at room temperature for 3 days. The reaction was concentrated under reduced pressure and extracted with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography to produce the title compound (17 mg, 4%).

[Example 152] (R)-(1-methylpyrrolidin-3-yl)methyl(3'-(hydroxymethyl)-[1,1'-biphenyl]-2-yl) Synthesis of carbamates

(R)-(1-methylpyrrolidin-3-yl)methyl(2-bromophenyl)carbamate (395 mg, 1.26 mmol) (Synthesis Example F) was dissolved in a mixed solution of toluene (15 mL) and ethanol (2 mL). 3-(Hydroxymethyl)phenylboronic acid (211 mg, 1.39 mmol), potassium carbonate (348 mg, 2.52 mmol) and tetrakis(triphenylphosphine)palladium (146 mg, 0.13 mmol) were added thereto. The reactants were stirred at 110° C. for 12 hours and cooled to room temperature. They were filtered through celite and the solvent was removed by concentrating under reduced pressure. They were extracted with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (126 mg, 29%).

[Examples 153 to 190]

The compounds of Examples 153 to 190 were prepared in the same manner as in Example 152 using the starting materials and reaction materials in Table 23.

[Table 23] Examples 153 to 190

[Example 191] (R)-(1-methylpyrrolidin-3-yl)methyl(3',5'-dimethyl-[1,1'-biphenyl]-2-yl) Synthesis of carbamates

R)-(1-methylpyrrolidin-3-yl)methyl(2-bromophenyl)carbamate (220 mg, 0.70 mmol) (Synthesis Example F) was dissolved in a mixed solution of ethanol (5 mL) and water (5 mL). 3,5-dimethylboronic acid (211 mg, 1.41 mmol), potassium carbonate (194 mg, 1.41 mmol), bis(acetato)dicyclohexylphenylphosphine palladium(II) and polymer-supported FibreCat ^™ (28 mg) were added thereto. The reactants were stirred at 110°C in a microwave oven for 30 minutes and cooled to room temperature. They were filtered through celite and the solvent was removed by concentration under reduced pressure. They were extracted with water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (134 mg, 56%).

[Examples 192 to 195]

The compounds of Examples 192 to 195 were prepared in the same manner as in Example 191 using the starting materials and reaction materials in Table 24.

[Table 24] Examples 192 to 195

[Example 196] (R)-(1-ethylpyrrolidin-3-yl)methyl (3'-chloro-4',5-difluoro-[1,1'-biphenyl]-2- Synthesis of 2-amino-3-aminocarbamate

[Step 1] Synthesis of (R)-(1-ethylpyrrolidin-3-yl)methyl(2-bromo-4-fluorophenyl)carbamate

The title compound (4.5 g, 79%) was prepared in the same manner as in Synthesis Example F using 2-bromo-4-fluorobenzoic acid (3 g, 13.70 mmol) and (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (3.31 g, 16.44 mmol) as starting materials.

¹ H NMR (CDCl ₃ ): δ8.00(s,1H),7.28-7.24(m,1H),7.05-7.00(m,1H), 4.21-4.10(m,2H),3.06-3.03(m,1H),2.90-2.87(m,1H),2.84-2.71(m,5H), 2.17-2.12(m,1H),1.76-1.71(m,1H),1.24(t,3H,J＝7.2Hz)

[Step 2] (R)-(1-ethylpyrrolidin-3-yl)methyl(3'-chloro-4',5-difluoro-[1,1'-biphenyl]-2-yl) Synthesis of carbamates

The title compound (143 mg, 76%) was prepared in the same manner as in Example 136 using (R)-(1-ethylpyrrolidin-3-yl)methyl(2-bromo-4-fluorophenyl)carbamate (165 mg, 0.48 mmol) and (3-chloro-4-fluorophenyl)boronic acid (167 mg, 0.96 mmol) as starting materials.

[Example 197] Synthesis of (S)-(1-methylpyrrolidin-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate become

[1,1'-Biphenyl]-2-carboxylic acid (1 g, 5.05 mmol) was dissolved in toluene (20 mL). Biphenylphosphoryl azide (1.4 mL, 6.05 mmol) and triethylamine (0.71 mL, 5.05 mmol) were added thereto. The mixture was stirred at room temperature for 30 minutes and then stirred at reflux for another hour at room temperature. The reaction mixture was cooled to room temperature, and (S)-(1-methylpyrrolidin-2-yl)methanol (0.72 mL, 6.05 mmol) was added thereto, followed by stirring at reflux for 12 hours. The reaction mixture was cooled to room temperature. The solvent was removed by concentration under reduced pressure. The mixture was extracted with water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (458 mg, 29%).

