BR112016001746B1 - BIPHENYL DERIVATIVE, METHOD FOR ITS PREPARATION AND USE OF A COMPOSITION CONTAINING THE COMPOUND - Google Patents

Abstract

BIPHENYL DERIVATIVE, METHOD OF PREPARATION, M3 MUSCARINIC RECEPTOR ANTAGONIST CONTAINING THE COMPOUND AND USE OF A COMPOSITION CONTAINING THE COMPOUND. The present invention provides new biphenyl derivatives, isomers thereof, or pharmaceutically acceptable salts thereof, methods for preparing the same, and a pharmaceutical composition containing the same. The novel biphenyl derivatives, isomers thereof, or pharmaceutically acceptable salts thereof, as disclosed in the present invention, act as muscarinic M3 receptor antagonists and, as such, are useful for the prevention or treatment of a disease selected from the group consisting of disease chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, Alzheimer's disease, senile dementia, glaucoma, schizophrenia, gastroesophageal reflux disease, cardiac arrhythmia, and hypersalivation syndromes.

Description

technical field

[0001] The present invention relates to new muscarinic M3 receptor antagonists, and more particularly to new biphenyl derivatives that have muscarinic M3 receptor antagonist activity, or isomers thereof, pharmaceutically acceptable salts thereof, or hydrates thereof, methods for preparation thereof, and a pharmaceutical composition containing them as an active ingredient.

Fundamentals of the technique

[0002] Muscarinic receptors are found in all parts of the human body, including in the brain and salivary glands. These receptors are members of the G protein-coupled receptors, and are further divided into five subtypes (M1 to M5). Among these subtypes, the M1, M2 and M3 receptors are widely found in animal and human tissues, and their pharmacological properties have been elucidated. The M1 muscarinic receptor is mainly expressed in the cerebral cortex, and is involved in the regulation of higher cognitive functions. The M2 receptor is found primarily in the smooth muscles of the heart and bladder, and is involved in regulating heart rate. It is known that the M3 receptor is extensively expressed in many peripheral tissues and is involved in stimulation of the gastrointestinal tract and urinary tract, and in salivation. 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.

[0003] Generally, it has been found that muscarinic receptor antagonists are useful for the treatment of various diseases, for example, chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, Alzheimer's disease , senile dementia, glaucoma, schizophrenia, gastroesophageal reflux disease, cardiac arrhythmia and hypersalivation syndromes (Invest. Drugs, 1997, 6(10), 1,3951,411, Drugs Future, 1997, 22(2) 135-137, Drugs Future , 1996, 21(11), 1105-1108, Drugs Future, 1997, 22(7), 733-737).

[0004] At the same time, it is known that, among muscarinic receptors, M2 and M3 receptors are predominant in the human bladder and participate in the regulation of bladder contraction. The M2 receptor is present in the bladder in an amount that is at least three times greater than that of the M3 receptor, and participates in beta receptor inhibition of bladder relaxation, and is not directly involved in bladder contraction. Thus, it appears that the M3 receptor plays the most important role in bladder contraction. Therefore, selective M3 receptor antagonists exhibit excellent inhibitory effects against muscarinic bladder contraction, but inhibit salivary secretion to cause dry mouth.

[0005] Consequently, the present inventors have prepared new derivatives that can exhibit functional activity by their selective binding to the M3 muscarinic receptor and have minimized side effects, thus completing the present invention.

Revelation Technical problem

[0006] It is an object of the present invention to provide new biphenyl derivatives or pharmaceutically acceptable salts thereof.

[0007] Another object of the present invention is to provide methods for preparing new biphenyl derivatives or pharmaceutically acceptable salts thereof.

[0008] Yet another object of the present invention is to provide a muscarinic M3 receptor antagonist containing novel biphenyl derivatives, pharmaceutically acceptable salts thereof, or hydrates thereof, as an active ingredient.

Technical solution

[0009] The present invention provides new biphenyl derivatives or pharmaceutically acceptable salts thereof.

[0010] The present invention also provides methods for preparing novel biphenyl derivatives or pharmaceutically acceptable salts thereof.

[0011] The present invention also provides muscarinic M3 receptor antagonists which contain novel biphenyl derivatives, pharmaceutically acceptable salts thereof, or hydrates thereof as an active ingredient.

[0012] As used herein, the term "alkyl" means a straight or branched hydrocarbon radical. For example, C1-C6 alkyl is an aliphatic hydrocarbon 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.

[0013] As used herein, the term "alkoxy" means the radical in which the hydrogen atom of a hydroxyl group is replaced with alkyl. For example, C1-C6 alkoxy is intended to include all methoxy, ethoxy, propoxy, n-butoxy, n-pentyloxy, isopropoxy, sec-butoxy, tert-butoxy, neopentyloxy, isopentyloxy and the like.

New biphenyl derivatives

[0014] The present invention provides new biphenyl derivatives represented by the following Formula 1, or pharmaceutically acceptable salts thereof: wherein: R1 is hydrogen, halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl or C1-C6 alkoxy; R2, R3 and R4 are each independently hydrogen, halogen, substituted or unsubstituted amino, nitro, cyano, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 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.

[0015] In a preferred embodiment of the present invention, R1 in Formula 1 can be hydrogen or halogen; R2, R3 and R4 may each independently be hydrogen, halogen or C1-C6 alkyl; and R5 can be C1-C6 alkyl.

[0016] In another preferred embodiment of the present invention, R1 in Formula 1 may be hydrogen; R2, R3 and R4 may each independently be hydrogen or halogen; R5 can be C1-C6 alkyl; and n can be 0 or 1.

[0017] In the present invention, pharmaceutically acceptable salts are preferably acid addition salts formed with pharmaceutically acceptable free acids. Free acids that can be used in the present invention include organic acids and inorganic acids. Inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., and organic acids include 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, embonic acid, glutamic acid, aspartic acid etc.

[0018] Furthermore, compounds of Formula 1 or pharmaceutically acceptable salts thereof may exhibit polymorphism, and may also exist as solvates (e.g., hydrates, etc.). Furthermore, the compounds of the present invention can also exist as individual stereoisomers or mixtures of stereoisomers.

[0019] The present invention is also directed to new biphenyl derivatives selected from the group consisting of the following compounds: 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.

Methods for the preparation of new biphenyl derivatives

[0020] The present invention provides methods for preparing the compounds of formula 1 or pharmaceutically acceptable salts thereof (Preparation Methods 1 to 4).

Preparation method 1

[0021] The method for preparing the compounds of formula 1 or pharmaceutically acceptable salts thereof according to the present invention may comprise a step of reacting a compound of formula 2 below with a compound of formula 3 below in the presence of a synthesis reagent of carbamate: wherein R1 to R5 and n are as defined in formula 1.

[0022] The carbamate synthesis reagent preferably comprises an azide compound. Specifically, the carbamate synthesis reagent that is used in the present invention can be a mixture of diphenylphosphoryl azide (DPPA) and triethylamine, a mixture of propylphosphonic anhydride (T3P), trimethylsilyl azide (TMSN3) and triethylamine, a mixture of sodium azide (NaN3), tetrabutylammonium bromide and zinc(II) triflate, or the like.

[0023] In addition, the carbamate synthesis reaction can be carried out at a temperature between 100°C and 120°C for 4 to 12 hours.

