NZ736557B2 - The Biphenyl Derivative and Method for Preparing Same - Google Patents

The Biphenyl Derivative and Method for Preparing Same Download PDF

Info

Publication number
NZ736557B2
NZ736557B2 NZ736557A NZ73655714A NZ736557B2 NZ 736557 B2 NZ736557 B2 NZ 736557B2 NZ 736557 A NZ736557 A NZ 736557A NZ 73655714 A NZ73655714 A NZ 73655714A NZ 736557 B2 NZ736557 B2 NZ 736557B2
Authority
NZ
New Zealand
Prior art keywords
biphenyl
carbamate
methyl
methylpyrrolidinyl
fluoro
Prior art date
Application number
NZ736557A
Other versions
NZ736557A (en
Inventor
Chong Hwan Cho
Kang Hun Cho
Sung Hak Choi
Sun Ho Choi
Weon Bin Im
Mi Yeon Kim
Soon Hoe Kim
Min Jung Lee
Jung Sang Park
Original Assignee
Dong A St Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020130090175A external-priority patent/KR101538846B1/en
Application filed by Dong A St Co Ltd filed Critical Dong A St Co Ltd
Publication of NZ736557A publication Critical patent/NZ736557A/en
Publication of NZ736557B2 publication Critical patent/NZ736557B2/en

Links

Abstract

The present invention provides biphenyl derivatives, isomers thereof, or pharmaceutically acceptable salts thereof, methods for preparing the same, and a pharmaceutical composition containing the same. The biphenyl derivatives, isomers thereof, or pharmaceutically acceptable salts thereof, as disclosed in the present invention, act as muscarinic M3 receptor antagonists, and thus are useful 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 hyper-salivation syndromes. osed in the present invention, act as muscarinic M3 receptor antagonists, and thus are useful 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 hyper-salivation syndromes.

Description

【DESCRIPTION 】 【Invention Title 】 The Biphenyl Derivative and Method for Preparing Same 【Technical Field 】 The present invention relates to novel muscarinic M3 receptor antagonists, and more particularly, to novel biphenyl derivatives having muscarinic M3 receptor antagonist activity, or isomers thereof, pharmaceutically acceptable salts thereof, or hydrates thereof, methods for preparing the same, and a pharmaceutical composition containing the same as an active ingredient.
【Background Art 】 Muscarinic receptors are found in all parts of the human body, including the brain and salivary glands. Such receptors are members of G-protein coupled receptors, and are further divided into five subtypes (M1 to M5). Among these subtypes, M1, M2 and M3 receptors are extensively found in tissues of animal and human, and their pharmacological properties have been elucidated.
Muscarinic M1 receptor is expressed mainly in cerebral cortex, and is involved in the regulation of higher cognitive functions. The M2 receptor is found mainly in heart and bladder smooth muscles, and is involved in regulation of 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 the urinary tract, and salivation. The M4 and M5 receptors 1001965344 are found in the brain, and the M4 receptor is mainly involved in movement, but the role of the M5 receptor remains obscure.
Generally, it was 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 hyper-salivation syndromes (Invest. Drugs, 1997, 6 (10), 1395-1411, Drugs Future, 1997, 22 (2) 135-137, Drugs Future, 1996, 21 (11), 1105-1108, Drugs Future, 1997, 22 (7), 733-737).
Meanwhile, it is known that, among the muscarinic receptors, the M2 and M3 receptors are predominant in human bladder and play a role in the regulation of bladder contraction. The M2 receptor is present in the bladder in an amount that is at least three times larger than the M3 receptor, and it plays a role in inhibiting bladder relaxation by beta-receptor rather than being involved directly in bladder contraction. Thus, the M3 receptor appears to play the most important role in bladder contraction. Therefore, selective antagonists against the M3 receptor exhibit excellent inhibitory effects against muscarinic bladder contraction, but inhibit salivary secretion to cause dry mouth. 1001965344 Accordingly, the present inventors have prepared novel derivatives that can exhibit functional activity by their selective binding to the muscarinic M3 receptor and have minimized side effects, thereby completing the present invention.
【Disclosure 】 【Technical Problem 】 It is an object of the present invention to provide novel biphenyl derivatives or pharmaceutically acceptable salts thereof.
Another object of the present invention is to provide methods for preparing novel biphenyl derivatives or pharmaceutically acceptable salts thereof.
Still 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 】 The present invention provides novel biphenyl derivatives or pharmaceutically acceptable salts thereof.
The present invention also provides methods for preparing novel biphenyl derivatives or pharmaceutically acceptable salts thereof.
The present invention also provides muscarinic M3 receptor antagonists containing novel biphenyl derivatives, pharmaceutically acceptable salts thereof, or hydrates thereof as an active ingredient. 1001965344 As used herein, the term "alkyl" means a straight or branched hydrocarbon radical. For example, C -C 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.
As used herein, the term "alkoxy" means a radical wherein the hydrogen atom of a hydroxyl group is substituted with alkyl. For example, C -C alkoxy is intended to include all methoxy, ethoxy, propoxy, n-butoxy, n-pentyloxy, isopropoxy, sec-butoxy, tert-butoxy, neopentyloxy, isopentyloxy and the like.
Novel Biphenyl Derivatives The present invention provides novel biphenyl derivatives represented by the following Formula 1, or pharmaceutically acceptable salts thereof: [Formula 1] wherein R is hydrogen, halogen, hydroxy, substituted or unsubstituted C -C alkyl, or C -C alkoxy; 1 6 1 6 1001965344 R, R and R are each independently hydrogen, halogen, 2 3 4 substituted or unsubstituted amino, nitro, cyano, hydroxy, substituted or unsubstituted C -C alkyl, substituted or unsubstituted C -C alkoxy, or -C(O)R ; 1 6 6 R is hydrogen or C -C alkyl; 1 6 n is 0 or 1; and R is hydrogen or amino.
In a preferred embodiment of the present invention, R in Formula 1 may be hydrogen or halogen; R , R and R may 2 3 4 each independently be hydrogen, halogen, or C -C alkyl; and R may be C -C alkyl. 1 6 In another preferred embodiment of the present invention, R in Formula 1 may be hydrogen; R , R and R may 1 2 3 4 each independently be hydrogen or halogen; R may be C -C 1 6 alkyl; and n may be 0 or 1.
In the present invention, the pharmaceutically acceptable salts are preferably acid addition salts formed with pharmaceutically acceptable free acids. Free acids that may be used in the present invention include organic acids and inorganic acids. The inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc, and the 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. 1001965344 In addition, the compounds of Formula 1 or pharmaceutically acceptable salts thereof can show polymorphism, and can 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.
The present invention is also directed to novel biphenyl derivatives selected from the group consisting of the following compounds: 1) 2-(1-methylpyrrolidinyl)ethyl (4'-fluoro-[1,1'- biphenyl]yl)carbamate; 2) 2-(1-methylpyrrolidinyl)ethyl (3',5'-difluoro- [1,1'-biphenyl]yl)carbamate; 3) 2-(1-methylpyrrolidinyl)ethyl (3',4',5'- trifluoro-[1,1'-biphenyl]yl)carbamate; 4) 2-(1-methylpyrrolidinyl)ethyl (3'-fluoro-[1,1'- biphenyl]yl)carbamate; ) 2-(1-methylpyrrolidinyl)ethyl (4'-methoxy- [1,1'-biphenyl]yl)carbamate; 6) 2-(1-methylpyrrolidinyl)ethyl [1,1'-biphenyl]- 2-ylcarbamate; 7) 2-(1-methylpyrrolidinyl)ethyl (4'-chloro-[1,1'- biphenyl]yl)carbamate; 8) 2-(1-methylpyrrolidinyl)ethyl (3'-chloro-[1,1'- biphenyl]yl)carbamate; 9) 2-(1-methylpyrrolidinyl)ethyl (3',5'-dichloro- [1,1'-biphenyl]yl)carbamate; 1001965344 ) 2-(1-methylpyrrolidinyl)ethyl (4'- trifluoromethoxy-[1,1'-biphenyl]yl)carbamate; 11) 2-(1-methylpyrrolidinyl)ethyl (4'-nitro-[1,1'- biphenyl]yl)carbamate; 12) 2-(1-methylpyrrolidinyl)ethyl (3'- trifluoromethyl-[1,1'-biphenyl]yl)carbamate; 13) 2-(1-methylpyrrolidinyl)ethyl (4'- trifluoromethyl-[1,1'-biphenyl]yl)carbamate; 14) 2-(1-methylpyrrolidinyl)ethyl ((3'-fluoro-4'- methyl)-[1,1'-biphenyl]yl)carbamate; ) 2-(1-methylpyrrolidinyl)ethyl (3'-methyl- [1,1'-biphenyl]yl)carbamate; 16) 2-(1-methylpyrrolidinyl)ethyl (3'-ethoxy- [1,1'-biphenyl]yl)carbamate; 17) 2-(1-methylpyrrolidinyl)ethyl (3'-chloro fluoro-[1,1'-biphenyl]yl)carbamate; 18) 2-(1-methylpyrrolidinyl)ethyl (3',5-difluoro- [1,1'-biphenyl]yl)carbamate; 19) 2-(1-methylpyrrolidinyl)ethyl (4',5-difluoro- [1,1'-biphenyl]yl)carbamate; ) 2-(1-methylpyrrolidinyl)ethyl (3',5,5'- trifluoro-[1,1'-biphenyl]yl)carbamate; 21) 2-(1-methylpyrrolidinyl)ethyl (5-fluoro-[1,1'- biphenyl]yl)carbamate; 22) 2-(1-methylpyrrolidinyl)ethyl (5-fluoro-3'- methyl-[1,1'-biphenyl]yl)carbamate; 1001965344 23) 2-(1-methylpyrrolidinyl)ethyl (4-fluoro-[1,1'- biphenyl]yl)carbamate; 24) 2-(1-methylpyrrolidinyl)ethyl (3',4-difluoro- [1,1'-biphenyl]yl)carbamate; 25) 2-(1-methylpyrrolidinyl)ethyl (4-methoxy- [1,1'-biphenyl]yl)carbamate; 26) 2-(1-methylpyrrolidinyl)ethyl (5-methyl-[1,1'- biphenyl]yl)carbamate; 27) 2-(1-methylpyrrolidinyl)ethyl (3'-fluoro methyl-[1,1'-biphenyl]yl)carbamate; 28) 2-(1-methylpyrrolidinyl)ethyl (4'-cyano-[1,1'- biphenyl]yl)carbamate; 29) 2-(1-methylpyrrolidinyl)ethyl (3'-(3- hydroxypropyl)-[1,1'-biphenyl]yl)carbamate; 30) 2-(1-methylpyrrolidinyl)ethyl (4'- (dimethylamino)-[1,1'-biphenyl]yl)carbamate; 31) 2-(1-methylpyrrolidinyl)ethyl (4'-(tert- butyl)-[1,1'-biphenyl]yl)carbamate; 32) 2-(1-methylpyrrolidinyl)ethyl (2'-amino-[1,1'- biphenyl]yl)carbamate; 33) 2-(1-methylpyrrolidinyl)ethyl (3'-amino-[1,1'- biphenyl]yl)carbamate; 34) 2-(1-methylpyrrolidinyl)ethyl (2'-fluoro- [1,1'-biphenyl]yl)carbamate; 35) 2-(1-methylpyrrolidinyl)ethyl (2'-chloro- [1,1'-biphenyl]yl)carbamate; 1001965344 36) 2-(1-methylpyrrolidinyl)ethyl (2'-hydroxy- [1,1'-biphenyl]yl)carbamate; 37) 2-(1-methylpyrrolidinyl)ethyl (3'-tert-butyl- '-methyl-[1,1'-biphenyl]yl)carbamate; 38) 2-(1-methylpyrrolidinyl)ethyl (4'-fluoro-3'- (trifluoromethyl)-[1,1'-biphenyl]yl)carbamate; 39) 2-(1-methylpyrrolidinyl)ethyl (4'-amino-3'- chloro-[1,1'-biphenyl]yl)carbamate; 40) 2-(1-methylpyrrolidinyl)ethyl (3'-hydroxy- [1,1'-biphenyl]yl)carbamate; 41) 2-(1-methylpyrrolidinyl)ethyl (3'-chloro-4’- fluoro-[1,1'-biphenyl]yl)carbamate; 42) 2-(1-methylpyrrolidinyl)ethyl (3',4',5- trifluoro-[1,1'-biphenyl]yl)carbamate; 43) 2-(1-methylpyrrolidinyl)ethyl (3',4'-dichloro- -fluoro-[1,1'-biphenyl]yl)carbamate; 44) 2-(1-methylpyrrolidinyl)ethyl (3'-ethyl fluoro-[1,1'-biphenyl]yl)carbamate; 45) 2-(1-methylpyrrolidinyl)ethyl (5-fluoro-3',5'- dimethyl-[1,1'-biphenyl]yl)carbamate; 46) 2-(1-methylpyrrolidinyl)ethyl (3'-amino fluoro-[1,1'-biphenyl]yl)carbamate; 47) 2-(1-methylpyrrolidinyl)ethyl (5- (trifluoromethyl)-[1,1'-biphenyl]yl)carbamate; 48) 2-(1-methylpyrrolidinyl)ethyl (4'-fluoro (trifluoromethyl)-[1,1'-biphenyl]yl)carbamate; 1001965344 49) 2-(1-methylpyrrolidinyl)ethyl (3'-fluoro (trifluoromethyl)-[1,1'-biphenyl]yl)carbamate; 50) 2-(1-methylpyrrolidinyl)ethyl (3',5'-difluoro- -(trifluoromethyl)-[1,1'-biphenyl]yl)carbamate; 51) 2-(1-methylpyrrolidinyl)ethyl (3'-chloro (trifluoromethyl)-[1,1'-biphenyl]yl)carbamate; 52) 2-(1-methylpyrrolidinyl)ethyl (3'-chloro-5,5'- difluoro-[1,1'-biphenyl]yl)carbamate; 53) 2-(1-methylpyrrolidinyl)ethyl (3'-chloro-4',5- difluoro-[1,1'-biphenyl]yl)carbamate; 54) 2-(1-methylpyrrolidinyl)ethyl (4'-chloro-3',5- difluoro-[1,1'-biphenyl]yl)carbamate; 55) 2-(1-methylpyrrolidinyl)ethyl (3',5'-dichloro- -fluoro-[1,1'-biphenyl]yl)carbamate; 56) 2-(1-methylpyrrolidinyl)ethyl (3',5'-dichloro- 4',5-difluoro-[1,1'-biphenyl]yl)carbamate; 57) 2-(1-methylpyrrolidinyl)ethyl (3'-chloro fluoro-5'-hydroxy-[1,1'-biphenyl]yl)carbamate; 58) 2-(1-methylpyrrolidinyl)ethyl (3'-chloro fluoro-4'-hydroxy-[1,1'-biphenyl]yl)carbamate; 59) 2-(1-methylpyrrolidinyl)ethyl (5-fluoro-3',4'- dimethyl-[1,1'-biphenyl]yl)carbamate; 60) 2-(1-methylpyrrolidinyl)ethyl (5-methoxy- [1,1'-biphenyl]yl)carbamate; 61) 2-(1-methylpyrrolidinyl)ethyl (3'-fluoro methoxy-[1,1'-biphenyl]yl)carbamate; 1001965344 62) 2-(1-methylpyrrolidinyl)ethyl (3',5'-difluoro- -methoxy-[1,1'-biphenyl]yl)carbamate; 63) 2-(1-methylpyrrolidinyl)ethyl (3'-chloro methoxy-[1,1'-biphenyl]yl)carbamate; 64) 2-(1-methylpyrrolidinyl)ethyl (3',5'-dichloro- -methoxy-[1,1'-biphenyl]yl)carbamate; 65) 2-(1-methylpyrrolidinyl)ethyl (3'-chloro-4'- fluoromethoxy-[1,1'-biphenyl]yl)carbamate; 66) 2-(1-methylpyrrolidinyl)ethyl (5-chloro-[1,1'- biphenyl]yl)carbamate; 67) 2-(1-methylpyrrolidinyl)ethyl (5-chloro-3'- fluoro-[1,1'-biphenyl]yl)carbamate; 68) 2-(1-methylpyrrolidinyl)ethyl (5-chloro-4'- fluoro-[1,1'-biphenyl]yl)carbamate; 69) 2-(1-methylpyrrolidinyl)ethyl (5-chloro-3',5'- difluoro-[1,1'-biphenyl]yl)carbamate; 70) 2-(1-methylpyrrolidinyl)ethyl (3',5-dichloro- [1,1'-biphenyl]yl)carbamate; 71) 2-(1-methylpyrrolidinyl)ethyl (3',5,5'- trichloro-[1,1'-biphenyl]yl)carbamate; 72) 2-(1-methylpyrrolidinyl)ethyl (3',5-dichloro- '-fluoro-[1,1'-biphenyl]yl)carbamate; 73) 2-(1-methylpyrrolidinyl)ethyl (3',5-dichloro- 4'-fluoro-[1,1'-biphenyl]yl)carbamate; 74) (R)-(1-methylpyrrolidinyl)methyl (3'-fluoro- 4'-formyl-[1,1'-biphenyl]yl)carbamate; 1001965344 75) 2-(1-methylpyrrolidinyl)ethyl (3',5'-difluoro- -hydroxy-[1,1'-biphenyl]yl)carbamate; 76) 2-(1-methylpyrrolidinyl)ethyl (3',5'-dichloro- -hydroxy-[1,1'-biphenyl]yl)carbamate; 77) 2-(1-methylpyrrolidinyl)ethyl (3'-chloro-4'- fluorohydroxy-[1,1'-biphenyl]yl)carbamate; 78) (R)-pyrrolidinylmethyl [1,1'-biphenyl] ylcarbamate; 79) (S)-pyrrolidinylmethyl [1,1'-biphenyl] ylcarbamate; 80) (R)-pyrrolidinylmethyl (3',5'-difluoro-[1,1'- biphenyl]yl)carbamate; 81) (S)-pyrrolidinylmethyl (3',5'-difluoro-[1,1'- biphenyl]yl)carbamate; 82) (S)-pyrrolidinylmethyl (5-fluoro-[1,1'- biphenyl]yl)carbamate; 83) (S)-pyrrolidinylmethyl (5-fluoro-3'-methyl- [1,1'-biphenyl]yl)carbamate; 84) (R)-pyrrolidinylmethyl (3',5,5'-trifluoro- [1,1'-biphenyl]yl)carbamate; 85) (S)-pyrrolidinylmethyl (3',5,5'-trifluoro- [1,1'-biphenyl]yl)carbamate; 86) (R)-pyrrolidinylmethyl (5-methyl-[1,1'- biphenyl]yl)carbamate; 87) (R)-pyrrolidinylmethyl (3'-fluoromethyl- [1,1'-biphenyl]yl)carbamate; 1001965344 