[Examples 198 to 207]

The compounds of Examples 198 to 207 were prepared in the same manner as in Example 197 using the starting materials and reaction materials in Table 25.

[Table 25] Examples 198 to 207

[Example 208] (S)-(1-methylpyrrolidin-2-yl)methyl(5-fluoro-3',5'-dimethyl-[1,1'-biphenyl]- Synthesis of 2-aminocarbamate

(S)-(1-Methylpyrrolidin-2-yl)methyl(2-bromo-4-fluorophenyl)carbamate (200 mg, 0.60 mmol) (Synthesis Example N) was dissolved in a mixed solution of acetonitrile (3 mL) and water (3 mL). 3,5-Dimethylphenylboronic acid (181 mg, 1.20 mmol), sodium carbonate (95 mg, 0.90 mmol), and dichlorobis(triphenylphosphine)palladium (2 mg, 0.003 mmol) were added. The reaction was stirred at 150°C in a microwave oven for 10 minutes and cooled to room temperature. It was filtered through celite and the solvent was removed by concentration under reduced pressure. It was extracted with water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography to prepare the title compound (98 mg, 46%).

[Examples 209 to 226]

The compounds of Examples 209 to 226 were prepared in the same manner as in Example 208 using the starting materials and reaction materials in Table 26.

[Table 26] Examples 209 to 226

[Experimental Example 1] Binding assay to human muscarinic M3 receptor

A cell membrane protein overexpressing the human muscarinic M3 receptor (Perkin Elmer), [ ³ H]-methylscopolamine, and various concentrations of the test compound were incubated in 0.2 ml of Tris-HCl buffer at 25°C for 120 minutes. The mixture was filtered through a glass fiber filter (Whatman GF/B) under suction, and the filtrate was washed five times with 1 ml of Tris-HCl buffer. The radioactivity of [ ³ H]-methylscopolamine adsorbed on the filter was measured using a liquid scintillation counter. Nonspecific binding was assessed in the presence of 5 μM atropine. The affinity of the compounds of the present invention for the muscarinic M3 receptor was calculated as a dissociation constant (K _i ), which can be calculated from the concentration (IC ₅₀ ) of the test compound that inhibits 50% binding of [ ³ H]-methylscopolamine (i.e., labeled ligand) according to Cheng and Prusoff [Cheng and Prusoff, Biochem. Pharmacol., ₂₂ , 3099, 1973]. In the table below, compounds with stronger binding affinity for the human muscarinic M3 receptor have lower dissociation constants (K _i ).

[Table 27] Binding affinity to human muscarinic M3 receptor

[Experimental Example 2] Determination of antagonistic effect on human muscarinic M3 receptor

The antagonism of various compounds of the present invention against the human M3 receptor was assayed in Cos-7 cells transfected with a plasmid encoding the human muscarinic M3 receptor. Cells were pretreated with various concentrations of the test compound for 3 minutes, and then treated with carbachol (i.e., a muscarinic receptor agonist) to measure changes in intracellular calcium. A Calcium 5 assay (Molecular Devices) and a Flex3 device (Molecular Devices) were used to measure calcium concentrations. The amount of calcium before and after carbachol treatment was set to 0% and 100%, respectively. The compound's inhibition rate (%) was calculated relative to the increase in intracellular calcium in response to carbachol. The antagonistic potency of the test compound against _the human muscarinic M3 receptor was calculated as a functional inhibition constant ( _Kb ), which can be calculated from the concentration of the compound that inhibits 50% of the carbachol activity ( _IC50 ) according to the Cheng and Prusoff equation. The compounds used in the experiments were confirmed to be antagonists against human muscarinic M3 receptors, and lower K _i values indicated superior antagonistic potency.

[Table 28] Antagonistic potency against human muscarinic M3 receptor

[Experimental Example 3] Experiment on Rhythmic Bladder Contraction in Rats (In Vivo)

Female Sprague-Dawley rats were anesthetized with halothane and a polyethylene catheter was inserted through the urethra, lying upright and fixed. The bladder was drained of urine through the catheter by gently massaging the abdomen of the rat and then removed. A three-way valve was connected to the catheter, and a pressure sensor was connected to one side of the three-way valve to measure the pressure, and a syringe was installed on the other side to inject a 37°C saline solution. The saline solution was slowly injected until regular bladder contractions occurred repeatedly. When regular bladder contractions occurred stably, the test compound was administered intravenously through the tail vein. The inhibitory effect of the test compound was evaluated by measuring the degree of reduction in bladder contraction. When the compound of the present invention was administered at a dose of at least 0.3 mg/kg or more, the compound significantly reduced the amplitude of bladder contraction.