Preparation method 2

[0024] Furthermore, the method for preparing compounds of formula 1 or pharmaceutically acceptable salts thereof according to the present invention may comprise the steps of: reacting a compound of formula 2 below with a compound of formula 3a below in the presence of a carbamate synthesis reagent for preparing 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: wherein R1 to R4 and n are as defined in formula 1, and PG1 is an amine protecting group which may be selected from the group consisting of Boc (tert-butyloxycarbonyl), benzyl, tert-butyl, PMB (4-methoxybenzyl) , Fmoc (fluorenylmethyloxycarbonyl), Ts (tosylate), MOM (methoxymethyl), THP (tetrahydropyranyl), TBDMS (tert-butyldimethylsilyl) and TBDPS (tert-butyldiphenylsilyl).

[0025] Carbamate synthesis reagent and reaction conditions are the same as described above for preparation method 1.

[0026] In addition, palladium-carbon (Pd-C), a strong acid such as trifluoroacetic acid, sulfuric acid, hydrobromic acid or the like; or a base such as, for example, piperidine; cerium(IV) ammonium nitrate; tetra-n-butyl ammonium fluoride or the like can be used in the amine protecting group removal reaction. The reaction can be carried out at room temperature for 3 to 12 hours.

[0027] In addition, the R5 substituent introduction reaction can be carried out using formaldehyde, acetic acid and zinc solution, or it can be carried out using 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 up to 120°C for 5 to 12 hours.

[0028] At the same time, the compound of formula 2 can be prepared by a method comprising the steps of: reacting a compound of formula 5 below in the presence of an acid to prepare a compound of formula 6 below, having a group of protection of carboxylic acid introduced therein; coupling the compound of formula 6 with a compound of formula 7 below to prepare a compound of formula 8 below; and deesterifying the compound of formula 8 in the presence of a base: wherein R1 to R5 and n are as defined in formula 1; X is halogen; and PG2 is a protecting group which may be selected from the group consisting of a C1-C4 alkyl, benzyl, PMB (4-methoxybenzyl), THP (tetrahydropyranyl), TBDMS (tert-butyldimethylsilyl) and TBDPS (tert-butyldiphenylsilyl) group .

[0029] 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 a solvent. The reaction can be carried out at a temperature between 80°C and 100°C for 4 to 24 hours.

[0030] Furthermore, the base which is used in the coupling reaction is preferably selected from potassium carbonate and sodium carbonate. A catalyst that is used in the coupling reaction can be tetrakis-triphenylphosphine palladium or dichlorobis-triphenylphosphine palladium, and a solvent that is used in the coupling reaction can be toluene, a mixture of toluene and ethanol, a mixture of ethanol and water, a mixture of acetonitrile and water, or the like. Furthermore, the coupling reaction can be carried out at a temperature between 100°C and 120°C for 10 minutes to 12 hours.

[0031] Furthermore, the base which is used in the deesterification reaction is preferably selected from sodium hydroxide and potassium hydroxide, and a solvent which is used in the deesterification reaction may be ethanol or a mixture of ethanol and water. The deesterification reaction can be carried out at a temperature between 100°C and 120°C for 2 to 12 hours.

Preparation method 3

[0032] Furthermore, the method for preparing the compounds of formula 1 or pharmaceutically acceptable salts thereof according to the present invention may comprise the steps of: reacting a compound of formula 5 below with a compound of formula 3 below in the presence of a carbamate synthesis reagent for preparing a compound of formula 9 below; and coupling a compound of the following formula 7 to the compound of formula 9: wherein R1 to R5 and n are as defined in formula 1, and X is halogen.

[0033] Carbamate synthesis reagent and reaction conditions are the same as described above for preparation method 1.

[0034] In addition, the coupling reaction reagents and reaction conditions are the same as described above for preparation method 1 2.

Preparation method 4

[0035] Furthermore, the method for preparing the compounds of formula 1 or pharmaceutically acceptable salts thereof according to the present invention may comprise the steps of: reacting a compound of the following formula 5 with a compound of the following formula 3a in the presence of a carbamate synthesis reagent for preparing a compound of formula 9a below; deprotection of the compound of formula 9a to obtain a compound of the following formula 9b; introducing an R5 substituent into the compound of formula 9b to prepare a compound of formula 9 below; and coupling a compound of the following formula 7 to the compound of formula 9: wherein R1 to R5 and n are as defined in formula 1; X is halogen; and PG1 is as defined in Preparation Method 2.

[0036] Carbamate synthesis reagent and reaction conditions are as described above for preparation method 1.

[0037] In addition, the deprotection reaction, the R5 substituent introduction reaction and the coupling reaction are as described above for preparation method 2.

Pharmaceutical composition containing novel biphenyl derivatives

[0038] The present invention provides a muscarinic M3 receptor antagonist containing the compound of formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof, as an active ingredient.

[0039] In the present invention, the M3 muscarinic receptor antagonist can be a composition for the prevention or treatment of a disease selected from the group consisting of chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis , chronic cystitis, Alzheimer's disease, senile dementia, glaucoma, schizophrenia, gastroesophageal reflux disease, cardiac arrhythmia and hypersalivation syndromes.

[0040] In the present invention, the muscarinic M3 receptor antagonist may contain, in addition to the compound of formula 1 or a pharmaceutically acceptable salt thereof, one or more active ingredients that exhibit the same or similar function as the compound of formula 1 or a pharmaceutically acceptable salt thereof. acceptable of this.

[0041] For administration, the composition of the present invention may further comprise at least one pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier that is used in the composition of the present invention can be saline, sterile water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, or a mixture of one or more of these. If necessary, other conventional additives such as, for example, antioxidants, buffers or bacteriostatic agents, can be added to the composition of the present invention. Furthermore, diluents, dispersants, surfactants, binders and lubricants can be further added to the composition to formulate injectable formulations such as, for example, aqueous solutions, suspensions or emulsions, pills, capsules, granules or tablets. Furthermore, the composition of the present invention can preferably be formulated, depending on the particular diseases or its components, using a suitable method known in the art or the method described in "Remington's Pharmaceutical Science", Merck Publishing Company, Easton PA.

[0042] Furthermore, when the muscarinic M3 receptor antagonist of the present invention is for oral administration, the compound of formula 1 or a pharmaceutically acceptable salt thereof may be contained in an amount of 195% by weight, preferably 1-70% by weight. weight, based on the total weight of the M3 receptor antagonist.

[0043] The pharmaceutical composition of the present invention can be administered orally or can be administered parenterally in the form of injectable solutions, suppositories, transdermal agents, inhalation agents or intravesical agents.

[0044] The present invention also provides a method for treating or alleviating a disease related to activity at the muscarinic M3 receptor, the method comprising administering a muscarinic M3 receptor antagonist containing the compound of formula 1 or a pharmaceutically acceptable salt as an active ingredient to mammals, including humans in need of muscarinic M3 receptor antagonistic activity.

[0045] The muscarinic M3 receptor antagonist of the present invention can be used alone or in combination with surgery, hormone therapy, pharmacological therapy and a biological response modifier in order to prevent or treat a disease related to activity at the muscarinic M3 receptor.