88) (S)-pyrrolidinylmethyl (4'-fluoro-[1,1'- biphenyl]yl)carbamate; 89) (R)-(1-methylpyrrolidinyl)methyl [1,1'- biphenyl]ylcarbamate; 90) (S)-(1-methylpyrrolidinyl)methyl [1,1'- biphenyl]ylcarbamate; 91) (R)-(1-methylpyrrolidinyl)methyl (3',5'- difluoro-[1,1'-biphenyl]yl)carbamate; 92) (S)-(1-methylpyrrolidinyl)methyl (3',5'- difluoro-[1,1'-biphenyl]yl)carbamate; 93) (S)-(1-methylpyrrolidinyl)methyl (5-fluoro- [1,1'-biphenyl]yl)carbamate; 94) (S)-(1-methylpyrrolidinyl)methyl (5-fluoro-3'- methyl-[1,1'-biphenyl]yl)carbamate; 95) (R)-(1-methylpyrrolidinyl)methyl (3',5,5'- trifluoro-[1,1'-biphenyl]yl)carbamate; 96) (S)-(1-methylpyrrolidinyl)methyl (3',5,5'- trifluoro-[1,1'-biphenyl]yl)carbamate; 97) (R)-(1-methylpyrrolidinyl)methyl (5-methyl- [1,1'-biphenyl]yl)carbamate; 98) (R)-(1-methylpyrrolidinyl)methyl (3'-fluoro methyl-[1,1'-biphenyl]yl)carbamate; 99) (S)-(1-methylpyrrolidinyl)methyl (4'-fluoro- [1,1'-biphenyl]yl)carbamate; 100) (R)-(1-methylpyrrolidinyl)methyl (3'-methyl- [1,1'-biphenyl]yl)carbamate; 1001965344 101) (S)-(1-methylpyrrolidinyl)methyl (3'-methyl- [1,1'-biphenyl]yl)carbamate; 102) (R)-(1-ethylpyrrolidinyl)methyl [1,1'- biphenyl]ylcarbamate; 103) (S)-(1-ethylpyrrolidinyl)methyl [1,1'- biphenyl]ylcarbamate; 104) (R)-(1-ethylpyrrolidinyl)methyl (3'-methyl- [1,1'-biphenyl]yl)carbamate; 105) (S)-(1-ethylpyrrolidinyl)methyl (3'-methyl- [1,1'-biphenyl]yl)carbamate; 106) (S)-(1-ethylpyrrolidinyl)methyl [1,1'- biphenyl]ylcarbamate; 107) (S)-(1-isobutylpyrrolidinyl)methyl [1,1'- biphenyl]ylcarbamate; 108) (S)-(1-methylpyrrolidinyl)methyl (3',5- difluoro-[1,1'-biphenyl]yl)carbamate; 109) (R)-(1-methylpyrrolidinyl)methyl [1,1'- biphenyl]ylcarbamate; 110) (R)-(1-methylpyrrolidinyl)methyl (3'-methyl- [1,1'-biphenyl]yl)carbamate; 111) (R)-(1-methylpyrrolidinyl)methyl (5-fluoro- 3'-methyl-[1,1'-biphenyl]yl)carbamate; 112) (S)-(1-isopropylpyrrolidinyl)methyl [1,1'- biphenyl]ylcarbamate; 113) (R)-(1-methylpyrrolidinyl)methyl (3'-fluoro- [1,1'-biphenyl]yl)carbamate; 1001965344 114) (R)-(1-methylpyrrolidinyl)methyl (4'-fluoro- [1,1'-biphenyl]yl)carbamate; 115) (R)-(1-methylpyrrolidinyl)methyl (3',4'- difluoro-[1,1'-biphenyl]yl)carbamate; 116) (S)-(1-methylpyrrolidinyl)methyl (3'-fluoro- [1,1'-biphenyl]yl)carbamate; 117) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro- [1,1'-biphenyl]yl)carbamate; 118) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro- [1,1'-biphenyl]yl)carbamate; 119) (S)-(1-methylpyrrolidinyl)methyl (3',5'- dichloro-[1,1'-biphenyl]yl)carbamate; 120) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro- '-fluoro-[1,1'-biphenyl]yl)carbamate; 121) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro- 4'-fluoro-[1,1'-biphenyl]yl)carbamate; 122) (S)-(1-methylpyrrolidinyl)methyl (5-fluoro- 3',5'-dimethyl-[1,1'-biphenyl]yl)carbamate; 123) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro- 5-fluoro-5'-hydroxy-[1,1'-biphenyl]yl)carbamate; 124) (S)-(1-methylpyrrolidinyl)methyl (4',5- difluoro-[1,1'-biphenyl]yl)carbamate; 125) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro- -fluoro-[1,1'-biphenyl]yl)carbamate; 126) (S)-(1-methylpyrrolidinyl)methyl (3',5'- dichlorofluoro-[1,1'-biphenyl]yl)carbamate; 1001965344 127) (S)-(1-methylpyrrolidinyl)methyl (4'-chloro- -fluoro-[1,1'-biphenyl]yl)carbamate; 128) (S)-(1-methylpyrrolidinyl)methyl (3',4'- dichlorofluoro-[1,1'-biphenyl]yl)carbamate; 129) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro- ,5'-difluoro-[1,1'-biphenyl]yl)carbamate; 130) (R)-(1-methylpyrrolidinyl)methyl (3',4'- dichloro-[1,1'-biphenyl]yl)carbamate; 131) (R)-(1-methylpyrrolidinyl)methyl (3',5'- dichloro-[1,1'-biphenyl]yl)carbamate; 132) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro- '-fluoro-[1,1'-biphenyl]yl)carbamate; 133) (R)-(1-methylpyrrolidinyl)methyl (5-fluoro- 3'-amino-[1,1'-biphenyl]yl)carbamate; 134) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro- -fluoro-5'-hydroxy-[1,1'-biphenyl]yl)carbamate; 135) (R)-(1-methylpyrrolidinyl)methyl (3',5'- dichlorofluoro-[1,1'-biphenyl]yl)carbamate; 136) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro- 4'-fluoro-[1,1'-biphenyl]yl)carbamate; 137) (R)-(1-methylpyrrolidinyl)methyl (3'-hydroxy- [1,1'-biphenyl]yl)carbamate; 138) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro- '-(trifluoromethyl)-[1,1'-biphenyl]yl)carbamate; 139) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro- -fluoro-5'-methoxy-[1,1'-biphenyl]yl)carbamate; 1001965344 140) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro- -fluoro-5'-(trifluoromethyl)-[1,1'-biphenyl] yl)carbamate; 141) (R)-(1-methylpyrrolidinyl)methyl (4',5- difluoro-[1,1'-biphenyl]yl)carbamate; 142) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro- ,5'-difluoro-[1,1'-biphenyl]yl)carbamate; 143) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro- 4',5-dlfluoro-[1,1'-biphenyl]yl)carbamate; 144) (R)-(1-methylpyrrolidinyl)methyl (2',5- difluoro-[1,1'-biphenyl]yl)carbamate; 145) (R)-(1-methylpyrrolidinyl)methyl (3',5- dichloro-[1,1'-biphenyl]yl)carbamate; 146) (R)-(1-methylpyrrolidinyl)methyl (3',5- dichloro-4'-fluoro-[1,1'-biphenyl]yl)carbamate; 147) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro- 4'-fluoromethoxy-[1,1'-biphenyl]yl)carbamate; 148) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro- '-fluoro-[1,1'-biphenyl]yl)carbamate; 149) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro- 4'-fluoro-[1,1'-biphenyl]yl)carbamate; 150) (R)-(1-ethylpyrrolidinyl)methyl (3'-chloro- 4'-fluoro-[1,1'-biphenyl]yl)carbamate; 151) (R)-(1-isopropylpyrrolidinyl)methyl (3'- chloro-4'-fluoro-[1,1'-biphenyl]yl)carbamate; 152) (R)-(1-methylpyrrolidinyl)methyl (3'- (hydroxymethyl)-[1,1'-biphenyl]yl)carbamate; 1001965344 153) (R)-(1-methylpyrrolidinyl)methyl (3'- carbamoyl-[1,1'-biphenyl]yl)carbamate; 154) (R)-(1-methylpyrrolidinyl)methyl (3'-amino- [1,1'-biphenyl]yl)carbamate; 155) (R)-(1-methylpyrrolidinyl)methyl (3'-cyano- [1,1'-biphenyl]yl)carbamate; 156) (R)-(1-methylpyrrolidinyl)methyl (2'-fluoro- [1,1'-biphenyl]yl)carbamate; 157) (R)-(1-methylpyrrolidinyl)methyl (2',4'- difluoro-[1,1'-biphenyl]yl)carbamate; 158) (R)-(1-methylpyrrolidinyl)methyl (2',3'- difluoro-[1,1'-biphenyl]yl)carbamate; 159) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro- 6'-fluoro-[1,1'-biphenyl]yl)carbamate; 160) (S)-(1-methylpyrrolidinyl)methyl (3'-fluoro- [1,1'-biphenyl]yl)carbamate; 161) (S)-(1-methylpyrrolidinyl)methyl (3',5'- difluoro-[1,1'-biphenyl]yl)carbamate; 162) (S)-(1-methylpyrrolidinyl)methyl (3',4'- difluoro-[1,1'-biphenyl]yl)carbamate; 163) (S)-(1-methylpyrrolidinyl)methyl (2',4',5'- trifluoro-[1,1'-biphenyl]yl)carbamate; 164) (S)-(1-methylpyrrolidinyl)methyl (4'-chloro- [1,1'-biphenyl]yl)carbamate; 165) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro- [1,1'-biphenyl]yl)carbamate; 1001965344 166) (S)-(1-methylpyrrolidinyl)methyl (3',4'- dichloro-[1,1'-biphenyl]yl)carbamate; 167) (S)-(1-methylpyrrolidinyl)methyl (2',4'- dichloro-[1,1'-biphenyl]yl)carbamate; 168) (S)-(1-methylpyrrolidinyl)methyl (3'-hydroxy- [1,1'-biphenyl]yl)carbamate; 169) (S)-(1-methylpyrrolidinyl)methyl (3'-cyano- [1,1'-biphenyl]yl)carbamate; 170) (S)-(1-methylpyrrolidinyl)methyl (3'-amino- [1,1'-biphenyl]yl)carbamate; 171) (S)-(1-methylpyrrolidinyl)methyl (3',4',5- trifluoro-[1,1'-biphenyl]yl)carbamate; 172) (S)-(1-methylpyrrolidinyl)methyl (3',5,5'- trifluoro-[1,1'-biphenyl]yl)carbamate; 173) (S)-(1-methylpyrrolidinyl)methyl (2',4',5,5'- tetrafluoro-[1,1'-biphenyl]yl)carbamate; 174) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro- -fluoro-[1,1'-biphenyl]yl)carbamate; 175) (S)-(1-methylpyrrolidinyl)methyl (4'-chloro- 5-fluoro-[1,1'-biphenyl]yl)carbamate; 176) (S)-(1-methylpyrrolidinyl)methyl (2',4'- dichlorofluoro-[1,1'-biphenyl]yl)carbamate; 177) (S)-(1-methylpyrrolidinyl)methyl (3',4'- dichlorofluoro-[1,1'-biphenyl]yl)carbamate; 178) (S)-(1-methylpyrrolidinyl)methyl (3'-cyano fluoro-[1,1'-biphenyl]yl)carbamate; 1001965344 179) (S)-(1-methylpyrrolidinyl)methyl (3'-hydroxy- -fluoro-[1,1'-biphenyl]yl)carbamate; 180) (S)-(1-methylpyrrolidinyl)methyl (5-fluoro- 3'-(trifluoromethyl)-[1,1'-biphenyl]yl)carbamate; 181) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro- 4,4',5-trifluoro-[1,1'-biphenyl]yl)carbamate; 182) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro- 4,5-difluoro-[1,1'-biphenyl]yl)carbamate; 183) 2-(1-methylpyrrolidinyl)ethyl (2',4'- difluoro-[1,1'-biphenyl]yl)carbamate; 184) 2-(1-methylpyrrolidinyl)ethyl (2',3'- difluoro-[1,1'-biphenyl]yl)carbamate; 185) 2-(1-methylpyrrolidinyl)ethyl (2',6'- difluoro-[1,1'-biphenyl]yl)carbamate; 186) 2-(1-methylpyrrolidinyl)ethyl (5'-chloro-2'- fluoro-[1,1'-biphenyl]yl)carbamate; 187) (S)-(1-methylpyrrolidinyl)methyl (2'-fluoro- [1,1'-biphenyl]yl)carbamate; 188) (S)-(1-methylpyrrolidinyl)methyl (2',4'- difluoro-[1,1'-biphenyl]yl)carbamate; 189) (S)-(1-methylpyrrolidinyl)methyl (2',3'- difluoro-[1,1'-biphenyl]yl)carbamate; 190) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro- 6'-fluoro-[1,1'-biphenyl]yl)carbamate; 191) (R)-(1-methylpyrrolidinyl)methyl (3',5'- dimethyl-[1,1'-biphenyl]yl)carbamate; 1001965344 192) (R)-(1-methylpyrrolidinyl)methyl (5-fluoro- 3'-methyl-[1,1'-biphenyl]yl)carbamate; 193) (R)-(1-methylpyrrolidinyl)methyl (5-fluoro- 3',5'-dimethyl-[1,1'-biphenyl]yl)carbamate; 194) (R)-(1-methylpyrrolidinyl)methyl (3',5- difluoro-[1,1'-biphenyl]yl)carbamate; 195) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro- -fluoro-[1,1'-biphenyl]yl)carbamate; 196) (R)-(1-ethylpyrrolidinyl)methyl (3'-chloro- 4',5-difluoro-[1,1'-biphenyl]yl)carbamate; 197) (S)-(1-methylpyrrolidinyl)methyl [1,1'- biphenyl]ylcarbamate; 198) (S)-(1-methylpyrrolidinyl)methyl (4'-fluoro- [1,1'-biphenyl]yl)carbamate; 199) (S)-(1-methylpyrrolidinyl)methyl (3'-methyl- [1,1'-biphenyl]yl)carbamate; 200) (S)-(1-methylpyrrolidinyl)methyl (5-fluoro- [1,1'-biphenyl]yl)carbamate; 201) (S)-(1-methylpyrrolidinyl)methyl (5-fluoro- 3'-methyl-[1,1'-biphenyl]yl)carbamate; 202) (S)-(1-methylpyrrolidinyl)methyl (3',5- difluoro-[1,1'-biphenyl]yl)carbamate; 203) (S)-(1-methylpyrrolidinyl)methyl (4',5- difluoro-[1,1'-biphenyl]yl)carbamate; 204) (S)-(1-methylpyrrolidinyl)methyl (4-fluoro- [1,1'-biphenyl]yl)carbamate; 1001965344 205) (S)-(1-methylpyrrolidinyl)methyl (3',4- difluoro-[1,1'-biphenyl]yl)carbamate; 206) (S)-(1-methylpyrrolidinyl)methyl (5-methyl- [1,1'-biphenyl]yl)carbamate; 207) (S)-(1-methylpyrrolidinyl)methyl (3'-fluoro- -methyl-[1,1'-biphenyl]yl)carbamate; 208) (S)-(1-methylpyrrolidinyl)methyl (5-fluoro- 3',5'-dimethyl-[1,1'-biphenyl]yl)carbamate; 209) (S)-(1-methylpyrrolidinyl)methyl (4'-(tert- butyl)fluoro-[1,1'-biphenyl]yl)carbamate; 210) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro- ,5'-difluoro-[1,1'-biphenyl]yl)carbamate; 211) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro- 4',5-difluoro-[1,1'-biphenyl]yl)carbamate; 212) (S)-(1-methylpyrrolidinyl)methyl (4'-chloro- 3',5-difluoro-[1,1'-biphenyl]yl)carbamate; 213) (S)-(1-methylpyrrolidinyl)methyl (3'-amino fluoro-[1,1'-biphenyl]yl)carbamate; 214) (S)-(1-methylpyrrolidinyl)methyl (2',5- difluoro-3'-(trifluoromethyl)-[1,1'-biphenyl] yl)carbamate; 215) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro- -fluoro-5'-(trifluoromethyl)-[1,1'-biphenyl] yl)carbamate; 216) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro- -fluoro-5'-hydroxy-[1,1'-biphenyl]yl)carbamate; 1001965344 217) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro- -fluoro-5'-methoxy-[1,1'-biphenyl]yl)carbamate; 218) (S)-(1-methylpyrrolidinyl)methyl (5-fluoro- 2',4'-bis(trifluoromethyl)-[1,1'-biphenyl]yl)carbamate; 219) (S)-(1-methylpyrrolidinyl)methyl (3'-ethoxy- -fluoro-[1,1'-biphenyl]yl)carbamate; 220) (S)-(1-methylpyrrolidinyl)methyl (5-fluoro- 3',4'-dimethoxy-[1,1'-biphenyl]yl)carbamate; 221) (S)-(1-methylpyrrolidinyl)methyl (5-fluoro- 3',5'-dimethoxy-[1,1'-biphenyl]yl)carbamate; 222) (S)-(1-methylpyrrolidinyl)methyl (5-methoxy- [1,1'-biphenyl]yl)carbamate; 223) (S)-(1-methylpyrrolidinyl)methyl (3'-fluoro- -methoxy-[1,1'-biphenyl]yl)carbamate; 224) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro- -methoxy-[1,1'-biphenyl]yl)carbamate; 225) (S)-(1-methylpyrrolidinyl)methyl (3',4'- dichloromethoxy-[1,1'-biphenyl]yl)carbamate; and 226) (S)-(1-methylpyrrolidinyl)methyl (3',5'- dichloromethoxy-[1,1'-biphenyl]yl)carbamate.
Methods for Preparation of Novel Biphenyl Derivatives 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 The method for preparing the compounds of formula 1 or pharmaceutically acceptable salts thereof according to 1001965344 the present invention may comprise a step of reacting a compound of the following formula 2 with a compound of the following formula 3 in the presence of a carbamate synthesis reagent: [Formula 2] [Formula 3] wherein R to R and n are the same as defined in formula 1.
The carbamate synthesis reagent preferably comprises an azide compound. Specifically, the carbamate synthesis reagent that is used in the present invention may be a mixture of diphenylphosphoryl azide (DPPA) and triethylamine, a mixture of propylphosphonic anhydride (T3P), trimethylsilyl azide (TMSN) and triethylamine, a mixture of sodium azide (NaN ), tetrabutylammonium bromide and zinc(II) triflate, or the like.
In addition, the carbamate synthesis reaction may be performed at a temperature between 100°C and 120°C for 4 to 12 hours.
Preparation Method 2 1001965344 In addition, 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 2 with a compound of the following formula 3a in the presence of a carbamate synthesis reagent to prepare a compound of the following formula 4; removing an amine protecting group from the compound of formula 4 to prepare a compound of the following formula 1a; and introducing an R substituent into the compound of formula 1a: [Formula 2] [Formula 3a] [Formula 4] [Formula 1a] 1001965344 wherein R to R and n are the same as defined in formula 1, and PG 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).
The carbamate synthesis reagent and the reaction conditions are the same as described above for preparation method 1.
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 piperidine; ammonium cerium (IV) nitrate; tetra-n-butyl ammonium fluoride or the like may be used in the reaction of removing amine protecting group. The reaction may be carried out at room temperature for 3 to 12 hours.