[Table 29] Rhythmic bladder contractions in rats

[Example 4] Acute toxicity test on rats after oral administration

In order to confirm the acute toxicity of the compound of the present invention, the following experiment was performed. Low-dose, medium-dose and high-dose groups were prepared, wherein the compound of the embodiment was administered at 100 mg/kg, 300 mg/kg and 1000 mg/kg, respectively. A methylcellulose solution (0.5%) was prepared and orally administered to 3 rats in each group (i.e., 6-week-old Sprague-Dawley (SD) rats of both sexes; male rats of 142-143 g; female rats of 126.3-127.3 g) at a volume of 10 mL/kg. Mortality, clinical signs and body weight, etc. were measured for 4 days, and the approximate lethal dose (ALD) thus found is described in Table 30 below. As shown in Table 30, the approximate lethal dose of the test compound was 1000 mg/kg or higher, so the compound was determined to be a safe drug.

[Table 30] Approximate lethal dose

Example Approximate lethal dose (ALD) Example Approximate lethal dose (ALD) 15 >1000 100 >1000 53 >1000 136 >1000 89 >1000 143 >1000 90 >1000 150 >1000 91 >1000 199 >1000

Industrial Applicability

The novel biphenyl derivatives, their isomers or pharmaceutically acceptable salts of the present invention act as muscarinic M3 receptor antagonists and are therefore useful for preventing or treating diseases selected from the group consisting of chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spastic colitis, chronic cystitis, Alzheimer's disease, senile dementia, glaucoma, schizophrenia, gastroesophageal reflux disease, arrhythmia and hypersalivation syndrome.

Claims (15)