Method for preventing or treating diseases related to the M3 muscarinic receptor

[0046] The present invention also provides a method for preventing or treating a disease related to the M3 muscarinic receptor, for example, a disease selected from chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, Alzheimer's disease, senile dementia, glaucoma, schizophrenia, gastroesophageal reflux disease, cardiac arrhythmia and hypersalivation syndromes, the method comprising administering to subjects in need a composition which contains, as an active ingredient, the compound of formula 1, or an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0047] The composition that is used in the prevention or treatment method of the present invention includes the pharmaceutical composition as described herein.

[0048] Furthermore, individuals in need of the prevention or treatment method of the present invention include mammals, particularly humans.

advantageous effects

[0049] The biphenyl derivatives according to the present invention have affinity and selectivity for the M3 muscarinic receptor and are less toxic. Thus, these biphenyl derivatives can be used as agents for preventing or treating various diseases, particularly diseases of the urinary system such as, for example, enuresis, nervous pollakiuria, neurogenic bladder, unstable bladder, chronic cystitis, cystospasm, urinary incontinence, or frequent urination, respiratory system disorders such as chronic obstructive pulmonary disease, chronic bronchitis, asthma, or rhinitis, and digestive disorders such as irritable bowel syndrome, spastic colitis or diverticulitis, in which the M3 muscarinic receptor It is involved.

[0050] Particularly, as the biphenyl derivatives of the present invention have high selectivity for the M2 muscarinic receptor and the M3 muscarinic receptor that is present in smooth muscle, glandular tissues and the like, these biphenyl derivatives are M3 receptor antagonists that have fewer side effects and, therefore, are very useful as agents for preventing or treating urinary incontinence, frequent urination, chronic bronchitis, chronic obstructive pulmonary disease, asthma, rhinitis, and the like.

Examples

[0051] The present disclosure will be described more fully below with reference to the accompanying synthesis examples, examples and experimental examples. However, the Examples according to the present invention can be modified in various ways, and the scope of the present invention should not be construed as being limited by the following Examples. Examples of the present invention are provided in order that those skilled in the art may sufficiently understand the present invention.

[0052] In addition, the agents set forth below were purchased from Aldrich Korea, Acros, Lancaster, TCI, unless otherwise specified. 1H-NMR used here was Varian 400 MHz, and the microwave oven used here was Monowave 300 from Anton Paar company.[Synthesis example 1] Synthesis of 4'-fluoro-[1,1'-biphenyl]-2- acid carboxylic [Step 1] Synthesis of ethyl-2-bromobenzoate

[0053] 2-Bromobenzoic acid (5 g, 24.87 mmol) was dissolved in ethanol (100 ml). Sulfuric acid (5 ml) was added thereto and stirred under reflux for 24 hours. After the reaction was over, the reagent was cooled to room temperature. The solvent was removed by concentration of the reagent under reduced pressure, and extracted with water and ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (4.9 g, 86%). [Step 2] Synthesis of Ethyl 4'-Fluoro-[1,1'-biphenyl]-2-carboxylate

[0054] 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-fluorophenyl boronic 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 thereto. The reagent was stirred at 100°C for 6 hours, cooled to room temperature and filtered through celite. The solvent was removed by concentration of the reagent under reduced pressure. It was extracted with water and ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (948 mg, 89%). [Step 3] Synthesis of 4'-Fluoro-[1,1'-biphenyl]-2-carboxylic acid

[0055] Ethyl 4'-fluoro-[1,1'-biphenyl]-2-carboxylate (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 under reflux for 12 hours. The reagent was cooled to room temperature. The solvent was removed by concentration of the reagent under reduced pressure. It was extracted with 1N hydrochloric acid and dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated to prepare the title compound (747 mg, 89%). [Synthesis Examples 2 to 15]

[0056] 2-Bromobenzoic acid as a starting material and reagent materials in Table 1 were used to prepare the compounds of Synthesis Examples 2 to 15 in the same way as Synthesis Example 1. [Table 1] Synthesis Examples 1 to 15 [Synthesis Example 16] Synthesis of 3'-chloro-5-fluoro-[1,1'-biphenyl]-2-carboxylic acid [Step 1] Ethyl 2-bromo-4-fluorobenzoate

[0057] 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 thereto and stirred under reflux for 24 hours. The reagent was cooled to room temperature after the reaction was over. The solvent was removed by concentration of the reagent under reduced pressure. It was extracted with water and ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (2.29 g, 87%). [Step 2] Ethyl 3'-chloro-5-fluoro-[1,1'-biphenyl]-2-carboxylate

[0058] Ethyl 2-bromo-4-fluorobenzoate (1.1 g, 4.47 mmol) prepared in Step 1 was dissolved in toluene (20 ml). 3-Chlorophenyl boronic 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 thereto. The reagent was stirred at 100°C for 6 hours and cooled to room temperature. It was filtered through celite and the solvent was removed by concentration of the reagent under reduced pressure. It was extracted with water and ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (850 mg, 69%). [Step 3] 3'-Chloro-5-fluoro-[1,1'-biphenyl]-2-carboxylic acid

[0059] Ethyl 3'-chloro-5-fluoro-[1,1'-biphenyl]-2-carboxylate (850 mg, 3.05 mmol) prepared in Step 2 was dissolved in ethanol (20 ml). 2N Sodium hydroxide solution (4.57 ml, 9.15 mmol) was added thereto and stirred under reflux for 12 hours. The reagent was cooled to room temperature. The solvent was removed by concentration of the reagent under reduced pressure and extracted with 1N hydrochloric acid and dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated to prepare the title compound (650 mg, 85%). [Synthesis Examples 17 to 26]

[0060] The starting materials and reagent materials in Table 2 were used to prepare the compounds of Synthesis Examples 17 to 26 in the same way as Synthesis Example 16. [Table 2] Synthesis Examples 16 to 26 [Synthesis Example A] Synthesis of 2-(1-methylpyrrolidin-2-yl)ethyl (2-iodophenyl)carbamate

[0061] 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 µl, 4.03 mmol) were added thereto. It was stirred at room temperature for 30 minutes, then stirred under reflux for 1 hour. The reagent was cooled to room temperature. 2-(2-Hydroxyethyl)-1-methylpyrrolidine (651 µl, 4.84 mmol) was added thereto and stirred under reflux for 12 hours. The reagent was cooled to room temperature. The solvent was removed by concentration of the reagent under reduced pressure and it was extracted with water and ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (1.16 g, 77%). [Synthesis Examples B-E]

[0062] The starting materials in Table 3 were used instead of 2-iodobenzoic acid to prepare the compounds of Synthesis Examples BE in the same way as Synthesis Example A. [Table 3] Synthesis Examples AE [Synthesis Example F] Synthesis of (R)-(1-methylpyrrolidin-3-yl)methyl (2-bromophenyl)carbamate [Step 1] Synthesis of (R)-tert-butyl 3-((((2-bromophenyl)carbamoyl)oxy)methyl)pyrrolidine-1-carboxylate

[0063] 2-Bromobenzoic acid (4.5 g, 22.4 mmol) was dissolved in toluene (100 ml) and biphenylphosphoryl azide (5.8 ml, 26.9 mmol) and triethylamine (3.15 ml, 22, 4 mmol) were added to it. It was stirred at room temperature for 30 minutes, then stirred under reflux for 1 hour. The reagent was cooled to room temperature, (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (5.41 g, 26.9 mmol) was added thereto, and stirred under reflux for 12 hours . The reagent was cooled to room temperature. The solvent was removed by concentration of the reagent under reduced pressure. It was extracted with water and dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (8.1 g, 91%). [Step 2] Synthesis of ((R)-pyrrolidin-3-ylmethyl-(2-bromophenyl)carbamate)