In addition, the reaction of introducing the R substituent may be carried out using formaldehyde solution, acetic acid and zinc, or may be carried out using alkyl halide, potassium carbonate, potassium iodide or 1001965344 triethylamine. Water or dimethylformamide may be used as a solvent. The reaction may be performed at room temperature to 120°C for 5-12 hours.
Meanwhile, the compound of formula 2 can be prepared by a method comprising 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 the following formula 7 to prepare a compound of the following formula 8; and de-esterifying the compound of formula 8 in the presence of a base: [Formula 5] [Formula 6] [Formula 7] HO OH 1001965344 [Formula 8] wherein R to R and n are the same as defined in formula 1; X is halogen; and PG is a protecting group that may be selected from the group consisting of a C -C alkyl group, benzyl, PMB (4-methoxybenzyl), THP (tetrahydropyranyl), TBDMS (tert-butyldimethylsilyl), and TBDPS (tert- butyldiphenylsilyl).
In the reaction of introducing the carboxylic acid protecting group, thionyl chloride or sulfuric acid is preferably used as the acid, and ethanol or methanol may be used as a solvent. The reaction may be performed at a temperature between 80°C and 100°C for 4 to 24 hours.
In addition, the base that is used in the coupling reaction is preferably selected from among potassium carbonate and sodium carbonate. A catalyst that is used in the coupling reaction may be tetrakistriphenylphosphine palladium or dichlorobistriphenylphosphine palladium, and a solvent that is used in the coupling reaction may 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 may be 1001965344 performed at a temperature between 100°C and 120°C for 10 minutes to 12 hours.
Furthermore, the base that is used in the de- esterification reaction is preferably selected from among sodium hydroxide and potassium hydroxide, and a solvent that is used in the de-esterification reaction may be ethanol or a mixture of ethanol and water. The de- esterification reaction may be performed at a temperature between 100°C and 120°C for 2 to 12 hours.
Preparation Method 3 In addition, 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 3 in the presence of a carbamate synthesis reagent to prepare a compound of the following formula 9; and coupling a compound of the following formula 7 to the compound of formula 9: [Formula 5] [Formula 3] [Formula 9] 1001965344 [Formula 7] HO OH wherein R to R and n are the same as defined in formula 1, and X is halogen.
The carbamate synthesis reagent and the reaction conditions are the same as described above for preparation method 1.
In addition, the coupling reaction reagents and the reaction conditions are the same as described above for preparation method 2.
Preparation Method 4 In addition, 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 to prepare a compound of the following formula 9a; deprotecting the compound of formula 9a to obtain a compound of the following formula 9b; introducing an R substituent into the compound of the 1001965344 formula 9b to prepare a compound of the following formula 9; and coupling a compound of the following formula 7 to the compound of formula 9: [Formula 5] [Formula 3a] [Formula 9a] H PG [Formula 9b] [Formula 9] [Formula 7] 1001965344 HO OH wherein R to R and n are the same as defined in formula 1; X is halogen; and PG is the same as defined in preparation method 2.
The carbamate synthesis reagent and the reaction conditions are as described above for preparation method 1.
In addition, the deprotection reaction, the reaction of introducing the R substituent and the coupling reaction are as described above for preparation method 2.
Pharmaceutical Composition Containing Novel Biphenyl Derivatives 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.
In the present invention, the muscarinic M3 receptor antagonist may 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 hyper-salivation syndromes. 1001965344 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 showing a function equal or similar to the compound of formula 1 or a pharmaceutically acceptable salt thereof.
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 may be physiological saline, sterile water, Ringer’s solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, or a mixture of one or more thereof. If necessary, other conventional additives such as antioxidants, buffers or bacteriostatic agents may be added to the composition of the present invention. In addition, diluents, dispersants, surfactants, binders and lubricants may further be added to the composition to formulate injectable formulations such as aqueous solutions, suspensions or emulsions, pills, capsules, granules or tablets. Furthermore, the composition of the present invention may preferably be formulated depending on particular diseases or their components, using a suitable method known in the art or the method described in Remington’s Pharmaceutical Science, Merck Publishing Company, Easton PA. 1001965344 In addition, 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 1-95 wt%, preferably 1-70 wt%, based on the total weight of the M3 receptor antagonist.
The pharmaceutical composition of the present invention may be administered orally or may be administered parenterally in the form of injectable solutions, suppositories, transdermal agents, inhalation agents or intravesical agents.
The present invention also provides a method for treating or alleviating a disease related to the activity on 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 antagonist activity.
The muscarinic M3 receptor antagonist of the present invention may be used alone or in combination with surgery, hormone therapy, drug therapy and a biological response modifier in order to prevent or treat a disease related to the activity on muscarinic M3 receptor.
Method for Prevention or Treatment of Muscarinic M3 Receptor-Related Diseases 1001965344 The present invention also provides a method for preventing or treating a muscarinic M3 receptor-related disease, for example, a disease selected from among 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 hyper-salivation syndromes, the method comprising administering to subjects in need thereof a composition containing, as an active ingredient, the compound of formula 1, or an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
The composition that is used in the preventing or treating method of the present invention includes the pharmaceutical composition as described herein.
In addition, the subjects in need of the preventing or treating method of the present invention include mammals, particularly humans.
【Advantageous Effects 】 The biphenyl derivatives according to the present invention have affinity and selectivity for the muscarinic M3 receptor and less toxic. Thus, these biphenyl derivatives can be used as agents for preventing or treating various diseases, particularly urinary system diseases such as enuresis, nervous pollakiuria, neurogenic bladder, unstable bladder, chronic cystitis, cystospasm, 1001965344 urinary incontinence, or frequent urination, respiratory system diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma, or rhinitis, and digestive diseases such as irritable bowel syndrome, spastic colitis or diverticulitis, in which the muscarinic M3 receptor is involved.
Particularly, because the biphenyl derivatives of the present invention have high selectivity for the muscarinic M2 receptor and the muscarinic M3 receptor that is present in smooth muscles, gland tissues and the like, these biphenyl derivatives are M3 receptor antagonists having less side effects, and thus 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 】 The present disclosure will be described more fully hereinafter 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 interpreted as being limited to the following Examples. The Examples of the present invention are provided so that those skilled in the art can sufficiently understand the present invention.
Furthermore, agents stated hereinafter were purchased from Aldrich Korea, Acros, Lancaster, TCI unless otherwise 1001965344 specified. H NMR used herein was Varian 400 MHz, and Microwave oven used herein was Monowave 300 of Anton Paar company.
[Synthesis Example 1] Synthesis of 4'-fluoro-[1,1'- biphenyl] carboxylic acid [Step 1] Synthesis of ethylbromobenzoate 2-Bromobenzoic acid (5g, 24.87mmol) was dissolved in ethanol (100mL). Sulfuric acid (5mL) was added thereto and stirred under reflux for 24 hours. After reaction was terminated, the reactant was cooled to room temperature. The solvent was removed by concentrating the reactant under reduced pressure, and extracted with water and ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the titled compound (4.9g, 86%).
[Step 2] Synthesis of ethyl 4'-fluoro-[1,1'-biphenyl] carboxylate 1001965344 Ethylbromobenzoate (1g, 4.37mmol) prepared in Step 1 was dissolved in a mixed solution of toluene (20mL) and ethanol (4mL), and then 4-fluorophenyl boronic acid (672mg, 4.80mmol), potassium carbonate (1.21g, 8.73mmol) and tetrakis triphenylphosphine palladium (504mg, 0.44mmol) were added thereto. The reactant was stirred at 100 ℃ for 6 hours, cooled to room temperature and filtered through celite. The solvent was removed by concentrating the reactant under reduced pressure. The same 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 titled compound (948mg, 89%).
[Step 3] Synthesis of 4'-fluoro-[1,1'-biphenyl] carboxylic acid 1001965344 Ethyl 4'-fluoro-[1,1'-biphenyl]carboxylate (948mg, 3.33mmol) prepared in Step 2 was dissolved in ethanol (20mL). 2N-sodium hydroxide solution (5.82mL, 11.64mmol) was added thereto and stirred under reflux for 12 hours.
The reactant was cooled to room temperature. The solvent was removed by concentrating the reactant under reduced pressure. The same was extracted with 1N-hydrochloric acid and dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated to prepare the titled compound (747mg, 89%).
[Synthesis Examples 2-15] 2-Bromobenzoic acid as a starting material and reacting materials in Table 1 were used to prepare compounds of Synthesis Examples 2-15 in the same manner as Synthesis Example 1.
[Table 1] Synthesis Examples 1-15 Synthesis Chemical Name Reacting Material Example 4'-Fluoro-[1,1'- 4-Fluorophenyl boronic 1 biphenyl] acid carboxylic acid 3',5'-Difluoro-[1,1'- 3,5-Difluorophenyl 2 biphenyl] boronic acid carboxylic acid 3',4',5'-Trifluoro- 3,4,5-Trifluorophenyl 3 [1,1'-biphenyl] boronic acid carboxylic acid 1001965344 3'-Fluoro-[1,1'- 3-Fluorophenyl boronic 4 biphenyl] acid carboxylic acid 4'-Methoxy-[1,1'- 4-Methoxyphenyl boronic biphenyl] acid carboxylic acid 4'-Chloro-[1,1'- 4-Chlorophenyl boronic 6 biphenyl] acid carboxylic acid 3'-Chloro-[1,1'- 3-Chlorophenyl boronic 7 biphenyl] acid carboxylic acid 3',5'-Dichloro-[1,1'- 3,5-Dichlorophenyl 8 biphenyl] boronic acid carboxylic acid 4'-Trifluoromethoxy- 4-Trifluoromethoxyphenyl 9 [1,1'-biphenyl] boronic acid carboxylic acid 4'-Nitro-[1,1'- 4-Nitrophenyl boronic biphenyl] acid carboxylic acid 3'-Trifluoromethyl- 3-Trifluoromethylphenyl 11 [1,1'-biphenyl] boronic acid carboxylic acid 4'-Trifluoromethyl- 4-Trifluoromethylphenyl 12 [1,1'-biphenyl] boronic acid carboxylic acid 3'-Fluoro-4'-methyl- 3-Fluoromethylphenyl 13 [1,1'-biphenyl] boronic acid carboxylic acid 1001965344 3'-Methyl-[1,1'- 3-Methylphenyl boronic 14 biphenyl] acid carboxylic acid 3'-Ethoxy-[1,1'- 3-Ethoxyphenyl boronic biphenyl] acid carboxylic acid [Synthesis Example 16] Synthesis of 3'-chlorofluoro- [1,1'-biphenyl]carboxylic adid [Step 1] Ethyl 2-bromofluorobenzoate 2-Bromofluorobenzoic acid (2.37g, 10.82mmol) was dissolved in ethanol (100mL). Thionyl chloride (1.57mL, 21.64mmol) was added thereto and stirred under reflux for 24 hours. The reactant was cooled to room temperature after the reaction was terminated. The solvent was removed by concentrating the reactant under reduced pressure. The same 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 titled compound (2.29g, 87%).
[Step 2] Ethyl 3'-chlorofluoro-[1,1'-biphenyl] carboxylate 1001965344 Ethyl 2-bromofluorobenzoate (1.1g, 4.47mmol) prepared in Step 1 was dissolved in toluene (20mL). 3- Chlorophenyl boronic acid (766mg, 4.90mmol), potassium carbonate (1.23g, 8.90mmol) and tetrakis triphenylphosphine palladium (520mg, 0.44mmol) were added thereto. The reactant was stirred at 100 ℃ for 6 hours and cooled to room temperature. The same was filtered through celite and the solvent was removed by concentrating the reactant under reduced pressure. The same 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 titled compound (850mg, 69%).
[Step 3] 3'-Chlorofluoro-[1,1'-biphenyl]carboxylic acid Ethyl 3'-chlorofluoro-[1,1'-biphenyl] carboxylate (850mg, 3.05mmol) prepared in Step 2 was dissolved in ethanol (20mL). 2N-sodium hydroxide solution (4.57mL, 9.15mmol) was added thereto and stirred under reflux for 12 hours. The reactant was cooled to room 1001965344 temperature. The solvent was removed by concentrating the reactant under reduced pressure and extracted with 1N- hydrochloric acid and dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated to prepare the titled compound (650mg, 85%).
[Synthesis Examples 17-26] The starting materials and reacting materials in Table 2 were used to prepare compounds of Synthesis Examples 17-26 in the same manner as Synthesis Example 16.
[Table 2] Synthesis Examples 16-26 Synthesis Starting Reacting Chemical Name Example Material Material 3'-Chloro 2-Bromo 3-Chlorophenyl fluoro-[1,1'- fluorobenzoic boronic acid biphenyl] acid carboxylic acid 3',5-Difluoro- 2-Bromo 3-Fluorophenyl [1,1'- fluorobenzoic boronic acid biphenyl] acid carboxylic acid 4',5-Difluoro- 2-Bromo 4-Fluorophenyl [1,1'- fluorobenzoic boronic acid biphenyl] acid carboxylic acid 3',5,5'- 2-Bromo 3,5- Trifluoro- fluorobenzoic Difluorophenyl 19 [1,1'- acid boronic acid biphenyl] carboxylic acid 1001965344 -Fluoro-[1,1'- 2-Bromo Phenyl boronic biphenyl] fluorobenzoic acid carboxylic acid acid -Fluoro-3'- 2-Bromo 3-Methylphenyl methyl-[1,1'- fluorobenzoic boronic acid biphenyl] acid carboxylic acid 4-Fluoro-[1,1'- 2-Bromo Phenyl boronic 22 biphenyl] fluorobenzoic acid carboxylic acid acid 3',4-Difluoro- 2-Bromo 3-Fluorophenyl [1,1'- fluorobenzoic boronic acid biphenyl] acid carboxylic acid 4-Methoxy- 2-Bromo Phenyl boronic [1,1'- methoxybenzoic acid biphenyl] acid carboxylic acid -Methyl-[1,1'- 2-Bromo Phenyl boronic biphenyl] methylbenzoic acid carboxylic acid acid 3'-Fluoro 2-Bromo 3-Fluorophenyl methyl-[1,1'- methylbenzoic boronic acid biphenyl] acid carboxylic acid [Synthesis Example A] Synthesis of 2-(1-methylpyrrolidin yl)ethyl (2-iodophenyl)carbamate 1001965344 2-Iodobenzoic acid (1g, 4.03mmol) was dissolved in toluene (50mL). Biphenylphosphoryl azide (1.04mL, 4.84mmol) and triethylamine (566uL, 4.03mmol) were added thereto. The same was stirred at room temperature for 30 minutes, and then stirred under reflux for 1 hour. The reactant was cooled to room temperature. 2-(2- Hydroxyethyl)methylpyrrolidine (651uL, 4.84mmol) was added thereto and stirred under reflux for 12 hours. The reactant was cooled to room temperature. The solvent was removed by concentrating the reactant under reduced pressure and the same 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 titled compound (1.16g, 77%).
[Synthesis Examples B-E] The starting materials in Table 3 were used instead of 2-iodobenzoic acid to prepare compounds of Synthesis Examples B-E in the same manner as Synthesis Example A.
[Table 3] Synthesis Examples A-E Synthesis Chemical Name Starting Material Example 2-(1-Methylpyrrolidin 2-Iodobenzoic acid yl)ethyl (2- (1g, 4.03mmol) iodophenyl)carbamate (1.16g, 77%) 1001965344 2-(1-Methylpyrrolidin 2-Bromo yl)ethyl (2-bromofluorobenzoic acid fluorophenyl)carbamate (2.5g, 11.42mmol) (3.7g, 94%) 2-(1-Methylpyrrolidin 2-Bromo yl)ethyl (2-bromo (trifluoromethyl)benzo (trifluoromethyl)phenyl)ca ic acid (2g, 7.43mmol) rbamate (1.72g, 94%) 2-(1-Methylpyrrolidin 2-Bromo yl)ethyl (2-bromomethoxybenzoic acid methoxyphenyl)carbamate (2g, 7.43mmol) (2.5g, 81%) 2-(1-Methylpyrrolidin 2-Bromo yl)ethyl (2-bromo chlorobenzoic acid chlorophenyl)carbamate (2.5g, 10.62mmol) (38g, 99%) [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)pyrrolidinecarboxylate 1001965344 2-Bromobenzoic acid (4.5g, 22.4mmol) was dissolved in toluene (100mL) and biphenylphosphoryl azide (5.8mL, 26.9mmol) and triethylamine (3.15mL, 22.4mmol) were added thereto. The same was stirred at room temperature for 30 minutes, and then stirred under reflux for 1 hour. The reactant was cooled to room temperature, (R)-tert-butyl 3- (hydroxymethyl)pyrrolidinecarboxylate (5.41g, 26.9mmol) was added thereto, and stirred under reflux for 12 hours.
The reactant was cooled to room temperature. The solvent was removed by concentrating the reactant under reduced pressure. The same 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 titled compound (8.1g, 91%).
[Step 2] Synthesis of ((R)-pyrrolidinylmethyl (2- bromophenyl)carbamate (R)-tert-butyl 3-((((2-bromophenyl) carbamoyl)oxy)methyl)pyrrolidinecarboxylate (8.1g, .29mmol) prepared in Step 1 was dissolved in dichloromethane (100mL). Trifluoroacetic acid (50mL) was added thereto and stirred at room temperature for 2 hours.
The solvent was removed by concentrating the reactant under reduced pressure, and the same 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 1001965344 column chromatography to prepare the titled compound (3.94g, 65%).
[Step 3] Synthesis of (R)-(1-methylpyrrolidinyl)methyl (2-bromophenyl)carbamate (R)-pyrrolidinylmethyl (2-bromophenyl)carbamate (3.94g, 13.13mmol) prepared in Step 2 was dissolved in water (100mL). Acetic acid (5mL), formaldehyde solution (15mL) and zinc powder (1.5g) were sequentially added thereto and stirred at room temperature for 12 hours. The reactant 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 titled compound (3.06g, 75%).
[Synthesis Examples G-L] The starting materials and reacting materials in Table 4 were used to prepare compounds of Synthesis Examples G-L in the same manner as Synthesis Example F.