1. A biphenyl derivative, its stereoisomer, or a pharmaceutically acceptable salt thereof, represented by Formula 1: [Formula 1] in _R1 is hydrogen, halogen, hydroxyl, _C1 - _C6 alkyl, or _C1 - _C6 alkoxy; _R2 , _R3 and _R4 are each independently hydrogen, halogen, amino, nitro, cyano, hydroxyl, _C1 - _C6 alkyl, _C1 - _C6 alkoxy or -C(O) _R6 ; _R5 is hydrogen or _C1 - _C6 alkyl; n is 0 or 1; and _R6 is hydrogen or amino. 2. The biphenyl derivative, its stereoisomer, or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein _R1 is hydrogen or halogen; _R2 , _R3 , and _R4 are each independently hydrogen, halogen, or _C1 - _C6 alkyl; and _R5 is _C1 - _C6 alkyl. 3. The biphenyl derivative, its stereoisomer, or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein _R1 is hydrogen; _R2 , _R3 , and _R4 are independently hydrogen or halogen; _R5 is a _C1 - _C6 alkyl group; and n is 0 or 1. 4. A biphenyl derivative, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the biphenyl derivative is selected from the following compounds: 1) 2-(1-methylpyrrolidone-2-yl)ethyl(4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 2) 2-(1-methylpyrrolidone-2-yl)ethyl(3',5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 3) 2-(1-methylpyrrolidone-2-yl)ethyl(3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamate; 4) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 5) 2-(1-methylpyrrolidone-2-yl)ethyl(4'-methoxy-[1,1'-biphenyl]-2-yl)carbamate; 6) 2-(1-methylpyrrolidone-2-yl)ethyl[1,1'-biphenyl]-2-ylcarbamate; 7) 2-(1-methylpyrrolidone-2-yl)ethyl(4'-chloro-[1,1'-biphenyl]-2-yl)carbamate; 8) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-chloro-[1,1'-biphenyl]-2-yl)carbamate; 9) 2-(1-methylpyrrolidone-2-yl)ethyl(3',5'-dichloro-[1,1'-biphenyl]-2-yl)carbamate; 10) 2-(1-methylpyrrolidone-2-yl)ethyl(4'-trifluoromethoxy-[1,1'-biphenyl]-2-yl)carbamate; 11) 2-(1-methylpyrrolidone-2-yl)ethyl(4'-nitro-[1,1'-biphenyl]-2-yl)carbamate; 12) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-trifluoromethyl-[1,1'-biphenyl]-2-yl)carbamate; 13) 2-(1-methylpyrrolidone-2-yl)ethyl(4'-trifluoromethyl-[1,1'-biphenyl]-2-yl)carbamate; 14) 2-(1-methylpyrrolidone-2-yl)ethyl((3'-fluoro-4'-methyl)-[1,1'-biphenyl]-2-yl)carbamate; 15) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate; 16) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-ethoxy-[1,1'-biphenyl]-2-yl)carbamate; 17) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-chloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 18) 2-(1-methylpyrrolidone-2-yl)ethyl(3',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 19) 2-(1-methylpyrrolidone-2-yl)ethyl(4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 20) 2-(1-methylpyrrolidone-2-yl)ethyl(3',5,5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamate; 21) 2-(1-methylpyrrolidone-2-yl)ethyl(5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 22) 2-(1-methylpyrrolidone-2-yl)ethyl(5-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl)carbamate; 23) 2-(1-methylpyrrolidone-2-yl)ethyl(4-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 24) 2-(1-methylpyrrolidone-2-yl)ethyl(3',4-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 25) 2-(1-methylpyrrolidone-2-yl)ethyl(4-methoxy-[1,1'-biphenyl]-2-yl)carbamate; 26) 2-(1-methylpyrrolidone-2-yl)ethyl(5-methyl-[1,1'-biphenyl]-2-yl)carbamate; 27) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-fluoro-5-methyl-[1,1'-biphenyl]-2-yl)carbamate; 28) 2-(1-methylpyrrolidone-2-yl)ethyl(4'-cyano-[1,1'-biphenyl]-2-yl)carbamate; 29) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-(3-hydroxypropyl)-[1,1'-biphenyl]-2-yl)carbamate; 30) 2-(1-methylpyrrolidone-2-yl)ethyl(4'-(dimethylamino)-[1,1'-biphenyl]-2-yl)carbamate; 31) 2-(1-methylpyrrolidone-2-yl)ethyl(4'-(tert-butyl)-[1,1'-biphenyl]-2-yl)carbamate; 32) 2-(1-methylpyrrolidone-2-yl)ethyl(2'-amino-[1,1'-biphenyl]-2-yl)carbamate; 33) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-amino-[1,1'-biphenyl]-2-yl)carbamate; 34) 2-(1-methylpyrrolidone-2-yl)ethyl(2'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 35) 2-(1-methylpyrrolidone-2-yl)ethyl(2'-chloro-[1,1'-biphenyl]-2-yl)carbamate; 36) 2-(1-methylpyrrolidone-2-yl)ethyl(2'-hydroxy-[1,1'-biphenyl]-2-yl)carbamate; 37) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-tert-butyl-5'-methyl-[1,1'-biphenyl]-2-yl)carbamate; 38) 2-(1-methylpyrrolidone-2-yl)ethyl(4'-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate; 39) 2-(1-methylpyrrolidone-2-yl)ethyl(4'-amino-3'-chloro-[1,1'-biphenyl]-2-yl)carbamate; 40) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-hydroxy-[1,1'-biphenyl]-2-yl)carbamate; 41) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 42) 2-(1-methylpyrrolidone-2-yl)ethyl(3',4',5-trifluoro-[1,1'-biphenyl]-2-yl)carbamate; 43) 2-(1-methylpyrrolidone-2-yl)ethyl(3',4'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 44) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 45) 2-(1-methylpyrrolidone-2-yl)ethyl(5-fluoro-3',5'-dimethyl-[1,1'-biphenyl]-2-yl)carbamate; 46) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-amino-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 47) 2-(1-methylpyrrolidone-2-yl)ethyl(5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate; 48) 2-(1-methylpyrrolidone-2-yl)ethyl(4'-fluoro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate; 49) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-fluoro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate; 