[0064] (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 (100ml). Trifluoroacetic acid (50 ml) was added thereto and stirred at room temperature for 2 hours. The solvent was removed by concentration of the reagent under reduced pressure, and it was extracted with 2N sodium hydroxide solution and dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (3.94 g, 65%). [Step 3] Synthesis of (R)-(1-methylpyrrolidin-3-yl)-(2-bromophenyl)carbamate )methyl

[0065] (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 sequentially added thereto and stirred at room temperature for 12 hours. The reagent was filtered, neutralized with 2N sodium hydroxide solution and extracted with water and dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (3.06 g, 75%). [Synthetic Examples G-L]

[0066] The starting materials and reagent materials in Table 4 were used to prepare the compounds of Synthesis Examples GL in the same way as Synthesis Example F. [Table 4] Synthesis Examples FL [Synthesis example M] Synthesis of (S)-(1-methylpyrrolidin-2-yl)methyl(2-bromophenyl)carbamate

[0067] 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 to it. It was stirred at room temperature for 30 minutes, then stirred under reflux for 1 hour. The reagent was cooled to room temperature. (S)-(1-methylpyrrolidin-2-yl)methanol (1.42 ml, 11.94 mmol) was added thereto and stirred under reflux for 4 hours. The reagent was cooled to room temperature. The solvent was removed by concentration of the reagent under reduced pressure. It was extracted with water and dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (1.4 g, 45%). [Synthetic Examples N-P]

[0068] The starting materials and reagent materials in Table 5 were used to prepare the compounds of Synthesis Examples NP in the same way as Synthesis Example M. [Table 5] Synthesis Examples MP Example [Table 6] Example Compounds [Example 1] Synthesis of 2-(1-methylpyrrolidin-2-yl)ethyl (4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate

[0069] 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 µl, 4.15 mmol) and triethylamine (486 µl, 3.46 mmol) were added to it. It was stirred at room temperature for 30 minutes, and then stirred again under reflux for 1 hour. The reagent was cooled to room temperature. 2-(2-Hydroxyethyl)-1-methylpyrrolidine (558 µl, 4.15 mmol) was added thereto and stirred under reflux for 12 hours. The reagent 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 with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (280 mg, 24%).[Examples 2-16]

[0070] The starting materials in Table 7 were used instead of 4'-fluoro-[1,1'-biphenyl]-2-carboxylic acid (747 mg, 3.46 mmol) (Synthesis Example 1) to prepare the compounds of Examples 2-16 in the same way as Example 1.[Table 7] Examples 2-16 [Example 17] Synthesis of 2-(1-methylpyrrolidin-2-yl)ethyl (3'-chloro-5-fluoro-[1,1'-biphenyl]-2-yl)carbamate

[0071] 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 µl, 1.44 mmol) and triethylamine (202 µl, 1.44 mmol) were added to it. It was stirred at room temperature for 30 minutes, and then stirred again under reflux for 1 hour. The reagent was cooled to room temperature. 2-(2-Hydroxyethyl)-1-methylpyrrolidine (194 µl, 1.44 mmol) was added thereto and then stirred under reflux for 12 hours. The reagent 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 with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (93 mg, 21%). [Examples 18-27]

[0072] The starting materials in Table 8 were used instead of 3'-chloro-5-fluoro-[1,1'-biphenyl]-2-carboxylic acid (300 mg, 1.20 mmol) (Synthesis example 16) to prepare the compounds of Examples 18-27 in the same way as Example 17. [Table 8] Examples 18-27 [Example 28] Synthesis of 2-(1-methylpyrrolidin-2-yl)ethyl (4'-cyano-[1,1'-biphenyl]-2-yl)carbamate

[0073] 2-(1-Methylpyrrolidin-2-yl)ethyl (2-iodophenyl)carbamate (600 mg, 1.6 mmol) (Synthesis Example A) was dissolved in a mixed solution of toluene (20 ml) and ethanol (4ml). 4-Cyanophenyl boronic acid (259 mg, 1.76 mmol), potassium carbonate (442 mg, 3.2 mmol) and tetrakis triphenylphosphine palladium (370 mg, 0.32 mmol) were added thereto. The reagent was stirred at 110°C for 12 hours 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, and then the organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (193 mg, 35%). [Examples 29-32]

[0074] 2-(1-Methylpyrrolidin-2-yl)ethyl (2-iodophenyl)carbamate from Synthesis Example A as a starting material and reaction materials in Table 9 were used to prepare the compounds of Examples 29-32 from same way as Example 28.[Table 9] Examples 29-32 [Example 33] Synthesis of 2-(1-methylpyrrolidin-2-yl)ethyl (3'-amino-[1,1'-biphenyl]-2-yl)carbamate

[0075] 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-Aminophenyl boronic 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 reagent was stirred at 110°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 with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (192 mg, 16%). [Examples 34-41]

[0076] 2-(1-Methylpyrrolidin-2-yl)ethyl (2-iodophenyl)carbamate from Synthesis Example A as a starting material and reagent materials in Table 10 were used to prepare the compounds of Examples 34-41 thereof so that Example 33.[Table 10] Examples 34-41 [Example 42] Synthesis of 2-(1-methylpyrrolidin-2-yl)ethyl (3',4',5-trifluoro-[1,1'-biphenyl]-2-yl)carbamate

[0077] 2-(1-Methylpyrrolidin-2-yl)ethyl (2-bromo-4-fluorophenyl)carbamate (400 mg, 1.16 mmol) (Synthesis Example B) was dissolved in toluene (20 ml). 3,4-Fluorophenyl diboronic acid (280 mg, 1.74 mmol), potassium carbonate (321 mg, 2.32 mmol) and tetrakis triphenylphosphine palladium (140 mg, 0.12 mmol) were added thereto. The reagent was stirred at 120°C for 12 hours 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 with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (15 mg, 3%). [Examples 43-46]

[0078] 2-(1-Methylpyrrolidin-2-yl)ethyl (2-bromo-4-fluorophenyl)carbamate from Synthesis Example B as a starting material and reagent materials in Table 11 were used to prepare the compounds of Examples 43 -46 in the same way as Example 42.[Table 11] Examples 43-46 [Examples 47-51]

[0079] 2-(1-Methylpyrrolidin-2-yl)ethyl (2-bromo-4-(trifluoromethyl)phenyl)carbamate from Synthesis Example C as a starting material instead of 2-(1-methylpyrrolidin-2- yl)ethyl(2-bromo-4-fluorophenyl)carbamate from Synthesis Example B and reagent materials in Table 12 were used to prepare the compounds of Examples 47-51 in the same manner as Example 42. [Table 12] Examples 47- 51 [Example 52] Synthesis of 2-(1-methylpyrrolidin-2-yl)ethyl (3'-chloro-5,5'-difluoro-[1,1'-biphenyl]-2-yl)carbamate

[0080] 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). (3-Chloro-5-fluorophenyl)boronic acid (303 mg, 1.74 mmol), sodium carbonate (184 mg, 1.74 mmol) and dichlorobis triphenylphosphine palladium (31 mg, 0.04 mmol) were added to it. . The reagent was stirred at 110°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 with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (51 mg, 15%). [Examples 53-59]