[Table 4] Synthesis Examples F-L Synthesis Chemical Name Starting Material Reacting Material Example 1001965344 (R)-(1- 2-Bromobenzoic (R)-tert-butyl 3- methylpyrrolidin-acid (4.5g, (hydroxymethyl)pyrro F 3-yl)methyl (2- 22.4mmol) lidinecarboxylate bromophenyl)carba (5.41g, 26.9mmol) mate (3.06g, 75%) (S)-(1- 2-Bromobenzoic (S)-tert-butyl 3- methylpyrrolidin- acid (hydroxymethyl)pyrro G 3-yl)methyl (2- lidinecarboxylate bromophenyl)carba mate (R)-(1- 2-Bromo (R)-tert-butyl 3- methylpyrrolidin- fluorobenzoic (hydroxymethyl)pyrro 3-yl)methyl (2- acid (5g, lidinecarboxylate H bromo 22.83mmol) (5.51g, 27.4mmol) fluorophenyl)carb amate (2.29g, %) Synthesis of (S)- 2-Bromo (S)-tert-butyl 3- (1- fluorobenzoic (hydroxymethyl)pyrro methylpyrrolidin- acid lidinecarboxylate I 3-yl)methyl (2- bromo fluorophenyl)carb amate (R)-(1- 2-Bromo (R)-tert-butyl 3- methylpyrrolidin- chlorobenzoic (hydroxymethyl)pyrro 3-yl)methyl (2- acid (5g, lidinecarboxylate bromo 21.23mmol) (5.1g, 25.48mmol) chlorophenyl)carb amate (2.5g, 34%) 1001965344 (R)-(1- 2-Bromo (R)-tert-butyl 3- methylpyrrolidin- methoxybenzoic (hydroxymethyl)pyrro 3-yl)methyl (2- acid (3g, lidinecarboxylate K bromo 12.98mmol) (3.9g, 19.47mmol) methoxyphenyl)car bamate (2.3g, 52%) (R)-(1- 2-Bromo-4,5- (R)-tert-butyl 3- methylpyrrolidin- difluorobenzoic (hydroxymethyl)pyrro 3-yl)methyl (2- acid (1.5g, lidinecarboxylate L bromo-4,5- 6.33mmol) (2.55g, 12.65mmol) difluoro phenyl)carbamate (884mg, 40%) [Synthesis Example M] Synthesis of (S)-(1-methylpyrrolidin- 2-yl)methyl (2-bromophenyl)carbamate 2-Bromobenzoic acid (2g, 9.95mmol) was dissolved in toluene (75mL), and then biphenylphosphoryl azide (2.57mL, 11.94mmol) and triethylamine (1.4mL, 9.95mmol)were added thereto. The same was stirred at room temperature for 30 minutes, and then stirred under reflux for 1 hour. The reactant was cooled to room temperature. (S)-(1- methylpyrrolidinyl)methanol (1.42mL, 11.94mmol) was added thereto and stirred under reflux for 4 hours. The reactant was cooled to room temperature. The solvent was removed by concentrating the reactant under reduced pressure. The same was extracted with water and 1001965344 dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated.
The resulting residue was purified with column chromatography to prepare the titled compound (1.4g, 45%).
[Synthesis Examples N-P] The starting materials and reacting materials in Table 5 were used to prepare compounds of Synthesis Examples N-P in the same manner as Synthesis Example M.
[Table 5] Synthesis Examples M-P Synthesis Chemical Name Starting Material Reacting Material Example (S)-(1- 2-Bromobenzoic (S)-(1- methylpyrrolidi acid (2g, methylpyrrolidin- nyl)methyl 9.95mmol) 2-yl)methanol M (2- (1.42mL, bromophenyl)car 11.94mmol) bamate (1.4g, 45%) (S)-(1- 2-Bromo (S)-(1- methylpyrrolidi fluorobenzoic methylpyrrolidin- nyl)methyl acid (4g, 2-yl)methanol N (2-bromo 18.26mmol) (2.6mL, fluorophenyl)ca 21.91mmol) rbamate (2.86g, 47%) 1001965344 (S)-(1- 2-Bromo (S)-(1- methylpyrrolidi methoxybenzoic methylpyrrolidin- nyl)methyl acid (600mg, 2-yl)methanol O (2-bromo 2.60mmol) (463uL, 3.90mmol) methoxyphenyl)c arbamate (600mg, 67%) (S)-(1- 2-Bromo-4,5- (S)-(1- methylpyrrolidi difluorobenzoic methylpyrrolidin- nyl)methyl acid(1g, 2- P (2-bromo-4,5- 4.22mmol) yl)methanol(730mg difluorophenyl) , 6.33mmol) carbamate (737mg, 50%) Example [Table 6] Compounds of Examples Example Compound NMR Value 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (4'-fluoro-[1,1'- 8.10-7.99(m, 1H), biphenyl]yl)carbamate 7.38-7.26(m, 3H), 7.20-7.06(m, 4H), 6.52-6.41(bs, 1H), 1 4.21-4.08(m, 2H), 3.12-2.99(m, 1H), 2.29(m, 3H), 2.20- 1.87(m, 4H), 1.83- 1.61(m, 2H), 1.61- 1.40(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3',5'-difluoro- 8.11-7.96(m, 1H), [1,1'-biphenyl] 7.45-7.32(m, 1H), yl)carbamate 7.21-7.07(m, 2H), 6.98-6.79(m, 3H), 2 6.55-6.39(bs, 1H), 4.27-4.10(m, 2H), 3.14-2.99(m, 1H) 2.30(s, 3H), 2.21- 1.85(m, 4H), 1.85- 1.41(m, 4H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3',4',5'- 8.00-7.88(m, 1H), trifluoro-[1,1'-biphenyl] 7.43-7.30(m, 1H), yl)carbamate 7.29-7.08(m, 2H), 7.05-6.91(m, 2H), 3 6.69-6.52(bs, 1H), 4.25-4.06(m, 2H), 3.25-3.08(m, 1H), 2.47-2.17(m, 5H) 2.14-1.91(m, 2H), 1.90-1.45(m, 4H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-fluoro[1,1'- 8.13-7.96(m, 1H), biphenyl]yl)carbamate 7.50-7.28(m, 2H), 7.22-7.00(m, 5H), 4 6.60-6.45(bs, 1H), 4.25-4.07(m, 2H), 3.13-2.99(m, 1H), 2.31(s, 3H), 2.22- 1.41(m, 8H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (4'-methoxy-[1,1'- 8.13-7.99(m, 1H), biphenyl]yl)carbamate 7.35-7.22(m, 4H), 7.20-7.14(m, 1H), 7.12-7.06(m, 1H), 7.03-6.95(m, 2H), 6.63-6.56(bs, 1H), 4.23-4.10(m, 2H), 3.85(s, 3H), 3.10- 3.01(m, 1H), 2.28(s, 3H) 2.17- 1.88(m, 4H), 1.84- 1.62(m, 2H), 1.62- 1.41(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl [1,1'-biphenyl]8.11(s, 1H), ylcarbamate 7.45(t, 1H), 7.38(d, 1H), 7.34(dd, 2H), 7.21(dd, 2H), 7.12(t, 1H), 6.99(t, 1H), 6 6.64(s, 1H), 4.18- 4.14(m, 2H), 3.09- 3.01(m, 1H), 2.40(s, 3H), 2.34(m, 3H), 2.12- 2.06 (m, 2H), 1.91- 1.82(m, 1H), 1.78- 1.66(m, 2H), 1.60- 1.56(m, 1H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (4'-chloro-[1,1'- 8.11-7.94(m, 1H), biphenyl]yl)carbamate 7.55-6.97(m, 7H), 6.55-6.35(bs, 1H), 4.25-3.98(m, 2H), 3.14-2.94(m, 1H) 2.29(s, 3H), 2.20- 1.84(m, 4H), 1.81- 1.37(m, 4H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-chloro-[1,1'- 8.06(s, 1H), 7.41- biphenyl]yl)carbamate 7.35(m, 4H), 7.26- 7.22(m, 1H), 7.19- 7.16(m, 1H), 7.14- 7.10(m, 1H), 6.47(s, 1H), 4.22- 4.15(m, 2H), 3.07- 3.02(m, 1H), 2.29(s, 3H), 2.16- 2.06(m, 2H), 2.03- 1.91(m, 2H), 1.78- 1.62(m, 2H), 1.60- 1.47(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3',5'-dichloro- 8.01(s, 1H), 7.39- [1,1'-biphenyl] 7.35(m, 2H), 7.22- yl)carbamate 7.20(m, 2H), 7.17- 7.11(m, 2H), 6.42(s, 1H), 4.22- 9 4.13(m, 2H), 3.10- 3.01(s, 1H), 2.30(s, 3H), 2.08- Cl Cl 2.04(m, 2H), 2.03- 1.90(m, 2H), 1.78- 1.60(m, 2H), 1.58- 1.42(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (4'- 8.03(s, 1H), 7.39- trifluoromethoxy-[1,1'- 7.34(m, 3H), 7.31- biphenyl]yl)carbamate 7.291(m, 2H), 7.19- 7.11(m, 2H), 6.44(s, 1H), 4.24- 4.15(m, 2H), 3.04- 3.00(m, 1H), 2.27(s, 3H), 2.04- 2.01(m, 2H), 2.00- 1.88(m, 2H), 1.80- 1.63(m, 2H), 1.59- 1.44(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (4'-nitro-[1,1'- 8.27-8.24(m, 1H), biphenyl]yl)carbamate 7.55-7.52(m, 1H), 7.41-7.37(m, 1H), 7.22-7.00(m, 3H), 7.01-6.97(m, 1H), 11 4.14-4.05(m, 2H), 3.37-3.35(m, 1H), 2.50(s, 3H), 2.10- 2.04(m, 2H), 1.93- 1.88(m, 2H), 1.81- 1.77(m, 2H), 1.66- 1.62(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'- 8.10-7.92(m, 1H), trifluoromethyl-[1,1'- 7.73-7.46(m, 3H), biphenyl]yl)carbamate 7.44-7.31(m, 1H), 7.31-7.05(m, 2H), 12 6.55-6.34(bs, 1H), 4.26-4.02(m, 2H), 3.20-3.00(m, 1H), 2.31(s, 3H), 2.25- 1.88(m, 4H) 1.86- 1.40(m, 4H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (4'-8.04(s, 1H), trifluoromethyl-[1,1'- 7.72(d, 2H, biphenyl]yl)carbamate J=8.0Hz), 7.48(d, 2H, J=8.4Hz), 7.41- 7.36(m, 1H), 7.20- 7.13(m, 2H), 13 6.41(s, 1H), 4.18- 4.14(m, 2H), 3.06- 3.01(s, 1H), 2.27(s, 3H), 2.18- 2.04(m, 2H), 2.02- 1.87(m, 2H), 1.77- 1.68(m, 2H), 1.57- 1.43(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl ((3'-fluoro-4'- 8.11-7.99(m, 1H), methyl)-[1,1'-biphenyl] 7.39-7.30(m, 1H), yl)carbamate 7.30-7.14(m, 2H), 7.14-7.07(m, 1H), 7.06-6.95(m, 2H), 6.64-6.54(bs, 1H), 4.26-4.08(m, 2H), 3.30-3.09(m, 1H), 2.36(s, 3H), 2.32(s, 3H), 2.30- 2.14(m, 2H) 2.13- 1.92(m, 2H), 1.92- 1.46(m, 4H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-methyl-[1,1'- 8.10(s, 1H), 7.38- biphenyl]yl)carbamate 7.33(m, 2H), 7.26- 7.17(m, 3H), 7.15- 7.09(m, 1H), 6.66(s, 1H), 4.19- 4.16(m, 2H), 3.21- 3.01 (s, 1H), 2.41(s, 3H), 2.28(s, 3H), 2.23- 2.12(m, 2H), 2.10- 1.91(m, 2H), 1.83- 1.63(m, 2H), 1.60- 1.43(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-ethoxy-[1,1'- 8.10(s, 1H), 7.37- biphenyl]yl)carbamate 7.31(m, 2H), 7.23- 7.18(m, 2H), 7.11- 7.08(m, 1H), 7.00- 6.86(m, 2H), 6.70(s, 1H), 4.17- 16 4.01(m, 4H), 3.18- 3.15(m, 1H), 2.36(s, 3H), 2.23- 2.16(m, 2H), 2.08- 1.91(m, 2H), 1.81- 1.71(m, 2H), 1.63- 1.41(m, 2H), 1.40- 1.38(m, 3H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-chloro 7.94(s, 1H), 7.41- fluoro-[1,1'-biphenyl] 7.36(m, 2H), yl)carbamate 7.32(s, 1H), 7.22- 7.20(m, 1H), 7.07- 7.02(m, 1H), 6.92- 6.89(m, 1H), 17 6.38(s, 1H), 4.17- 4.13(m, 2H), 3.04- 3.00(m, 1H), 2.27(s, 3H), 2.15- 2.03(m, 2H), 2.00- 1.87(m, 2H), 1.80- 1.64(m, 2H), 1.56- 1.40(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3',5-difluoro- 7.86(s, 1H), 7.44- [1,1'-biphenyl] 7.39(m, 1H), 7.26- yl)carbamate 7.22(m, 1H), 7.17- 7.08(m, 1H), 7.06- 7.02(m, 1H), 7.01- 6.91(m, 2H), 6.75(s, 1H), 4.15- 4.06(m, 2H), 3.30- 3.27(m, 1H), 2.47(s, 3H), 2.10- 1.93(m, 2H), 1.87- 1.73(m, 2H), 1.70- 1.54(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (4',5-difluoro- 7.97(s, 1H), 7.32- [1,1'-biphenyl] 7.26(m, 1H), 7.24- yl)carbamate 7.21(m, 1H), 7.19- 7.13(m, 2H), 7.07- 7.00(m, 1H), 6.92- 6.90(m, 1H), 19 6.48(s, 1H), 4.16- 4.10(m, 2H), 3.20- 3.17(m, 1H), 2.26(s, 3H), 2.17- 2.15(m, 2H), 2.07- 1.96(m, 2H), 1.83- 1.72(m, 2H), 1.69- 1.65(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3',5,5'-trifluoro- 7.82-7.66(bs, 1H), [1,1'-biphenyl] 7.12-6.75(m, 5H), yl)carbamate 4.27-3.99(m, 2H), 3.51-3.30(bs, 1H) 2.75-2.34(m, 5H), 2.20-1.55(m, 6H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (5-fluoro-[1,1'- 7.98(s, 1H), 7.50- biphenyl]yl)carbamate 7.39(m, 3H), 7.34- 7.27(m, 2H), 7.06- 7.01(m, 1H), 6.98- 6.92(m, 1H), 6.45(s, 1H), 4.17- 4.07(m, 2H), 3.05- 3.01(m, 1H), 2.27(s, 3H), 2.22- 2.02(m, 2H), 2.01- 1.80(m, 2H), 1.78- 1.61(m, 2H), 1.58- 1.40(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (5-fluoro-3'- 8.01(s, 1H), 7.36- methyl-[1,1'-biphenyl] 7.32(m, 1H), 7.27- yl)carbamate 7.21(m, 2H), 7.13- 7.11(m, 1H), 7.05- 7.00(m, 1H), 6.96- 6.90(m, 1H), 6.51(s, 1H), 4.16- 4.09(m, 2H), 3.06- 3.02(m, 1H), 2.39(s, 3H), 2.28(s, 3H), 2.18- 2.07(m, 2H), 2.05- 1.88(m, 2H), 1.81- 1.62(m, 2H), 1.58- 1.44(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (4-fluoro-[1,1'- 7.97(s, 1H), 7.48- biphenyl]yl)carbamate 7.45(m, 2H), 7.42- 7.40(m, 1H), 7.32- 7.30(m, 2H), 7.15- 7.11(m, 1H), 6.82- 6.79(m, 1H), 23 6.66(s, 1H), 4.18- 4.14(m, 2H), 3.06- 3.04(m, 1H), 2.30(s, 3H), 2.15- 2.00(m, 2H), 1.99- 1.91(m, 2H), 1.69- 1.58(m, 2H), 1.56- 1.48(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3',4-difluoro- 7.97(s, 1H), 7.48- [1,1'-biphenyl] 7.44(m, 1H), 7.28- yl)carbamate 7.17(m, 2H), 7.15- 7.11(m, 1H), 7.05- 6.97(m, 1H), 6.86- 6.80(m, 1H), 24 6.68(s, 1H), 4.19- 4.13(m, 2H), 3.31- 3.28(m, 1H), 2.48(s, 3H), 2.19- 2.07(m, 2H), 1.95- 1.88(m, 2H), 1.85- 1.70(m, 2H), 1.67- 1.54(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (4-methoxy-[1,1'- 7.80(s, 1H), 7.44- biphenyl]yl)carbamate 7.36(m, 1H), 7.34- 7.29(m, 3H), 7.09- 7.07(m, 1H), 6.68- 6.64(m, 2H), 4.20- 4.14(m, 2H), 3.82(s, 3H), 3.04- 3.00(m, 1H), 2.26(s, 3H), 2.14- 2.00(m, 2H), 2.13- 1.87(m, 2H), 1.79- 1.59(m, 2H), 1.56- 1.40 (m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (5-methyl-[1,1'- 7.91 (s, 1H), 7.46- biphenyl]yl)carbamate 7.42(m, 2H), 7.38- 7.29(m, 2H), 7.22- 7.18(m, 1H), 7.02(s, 1H), 6.54(s, 1H), 4.18- 26 4.10(m, 2H), 3.21- 3.10(m, 1H), 2.32(s, 3H), 2.31(s, 3H), 2.22- 2.16(m, 2H), 2.12- 1.91(m, 2H), 1.81- 1.68(m, 2H), 1.65- 1.48(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-fluoro 7.92 (s, 1H), 7.44- methyl-[1,1'-biphenyl] 7.38(m, 2H), 7.20- yl)carbamate 7.15(m, 1H), 7.13- 7.09(m, 1H), 7.07- 6.97(m, 2H), 6.55(s, 