50)2-(1-methylpyrrolidone-2-yl)ethyl(3',5'-difluoro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate; 51) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate; 52) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-chloro-5,5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 53) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-chloro-4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 54) 2-(1-methylpyrrolidone-2-yl)ethyl(4'-chloro-3',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 55) 2-(1-methylpyrrolidone-2-yl)ethyl(3',5'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 56) 2-(1-methylpyrrolidone-2-yl)ethyl(3',5'-dichloro-4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 57) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-chloro-5-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)carbamate; 58) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-chloro-5-fluoro-4'-hydroxy-[1,1'-biphenyl]-2-yl)carbamate; 59) 2-(1-methylpyrrolidone-2-yl)ethyl(5-fluoro-3',4'-dimethyl-[1,1'-biphenyl]-2-yl)carbamate; 60) 2-(1-methylpyrrolidone-2-yl)ethyl(5-methoxy-[1,1'-biphenyl]-2-yl)carbamate; 61) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-fluoro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate; 62) 2-(1-methylpyrrolidone-2-yl)ethyl(3',5'-difluoro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate; 63) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate; 64) 2-(1-methylpyrrolidone-2-yl)ethyl(3',5'-dichloro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate; 65) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-chloro-4'-fluoro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate; 66) 2-(1-methylpyrrolidone-2-yl)ethyl(5-chloro-[1,1'-biphenyl]-2-yl)carbamate; 67) 2-(1-methylpyrrolidone-2-yl)ethyl(5-chloro-3'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 68) 2-(1-methylpyrrolidone-2-yl)ethyl(5-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 69) 2-(1-methylpyrrolidone-2-yl)ethyl(5-chloro-3',5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 70) 2-(1-methylpyrrolidone-2-yl)ethyl(3',5-dichloro-[1,1'-biphenyl]-2-yl)carbamate; 71) 2-(1-methylpyrrolidone-2-yl)ethyl(3',5,5'-trichloro-[1,1'-biphenyl]-2-yl)carbamate; 72) 2-(1-methylpyrrolidone-2-yl)ethyl(3',5-dichloro-5'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 73) 2-(1-methylpyrrolidone-2-yl)ethyl(3',5-dichloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 74)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-fluoro-4'-formyl-[1,1'-biphenyl]-2-yl)carbamate; 75)2-(1-methylpyrrolidone-2-yl)ethyl(3',5'-difluoro-5-hydroxy-[1,1'-biphenyl]-2-yl)carbamate; 76) 2-(1-methylpyrrolidone-2-yl)ethyl(3',5'-dichloro-5-hydroxy-[1,1'-biphenyl]-2-yl)carbamate; 77) 2-(1-methylpyrrolidone-2-yl)ethyl(3'-chloro-4'-fluoro-5-hydroxy-[1,1'-biphenyl]-2-yl)carbamate; 78)(R)-pyrrolidine-3-ylmethyl[1,1'-biphenyl]-2-ylcarbamate; 79)(S)-pyrrolidine-3-ylmethyl[1,1'-biphenyl]-2-ylcarbamate; 80)(R)-pyrrolidine-3-ylmethyl(3',5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 81)(S)-pyrrolidine-3-ylmethyl(3',5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 82)(S)-pyrrolidine-3-ylmethyl(5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 83)(S)-pyrrolidine-3-ylmethyl(5-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl)carbamate; 84)(R)-pyrrolidine-3-ylmethyl(3',5,5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamate; 85)(S)-pyrrolidine-3-ylmethyl(3',5,5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamate; 86)(R)-pyrrolidine-3-ylmethyl(5-methyl-[1,1'-biphenyl]-2-yl)carbamate; 87)(R)-pyrrolidine-3-ylmethyl(3'-fluoro-5-methyl-[1,1'-biphenyl]-2-yl)carbamate; 88)(S)-pyrrolidine-2-ylmethyl(4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 89)(R)-(1-methylpyrrolidone-3-yl)methyl[1,1'-biphenyl]-2-ylcarbamate; 90)(S)-(1-methylpyrrolidone-3-yl)methyl[1,1'-biphenyl]-2-ylcarbamate; 91)(R)-(1-methylpyrrolidone-3-yl)methyl(3',5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 92)(S)-(1-methylpyrrolidone-3-yl)methyl(3',5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 93)(S)-(1-methylpyrrolidone-3-yl)methyl(5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 94)(S)-(1-methylpyrrolidone-3-yl)methyl(5-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl)carbamate; 95)(R)-(1-methylpyrrolidone-3-yl)methyl(3',5,5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamate; 96)(S)-(1-methylpyrrolidone-3-yl)methyl(3',5,5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamate; 97)(R)-(1-methylpyrrolidone-3-yl)methyl(5-methyl-[1,1'-biphenyl]-2-yl)carbamate; 98)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-fluoro-5-methyl-[1,1'-biphenyl]-2-yl)carbamate; 99)(S)-(1-methylpyrrolidone-2-yl)methyl(4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 100)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate; 101)(S)-(1-methylpyrrolidone-3-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate; 102)(R)-(1-ethylpyrrolidone-3-yl)methyl[1,1'-biphenyl]-2-ylcarbamate; 103)(S)-(1-ethylpyrrolidone-3-yl)methyl[1,1'-biphenyl]-2-ylcarbamate; 104)(R)-(1-ethylpyrrolidone-3-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate; 105)(S)-(1-ethylpyrrolidone-3-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate; 106)(S)-(1-ethylpyrrolidone-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate; 107)(S)-(1-Isobutylpyrrolidone-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate; 