[0081] 2-(1-Methylpyrrolidin-2-yl)ethyl (2-bromo-4-fluorophenyl)carbamate from Synthesis Example B as a starting material and reagent materials in Table 13 were used to prepare the compounds of Examples 53 -59 in the same way as Example 52.[Table 13] Examples 53-59 [Examples 60-65]

[0082] 2-(1-Methylpyrrolidin-2-yl)ethyl (2-bromo-4-methoxyphenyl)carbamate from Synthetic Example D instead of 2-(1-methylpyrrolidin-2-yl)ethyl (2-bromo- 4-fluorophenyl)carbamate from Synthesis Example B as a starting material and reagent materials in Table 14 were used to prepare the compounds of Examples 60-65 in the same manner as Example 52. [Table 14] Examples 60-65 [Examples 66-73]

[0083] 2-(1-Methylpyrrolidin-2-yl)ethyl (2-bromo-4-chlorophenyl)carbamate from Synthetic Example E instead of 2-(1-methylpyrrolidin-2-yl)ethyl (2-bromo- 4-fluorophenyl)carbamate from Synthesis Example B as a starting material and reagent materials in Table 15 were used to prepare the compounds of Examples 66-73 in the same manner as Example 52. [Table 15] Examples 66-73 [Example 74] Synthesis of (R)-(1-methylpyrrolidin-3-yl)methyl(3'-fluoro-4'-formyl-[1,1'-biphenyl]-2-yl)carbamate

[0084] (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) were used as starting materials to prepare the title compound (124 mg, 50%) in the same manner as Example 52. [Example 75] Synthesis of 2-(1-methylpyrrolidin-2-yl) Ethyl (3',5'-difluoro-5-hydroxy-[1,1'-biphenyl]-2-yl)carbamate

[0085] 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 (10ml). A 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 the reaction was over, the reagent was extracted with water and dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (68 mg, 55%). [Example 76] Synthesis of 2-(1-methylpyrrolidin-2-yl)ethyl (3',5'-dichloro- 5-hydroxy-[1,1'-biphenyl]-2-yl)carbamate

[0086] 2-(1-Methylpyrrolidin-2-yl)ethyl (3',5'-dichloro-5-methoxy-[1,1'-biphenyl]-2-yl)carbamate (90 mg, 0.21 mmol ) (Example 64) was used instead of Example 62 to prepare the title compound (10 mg, 12%) in the same manner as Example 75. [Example 77] Synthesis of 2-(1-methylpyrrolidin-2-yl) Ethyl (3'-chloro-4'-fluoro-5-hydroxy-[1,1'-biphenyl]-2-yl)carbamate

[0087] 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) was used instead of Example 62 to prepare the title compound (130 mg, 96%) in the same manner as Example 75. [Example 78] Synthesis of (R)-pyrrolidin-3-ylmethyl [1,1'-biphenyl]-2-ylcarbamate [Step 1] (R)-tert-butyl 3-((([1,1'-biphenyl]-2-ylcarbamoyl)oxy)methyl)pyrrolidine-1-carboxylate

[0088] [1,1'-Biphenyl]-2-carboxylic acid (2 g, 10.09 mmol) was dissolved in toluene (50 mL), 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 again under reflux for 1 hour. The reagent was cooled to room temperature. (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (2.44 g, 12.11 mmol) was added thereto and stirred under reflux for 12 hours. The reagent 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 with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (3g, 75%).

[0089] 1H-NMR (CDCl3): δ 8.15-7.97 (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

[0090] (R)-tert-butyl 3-((([1,1'-biphenyl]-2-ylcarbamoyl)oxy)methyl)pyrrolidine-1-carboxylate (3 g, 7.57 mmol) was dissolved in dichloromethane (80ml). Trifluoroacetic acid (40 ml) was added thereto and stirred at room temperature for 2 hours. The solvent was removed by concentration of the reagent under reduced pressure and it was extracted with 2N sodium hydroxide solution and dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (1.73 g, 77%). [Examples 79-88]

[0091] Starting materials and reagent materials in Table 16 were used to prepare the compounds of Examples 79-88 in the same manner as Example 78. [Table 16] Examples 79-88 [Example 89] Synthesis of (R)-(1-methylpyrrolidin-3-yl)methyl[1,1'-biphenyl]-2-ylcarbamate

[0092] (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 sequentially added thereto and stirred at room temperature for 12 hours. The reagent was filtered, neutralized with 2N sodium hydroxide and extracted with water and dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (209 mg, 28%). [Examples 90-99]

[0093] Starting materials in Table 17 were used instead of (R)-pyrrolidin-3-ylmethyl [1,1'-biphenyl]-2-ylcarbamate to prepare the compounds of Examples 90-99 in the same manner as Example 89.[Table 17] Examples 90-99 [Example 100] Synthesis of (R)-(1-methylpyrrolidin-3-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate [Step 1] Synthesis of (R)-pyrrolidin-3-ylmethyl (3'-methyl-[1,1'-biphenyl]-2-yl)carbamate

[0094] 3'-Methyl-[1,1'-biphenyl]-2-carboxylic acid (Synthesis Example 14) and (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate were used as materials of starting to prepare the title compound in the same manner as Example 78.

[0095] 1H-NMR (CDCl3): δ 8.13-7.97 (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] Synthesis of (R) -(1-methylpyrrolidin-3-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate

[0096] (R)-pyrrolidin-3-ylmethyl biphenyl]-2-yl)carbamate (600 mg, 1.93 mmol) prepared in Step 1 was used to prepare the title compound (30 mg, 5%) from the same as Example 89. [Example 101] Synthesis of (S)-(1-methylpyrrolidin-3-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate [Step 1] Synthesis of (S)-pyrrolidin-3-ylmethyl (3'-methyl-[1,1'-biphenyl]-2-yl)carbamate

[0097] 3'-Methyl-[1,1'-biphenyl]-2-carboxylic acid (Synthesis Example 14) and (S)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate were used as materials of starting to prepare the title compound in the same manner as Example 78.

[0098] 1H-NMR (CDCl3): δ 8.15-7.99 (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] Synthesis of (S)-(1-methylpyrrolidin-3-yl)methyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate

[0099] (S)-pyrrolidin-3-ylmethyl(3'-methyl-[1,1'-biphenyl]-2-yl)carbamate (900 mg, 2.90 mmol) prepared in Step 1 was used to prepare the title compound (208 mg, 22%) in the same manner as Example 89. [Example 102] Synthesis of (R)-(1-ethylpyrrolidin-3-yl)methyl[1,1'-biphenyl]-2-ylcarbamate

[0100] (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 µl, 4.04 mmol) were added sequentially to it and stirred at 120°C for 12 hours. The reagent was cooled to room temperature and extracted with water and ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (142 mg, 13%). [Examples 103-105]

[0101] Starting materials in Table 18 were used instead of (R)-pyrrolidin-3-ylmethyl [1,1'-biphenyl]-2-ylcarbamate to prepare the compounds of Examples 103-105 in the same manner as Example 102.[Table 18] Examples 103-105 [Example 106] Synthesis of (S)-(1-ethylpyrrolidin-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate

[0102] (S)-pyrrolidin-2-ylmethyl [1,1'-biphenyl]-2-ylcarbamate (1 g, 3.37 mmol) and 2-iodoethane (323 µl, 4.04 mmol) were used as materials starting material to prepare the title compound (385 mg, 35%) in the same manner as Example 102. [Example 107] Synthesis of (S)-(1-isobutylpyrrolidin-2-yl)methyl[1,1'-biphenyl ]-2-ylcarbamate

[0103] (S)-pyrrolidin-2-ylmethyl [1,1'-biphenyl]-2-ylcarbamate (940 mg, 3.17 mmol) and 1-iodo-2-methylpropane (438 µl, 3.08 mmol) were used as starting materials to prepare the title compound (47 mg, 4%) in the same manner as Example 102. [Example 108] Synthesis of (S)-(1-methylpyrrolidin-3-yl)methyl(3',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate

[0104] 3',5-Difluoro-[1,1'-biphenyl]-2-carboxylic acid (800 mg, 3.42 mmol) (Synthetic example 17) and (S)-tert-butyl 3-(hydroxymethyl) )pyrrolidine-1-carboxylate (825 mg, 4.10 mmol) were used as starting materials to prepare the title compound (50 mg, 5%) in the same manner as Example 78 and Example 89. [Example 109] Synthesis of (R)-(1-methylpyrrolidin-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate [Step 1] Synthesis of (R)-pyrrolidin-2-ylmethyl [1,1'-biphenyl]-2-ylcarbamate

[0105] [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) were used as starting materials to prepare the title compound (730 mg, 60%) in the same manner as Example 78.

[0106] 1H-NMR (CDCl3): δ 8.09-8.08 (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

[0107] (R)-pyrrolidin-2-ylmethyl [1,1'-biphenyl]-2-ylcarbamate (730 mg, 2.46 mmol) was used as a starting material to prepare the title compound (183 mg, 24%) in the same manner as Example 89. [Example 110] Synthesis of (R)-(1-methylpyrrolidin-2-yl)methyl (3'-methyl-[1,1'-biphenyl]-2-yl) carbamate

[0108] 3'-Methyl-[1,1'-biphenyl]-2-carboxylic acid (700 mg, 3.3 mmol) (Synthetic example 14) and (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine -1-carboxylate (797 mg, 3.96 mmol) were used as starting materials to prepare the title compound (258 mg, 24%) in the same manner as Example 78 and Example 89. [Example 111] Synthesis of ( R)-(1-methylpyrrolidin-2-yl)methyl(5-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl)carbamate

[0109] 5-Fluoro-3'-methyl-[1,1'-biphenyl]-2-carboxylic acid (1 g, 4.34 mmol) (Synthesis Example 21) and (R)-tert-butyl 2- (hydroxymethyl)pyrrolidine-1-carboxylate (1.05 g, 5.21 mmol) were used as starting materials to prepare the title compound (52 mg, 4%) in the same manner as Example 78 and Example 89.[ Example 112] Synthesis of (S)-(1-isopropylpyrrolidin-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate [Step 1] Synthesis of (S)-pyrrolidin-2-ylmethyl [1,1'-biphenyl]-2-ylcarbamate

[0110] [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) were used as starting materials to prepare the title compound (3.06 g, 82%) in the same manner as Example 78.

[0111] 1H-NMR (CDCl3) δ 7.88 (m, 1H), 7.48-7.42 (m, 1H), 7.15-7.05 (m, 4H), 7.04-6 .92 (m, 1H), 6.40 (s, 1H), 4.784.76 (m, 1H), 3.23-3.21 (m, 1H), 2.87-2.73 (m, 4H ), 2.062.05 (m, 3H), 2.04-1.67 (m, 1H), 1.66-1.54 (m, 1H), 1.531.35 (m, 1H). [Step 2] Synthesis of (S)-(1-isopropylpyrrolidin-2-yl)methyl[1,1'-biphenyl]-2-ylcarbamate

[0112] (S)-pyrrolidin-2-ylmethyl [1,1'-biphenyl]-2-ylcarbamate (1 g, 3.37 mmol) and 2-iodopropyl (404 µl, 4.04 mmol) were used as materials starting material to prepare the title compound (78 mg, 7%) in the same manner as Example 102. [Example 113] Synthesis of (R)-(1-methylpyrrolidin-3-yl)methyl(3'-fluoro-[ 1,1'-biphenyl]-2-yl)carbamate

[0113] (R)-(1-methylpyrrolidin-3-yl)methyl(2-bromophenyl)carbamate (230 mg, 0.73 mmol) (Synthesis Example F) was dissolved in a mixed ethanol solution (5 ml) and water (5 ml). 3-Fluorophenylboronic acid (123 mg, 0.88 mmol), potassium carbonate (203 mg, 1.47 mmol), di(acetate)dicyclohexylphenyl-phosphine palladium(II) and polymer-bound FibreCatTM (30 mg) were added to he. The reagent was stirred at 110°C for 12 hours and then 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 with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (60 mg, 25%). [Examples 114-115]

[0114] Reagent materials in Table 19 were used instead of 3-fluorophenylboronic acid to prepare the compounds of Examples 114-115. [Table 19] Example 114-115 [Examples 116] Synthesis of (S)-(1-methylpyrrolidin-3-yl)methyl (3'-fluoro-[1,1'-biphenyl]-2-yl)carbamate

[0115] (S)-(1-methylpyrrolidin-3-yl)methyl(2-bromophenyl)carbamate (200 mg, 0.64 mmol) (Synthesis Example G) was dissolved in toluene (10 ml). 3-Fluorophenylboronic 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 reagent was stirred at 110°C for 12 hours 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 with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (102 mg, 49%). [Examples 117-129]

[0116] Starting materials and reagent materials in Table 20 were used to prepare the compounds of Examples 117-129 in the same manner as Example 116. [Table 20] Examples 117-129 [Example 130] Synthesis of (R)-(1-methylpyrrolidin-3-yl)methyl(3',4'-dichloro-[1,1'-biphenyl]-2-yl)carbamate

[0117] (R)-(1-methylpyrrolidin-3-yl)methyl (2-bromophenyl) carbamate (225 mg, 0.72 mmol) (Synthesis Example F) was dissolved in a mixed ethanol solution (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 reagent was stirred at 110°C for 6 hours 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 with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (151 mg, 56%). [Examples 131-135]

[0118] Starting materials and reagent materials in Table 21 were used to prepare the compounds of [Example 136] Synthesis of (R)-(1-methylpyrrolidin-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate

[0119] (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)boronic acid (279 mg, 1.60 mmol), sodium carbonate (170 mg, 1.60 mmol) and dichlorobis-triphenylphosphine palladium (28 mg, 0.04 mmol) were added to he. The reagent was stirred in a microwave oven at 110°C 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 with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (23 mg, 70%). [Examples 137-149]

[0120] Starting materials and reagent materials in Table 22 were used to prepare the compounds of Examples 137-149 in the same manner as Example 136. [Table 22] Examples 137-149 [Example 150] Synthesis of (R)-(1-ethylpyrrolidin-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate [Step 1] Synthesis of (R)-tert-butyl 3-((((3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamoyl)oxy)methyl)pyrrolidine- 1-carboxylate

[0121] (R)-tert-butylbromophenyl)carbamoyl)oxy)methyl) (4 g, 10.02 mmol) (Synthesis Example F, Step 1) and (3-chloro-4-fluoro)phenylboronic acid (3 .5 g, 20.04 mmol) were used as starting materials to prepare the title compound (3.4 g, 76%) in the same way as Example 42.