1H), 4.17- 27 4.07(m, 2H), 3.30- 3.23(m, 1H), 2.49(s, 3H), 2.37(s, 3H), 2.15- 2.05(m, 2H), 1.93- 1.90(m, 2H), 1.79- 1.76(m, 2H), 1.63- 1.61(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (4'-cyano-[1,1'- 8.06-7.93(m, 1H), biphenyl]yl)carbamate 7.75(d, 8.4Hz, 2H), 7.49(d, J=8.0Hz, 2H), 7.44-7.33(m, 1H), 7.21-7.09(m, 2H), 6.42-6.38(bs, 1H), 4.22-4.07(m, 2H), 3.11-2.98(m, 1H), 2.29(s, 3H), 2.19-1.85(m, 3H) 1.85-1.39(m, 5H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-(3- 8.03(s, 1H), 7.39- hydroxypropyl)-[1,1'- 7.28(m, 3H), 7.23- biphenyl]yl)carbamate 7.11(m, 3H), 7.05- 7.01(m, 1H), 6.67(s, 1H), 4.23- 4.14(m, 2H), 3.66- 3.60(m, 2H), 3.17- 3.03(m, 1H), 2.75- 2.71(m, 2H), 2.32(s, 3H), 2.24- 2.10(m, 2H), 2.05- 1.96 (m, 2H), 1.94- 1.83 (m, 2H), 1.81- 1.69(m, 2H), 1.61- 1.46(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (4'-8.11(s, 1H), (dimethylamino)-[1,1'- 7.28(t, 1H, biphenyl]yl)carbamate J=7.2Hz), 7.23- 7.19(m, 2H), 7.19- 7.17(m, 1H), 7.07(t, 1H, J=7.6Hz), 6.81(t, 2H, J=2.8Hz), N 6.74(s, 1H), 4.18- 4.14(m, 2H), 3.09- 3.01(m, 1H), 3.00(s, 9H), 2.14(s, 3H), 2.12- 2.06(m, 2H), 2.01- 1.92(m, 2H), 1.79- 1.66(m, 2H), 1.58- 1.46(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (4'-(tert-butyl)- 8.04(s, 1H), 7.48- [1,1'-biphenyl] 7.46(m, 2H), 7.35- yl)carbamate 7.27(m, 3H), 7.24- 7.19(m, 1H), 7.12- 7.08(m, 1H), 6.67(s, 1H), 4.17- 31 4.13(m, 2H), 3.10- 3.07(m, 1H), 2.30(s, 3H), 2.18- 1.99(m, 2H), 1.98- 1.90(m, 2H), 1.80- 1.62(m, 2H), 1.44- 1.36(m, 2H), 1.36(s, 9H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (2'-amino-[1,1'-8.11(s, 1H), biphenyl]yl)carbamate 7.37(t, 1H, J=8.0Hz), 7.22- 7.20(m, 2H), 7.13(t, 1H, J=7.6Hz), 7.06(d, 1H, J=7.6Hz), 6.86- 6.78(m, 2H), 4.15- 4.11(m, 2H), 3.08- 3.04(s, 1H), 2.25(s, 3H), 2.17- 2.10(m, 2H), 2.02- 1.90(m, 2H), 1.78- 1.66(m, 2H), 1.58- 1.46(m, 2H) 2-(1-Methylpyrrolidin H NMR(CD OD): δ yl)ethyl (3'-amino-[1,1'- 7.83(s, 1H), 7.29- biphenyl]yl)carbamate 7.15(m, 3H), 7.06- 7.00(m, 2H), 6.80- 6.77(m, 2H), 4.14- 4.10(m, 2H), 3.30(s, 3H), 3.20- 3.15(m, 1H), 2.45- 2.43(m, 2H), 2.10- 2.00 (m, 2H), 1.84- 1.81(m, 2H), 1.62- 1.47(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (2'-fluoro-[1,1'- 7.96(s, 1H), 7.42- biphenyl]yl)carbamate 7.36(m, 3H), 7.31- 7.14(m, 3H), 6.99- 6.97(m, 1H), 6.45(s, 1H), 4.15- 34 4.08(m, 2H), 3.26- 3.22(s, 1H), 2.39(s, 3H), 2.35- 2.25(m, 2H), 2.09- 1.96(m, 2H), 1.88- 1.64(m, 2H), 1.60- 1.53(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (2'-chloro-[1,1'- 8.01(s, 1H), 7.51- biphenyl]yl)carbamate 7.48(m, 1H), 7.41- 7.34(m, 2H), 7.28- 7.13(m, 3H), 6.96- 6.93(m, 1H), 6.26(s, 1H), 4.18- 4.05(m, 2H), 3.22- 3.20(s, 1H), 2.37(s, 3H), 2.35- 2.28(m, 2H), 2.07- 1.93(m, 2H), 1.84- 1.63(m, 2H), 1.57- 1.52(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (2'-hydroxy-[1,1'- 7.84(s, 1H), 7.39- biphenyl]yl)carbamate 7.33(m, 1H), 7.31- 7.12(m, 4H), 7.05- 7.01(m, 1H), 6.96- 6.90(m, 1H), 4.21- 36 4.09(m, 2H), 3.21- 3.14(s, 1H), 2.40(s, 3H), 2.36- 2.26(m, 2H), 2.13- 1.96(m, 2H), 1.84- 1.66(m, 2H), 1.64- 1.53(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-tert-butyl-5'- 8.11(s, 1H), 7.35- methyl-[1,1'-biphenyl] 7.27(m, 1H), 7.23- yl)carbamate 7.21(m, 2H), 7.18(s, 1H), 7.13- 7.09(m, 1H), 6.99(s, 1H), 6.74(s, 1H), 4.17- 37 4.12(m, 2H), 3.12- 3.09(m, 1H), 2.39(s, 3H), 2.30(s, 3H), 2.23- 2.11(m, 2H), 2.01- 1.98(m, 2H), 1.79- 1.66(m, 2H), 1.58- 1.46(m, 2H), 1.32(m, 9H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (4'-fluoro-3'- 7.99(s, 1H), 7.60- (trifluoromethyl)-[1,1'- 7.58(m, 1H), 7.56- biphenyl]yl)carbamate 7.53(m, 1H), 7.41- 7.36(m, 1H), 7.32- 7.27(m, 1H), 7.20- 7.14(m, 2H), 38 6.37(s, 1H), 4.18- 4.13(m, 2H), 3.14- 3.12(m, 1H), 2.34(s, 3H), 2.34- 2.21(m, 2H), 2.06- 1.93(m, 2H), 1.76- 1.68(m, 2H), 1.64- 1.46(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (4'-amino-3'-8.04(s, 1H), chloro-[1,1'-biphenyl] 7.30(t, 1H, yl)carbamate J=8.0Hz), 7.15- 7.12(m, 2H), 7.07- 7.03(m, 2H), 6.82(d, 1H, 39 J=8.4Hz), 6.59(s, 1H), 4.18-4.09(m, 2H), 3.08-3.04(m, 1H), 2.30(s, 3H), 2.25-2.10 (m, 2H), 2.08-1.91(m, 2H), 1.81-1.57(m, 2H), 1.56-1.43(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CD OD): δ yl)ethyl (3'-hydroxy-[1,1'- 7.84(s, 1H), 7.31- biphenyl]yl)carbamate 7.18(m, 3H), 7.06- 7.02(m, 2H), 6.82- 6.79(m, 2H), 4.11- 4.08(m, 2H), 3.30(s, 3H), 3.21- 3.18(m, 1H), 2.45- 2.43(m, 2H), 2.08- 2.01(m, 2H), 1.84- 1.82(m, 2H), 1.61- 1.45(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-chloro-4'- 8.06-7.93(bs, 1H), fluoro-[1,1'-biphenyl] 7.41-7.38(m, 1H), yl)carbamate 7.38-7.34(m, 1H), 7.23-7.19(m, 3H), 7.17-7.10(m, 2H), 6.51-6.44(bs, 1H), 4.20-4.12(m, 2H), 3.16-3.07(bs, 1H) 2.33(s, 3H), 2.25- 2.13(m, 2H), 2.07- 1.92(m, 2H), 1.84- 1.65(m, 2H), 1.65- 1.46(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3',4',5-trifluoro- 7.98(s, 1H), 7.29- [1,1'-biphenyl] 7.28(m, 1H), 7.17- yl)carbamate 7.14(m, 1H), 7.08- 7.03(m, 2H), 6.90(dd, 1H, J=8.8Hz, J=2.8Hz), 42 6.33(s, 1H), 4.17- 4.13(m, 2H), 3.05- 3.03(m, 1H), 2.28(s, 3H), 2.08- 2.03(m, 2H), 2.02- 1.89(m, 2H), 1.79- 1.63(m, 2H), 1.60- 1.42(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3',4'-dichloro7.94(s, 1H), fluoro-[1,1'-biphenyl] 7.54(d, 1H, yl)carbamate J=8.4Hz), 7.44(d, 1H, J=2.0Hz), 7.19(dd, 1H, J=8.4Hz, J=2.0Hz), 7.09-7.05(m, 1H), 6.91(dd, 1H, J=8.4Hz, J=2.8Hz), 6.38(s, 1H), 4.20- 4.14(m, 2H), 3.17- 3.16(m, 1H), 2.36(s, 3H), 2.07- 1.96(m, 2H), 1.83- 1.80(m, 2H), 1.77- 1.71(m, 2H), 1.58- 1.54(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-ethylfluoro-8.01(s, 1H), [1,1'-biphenyl] 7.38(t, 1H, yl)carbamate J=8.0Hz), 7.25- 7.23(m, 1H), 7.16- 7.13(m, 2H), 7.05- 7.00(m, 1H), 6.95- 6.92(m, 1H), 6.53(s, 1H), 4.17- 44 4.12(m, 2H), 3.05- 3.03(m, 1H), 2.68(q, 2H, J=7.6Hz), 2.28(s, 3H), 2.16-2.02(m, 2H), 2.00-1.88(m, 2H), 1.78-1.62(m, 2H), 1.59-1.41(m, 2H), 1.25(t, 3H, J=7.6Hz) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (5-fluoro-3',5'- 8.01(s, 1H), 7.03- dimethyl-[1,1'-biphenyl] 6.98(m, 2H), 6.93- yl)carbamate 6.89(m, 2H), 6.55(s, 1H), 4.20- 4.14(m, 2H), 3.03- 45 3.01(m, 1H), 2.38(s, 6H), 2.35(s, 3H), 2.09- 2.04(m, 2H), 2.03- 1.90(m, 2H), 1.79- 1.63(m, 2H), 1.59- 1.44(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-aminofluoro- 8.02(s, 1H), 7.25- [1,1'-biphenyl] 7.21(m, 2H), 7.03- yl)carbamate 6.99(m, 1H), 6.92- 6.89(m, 1H), 6.71- 6.67(m, 2H), 6.60(s, 2H), 4.16- 4.12(m, 2H), 3.04- 3.01(m, 1H), 2.28(s, 3H), 2.02- 1.97(m, 2H), 1.96- 1.89(m, 2H), 1.78- 1.63(m, 2H), 1.57- 1.41(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (5-8.29(d, 1H, (trifluoromethyl)-[1,1'- J=8.8Hz), 7.59(d, biphenyl]yl)carbamate 1H, J=8.8Hz), 7.52- 7.49(m, 2H), 7.46- 7.44(m, 2H), 7.36- 7.34(m, 2H), 47 6.78(s, 1H), 4.19- 4.16(m, 2H), 3.12- 3.10(m, 1H), 2.33(s, 3H), 2.17- 2.05(m, 2H), 2.03- 1.93(m, 2H), 1.78- 1.64(m, 2H), 1.53- 1.51(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (4'-fluoro8.27(d, 1H, (trifluoromethyl)-[1,1'- J=8.4Hz), 7.59(d, biphenyl]yl)carbamate 1H, J=8.8Hz), 7.41(d, 1H, J=1.2Hz), 7.34-7.31 (m, 2H), 7.22- 7.18(m, 2H), 6.70(s, 1H), 4.22- 4.16(m, 2H), 3.26- 3.24(m, 1H), 2.41(s, 3H), 2.35- 2.29(m, 2H), 2.13- 1.98(m, 2H), 1.88- 1.77(m, 2H), 1.62- 1.59(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-fluoro8.29(d, 1H, (trifluoromethyl)-[1,1'- J=8.8Hz), 7.61(d, biphenyl]yl)carbamate 1H, J=8.8Hz), 7.51- 7.45(m, 1H), 7.43(s, 1H), 7.18- 7.13(m, 2H), 7.08- 7.06(m, 1H), 6.71(s, 1H), 4.21- 4.17(m, 2H), 3.12- 3.10(m, 1H), 2.33(s, 3H), 2.19- 2.15(m, 2H), 2.07- 1.92(m, 2H), 1.74- 1.71(m, 2H), 1.53- 1.50(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3',5'-difluoro8.26(d, 1H, (trifluoromethyl)-[1,1'- J=8.8Hz), 7.62(d, biphenyl]yl)carbamate 1H, J=8.8Hz), 7.43(s, 1H), 6.93- 6.89(m, 3H), 6.78(s, 1H), 4.24- 4.19(m, 2H), 3.28- 3.21(m, 1H), 2.45(s, 3H), 2.15- 2.04(m, 2H), 1.89- 1.87(m, 2H), 1.82- 1.80(m, 2H), 1.67- 1.63(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-chloro 8.27(d, 1H, (trifluoromethyl)-[1,1'- J=8.4Hz), 7.61(d, biphenyl]yl)carbamate 1H, J=8.8Hz), 7.47- 7.43(m, 3H), 7.35(s, 1H), 7.25- 7.23(m, 1H), 51 6.75(s, 1H), 4.23- 4.17(m, 2H), 3.34- 3.32(m, 1H), 2.42(s, 3H), 2.11- 2.05(m, 2H), 2.02- 1.91(m, 2H), 1.90- 1.83(m, 2H), 1.83- 1.80(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-chloro-5,5'- 7.91(s, 1H), 7.22- difluoro-[1,1'-biphenyl] 7.20(m, 1H), 7.15- yl)carbamate 7.13(m, 1H), 7.10- 7.05(m, 1H), 6.99- 6.97(m, 1H), 6.92(dd, 1H, J=8.8Hz, J=2.8Hz), 6.44(s, 1H), 4.21- 4.14(m, 2H), 3.22- 3.19(m, 1H), 2.40(s, 3H), 2.32- 2.28(m, 2H), 2.10- 2.02(m, 2H), 1.86- 1.59(m, 2H), 1.26- 1.22(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-chloro-4',5-7.91(s, 1H), difluoro-[1,1'-biphenyl]7.39(dd, 1H, yl)carbamate J=7.2Hz, J=2.0Hz), 7.23-7.19(m, 2H), 7.08-7.04(m, 1H), 6.90(dd, 1H, J=8.4Hz, J=2.8Hz), 6.37(s, 1H), 4.18- 4.13(m, 2H), 3.14- 3.10(m, 1H), 2.33(s, 3H), 2.23- 2.16(m, 2H), 2.06- 1.91(m, 2H), 1.82- 1.65(m, 2H), 1.60- 1.51(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (4'-chloro-3',5- 7.81(s, 1H), 7.47- difluoro-[1,1'-biphenyl] 7.43(m, 1H), 7.19- yl)carbamate 7.11(m, 2H), 7.11- 6.95(m, 1H), 6.90(dd, 1H, J=8.8Hz, J=3.2Hz) 54 6.62(s, 1H), 4.14- 4.04(m, 2H), 3.21- 3.16(m, 1H), 2.37(s, 3H), 2.04- 1.95(m, 2H), 1.84- 1.69(m, 2H), 1.67- 1.61(m, 1H), 1.57- 1.48(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3',5'-dichloro 7.90(s, 1H), 7.41- fluoro-[1,1'-biphenyl] 7.40(m, 1H), 7.25- yl)carbamate 7.22(m, 2H), 7.10- 7.05(m, 1H), 6.91(dd, 1H, J=8.8Hz, J=2.8Hz), 55 6.38(s, 1H), 4.20- 4.16(m, 2H), 3.16- Cl Cl 3.12(m, 1H), 2.36(s, 3H), 2.23- 2.21(m, 2H), 2.09- 1.94(m, 2H), 1.80- 1.64(m, 2H), 1.56- 1.52(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3',5'-dichloro- 7.81(s, 1H), 7.31- 4',5-difluoro-[1,1'- 7.30(m, 1H), 7.19- biphenyl]yl)carbamate 7.18(m, 1H), 7.09- 7.04(m, 1H), 6.91- 6.62(m, 1H), 56 6.61(s, 1H), 4.20- 4.11(m, 2H), 3.26- 3.22(m, 1H), 2.42- 2.30(m, 4H), 2.11- 1.93(m, 2H), 1.88- 1.63(m, 2H), 1.61- 1.54(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-chloro 7.83(s, 1H), 7.03- fluoro-5'-hydroxy-[1,1'- 6.95(m, 1H), 6.91- biphenyl]yl)carbamate 6.88(m, 1H), 6.80(s, 1H), 6.73- 6.66(m, 2H), 4.12- 57 4.07(m, 2H), 3.21- 3.17(m, 1H), 2.35(s, 3H), 2.28- HO Cl 2.24(m, 2H), 1.82- 1.65(m, 2H), 1.62- 1.55(m, 2H), 1.25- 1.21(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-chloro 7.83(s, 1H), 7.25- fluoro-4'-hydroxy-[1,1'- 7.20(m, 1H), 7.05- biphenyl]yl)carbamate 6.92(m, 3H), 6.88(dd, 1H, J=8.8Hz, J=2.8Hz), 6.57(s, 1H), 4.14- 4.06(m, 2H), 3.22- 3.17(m, 1H), 2.40(s, 3H), 2.39- 2.29(m, 2H), 2.10- 1.97(m, 2H), 1.86- 1.66(m, 2H), 1.65- 1.54(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (5-fluoro-3',4'- 7.99(s, 1H), 7.22- dimethyl-[1,1'-biphenyl] 7.20(m, 1H), 7.08- yl)carbamate 6.97(m, 3H), 6.90(dd, 1H, J=9.2Hz, J=2.8Hz), 6.57(s, 1H), 4.15- 59 4.13(m, 2H), 3.16- 3.12(m, 1H), 2.31(s, 3H), 2.29(s, 6H), 2.02- 2.17(m, 2H), 2.00- 1.89(m, 2H), 1.76- 1.55(m, 2H), 1.53- 1.42(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (5-methoxy-[1,1'- 7.93(s, 1H), 7.46- biphenyl]yl)carbamate 7.40(m, 2H), 7.39- H 7.36(m, 1H), 7.35- 7.33(m, 2H), 6.89(dd, 1H, J=8.8Hz, J=2.8Hz), 6.77(d, 1H, 60 J=2.8Hz), 6.38(s, 1H), 4.15-4.10(m, 2H), 3.86(s, 3H), 3.14-3.11(m, 1H), 2.35(m, 3H), 2.26- 2.16(m, 2H), 2.06- 1.91(m, 2H), 1.82- 1.62(m, 2H), 1.60- 1.45(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-fluoro 7.82(s, 1H), 7.42- methoxy-[1,1'-biphenyl] 7.39(m, 1H), 7.14- yl)carbamate 7.10(m, 1H), 7.07- 7.05(m, 2H), H CO 6.90(dd, 1H, J=8.8Hz, J=3.2Hz), 6.75(d, 1H, 61 J=3.2Hz), 6.37(s, 1H), 4.17-4.13(m, 2H), 3.79(s, 3H), 3.21-3.18(m, 1H), 2.38(s, 3H), 2.30- 2.26(m, 2H), 2.09- 1.99(m, 2H), 1.74- 1.70(m, 