108)(S)-(1-methylpyrrolidone-3-yl)methyl(3',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 109)(R)-(1-methylpyrrolidone-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate; 110)(R)-(1-methylpyrrolidone-2-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate; 111)(R)-(1-methylpyrrolidone-2-yl)methyl(5-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl)carbamate; 112)(S)-(1-isopropylpyrrolidone-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate; 113)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 114)(R)-(1-methylpyrrolidone-3-yl)methyl(4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 115)(R)-(1-methylpyrrolidone-3-yl)methyl(3',4'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 116)(S)-(1-methylpyrrolidone-3-yl)methyl(3'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 117)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-[1,1'-biphenyl]-2-yl)carbamate; 118)(S)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-[1,1'-biphenyl]-2-yl)carbamate; 119)(S)-(1-methylpyrrolidone-3-yl)methyl(3',5'-dichloro-[1,1'-biphenyl]-2-yl)carbamate; 120)(S)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-5'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 121)(S)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 122)(S)-(1-methylpyrrolidone-3-yl)methyl(5-fluoro-3',5'-dimethyl-[1,1'-biphenyl]-2-yl)carbamate; 123)(S)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-5-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)carbamate; 124)(S)-(1-methylpyrrolidone-3-yl)methyl(4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 125)(S)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 126)(S)-(1-methylpyrrolidone-3-yl)methyl(3',5'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 127)(S)-(1-methylpyrrolidone-3-yl)methyl(4'-chloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 128)(S)-(1-methylpyrrolidone-3-yl)methyl(3',4'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 129)(S)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-5,5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 130)(R)-(1-methylpyrrolidone-3-yl)methyl(3',4'-dichloro-[1,1'-biphenyl]-2-yl)carbamate; 131)(R)-(1-methylpyrrolidone-3-yl)methyl(3',5'-dichloro-[1,1'-biphenyl]-2-yl)carbamate; 132)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-5'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 133)(R)-(1-methylpyrrolidone-3-yl)methyl(5-fluoro-3'-amino-[1,1'-biphenyl]-2-yl)carbamate; 134)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-5-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)carbamate; 135)(R)-(1-methylpyrrolidone-3-yl)methyl(3',5'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 136)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 137)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-hydroxy-[1,1'-biphenyl]-2-yl)carbamate; 138)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-5'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate; 139)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-5-fluoro-5'-methoxy-[1,1'-biphenyl]-2-yl)carbamate; 140)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-5-fluoro-5'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate; 141)(R)-(1-methylpyrrolidone-3-yl)methyl(4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 142)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-5,5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 143)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 144)(R)-(1-methylpyrrolidone-3-yl)methyl(2',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 145)(R)-(1-methylpyrrolidone-3-yl)methyl(3',5-dichloro-[1,1'-biphenyl]-2-yl)carbamate; 146)(R)-(1-methylpyrrolidone-3-yl)methyl(3',5-dichloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 147)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-4'-fluoro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate; 148)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-chloro-5'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 149)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 150)(R)-(1-ethylpyrrolidone-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 151)(R)-(1-isopropylpyrrolidone-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 152)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-(hydroxymethyl)-[1,1'-biphenyl]-2-yl)carbamate; 153)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-carbamoyl-[1,1'-biphenyl]-2-yl)carbamate; 154)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-amino-[1,1'-biphenyl]-2-yl)carbamate; 155)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-cyano-[1,1'-biphenyl]-2-yl)carbamate; 156)(R)-(1-methylpyrrolidone-3-yl)methyl(2'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 157)(R)-(1-methylpyrrolidone-3-yl)methyl(2',4'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 158)(R)-(1-methylpyrrolidone-3-yl)methyl(2',3'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 159)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-6'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 160)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 161)(S)-(1-methylpyrrolidone-2-yl)methyl(3',5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 162)(S)-(1-methylpyrrolidone-2-yl)methyl(3',4'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 163)(S)-(1-methylpyrrolidone-2-yl)methyl(2',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamate; 164)(S)-(1-methylpyrrolidone-2-yl)methyl(4'-chloro-[1,1'-biphenyl]-2-yl)carbamate; 