[0122] 1H-NMR (CDCl3): δ 8.01 (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] Synthesis of (R)-pyrrolidin-3-ylmethyl (3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate

[0123] (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 was used as a starting material to prepare the title compound (2.3 g, 87%) in the same manner as Example 78.

[0124] 1H-NMR (CDCl3): δ 7.98 (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] Synthesis of (R)-pyrrolidin-3-ylmethyl (3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate

[0125] (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 µl, 1.09 mmol) and bromoethane (118 µl, 1.58 mmol) were added sequentially to it and stirred at room temperature for 3 days. The reagent was concentrated under reduced pressure and extracted with water and dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (74 mg, 20%). [Example 151] Synthesis of (R)-(1-isopropylpyrrolidin-3-yl)methyl(3'-chloro- 4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate

[0126] (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 (20ml). Triethylamine (150 µl, 1.10 mmol) and 2-bromopropane (100 µl, 1.10 mmol) were sequentially added thereto and stirred at room temperature for 3 days. The reagent was concentrated under reduced pressure and extracted with water and dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (17 mg, 4%). [Example 152] Synthesis of (R)-(1-methylpyrrolidin-3-yl)methyl(3'-(hydroxymethyl)) -[1,1'-biphenyl]-2-yl)carbamate

[0127] (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 reagent was stirred at 110°C for 12 hours 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 with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (126 mg, 29%). [Examples 153-190]

[0128] Starting materials and reagent materials in Table 23 were used to prepare the compounds of Examples 153-190 in the same way as Example 152.[Table 23] Examples 153-190 [Example 191] Synthesis of (R)-(1-methylpyrrolidin-3-yl)methyl(3',5'-dimethyl-[1,1'-biphenyl]-2-yl)carbamate

[0129] (R)-(1-methylpyrrolidin-3-yl)methyl (2-bromophenyl) carbamate (220 mg, 0.70 mmol) (Synthesis Example F) was dissolved in a mixed ethanol solution (5 ml) and water (5 ml). 3,5-Dimethylboronic acid (211 mg, 1.41 mmol), potassium carbonate (194 mg, 1.41 mmol), di(acetate)dicyclohexylphenyl-phosphine palladium(II) and polymer-bound FibreCatTM (28 mg) were added to it. The reagent was stirred in a microwave oven at 110°C 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 with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (134 mg, 56%). [Examples 192-195]

[0130] Starting materials and reagent materials in Table 24 were used to prepare the compounds of Examples 192-195 in the same way as Example 191.[Table 24] Examples 192-195 [Example 196] Synthesis of (R)-(1-ethylpyrrolidin-3-yl)methyl(3'-chloro-4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate [Step 1] Synthesis of (R)-(1-ethylpyrrolidin-3-yl)methyl (2-bromo-4-fluorophenyl)carbamate

[0131] 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) were used as starting materials to prepare the title compound (4.5 g, 79%) in the same way as Synthesis Example F.

[0132] 1H-NMR (CDCl3): δ 8.00 (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 = 7.2 Hz). [Step 2] Synthesis of (R)- (1-ethylpyrrolidin-3-yl)methyl(3'-chloro-4',5-difluoro-[1,1'-biphenyl]-2-yl)carbamate

[0133] (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) were used as starting materials to prepare the title compound (143 mg, 76%) in the same manner as Example 136. [Example 197] Synthesis of (S)-(1-methylpyrrolidin-2) -yl)methyl[1,1'-biphenyl]-2-ylcarbamate

[0134] [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. It was stirred at room temperature for 30 minutes, and then stirred again under reflux at room temperature for 1 hour. The reagent was cooled to room temperature and (S)-(1-methylpyrrolidin-2-yl)methanol (0.72 ml, 6.05 mmol) was added thereto, and then stirred under reflux for 12 hours. The reagent was cooled to room temperature. The solvent was removed by concentration under reduced pressure. It was extracted with water and ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (458 mg, 29%). [Examples 198-207]

[0135] Starting materials and reagent materials in Table 25 were used to prepare the compounds of Examples 198-207 in the same way as Example 197.[Table 25] Examples 198-207 [Example 208] Synthesis of (S)-(1-methylpyrrolidin-2-yl)methyl(5-fluoro-3',5'-dimethyl-[1,1'-biphenyl]-2-yl)carbamate

[0136] (S)-(1-methylpyrrolidin-2-yl)methyl (2-bromo-4-fluorophenyl)carbamate (200 mg, 0.60 mmol) (Synthesis Example N) was dissolved in a mixed acetonitrile solution (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 thereto. The reagent was stirred in a microwave oven at 150°C 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 with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the title compound (98 mg, 46%). [Examples 209-226]

[0137] Starting materials and reagent materials in Table 26 were used to prepare the compounds of Examples 209-226 in the same way as Example 208.[Table 26] Examples 209-226

[Experimental example 1] Binding assay on human M3 muscarinic receptor

[0138] Cell membrane proteins (Perkin Elmer), in which the human M3 muscarinic receptor was overexpressed, [3H]-methyl scopolamine and test compounds at various concentrations were cultured in 0.2 ml of Tris-HCl buffer at 25° C for 120 minutes. They were filtered under suction through a glass fiber filter (Whatman GF/B), and then the filter was washed 5 times with 1 ml of Tris-HCl buffer. The radioactivity of [ 3 H]-methyl scopolamine adsorbed on the filter was measured by a liquid scintillation counter. Non-specific binding was evaluated under the presence of 5 µM atropine. The affinity of the compound of the present invention to the M3 muscarinic receptor was calculated as the dissociation constant (Ki), which can be calculated from the concentration (IC50) of test compounds that inhibit 50% of [ 3 H]-methyl scopolamine binding (ie, labeled linker) according to Cheng and Prusoff [Cheng and Prusoff, Biochem. Pharmacol., 22, 3099, 1973]. In the following Table, compounds that have stronger binding affinity for human muscarinic M3 receptor have lower dissociation constant (Ki).[Table 27] Binding affinity for human muscarinic M3 receptor

[Experimental example 2] Human M3 muscarinic receptor antagonism assay

[0139] The antagonism assay for various compounds of the present invention was performed on human M3 receptor antagonism in Cos-7 cells that were transfected with plasmid encoding human M3 muscarinic receptor. Test compounds at various concentrations were pre-treated to the cells for 3 minutes, and then changes in intracellular calcium were measured after treatment of the cells with carbachol (ie muscarinic receptor agonist). The “FLIPR® Calcium 5” assay (Molecular Devices) and the Flex3 device (Molecular Devices) were used to measure calcium concentration. Calcium amounts before and after carbachol treatment were defined as 0% and 100%, respectively. Inhibition rates (%) by compounds for the increase in intracellular calcium by carbachol were calculated. The antagonistic potency of test compounds at the human M3 muscarinic receptor was calculated as the functional inhibitory constant (Ki), which can be calculated from the concentration (IC50) of compound that inhibits 50% of carbachol activity according to the equation of Cheng and Prusoff. The compounds used in the experiment were identified as antagonists for the human muscarinic M3 receptor, and a lower Ki value means greater antagonistic potency.[Table 28] Antagonistic potency for the human muscarinic M3 receptor