2H), 1.56- 1.53(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3',5'-difluoro 7.72(s, 1H), 7.28- methoxy-[1,1'-biphenyl] 7.26(m, 1H), 6.92- yl)carbamate 6.79(m, 3H), 6.74- 6.73(m, 1H), H CO 6.29(s, 1H), 4.15- 4.10(m, 2H), 3.75(s, 3H), 3.15- 3.10(m, 1H), 2.34(s, 3H), 2.27- 2.25(m, 2H), 2.06- 1.96(m, 2H), 1.78- 1.69(m, 2H), 1.63- 1.50(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-chloro 7.82(s, 1H), 7.38- methoxy-[1,1'-biphenyl] 7.34(m, 2H), 7.23- yl)carbamate 7.21(m, 2H), H 6.90(dd, 1H, J=9.2Hz, J=2.8Hz), 6.74(d, 1H, J=2.8Hz), 6.28(s, 1H), 4.17-4.12(m, 2H), 3.78(s, 3H), 3.16-3.14(m, 1H), 2.35(s, 3H), 2.23- 2.18(m, 2H), 2.21- 1.93(m, 2H), 1.79- 1.64(m, 2H), 1.60- 1.50(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3',5'-dichloro 7.70(s, 1H), 7.36- methoxy-[1,1'-biphenyl] 7.35(m, 1H), 7.23- yl)carbamate 7.20(m, 2H), 6.90(dd, 1H, H CO J=8.8Hz, J=2.8Hz), 6.73-6.72(m, 1H), 6.58(s, 1H), 4.16- l l 4.08(m, 2H), 3.75(s, 3H), 3.28- 3.26(m, 1H), 2.43(s, 3H), 2.40- 2.38(m, 2H), 2.08- 2.02(m, 2H), 1.85- 1.72(m, 2H), 1.60- 1.57(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3'-chloro-4'- 7.70(s, 1H), 7.39- fluoromethoxy-[1,1'- 7.38(m, 1H), 7.21- biphenyl]yl)carbamate 7.19(m, 2H), 6.90(dd, 1H, H CO J=8.8Hz, J=2.8Hz), 6.72-6.71(m, 1H), 6.21(s, 1H), 4.15- 4.09(m, 2H), 3.76(s, 3H), 3.13- 3.11(m, 1H), 2.37(s, 3H), 2.30- 2.23(m, 2H), 2.02- 1.97(m, 2H), 1.79- 1.71(m, 2H), 1.62- 1.56(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (5-chloro-[1,1'- 8.04(s, 1H), 7.48- biphenyl]yl)carbamate 7.45(m, 2H), 7.43- 7.39(m, 1H), 7.32- 7.28(m, 3H), 7.23- 7.18(m, 1H), 6.56(s, 1H), 4.16- 4.12(m, 2H), 3.06- 3.02(m, 1H), 2.28(s, 3H), 2.12- 1.96(m, 2H), 1.94- 1.87(m, 2H), 1.76- 1.64(m, 2H), 1.57- 1.44(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (5-chloro-3'-8.03(s, 1H), fluoro-[1,1'-biphenyl] 7.44(q, 1H, yl)carbamate J=8.0Hz), 7.31(dd, 1H, J=8.8Hz, J=2.4Hz), 7.14- 7.10(m, 2H), 7.05- 7.03(m, 1H), 6.49(s, 1H), 4.17- 4.13(m, 2H), 3.03- 3.01(m, 2H), 2.29(s, 3H), 2.13- 1.98(m, 2H), 1.97- 1.88(m, 2H), 1.77- 1.64(m, 2H), 1.59- 1.42(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (5-chloro-4'- 8.02(s, 1H), 7.31- fluoro-[1,1'-biphenyl] 7.28(m, 3H), 7.18- yl)carbamate 7.14(m, 3H), 6.44(s, 1H), 4.17- 4.13(m, 2H), 3.04- 3.01(m, 1H), 2.28(s, 3H), 2.10- 2.00(m, 2H), 1.98- 1.87(m, 2H), 1.78- 1.65(m, 2H), 1.57- 1.44(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (5-chloro-3',5'- 7.99(s, 1H), 7.34- difluoro-[1,1'-biphenyl] 7.31(m, 2H), 7.17- yl)carbamate 7.16(m, 1H), 6.88- 6.84(m, 2H), 6.51(s, 1H), 4.18- 69 4.10(m, 2H), 3.16- 3.13(m, 1H), 2.36(s, 3H), 2.32- 2.29(m, 2H), 2.08- 1.96(m, 2H), 1.82- 1.61(m, 2H), 1.57- 1.49(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3',5-dichloro- 8.01(s, 1H), 7.43- [1,1'-biphenyl] 7.38(m, 2H), 7.32- yl)carbamate 7.30(m, 2H), 7.23- 7.21(m, 1H), 7.17(d, 1H, J=2.4Hz), 6.47(s, 1H), 4.18-4.13(m, 2H), 3.06-3.04(m, 1H), 2.25(s, 3H), 2.19-2.06(m, 2H), 2.05-1.90(m, 2H), 1.80-1.59(m, 2H), 1.58-1.44(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3',5,5'-trichloro-7.98(s, 1H), [1,1'-biphenyl] 7.41(s, 1H), yl)carbamate 7.33(dd, 1H, J=8.8Hz, J=2.4Hz), 7.23-7.22(m, 2H), 7.15(d, 1H, 71 J=2.4Hz), 6.39(s, 1H), 4.19-4.14(m, Cl Cl 2H), 3.09-3.05(m, 1H), 2.30(s, 3H), 2.19-2.07(m, 2H), 2.04-1.91(m, 2H), 1.77-1.61(m, 2H), 1.59-1.43(m, 2H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3',5-dichloro-5'-7.99(s, 1H), fluoro-[1,1'-biphenyl] 7.33(dd, 1H, yl)carbamate J=8.8Hz, J=2.4Hz), 7.21-7.13(m, 3H), 6.96(dd, 1H, J=8.8Hz, J=2.4Hz), 72 6.46(s, 1H), 4.20- 4.12(m, 2H), 3.11- F Cl 3.07(m, 1H), 2.32(s, 3H), 2.20- 2.14(m, 2H), 2.06- 1.91(m, 2H), 1.79- 1.62(m, 2H), 1.60- 1.45(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (3',5-dichloro-4'- 7.98(s, 1H), 7.39- fluoro-[1,1'-biphenyl] 7.37(m, 1H), 7.32- yl)carbamate 7.26(m, 1H), 7.23- 7.21(m, 2H), 7.19(d, 1H, J=2.8Hz), 6.41(s, 1H), 4.17-4.13(m, 2H), 3.06-3.03(m, 1H), 2.26(s, 3H), 2.39-2.10(m, 2H), 2.03-1.89(m, 2H), 1.80-1.59(m, 2H), 1.57-1.43(m, 2H) (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-fluoro-4'- 8.00-7.93(m, 2H), formyl-[1,1'-biphenyl] 7.41-7.37(t, 1H, yl)carbamate J=15.2Hz), 7.29- 7.27(d, 1H, J=8.0Hz), 7.23- 7.15(m, 3H), 74 6.51(s, 1H), 4.08- 3.97(m, 2H), 2.60- 2.56(t, 1H, J=17.2Hz), 2.49- 2.45(m, 3H), 2.29- 2.24(m, 4H), 1.96- 1.91(m, 1H), 1.48- 1.43(m, 1H) 1001965344 2-(1-Methylpyrrolidin H NMR(CD OD): δ yl)ethyl (3',5'-difluoro 7.19-7.17(m, 1H), hydroxy-[1,1'-biphenyl] 6.92-6.90(m, 2H), yl)carbamate 6.85-6.76(m, 2H), 6.72-6.71(m, 1H), 4.10-4.02(m, 2H), 3.70-3.61(m, 1H), 3.16-3.10(m, 2H), 2.83(s, 3H), 2.27- 2.13(m, 2H), 2.13- 2.02(m, 2H), 1.77- 1.72(m, 2H) 2-(1-Methylpyrrolidin H NMR(CD OD): δ yl)ethyl (3',5'-dichloro 7.33-7.32(m, 1H), hydroxy-[1,1'-biphenyl] 7.27-7.23(m, 1H), yl)carbamate 7.17-7.15(m, 1H), 7.05-7.01(m, 1H), 6.82-6.79(m, 1H), 6.72-6.71(m, 1H), 4.11-4.07(m, 2H), 3.50-3.47(m, 1H), Cl Cl 3.04-3.01(m, 2H), 2.70(s, 3H), 2.20- 2.16(m, 2H), 1.95- 1.90(m, 2H), 1.75- 1.70(m, 2H) 1001965344 2-(1-Methylpyrrolidin H NMR(CD OD): δ yl)ethyl (3'-chloro-4'- 7.44-7.42(m, 1H), fluorohydroxy-[1,1'- 7.27-7.22(m, 2H), biphenyl]yl)carbamate 7.16-7.14(m, 1H), 6.77-6.75(m, 1H), 6.70-6.69(m, 1H), 77 4.08-4.02(m, 2H), 3.64-3.57(m, 1H), 3.13-3.09(m, 2H), 2.86(s, 3H), 2.27- 2.22(m, 2H), 1.97- 1.93(m, 2H), 1.75- 1.70(m, 2H) (R)-pyrrolidinylmethyl H NMR(CDCl ): δ [1,1'-biphenyl] 8.17-7.98(bs, 1H), ylcarbamate 7.60-7.29(m, 6H), 7.26-7.06(m, 2H), 6.78-6.61(bs, 1H), 78 4.17-3.94(m, 2H), 3.09-2.81(m, 3H) 2.75-2.59(m, 1H), 2.56-2.33(m, 2H), 1.98-1.80(m, 1H), 1.54-1.35(m, 1H) 1001965344 (S)-pyrrolidinylmethyl H NMR(CDCl ): δ [1,1'-biphenyl] 8.07-7.89(bs, 1H), ylcarbamate 7.58-7.32(m, 6H), 7.32-7.13(m, 2H), 7.01-6.85(bs, 1H), 79 4.28-3.98(m, 3H), 3.47-3.17(m, 3H), 3.13-2.95(m, 1H), 2.80-2.62(m, 1H), 2.25-2.08(m, 1H), 1.89-1.70(m, 1H) (R)-pyrrolidinylmethyl H NMR(CDCl ): δ (3',5'-difluoro-[1,1'- 8.10-7.93(bs, 1H), biphenyl]yl)carbamate 7.45-7.30(m, 1H), 7,21-7.08(m, 2H), 6.98-6.79(m, 3H), 6.67-6.51(bs, 1H), 4.15-3.90(m, 2H), 3.11-2.76(m, 3H), 2.71-2.53(m, 8H), 2.48-2.29(m, 1H), 2.02-2.72(m, 2H), 1.49-1.29(m, 1H) 1001965344 (S)-pyrrolidinylmethyl H NMR(CDCl ): δ (3',5'-difluoro-[1,1'- 8.10-7.89(m, 1H), biphenyl]yl)carbamate 7.49-7.30(m, 1H), 7.22-7.04(m, 2H), 6.98-6.75(m, 3H), 6.68-6.50(bs, 1H), 4.19-3.85(m, 2H), 3.12-2.75(m, 3H) 2.72-2.52(bs, 1H), 2.52-2.27(m, 1H), 2.07-1.72(m, 2H), 1.50-1.31(m, 1H) (S)-pyrrolidinylmethyl H NMR(CDCl ): δ (5-fluoro-[1,1'-biphenyl] 7.81(s, 1H), 7.45- yl)carbamate 7.36(m, 3H), 7.33- 7.26(m, 2H), 7.06- 7.01(m, 1H), 6.97- 6.94(m, 1H), 4.12- 82 4.06(m, 2H), 3.35- 3.27(m, 1H), 3.23- 3.16(m, 1H), 3.05- 3.02(m, 1H), 2.69- 2.65(m, 1H), 2.17- 2.12(m, 1H), 1.82- 1.78(m, 2H) 1001965344 (S)-pyrrolidinylmethyl H NMR(CDCl ): δ (5-fluoro-3'-methyl-[1,1'- 7.82(s, 1H), 7.35- biphenyl]yl)carbamate 7.31(m, 1H), 7.20- 7.18(m, 1H), 7.18- 7.14(m, 1H), 7.13- 7.11(m, 1H), 7.07- 6.98(m, 1H), 6.95- 6.92(m, 1H), 4.13- 4.07(m, 2H), 3.38- 3.33(m, 2H), 3.25- 3.22(m, 1H), 3.09- 3.05(m, 1H), 2.69- 2.65(m, 1H), 2.38(s, 3H), 2.15- 2.13(m, 1H), 1.80- 1.76(m, 1H) (R)-pyrrolidinylmethyl H NMR(CDCl ): δ (3',5,5'-trifluoro-[1,1'- 7.98-7.79(bs, 1H), biphenyl]yl)carbamate 7.14-7.00(m, 1H), 7,00-6.78(m, 4H), 6.61-6.45(bs, 1H), 84 4.18-3.90(m, 2H), NH 3.13-2.80(m, 3H), 2.70-2.57(m, 1H), 2.51-2.21(m, 2H), 1.94-1.80(m, 1H), 1.49-1.35(m, 1H) 1001965344 (S)-pyrrolidinylmethyl H NMR(CDCl ): δ (3',5,5'-trifluoro-[1,1'- 7.96-7.77(bs, 1H), biphenyl]yl)carbamate 7.13-6.99(m, 1H), 6.99-6.76(m, 4H), 6.68-6.50(bs, 1H), 4.15-3.92(m, 2H), 3.16-2.90(bs, 3H), 2.90-2.30(m, 3H), 1.99-1.81(m, 1H), 1.53-1.35(m, 1H) (R)-pyrrolidinylmethyl H NMR(CDCl ): δ (5-methyl-[1,1'-biphenyl] 7.77 (s, 1H), 7.44- yl)carbamate 7.40(m, 2H), 7.37- 7.31(m, 2H), 7.20- 7.13(m, 2H), 7.04(s, 1H), 86 6.85(s, 1H), 4.13- 4.04(m, 2H), 2.78- 2.62(m, 3H), 2.32(s, 3H), 2.16- 2.09(m, 2H), 2.03(s, 1H), 1.79- 1.70(m, 2H) 1001965344 (R)-pyrrolidinylmethyl H NMR(CDCl ): δ (3'-fluoromethyl-[1,1'- 7.84 (s, 1H), 7.43- biphenyl]yl)carbamate 7.38(m, 1H), 7.17- 7.08(m, 2H), 7.04- 7.02(m, 2H), 7.01(s, 1H), 6.55(s, 1H), 4.08- 3.97(m, 2H), 2.47- 2.33(m, 3H), 2.32(s, 3H), 1.94- 1.80(m, 2H), 1.51- 1.40(m, 2H) (S)-pyrrolidinylmethyl H NMR(CDCl ): δ (4'-fluoro-[1,1'-biphenyl]- 8.13-7.94(m, 1H), 2-yl)carbamate 7.41-7.23(m, 3H), 7.20-7.02(m, 4H), 6.75-6.57(bs, 1H), 4.23-4.04(m, 1H), 88 HN 4.02-3.85(m, 1H), 3.47-3.30(m, 1H), 3.02-2.81(m, 2H), 2.57-2.25(bs, 1H), 1.95-1.59(m, 3H), 1.50-1.32(m, 1H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl [1,1'-biphenyl] 8.13-7.94(bs, 1H), ylcarbamate 7.55-7.27(m, 6H), 7,26-7.03(m, 2H), 6.77-6.59(bs, 1H), 89 4.18-3.94(m, 2H), 3.00-2.57(m, 4H), 2.54-2.49(m, 1H), 2.47(s, 3H), 2.10- 1.98(m, 1H) 1.67- 1.55(m, 1H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl [1,1'-biphenyl] 8.09-7.94(bs, 1H), ylcarbamate 7.56-7.31(m, 6H), 7.30-7.12(m, 2H), 6.86-6.72(bs, 1H), 90 4.19-4.02(m, 1H), 3.41-3.05(m, 3H), 2.97-2.77(m, 2H) 2.74(s, 3H), 2.29- 2.15(m, 1H), 1.89- 1.74(m, 1H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',5'-difluoro- 8.08-7.95(bs, 1H), [1,1'-biphenyl] 7.42-7.33(m, 1H), yl)carbamate 7.21-7.08(m, 2H), 6.98-6.79(m, 3H), 91 6.59-6.48(bs, 1H), H 4.13-3.95(m, 2H), 2.69-2.43(m, 3H), F F 2.40-2.14(m, 5H), 2.05-1.90(m, 1H), 1.57-1.42(m, 1H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',5'-difluoro- 8.08-7.95(bs, 1H), [1,1'-biphenyl] 7.42-7.33(m, 1H), yl)carbamate 7.21-7.08(m, 2H), 6.98-6.79(m, 3H), 92 6.59-6.48(bs, 1H), 4.13-3.95(m, 2H), 2.69-2.43(m, 3H), 2.40-2.14(m, 5H), 2.05-1.90(m, 1H), 1.57-1.42(m, 1H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (5-fluoro-[1,1'- 7.98(s, 1H), 7.49- biphenyl]yl)carbamate 7.39(m, 3H), 7.34- 7.32(m, 2H), 7.06- 7.01(m, 1H), 6.94- 6.91(m, 1H), 6.49(s, 1H), 4.08- 3.96(m, 2H), 2.61- 2.57(m, 1H), 2.53- 2.44(m, 3H), 2.30(s, 3H), 2.27- 2.22(m, 1H), 1.98- 1.89(m, 1H), 1.49- 1.41(m, 1H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (5-fluoro-3'- 7.97(s, 1H), 7.37- methyl-[1,1'-biphenyl] 7.33(m, 1H), 7.30- yl)carbamate 7.21(m, 2H), 7.13- 7.11(m, 1H), 7.04- 7.00(m, 1H), 6.95- 6.91(m, 1H), 6.58(s, 1H), 4.08- 3.98(m, 2H), 2.71- 2.66(m, 1H), 2.59- 2.46(m, 3H), 2.46- 2.33(m, 7H), 2.01- 1.97(m, 1H), 1.55- 1.48(m, 1H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',5,5'- 7.97-7.81(bs, 1H), trifluoro-[1,1'-biphenyl] 7.13-7.01(m, 1H), yl)carbamate 6.99-6.78(m, 4H), 6.57-6.41(bs, 1H), 4.13-3.94(m, 2H), 2.70-2.42(m, 4H), 2.05-2.88(m, 1H), 1.58-1.41(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',5,5'- 7.97-7.78(bs, 1H), trifluoro-[1,1'-biphenyl] 7.14-7.00(m, 1H), yl)carbamate 6.99-6.78(m, 4H), 6.63-6.45(bs, 1H), 4.14-3.93(m, 2H), 2.71-2.42(m, 4H), 2.40-2.23(bs, 4H), 2.05-1.88(m, 1H), 1.59-1.41(m, 1H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (5-methyl-[1,1'- 7.89 (s, 1H), 7.47- biphenyl]yl)carbamate 7.43(m, 2H), 7.39- 7.31(m, 2H), 7.22- 7.13(m, 2H), 7.02(s, 1H), 97 6.63(s, 1H), 4.09- 4.01(m, 2H), 2.67- 2.58(m, 3H), 2.52(s, 3H), 2.32(s, 3H), 2.11- 2.01(m, 2H), 1.65- 1.58(m, 2H) (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-fluoro 7.88 (s, 1H), 7.44- methyl-[1,1'-biphenyl] 7.38(m, 1H), 7.17- yl)carbamate 7.10(m, 2H), 7.09- 7.05(m, 2H), 7.01(s, 1H), 98 6.55(s, 1H), 4.09- 3.98(m, 2H), 2.38(s, 3H), 2.32(s, 3H), 2.61- 2.40(m, 3H), 2.15- 1.97(m, 2H), 1.56- 1.51(m, 2H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (4'-fluoro-[1,1'- 8.13-7.96(m, 1H), biphenyl]yl)carbamate 7.41-7.23(m, 3H), 7.20-7.02(m, 4H), 6.62-6.45(bs, 1H), 99 4.24-3.97(m, 2H), 3.10-2.96(m, 1H), 2.50-2.27(m, 4H), 2.27-2.13(m, 1H) 1.96-1.80(m, 1H), 1.80-1.51(m, 