165)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-chloro-[1,1'-biphenyl]-2-yl)carbamate; 166)(S)-(1-methylpyrrolidone-2-yl)methyl(3',4'-dichloro-[1,1'-biphenyl]-2-yl)carbamate; 167)(S)-(1-methylpyrrolidone-2-yl)methyl(2',4'-dichloro-[1,1'-biphenyl]-2-yl)carbamate; 168)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-hydroxy-[1,1'-biphenyl]-2-yl)carbamate; 169)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-cyano-[1,1'-biphenyl]-2-yl)carbamate; 170)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-amino-[1,1'-biphenyl]-2-yl)carbamate; 171)(S)-(1-methylpyrrolidone-2-yl)methyl(3',4',5-trifluoro-[1,1'-biphenyl]-2-yl)carbamate; 172)(S)-(1-methylpyrrolidone-2-yl)methyl(3',5,5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamate; 173)(S)-(1-methylpyrrolidone-2-yl)methyl(2',4',5,5'-tetrafluoro-[1,1'-biphenyl]-2-yl)carbamate; 174)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-chloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 175)(S)-(1-methylpyrrolidone-2-yl)methyl(4'-chloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 176)(S)-(1-methylpyrrolidone-2-yl)methyl(2',4'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 177)(S)-(1-methylpyrrolidone-2-yl)methyl(3',4'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 178)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-cyano-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 179)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-hydroxy-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 180)(S)-(1-methylpyrrolidone-2-yl)methyl(5-fluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate; 181)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-chloro-4,4',5-trifluoro-[1,1'-biphenyl]-2-yl)carbamate; 182)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-4,5-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 183)2-(1-methylpyrrolidone-2-yl)ethyl(2',4'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 184)2-(1-methylpyrrolidone-2-yl)ethyl(2',3'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 185)2-(1-methylpyrrolidone-2-yl)ethyl(2',6'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 186)2-(1-methylpyrrolidone-2-yl)ethyl(5'-chloro-2'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 187)(S)-(1-methylpyrrolidone-2-yl)methyl(2'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 188)(S)-(1-methylpyrrolidone-2-yl)methyl(2',4'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 189)(S)-(1-methylpyrrolidone-2-yl)methyl(2',3'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 190)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-chloro-6'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 191)(R)-(1-methylpyrrolidone-3-yl)methyl(3',5'-dimethyl-[1,1'-biphenyl]-2-yl)carbamate; 192)(R)-(1-methylpyrrolidone-3-yl)methyl(5-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl)carbamate; 193)(R)-(1-methylpyrrolidone-3-yl)methyl(5-fluoro-3',5'-dimethyl-[1,1'-biphenyl]-2-yl)carbamate; 194)(R)-(1-methylpyrrolidone-3-yl)methyl(3',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 195)(R)-(1-methylpyrrolidone-3-yl)methyl(3'-chloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 196)(R)-(1-ethylpyrrolidone-3-yl)methyl(3'-chloro-4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 197)(S)-(1-methylpyrrolidone-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate; 198)(S)-(1-methylpyrrolidone-2-yl)methyl(4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 199)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate; 200)(S)-(1-methylpyrrolidone-2-yl)methyl(5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 201)(S)-(1-methylpyrrolidone-2-yl)methyl(5-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl)carbamate; 202)(S)-(1-methylpyrrolidone-2-yl)methyl(3',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 203)(S)-(1-methylpyrrolidone-2-yl)methyl(4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 204)(S)-(1-methylpyrrolidone-2-yl)methyl(4-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 205)(S)-(1-methylpyrrolidone-2-yl)methyl(3',4-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 206)(S)-(1-methylpyrrolidone-2-yl)methyl(5-methyl-[1,1'-biphenyl]-2-yl)carbamate; 207)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-fluoro-5-methyl-[1,1'-biphenyl]-2-yl)carbamate; 208)(S)-(1-methylpyrrolidone-2-yl)methyl(5-fluoro-3',5'-dimethyl-[1,1'-biphenyl]-2-yl)carbamate; 209)(S)-(1-methylpyrrolidone-2-yl)methyl(4'-(tert-butyl)-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 210)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-chloro-5,5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 211)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-chloro-4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 212)(S)-(1-methylpyrrolidone-2-yl)methyl(4'-chloro-3',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate; 213)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-amino-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 214)(S)-(1-methylpyrrolidone-2-yl)methyl(2',5-difluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate; 215)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-chloro-5-fluoro-5'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate; 216)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-chloro-5-fluoro-5'-hydroxy-[1,1'-biphenyl]-2-yl)carbamate; 217)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-chloro-5-fluoro-5'-methoxy-[1,1'-biphenyl]-2-yl)carbamate; 