[Experimental example 3] Experiment on rhythmic bladder contractions in rats (in vivo)

[0140] A female Sprague-Dawley rat was anesthetized with halothane, and a polyethylene catheter was inserted through the urethra directly and fixed. Urine in the bladder was excreted through the catheter by gently massaging the rat's abdomen and then removing it. A three-way valve was connected to the catheter and a pressure transducer was connected to one side of the three-way valve to measure pressure, and a syringe was installed to the other side to inject saline at 37°C. Saline solution was slowly injected until regular bladder contractions occurred repeatedly. When regular bladder contractions were stably occurring, test compounds were administered intravenously through the tail vein. The inhibitory effect of test compounds was evaluated by measuring the degree of reduction in the amplitude of bladder contractions. The compounds of the present invention significantly reduced the amplitude of bladder contractions when the compounds were administered at least 0.3 mg/kg or more.[Table 29] Rhythmic bladder contraction in rats

[Experimental example 4] Acute toxicity test for oral administration in rats

[0141] In order to confirm the acute toxicity of the compounds of the present invention, the following experiment was carried out. A low dose group, a medium dose group and a high dose group, in which the compounds of the Examples were administered at 100 mg/kg, 300 mg/kg and 1000 mg/kg, respectively, were prepared. Methyl cellulose solution (0.5%) was prepared and administered orally to 3 rats from each group (i.e., male and female 6-week-old Sprague-Dawley (SD) rats; male rats weighing 142-143 g ; female rats weighing 126.3-127.3 g), in a volume of 10 ml/kg. Mortality, clinical signs and weight and the like were measured for 4 days, and an approximate lethal dose (ALD) discovered from them was explained in Table 30 below. As shown in Table 30, the approximate lethal dose of the test compounds was 1000 mg/kg or more and therefore the compounds were determined to be safe drugs. [Table 30] Approximate lethal dose

industrial applicability

[0142] The new biphenyl derivatives, isomers or pharmaceutically acceptable salts thereof according to the present invention act as a muscarinic M3 receptor antagonist and, therefore, may be useful for the prevention or treatment of a disease selected from the group that consists of chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, Alzheimer's disease, senile dementia, glaucoma, schizophrenia, gastroesophageal reflux disease, cardiac arrhythmia, and hypersalivation syndrome.

Claims (12)

1. Biphenyl derivative characterized by being represented by the following formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof: wherein: R1 is hydrogen, halogen, hydroxy, unsubstituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, or C1C6 alkoxy; R2, R3 and R4 are each independently hydrogen, halogen, unsubstituted amino, amino substituted with C1C6 alkyl, nitro, cyano, hydroxy, unsubstituted C1-C6 alkyl, C1-C6 alkyl substituted with halogen or hydroxy, C1- unsubstituted C6 alkoxy, halogen-substituted 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. Biphenyl derivative, isomer thereof or pharmaceutically acceptable salt thereof, according to claim 1, characterized by the fact that RI is hydrogen or halogen; R2, R3 and R4 are each independently hydrogen, halogen, or C1-C6 alkyl; and R5 is C1-C6 alkyl. 3. Biphenyl derivative, isomer thereof or pharmaceutically acceptable salt thereof, according to claim 1, characterized by the fact that Ri is hydrogen; R2, R3 and R4 are independently hydrogen or halogen; R5 is C1-C6 alkyl; and n is 0 or 1. 4. Biphenyl derivative, isomer thereof or pharmaceutically acceptable salt thereof, according to claim 1, characterized in that the new biphenyl derivative is selected from the group consisting of the following compounds: 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. 5. Method for preparing a compound of the following formula 1 or a pharmaceutically acceptable salt thereof, characterized in that the method comprises a step of reacting a compound of the following formula 2 with a compound of the following formula 3 in the presence of a reagent of carbamate synthesis: wherein R1 to R5 and n are as defined in claim 1. 6. Method for preparing a compound of the following formula 1 or a pharmaceutically acceptable salt thereof, characterized in that the method comprises the steps of: reacting a compound of the following formula 2 with a compound of the following formula 3a 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: wherein R1 to R5 and n are as defined in claim 1, and PG1 is an amine protecting group selected from the group consisting of Boc (tert-butyloxycarbonyl), benzyl, tert-butyl, PMB (4-methoxybenzyl), Fmoc ( fluorenylmethyloxycarbonyl), Ts (tosylate), MOM (methoxymethyl), THP (tetrahydropyranyl), TBDMS (tert-butyldimethylsilyl) and TBDPS (tert-butyldiphenylsilyl). 7. Method according to claim 5 or 6, characterized in that the compound of formula 2 is prepared by the steps of: reacting a compound of the following formula 5 in the presence of an acid to prepare a compound of the following formula 6 , which has a carboxylic acid protecting group introduced therein; coupling the compound of formula 6 with a compound of formula 7 below to prepare a compound of formula 8 below; and deesterifying the compound of formula 8 in the presence of a base: wherein R1 to R5 and n are as defined in claim 1; X is halogen; and PG2 is a protecting group selected from the group consisting of a C1-C4 alkyl, benzyl, PMB (4-methoxybenzyl), THP (tetrahydropyranyl), TBDMS (tert-butyldimethylsilyl) and TBDPS (tert-butyldiphenylsilyl) group. 8. Method for preparing a compound of the following formula 1 or a pharmaceutically acceptable salt thereof, characterized in that the method comprises the steps of: reacting a compound of the following formula 5 with a compound of the following formula 3 in the presence of a carbamate synthesis reagent to prepare a compound of formula 9 below; and coupling a compound of the following formula 7 to the compound of formula 9: wherein R1 to R5 and n are as defined in claim 1, and X is halogen. 9. Method for preparing a compound of the following formula 1 or a pharmaceutically acceptable salt thereof, characterized in that the method comprises the steps of: reacting a compound of the following formula 5 with a compound of the following formula 3a in the presence of a carbamate synthesis reagent for preparing a compound of formula 9a below; deprotecting the compound of formula 9a to prepare 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 the following formula 7 to the compound of formula 9: wherein R1 to R5 and n are as defined in claim 1; X is halogen; and PG1 is as defined in claim 6. 10. Method according to any one of claims 5, 6, 8 and 9, characterized in that the carbamate synthesis reagent comprises an azide compound. 11. Method according to claim 10, characterized in that the carbamate synthesis reagent is a mixture of diphenylphosphoryl azide (DPPA) and triethylamine, a mixture of propylphosphonic anhydride (T3P), trimethylsilyl azide (TMSN3) and triethylamine , or a mixture of sodium azide (NaN3), tetrabutylammonium bromide and zinc(II) triflate. 12. Use of a composition containing the compound, as defined in claim 1, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, the use being characterized by the fact that it is in the preparation of a medicine for the prevention or treatment of a disease selected from the group consisting of chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, Alzheimer's disease, senile dementia, glaucoma, schizophrenia, gastroesophageal reflux disease, cardiac arrhythmia, hypersalivation, enuresis, nervous frequency, neurogenic bladder, unstable bladder, cystospasm, frequent urination, overactive bladder and urinary urgency.