3H) (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-methyl-[1,1'- 8.13-7.96(bs, 1H), biphenyl]yl)carbamate 7.41-7.30(m, 2H), 7.30-7.03(m, 5H), 6.71-6.59(bs, 1H), 4.13-3.95(m, 2H), 2.72-2.59(m, 1H), 2.59-2.43(m, 3H), 2.40(s, 3H), 2.14- 2.22(m, 4H) 2.06- 1.87(m, 1H), 1.55- 1.42(m, 1H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-methyl-[1,1'- 8.15-7.99(bs, 1H), biphenyl]yl)carbamate 7.46-7.29(m, 2H), 7,28-7.02(m, 5H), 6.74-6.58(bs, 1H), 4.15-3.93(m, 2H), 2.70-2.43(m, 4H), 2.40(s, 3H), 2.31(s, 3H), 2.15- 2.17(m, 1H) 2.03- 1.86(m, 1H), 1.57- 1.40(m, 1H) (R)-(1-ethylpyrrolidin H NMR(CDCl ): δ yl)methyl [1,1'-biphenyl] 8.13-7.96(bs, 1H), ylcarbamate 7.54-7.26(m, 6H), 7,25-7.02(m, 2H), 6.72-6.55(bs, 1H), 4.15-3.92(m, 2H), 102 2.91-2.69(m, 1H), 2.69-2.35(m, 5H), 2.33-2.17(m, 1H), 2.04-1.87(m, 1H) 1.60-1.42(m, 1H), 1.00(t, 3H, J=7.2Hz) 1001965344 (S)-(1-ethylpyrrolidin H NMR(CDCl ): δ yl)methyl [1,1'-biphenyl] 8.15-7.97(bs, 1H), ylcarbamate 7.55-7.27(m, 6H), 7,24-7.05(m, 2H), 6.72-6.59(bs, 1H), H 4.14-3.94(m, 2H), 103 2.92-2.71(bs, 1H), 2.71-2.39(m, 5H), 2.38-2.22(m, 1H), 2.04-1.86(m, 1H), 1.59-1.44(m, 1H), 1.11(t, 3H, J=7.2Hz) (R)-(1-ethylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-methyl-[1,1'- 8.13-8.00(bs, 1H), biphenyl]yl)carbamate 7.42-7.27(m, 2H), 7.25-7.03(m, 5H), 6.69-6.59(bs, 1H), 4.13-3.95(m, 2H), 104 2.80-2.68(m, 1H), 2.68-2.32(m, 9H) 2.30-2.17(m, 1H), 2.03-1.89(m, 1H), 1.58-1.41(m, 1H), 1.18-1.04(t, 3H, J=7.6Hz) 1001965344 (S)-(1-ethylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-methyl-[1,1'- 8.13-7.99(m, 1H), biphenyl]yl)carbamate 7.43-7.27(m, 2H), 7.27-7.02(m, 5H), 6.72-6.58(bs, 1H), 4.13-3.94(m, 2H), 105 N 2.89-2.66(m, 1H), 2.66-2.15(m, 9H), 2.06-1.87(m, 1H), 1.57-1.40(m, 1H), 1.09(t, 3H, J=7.6Hz) (S)-(1-ethylpyrrolidin H NMR(CDCl ): δ yl)methyl [1,1'-biphenyl] 8.15-8.01(m, 1H), ylcarbamate 7.54-7.26(m, 6H), 7,22-7.05(m, 2H), 6.72-6.58(bs, 1H), 4.22-4.07(m, 1H), 106 4.07-3.93(m, 1H), 3.21-3.02(m, 1H), 2.92-2.59(m, 2H), 2.41-2.12(m, 2H) 1.95-1.50(m, 5H), 1.08(t, 3H, J=7.2Hz) 1001965344 (S)-(1-isobutylpyrrolidin H NMR(CDCl ): δ yl)methyl [1,1'-biphenyl] 8.18-8.02(m, 1H), ylcarbamate 7.53-7.27(m, 6H), 7,22-7.03(m, 2H), 6.69-6.54(bs, 1H), 4.18-3.83(m, 2H), 107 3.15-2.95(bs, 1H), 2.71-2.53(bs, 1H), 2.48-2.30(m, 1H), 2.23-2.02(m, 2H), 1.92-1.45(m, 5H), 0.84(t, 6H, J=6.8Hz) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',5-difluoro- 7.85(s, 1H), 7.46- [1,1'-biphenyl] 7.41(m, 1H), 7.15- yl)carbamate 7.03(m, 4H), 6.96- 6.93(m, 1H), 4.11- 108 4.03(m, 2H), 2.92- 2.90(m, 1H), 2.82- 2.68(m, 2H), 2.42(s, 3H), 2.12- 2.10(m, 2H), 1.71- 1.69(m, 2H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl [1,1'-biphenyl] 8.18-7.99(m, 1H), ylcarbamate 7.49-7.27(m, 6H), 7.22-7.15(m, 1H), 7.15-7.06(m, 1H), 6.72-6.60(bs, 1H), 4.24-3.98(m, 2H), 3.10-2.95(m, 1H), 2.52-2.40(m, 1H), 2.35(s, 3H) 2.26- 2.12(m, 1H), 1.97- 1.50(m, 4H) (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-methyl-[1,1'- 8.18-7.97(bs, 1H), biphenyl]yl)carbamate 7.41-7.28(m, 2H), 7,23-7.01(m, 5H), 110 6.78-6.62(bs, 1H), 4.12-3.97(m, 2H), 3.05-2.90(m, 1H), 2.52-2.11(m, 8H), 1.95-1.47(m, 4H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (5-fluoro-3'- 8.00(s, 1H), 7.34- methyl-[1,1'-biphenyl] 7.31(m, 1H), 7.21- yl)carbamate 7.19(m, 1H), 7.12- 7.06(m, 2H), 7.04- 6.99(m, 1H), 6.92- 6.89(m, 1H), 111 6.59(s, 1H), 4.18- 4.04(m, 2H), 3.06- 3.02(m, 1H), 2.38(s, 3H), 2.35(s, 3H), 2.22- 2.15(m, 2H), 1.92- 1.76(m, 2H), 1.68- 1.54(m, 2H) (S)-(1-isopropylpyrrolidin- H NMR(CDCl ): δ 2-yl)methyl [1,1'-biphenyl]- 8.15-8.01(m, 1H), 2-ylcarbamate 7.51-7.27(m, 6H), 7.21-7.06(m, 2H), 6.69-6.56(bs, 1H), 4.12-4.00(m, 1H), 112 3.87-3.76(m, 1H), 3.04-2.78(m, 3H) 2.53-2.40(m, 1H), 1.80-1.62(m, 4H), 1.08(d, 3H, J=6.4Hz), 0.99(d, 3H, J=6.4Hz) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-fluoro-[1,1'- 8.13-7.98(m, 1H), biphenyl]yl)carbamate 7.50-7.31(m, 2H), 7.21-7.00(m, 5H), 6.62-6.49(bs, 1H), 4.14-3.95(m, 2H), 2.75-2.42(m, 4H) 2.42-2.22(m, 4H), 2.03-1.87(m, 1H), 1.58-1.42(m, 1H) (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (4'-fluoro-[1,1'- 8.11-7.97(bs, 1H), biphenyl]yl)carbamate 7.42-7.27(m, 3H), 7.01-7.03(m, 4H), 6.57-6.42(bs, 1H), 4.13-3.92(m, 2H), 2.70-2.41(m, 4H), 2.41-2.20(m, 4H), F 2.06-1.94(m, 1H), 1.56-1.41(m, 1H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (3',4'-difluoro- 8.02-8.01(m, 1H), [1,1'-biphenyl] 7.38-7.06(m, 5H), yl)carbamate 6.47(s, 1H), 4.09- 3.98(m, 2H), 2.62- 115 2.58(t, 1H, J=17.2Hz), 2.55- 2.46(m, 3H), 2.37- 2.25(m, 4H), 2.04- 1.91(m, 2H), 1.51- 1.43(m, 1H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-fluoro-[1,1'- 8.12-7.98(bs, 1H), biphenyl]yl)carbamate 7.50-7.31(m, 2H), 7.24-7.02(m, 5H), 6.70-6.54(bs, 1H), 116 4.16-3.97(m, 2H), 2.77-2.65(m, 1H) 2.64-2.47(m, 3H), 2.45-2.28(m, 4H), 2.06-1.93(m, 1H), 1.61-1.47(m, 1H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro-[1,1'- 8.08-7.93(bs, 1H), biphenyl]yl)carbamate 7.47-7.27(m, 4H), 7.21-7.05(m, 3H), 6.67-6.53(bs, 1H), 4.15-3.93(m, 2H), 2.80-2.50(m, 4H), 2.50-2.24(bs, 4H), 2.09-1.92(m, 1H), 1.62-1.46(m, 1H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro-[1,1'- 8.07-7.92(bs, 1H), biphenyl]yl)carbamate 7.42-7.31(m, 4H), 7.27-7.21(m, 1H), 7.20-7.09(m, 2H), 118 6.66-6.56(bs, 1H), 4.13-3.97(m, 2H), 2.85-2.53(m, 4H), 2.52-2.35(m, 4H), 2.08-1.97(m, 1H), 1.63-1.52(m, 1H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',5'-dichloro- 8.02-7.83(bs, 1H), [1,1'-biphenyl] 7.48-7.32(m, 2H), yl)carbamate 7.33-7.21(m, 2H), 7.20-7.08(m, 2H), 119 6.77-6.56(bs, 1H), 4.15-3.95(m, 2H), 2.80-2.54(m, 4H) 2.54-2.30(m, 4H), 2.12-1.92(m, 1H), 1.67-1.49(m, 1H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro-5'- 8.03-7.89(bs, 1H), fluoro-[1,1'-biphenyl] 7.45-7.33(m, 1H), yl)carbamate 7.23-7.07(m, 4H), 7.05-6.95(m, 1H), 120 6.72-6.56(bs, 1H), 4.16-3.96(m, 2H), 2.78-2.50(m, 4H) 2.50-2.29(m, 4H), 2.10-1.92(m, 1H), 1.65-1.47(m, 1H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro-4'- 8.06-7.96(bs, 1H), fluoro-[1,1'-biphenyl] 7.49-7.32(m, 2H), yl)carbamate 7.25-7.19(m, 2H), 7.18-7.10(m, 2H), 121 6.65-6.47(bs, 1H), 4.17-3.95(m, 2H), 2.78-2.50(m, 4H) 2.50-2.25(m, 4H), 2.08-1.91(m, 1H), 1.62-1.47(m, 1H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (5-fluoro-3',5'- 8.03-7.88(bs, 1H), dimethyl-[1,1'-biphenyl] 7.05-6.96(m, 2H), yl)carbamate 6.95-6.87(m, 3H), 6.64-6.58(bs, 1H), 4.12-3.92(m, 2H), 2.68-2.57(m, 1H) 2.57-2.43(m, 3H), 2.34(s, 6H), 2.33- 2.15(m, 4H), 2.00- 1.77(m, 1H), 1.55- 1.45(m, 1H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro 7.77-7.60(bs, 1H), fluoro-5'-hydroxy-[1,1'- 7.13-6.86(m, 3H), biphenyl]yl)carbamate 6.79(s, 1H), 6.70(s, 1H), 6.53(s, 1H), 5.03- 4.50(bs, 1H), 4.33- 4.18(m, 1H), 4.18- 3.98(m, 1H), 3.08- HO Cl 2.95(bs, 1H), 2.95- 2.78(bs, 1H) 2.70- 2.31(m, 5H), 2.08- 1.90(bs, 1H), 1.90- 1.70(bs, 1H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (4',5-difluoro- 8.00-7.85(bs, 1H), [1,1'-biphenyl] 7.38-7.25(m, 2H), yl)carbamate 7.20-7.19(m, 2H), 7.03(td, 1H, J=8. 4Hz, 2.8Hz), 6.90(dd, 1H, 124 J=8.8Hz, 2.8Hz), 6.51-6.39(bs, 1H), F 4.12-3.90(m, 2H), 2.63-2.55(m, 1H) 2.55-2.39(m, 3H), 2.37-2.18(m, 4H), 1.99-1.85(m, 1H), 1.54-1.38(m, 1H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro 8.02-7.81(bs, 1H), fluoro-[1,1'-biphenyl] 7.53-7.30(m, 3H), yl)carbamate 7.26-7.19(m, 1H), F 7.05(td, 1H, J=8.0Hz, 2.8Hz), 6.91(dd, 1H, 125 J=8.8Hz, 2.8Hz), 6.54-6.45(bs, 1H), 4.13-3.86(m, 2H), 2.65-2.54(m, 1H) 2.54-2.42(m, 3H), 2.37-2.19(m, 4H), 2.00-1.86(m, 1H), 1.55-1.37(m, 1H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',5'-dichloro 7.92-7.76(bs, 1H), fluoro-[1,1'-biphenyl] 7.42-7.36(m, 1H), yl)carbamate 7.28-7.17(m, 2H), 7.06(td, 1h, J=8.8Hz, 2.8Hz), 6.90(dd, 1H, 126 J=8.8Hz, 2.8Hz), 6.51-6.39(bs, 1H), Cl Cl 4.12-3.90(m, 2H), 2.63-2.55(m, 1H) 2.55-2.39(m, 3H), 2.37-2.18(m, 4H), 2.00-1.85(m, 1H), 1.54-1.38(m, 1H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (4'-chloro 7.98-7.82(bs, 1H), fluoro-[1,1'-biphenyl] 7.49-7.38(m, 2H), yl)carbamate 7.34-7.20(m, 2H), 7.03(td, 1H, J=8.4Hz, 2.8Hz), 6.90(dd, 1H, 127 J=8.8Hz, 2.8Hz), 6.60-6.49(bs, 1H), 4.14-3.87(m, 2H), 2.66-2.59(m, 1H) 2.59-2.45(m, 3H), 2.42-2.15(m, 4H), 2.04-1.89(m, 1H), 1.57-1.42(m, 1H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',4'-dichloro 7.86-7.65(bs, 1H), fluoro-[1,1'-biphenyl] 7.58-7.39(m, 2H), yl)carbamate 7.26-7.16(m, 1H), 7.04(td, 1H, J=8.4Hz, 3.2Hz), 6.89(dd, 1H, 128 J=8.8Hz, 3.2Hz), 6.89-6.79(bs, 1H), 4.15-3.94(m, 2H), 2.90-2.73(m, 2H) 2.73-2.54(m, 3H), 2.52-2.19(m, 3H), 2.14-1.96(m, 1H), 1.70-1.54(m, 1H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro-5,5'- 7.97-7.76(bs, 1H), difluoro-[1,1'-biphenyl] 7.18-7.02(m, 3H), yl)carbamate 7.03-6.86(m, 2H), 6.54-6.42(bs, 1H), 129 4.03-3.85(m, 2H), 2.65-2.57(m, 1H) 2.57-2.41(m, 3H), 2.37-2.18(m, 4H), 2.02-1.87(m, 1H), 1.55-1.41(m, 1H) (R)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (3',4'-dichloro- 8.01-7.99(m, 1H), [1,1'-biphenyl] 7.54-7.51(d, 1H, yl)carbamate J=8Hz), 7.46(m, 1H), 7.38-7.34(m, 1H), 7.21-7.11(m, H 2H), 6.46(s, 1H), 4.09-3.98(m, 2H), 2.63-2.59(t, 1H, J=17.2Hz), 2.54- 2.47(m, 3H), 2.36- 2.26(m, 4H), 2.00- 1.93(m, 1H), 1.50- 1.45(m, 1H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (3',5'-dichloro- 8.01-7.97(m, 1H), [1,1'-biphenyl] 7.43-7.35(m, 2H), yl)carbamate 7.26-7.25(m, 2H), 7.18-7.11(m, 2H), 6.46(s, 1H), 4.10- 131 3.99(m, 2H), 2.67- 2.61(t, 1H, J=17.2Hz), 2.57- Cl Cl 2.50(m, 3H), 2.38- 2.28(m, 4H), 2.01- 1.93(m, 1H), 1.52- 1.48(m, 1H) (R)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (3'-chloro-5'- 8.01-7.99(m, 1H), fluoro-[1,1'-biphenyl] 7.39-7.35(m, 1H), yl)carbamate 7.18-7.11(m, 3H), 6.99-6.97(m, 1H), 6.48(s, 1H), 4.10- 132 3.99(m, 2H), 2.63- 2.59(t, 1H, J=17.2Hz), 2.53- F Cl 2.48(m, 3H), 2.36- 2.27(m, 4H), 2.00- 1.92(m, 1H), 1.51- 1.46(m, 1H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (5-fluoro-3'- 8.03(m, 1H), 7.25- amino-[1,1'-biphenyl] 7.21(m, 1H), 7.03- yl)carbamate 6.98(m, 1H), 6.92- 6.90(m, 1H), 6.72- 6.61(m, 3H), 4.08- 133 3.97(m, 2H),3.80(s, 1H), 2.66-2.62(t, 1H, J=17.2Hz), 2.53-2.46(m, 3H), 2.33-2.28(m, 4H), 2.01-1.93(m, 1H), 1.51-1.48(m, 1H) (R)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (3'-chloro 7.67(m, 1H), 7.06- fluoro-5'-hydroxy-[1,1'- 7.01(m, 1H), 6.97- biphenyl]yl)carbamate 6.94(m, 3H), 6.73- 6.72(m, 1H), 6.54(s, 1H), 4.35- 134 4.05(m, 2H), 3.01- 3.00(m, 1H), 2.89- 2.88(m, 1H), 2.59- 2.57(m, 2H), 2.47- 2.41(m, 4H), 1.97- 1.96(m, 1H), 1.80(m, 1H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (3',5'-dichloro 7.85(s, 1H), 7.41- fluoro-[1,1'-biphenyl] 7.40(t, 1H, yl)carbamate J=4.0Hz), 7.23(s, 2H), 7.10-7.05(m, 2H), 6.93-6.90(m, 2H), 6.36(s, 1H), 4.09-3.99(m, 2H), 2.63-2.59(t, 1H, Cl Cl J=17.2Hz), 2.56- 2.45(m, 3H), 2.32- 2.28(m, 4H), 2.01- 1.93(m, 1H), 1.50- 1.46(m, 1H) (R)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (3'-chloro-4'- 8.03-7.98(m, 1H), fluoro-[1,1'-biphenyl] 7.41-7.34(m, 2H), yl)carbamate 7.26-7.21(m, 2H), 7.17-7.10(m, 2H), 6.49(s, 1H), 4.09- 136 H 3.98(m, 2H), 2.63- 2.59(t, 1H, Cl J=17.2Hz), 2.51- 2.46(m, 3H), 2.36- 2.26(m, 4H), 2.00- 1.91(m, 1H), 1.51- 1.46(m, 1H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-hydroxy-[1,1'- 7.95-7.81(m, 1H), biphenyl]yl)carbamate 7.40-7.19(m, 3H), 7.18-7.06(m, 1H), 6.89-6.65(m, 4H), 137 H 4.34-4.18(m, 1H), 4.09-3.94(m, 1H), OH 2.89-2.51(m, 5H), 2.42(s, 3H), 2.07- 1.95(m, 1H), 1.78- 1.60(m, 1H) (R)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (3'-chloro-5'- 7.96-7.94(m, 1H), (trifluoromethyl)-[1,1'- 7.63(s, 1H), 7.55- biphenyl]yl)carbamate 7.52(m, 2H), 7.42- 7.37(m, 2H), 