218)(S)-(1-methylpyrrolidone-2-yl)methyl(5-fluoro-2',4'-bis(trifluoromethyl)-[1,1'-biphenyl]-2-yl)carbamate; 219)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-ethoxy-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate; 220)(S)-(1-methylpyrrolidone-2-yl)methyl(5-fluoro-3',4'-dimethoxy-[1,1'-biphenyl]-2-yl)carbamate; 221)(S)-(1-methylpyrrolidone-2-yl)methyl(5-fluoro-3',5'-dimethoxy-[1,1'-biphenyl]-2-yl)carbamate; 222)(S)-(1-methylpyrrolidone-2-yl)methyl(5-methoxy-[1,1'-biphenyl]-2-yl)carbamate; 223)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-fluoro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate; 224)(S)-(1-methylpyrrolidone-2-yl)methyl(3'-chloro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate; 225)(S)-(1-methylpyrrolidone-2-yl)methyl(3',4'-dichloro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate; and 226)(S)-(1-methylpyrrolidone-2-yl)methyl(3',5'-dichloro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate. 5. A method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof, said method comprising the step of reacting a compound of formula 2 with a compound of formula 3 in the presence of a carbamate synthesis reagent: [Equation 2] [Formula 3] [Formula 1] Wherein _R1 to _R5 and n are the same as those defined in claim 1. 6. A method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof, said method comprising the steps of: The compound of Formula 2 is reacted with the compound of Formula 3a in the presence of a carbamate synthesis reagent to prepare the compound of Formula 4. To prepare a compound of formula 1a by removing the amine protecting group from the compound of formula 4; and Introducing the _R5 substituent into the compound of formula 1a: [Equation 2] [Equation 3a] [Formula 4] [Equation 11a] [Formula 1] Wherein _R1 to _R5 and n are the same as those defined in claim 1; and _PG1 is an amine protecting group selected from tert-butoxycarbonyl, benzyl, tert-butyl, 4-methoxybenzyl, fluorenylmethoxycarbonyl, toluenesulfonyl, methoxymethyl, tetrahydropyranyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl. 7. The method of claim 5 or 6, wherein the compound of formula 2 is prepared by the following steps: The compound of Formula 5 is reacted in the presence of an acid to prepare a compound of Formula 6, wherein the compound of Formula 6 has a carboxylic acid protecting group introduced therein; Couple the compound of Formula 6 with the compound of Formula 7 to prepare the compound of Formula 8; and The compound of Formula 8 is deesterified in the presence of a base: [Formula 5] [Formula 6] [Formula 7] [Formula 8] Wherein _R1 to _R4 and n are the same as those defined in claim 1; X is a halogen; and _PG2 is a protecting group selected from _C1 - _C4 alkyl, benzyl, 4-methoxybenzyl, tetrahydropyranyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl. 8. A method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof, said method comprising the steps of: The compound of formula 5 is reacted with the compound of formula 3 in the presence of a carbamate synthesis reagent to prepare the compound of formula 9; and Couple the compound of Formula 7 to the compound of Formula 9: [Formula 5] [Formula 3] [Formula 9] [Formula 7] [Formula 1] Wherein _R1 to _R5 and n are the same as those defined in claim 1; and X is a halogen. 9. A method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof, said method comprising the steps of: The compound of formula 5 is reacted with the compound of formula 3a in the presence of a carbamate synthesis reagent to prepare the compound of formula 9a. The compound of formula 9a is deprotected to prepare the compound of formula 9b. Introducing the R ₅ substituent into the compound of formula 9b to prepare the compound of formula 9; and Couple the compound of Formula 7 to the compound of Formula 9: [Formula 5] [Equation 3a] [Formula 9a] [Formula 9b] [Formula 9] [Formula 7] [Formula 1] Wherein _R1 to _R5 and n are the same as those defined in claim 1; X is a halogen; and _PG1 is the same as those defined in claim 6. 10. The method of any one of claims 5, 6, 8 and 9, wherein the carbamate synthesis reagent comprises an azide compound. 11. The method of claim 10, wherein the carbamate synthesis reagent is a mixture of diphenylphosphonoazide and triethylamine, a mixture of propylphosphonic anhydride, trimethylsilyl azide and triethylamine, or a mixture of sodium azide, tetrabutylammonium bromide and zinc(II) trifluoromethanesulfonate. 12. A muscarinic M3 receptor antagonist comprising, as an active ingredient, the compound of claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof. 13. The muscarinic M3 receptor antagonist of claim 12, for the prevention or treatment of diseases selected from: chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spastic colitis, chronic cystitis, Alzheimer's disease, glaucoma, schizophrenia, gastroesophageal reflux disease, arrhythmia, hypersalivation syndrome, enuresis, neurogenic bladder, unstable bladder, bladder spasm, urinary frequency, overactive bladder, and urinary urgency. 14. The muscarinic M3 receptor antagonist as described in claim 12, used for the prevention or treatment of neurogenic urinary frequency or Alzheimer's disease. 15. Use of a composition comprising, as an active ingredient, the compound of claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of muscarinic M3 receptor-related diseases.