7.21- 7.17(m, 2H), 6.40(s, 1H), 4.09- 3.99(m, 2H), 2.64- 2.60(t, 1H, F C Cl J=17.2Hz), 2.55- 2.47(m, 3H), 2.36- 2.31(m, 4H), 2.00- 1.91(m, 1H), 1.51- 1.46(m, 1H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (3'-chloro 7.97(m, 1H), 7.07- fluoro-5'-methoxy-[1,1'- 7.03(m, 1H), 6.94- biphenyl]yl)carbamate 6.89(m, 2H), 6.74- 6.73(m, 1H), 6.45(s, 1H), 4.08- 3.99(m, 2H), 3.83- 3.79(m, 3H), 2.63- 2.59(t, 1H, CO C J=17.2Hz), 2.54- 2.47(m, 3H), 2.36- 2.27(m, 4H), 2.00- 1.91(m, 1H), 1.49- 1.45(m, 1H) (R)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (3'-chloro7.82(m, 1H), fluoro-5'-(trifluoromethyl)- 7.65(s, 1H), 7.54- [1,1'-biphenyl] 7.51(m, 2H), 7.13- yl)carbamate 7.08(m, 1H), 6.96- 6.93(m, 2H), 6.34(s, 1H), 4.07- 3.97(m, 2H), 2.60- 2.56(t, 1H, J=17.2Hz), 2.53- F C Cl 2.43(m, 3H), 2.34- 2.35(m, 4H), 1.98- 1.90(m, 1H), 1.49- 1.44(m, 1H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (4',5-difluoro- 7.93(m, 1H), 7.31- [1,1'-biphenyl] 7.29(m, 2H), 7.23- yl)carbamate 7.13(m, 2H), 7.06- 7.01(m, 1H), 6.91- 6.89(m, 1H), 6.42(s, 1H), 4.07- 3.96(m, 2H), 2.61- 2.56(t, 1H, J=17.2Hz), 2.53- 2.43(m, 3H), 2.35- 2.25(m, 4H), 2.00- 1.89(m, 1H), 1.51- 1.41(m, 1H) (R)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (3'-chloro-5,5'- 7.85(m, 1H), 7.14- difluoro-[1,1'-biphenyl] 7.13(m, 2H), 7.10- yl)carbamate 7.05(m, 1H), 6.98- 6.96(m, 1H), 6.93- 6.90(m, 1H), 6.43(s, 1H), 4.09- 3.99(m, 2H), 2.65- 2.60(t, 1H, F Cl J=17.2Hz), 2.55- 2.47(m, 3H), 2.36- 2.31(m, 4H), 2.02- 1.95(m, 1H), 1.52- 1.47(m, 1H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (3'-chloro-4',5- 7.85(m, 1H), 7.40- difluoro-[1,1'-biphenyl] 7.38(m, 1H), 7.26- yl)carbamate 7.19(m, 2H), 7.08- 7.03(m, 1H), 6.91- 6.88(m, 1H), 6.34(s, 1H), 4.08- 3.97(m, 2H), 2.61- 2.57(t, 1H, J=17.2Hz), 2.55- 2.47(m, 3H), 2.36- 2.25(m, 4H), 2.00- 1.90(m, 1H), 1.51- 1.44(m, 1H) (R)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (2',5-difluoro- 8.05(m, 1H), 7.44- [1,1'-biphenyl] 7.40(m, 1H), 7.31- yl)carbamate 7.23(m, 2H), 7.21- 7.17(m, 2H), 6.98- 6.96(m, 1H), 4.13- 4.07(m, 2H), 3.10- 3.08(m, 1H), 2.49- 2.45(m, 1H), 2.39(s, 3H), 2.29- 2.21(m, 1H), 1.95- 1.59(m, 4H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (3',5-dichloro- 7.87-7.85(m, 1H), [1,1'-biphenyl] 7.55-7.17(m, 5H), yl)carbamate 6.99(m, 1H), 6.55(s, 1H), 4.11- 4.02(m, 2H), 3.06- 145 3.02(m, 2H), 2.95- 2.89(m, 1H), 2.85- 2.81(m, 1H), 2.76- 2.66(m, 1H), 2.62(s, 3H), 2.18- 2.09(m, 1H), 1.78- 1.69(m, 1H) (R)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (3',5-dichloro-4'- 7.86-7.83(m, 1H), fluoro-[1,1'-biphenyl] 7.53-7.15(m, 4H), yl)carbamate 6.99(m, 1H), 6.50(s, 1H), 4.10- 4.02(m, 2H), 3.05- 146 3.02(m, 2H), 2.97- N 2.90(m, 1H), 2.84- 2.82(m, 1H), 2.77- 2.67(m, 1H), 2.60(s, 3H), 2.18- 2.10(m, 1H), 1.79- 1.69(m, 1H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (3'-chloro-4'- 7.70(s, 1H), 7.44- fluoromethoxy-[1,1'- 7.42(d, 1H, biphenyl]yl)carbamate J=7.2Hz), 7.26- 7.20(m, 2H), 6.93- H CO 6.90(m, 1H), 6.75(m, 1H), 6.66(s, 1H), 4.15- 4.00(m, 2H), 3.81(s, 3H), 3.42- 3.40(m, 1H), 2.81- 2.47(m, 2H), 2.34(s, 3H), 2.06- 1.60(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (3'-chloro-5'- 7.92(s, 1H), 7.43- fluoro-[1,1'-biphenyl] 7.27(m, 2H), 7.23- yl)carbamate 7.08(m, 3H), 7.03- 6.95(m, 1H), 148 6.79(s, 1H), 4.33- 4.19(m, 2H), 3.28- 3.26(m, 1H), 2.75(m, 1H), 2.49- F Cl 2.28(m, 4H), 1.98- 1.59(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (3'-chloro-4'- 7.90(s, 1H), 7.39- fluoro-[1,1'-biphenyl] 7.31(m, 2H), 7.22- yl)carbamate 7.05(m, 3H), 7.03- 6.97(m, 1H), 149 6.72(s, 1H), 4.26- H 4.11(m, 2H), 3.19- 3.14(m, 1H), 2.70- l 2.64(m, 1H), 2.42- 2.30(m, 4H), 1.99- 1.58(m, 4H) (R)-(1-ethylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro-4'- 7.97(s, 1H), 7.41- fluoro-[1,1'-biphenyl] 7.33(m, 2H), 7.23- yl)carbamate 7.21(m, 2H), 7.16- 7.10(m, 2H), 6.60(s, 1H), 4.10- 4.01(m, 2H), 2.74- 2.72(m, 1H), 2.65- 2.45 (m, 5H), 2.37- 2.34(m, 1H), 2.02- 1.93(m, 1H), 1.57- 1.49(m, 1H), 1.11(t, 3H, J=7.2Hz) 1001965344 (R)-(1-isopropylpyrrolidin- H NMR(CDCl ): δ 3-yl)methyl (3'-chloro-4'- 7.95(s, 1H), 7.41- fluoro-[1,1'-biphenyl] 7.34(m, 2H), 7.23- yl)carbamate 7.21(m, 2H), 7.18- 7.12(m, 2H), 6.68(s, 1H), 4.14- 4.04(m, 2H), 3.07- 151 N 3.05(m, 1H), 2.93- 2.90(m, 1H), 2.76- 2.74(m, 1H), 2.67- 2.64(m, 2H), 2.09- 2.02(m, 1H), 1.70- 1.65(m, 2H), 1.23(s, 6H) (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'- 8.10-7.92(bs, 1H), (hydroxymethyl)-[1,1'- 7.57-6.90(m, 7H), biphenyl]yl)carbamate 4.71(s, 1H), 4.21- 3.91(m, 3H), 2.73- 2.16(m, 9H) 2.08- 1.84(m, 1H), 1.64- 1.39(m, 1H) 1001965344 (R)-(1-methylpyrrolidin H NMR(DMSO): δ yl)methyl (3'-carbamoyl- 8.78(s, 1H), 8.20- [1,1'-biphenyl] 7.78(m, 3H), 7.78- yl)carbamate 7.20(m, 7H), 3.99- 3.65(bs, 2H), 3.55- 3.26(bs, 1H), 2.60- 1.97(m, 7H), 1.88- 1.63(bs, 1H), 1.41- 2 1.14(bs, 1H) (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-amino-[1,1'- 8.15-8.00(bs, 1H), biphenyl]yl)carbamate 7.43-7.13(m, 3H), 7.12-6.99(m, 1H), 6.82-6.55(m, 4H), 154 4.18-3.93(m, 2H), 3.87-3.67(bs, 2H), 2.72-2.41(m, 4H) 2.41-2.19(m, 4H), 2.03-1.83(m, 1H), 1.55-1.40(m, 1H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-cyano-[1,1'- 8.03-7.85(m, 1H), biphenyl]yl)carbamate 7.74-7.50(m, 4H), 7,47-7.32(m, 1H), 7.26-7.08(m, 2H), 155 6.71-6.47(bs, 1H), 4.15-3.90(m, 2H), 2.77-2.48(m, 4H), 2.48-2.25(bs, 4H), 2.09-1.88(m, 1H), 1.63-1.44(m, 1H) (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (2'-fluoro-[1,1'- 7.98(m, 1H), 7.43- biphenyl]yl)carbamate 7.38(m, 3H), 7.31- 7.29(m, 1H), 7,26- 7.25(m, 1H), 7.23- 7.16(m, 2H), 156 6.48(s, 1H), 4.11- 4.02(m, 2H), 2.94- 2.80(m, 1H), 2.51- 2.48(m, 1H), 2.44(s, 3H), 2.14- 2.01(m, 1H), 1.89- 1.55(m, 4H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (2',4'-difluoro- 7.91(m, 1H), 7.39- [1,1'-biphenyl] 7.36(m, 1H), 7.30- yl)carbamate 7.26(m, 1H), 7,19- 7.17(m, 2H), 7.00- 6.97(m, 2H), 6.95- 6.92(m, 1H), 6.70(s, 1H), 4.12- 4.06(m, 2H), 3.00- F 2.97(m, 1H), 2.75- 2.70(m, 1H), 2.60(s, 3H), 2.18- 2.14(m, 1H), 1.90- 1.52(m, 4H) (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (2',3'-difluoro- 7.84(m, 1H), 7.41- [1,1'-biphenyl] 7.39(m, 1H), 7.23- yl)carbamate 7.17(m, 4H), 7,09- 7.07(m, 1H), 4.18- 158 4.11(m, 2H), 3.27- 3.14(m, 1H), 2.89- 2.85(m, 1H), 2.74(s, 3H), 2.28- 2.23(m, 1H), 1.93- 1.48(m, 4H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro-6'- 7.94(m, 1H), 7.55- fluoro-[1,1'-biphenyl] 7.42(m, 1H), 7.30- yl)carbamate 7.22(m, 2H), 7,19- 7.15(m, 2H), 7.04- 7.00(m, 1H), 4.20- 4.08(m, 2H), 3.29- 3.17(m, 1H), 2.88- 2.85(m, 1H), 2.54(s, 3H), 2.33- 2.28(m, 1H), 2.01- 1.66(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-fluoro-[1,1'- 8.10–8.03(m, 1H), biphenyl]yl)carbamate 7.36-7.02(m, 6H), 6.89-6.85(m, 1H), 6.63(s, 1H), 4.22- 160 4.02(m, 2H), 3.07- 2.98(m, 1H), 2.51- 2.41(m, 1H), 2.39(s, 3H), 2.49- 2.14(m, 1H), 1.96- 1.52(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',5'-difluoro- 8.02–8.00(m, 1H), [1,1'-biphenyl] 7.37-7.25(m, 2H), yl)carbamate 7.17-7.08(m, 2H), 6.90-6.78(m, 2H), 6.60(s, 1H), 4.23- 4.03(m, 2H), 3.08- 2.99(m, 1H), 2.51- 2.36(m, 1H), 2.34(s, 3H), 2.29- 2.15(m, 1H), 1.99- 1.54(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',4'-difluoro- 8.10-8.08(d, 1H, [1,1'-biphenyl] J=8.0Hz), 7.39- yl)carbamate 7.10(m, 3H), 6.92- 6.83(m, 1H), 6.66- 6.61(m, 1H), 6.59(s, 1H), 6.52- 6.48(m, 1H), 4.28- 4.08(m, 2H), 3.14- 3.07(m, 1H), 2.59- 2.47(m, 1H), 2.38(s, 3H), 2.33- 2.21(m, 1H), 2.02- 1.58(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (2',4',5'- 8.11-8.09(d, 1H, trifluoro-[1,1'-biphenyl] J=8.0Hz), 7.33– yl)carbamate 7.23(m, 2H), 7.18- 7.14(m, 1H), 7.13- 7.10(m, 1H), 6.91- 6.87(m, 1H), 6.48(s, 1H), 4.26- 4.06(m, 2H), 3.12- 3.08(m, 1H), 2.53- 2.43(m, 1H), 2.37(s, 3H), 2.30- 2.20(m, 1H), 1.98- 1.63(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (4'-chloro-[1,1'- 8.02-8.00(d, 1H, biphenyl]yl)carbamate J=7.6Hz), 7.30- 7.23(m, 2H), 7.21- 7.09(m, 1H), 7.06- 7.04(d, 2H, J=8.8Hz), 6.77- 164 6.75(d, 2H, J=8.8Hz), 6.60(s, 1H), 4.28-4.08(m, 2H), 3.13-3.06(m, 1H), 2.57-2.45(m, 1H), 2.38(s, 3H), 2.33-2.22(m, 1H), 1.99-1.59(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro-[1,1'- 8.12-7.99(m, 1H), biphenyl]yl)carbamate 7.49-7.28(m, 4H), 7.28-7.02(m, 3H), 6.62-6.49(bs, 1H), 4.26-3.99(m, 2H), 165 N 3.12-2.98(m, 1H), 2.53-2.40(m, 1H), 2.36(s, 3H), 2.27- 2.14(m, 1H), 1.98- 1.81(m, 1H) 1.80- 1.55(m, 2H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',4'-dichloro- 8.10-8.08(d, 1H, [1,1'-biphenyl] J=8.0Hz), 7.65– yl)carbamate 7.61(dd, 2H, J=12.0Hz), 7.55- 7.42(m, 3H), 7.19- H 7.10(m, 1H), 6.57(s, 1H), 4.27- Cl 4.07(m, 2H), 3.13- 3.05(m, 1H), 2.57- 2.47(m, 1H), 2.38(s, 3H), 2.33- 2.21(m, 1H), 2.01- 1.60(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (2',4'-dichloro- 8.11-8.09(d, 1H, [1,1'-biphenyl] J=8.0Hz), 7.39– yl)carbamate 7.08(m, 5H), 6.92- 6.88(m, 1H), 6.32(s, 1H), 4.27- 4.12(m, 2H), 3.14- 3.08(m, 1H), 2.57- 2.53(m, 1H), 2.44(s, 3H), 2.31- 2.21(m, 1H), 2.01- 1.58(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-hydroxy-[1,1'- 7.98-7.96(d, 1H, biphenyl]yl)carbamate J=7.6Hz), 7.30– 7.26(m, 1H), 7.22- 7.14(m, 2H), 7.11- 7.05(m, 1H), 6.81- 6.77(t, 2H, OH J=16.8Hz), 6.73- 6.71(t, 1H, J=4.4Hz), 4.23- 4.08(m, 2H), 3.09- 3.05(m, 1H), 2.57- 2.50(m, 1H), 2.38(s, 3H), 2.36- 2.22(m, 1H), 1.99- 1.59(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-cyano-[1,1'- 8.02-8.00(d, 1H, biphenyl]yl)carbamate J=7.2Hz), 7.68– 7.65(m, 2H), 7.60- 7.54(m, 2H), 7.41- 7.37(m, 1H), 7.17- 7.16(d, 2H, J=4.4Hz), 6.42(s, 1H), 4.22-4.04(m, 2H), 3.06-3.02(m, 1H), 2.35(s, 3H), 2.30-2.24(q, 1H, J=16.0Hz), 2.02- 1.55(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-amino-[1,1'- 8.09-8.07(d, 1H, biphenyl]yl)carbamate J=7.6Hz), 7.41– 7.15(m, 4H), 7.08- 7.00(m, 1H), 6.94(s, 2H), 6.82(s, 1H), 6.42(s, 1H), 6.69- 6.66(t, 1H, J=14.8Hz), 6.61(s, 1H), 4.24-4.03(m, 2H), 3.11-3.02(m, 1H), 2.56-2.44(m, 1H), 2.40(s, 3H), 2.30-2.17(m, 1H), 1.96-1.58(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',4',5- 7.75(s, 1H), 7.23– trifluoro-[1,1'-biphenyl] 6.97(m, 4H), 6.90- yl)carbamate 6.85(m, 1H), 6.83(s, 1H), 4.31- 171 4.15(m, 2H), 3.26(m, 1H), 2.81(m, 1H), 2.54(m, 1H), 2.47(s, 3H), 2.03- 1.64(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',5,5'- 7.88(s, 1H), 7.06– trifluoro-[1,1'-biphenyl] 7.01(m, 2H), 6.90- yl)carbamate 6.78(m, 3H), 6.61(s, 1H), 4.18- 172 3.94(m, 2H), 3.05- 3.00(m, 1H), 2.45- 2.36(m, 1H), 2.33(s, 3H), 2.28- 2.12(m, 1H), 1.90- 1.52(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (2',4',5,5'- 7.82(s, 1H), 7.16– tetrafluoro-[1,1'-biphenyl]- 6.98(m, 3H), 6.93- 2-yl)carbamate 6.90(m, 1H), 6.60(s, 1H), 4.29- 4.07(m, 2H), 3.24(m, 1H), 2.51- 2.32(m, 2H), 2.15(s, 3H), 2.07- F 1.69(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro 7.94(s, 1H), 7.23– fluoro-[1,1'-biphenyl] 7.16(m, 2H), 7.07- yl)carbamate 7.02(m, 2H), 6.92- 6.89(m, 2H), 6.56(s, 1H), 4.20- 4.04(m, 2H), 3.07- 3.03(m, 1H), 2.48- 2.39(m, 1H), 2.36(s, 3H), 2.31- 2.19(m, 1H), 1.93- 1.55(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (4'-chloro7.89(s, 1H), fluoro-[1,1'-biphenyl] 7.24(s, 1H), yl)carbamate 7.22(s, 1H), 7.03- 6.98(m, 2H), 6.88- 6.85(m, 2H), 175 6.55(s, 1H), 4.16- 4.00(m, 2H), 3.04- 3.00(m, 1H), 2.47- 2.35(m, 1H), 2.32(s, 3H), 2.27- 2.16(m, 1H), 1.90- 1.51(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (2',4'-dichloro 7.89(s, 1H), 7.31– fluoro-[1,1'-biphenyl] 7.28(m, 1H), yl)carbamate 7.18(s, 1H), 7.16(s, 1H), 7.13- 7.04(m, 1H), 6.83- 6.81(m, 1H), Cl N 6.30(s, 1H), 4.16- 4.00(m, 2H), 3.04- 3.00(m, 1H), 2.47- 2.35(m, 1H), 2.32(s, 3H), 2.27- 2.16(m, 1H), 1.90- 1.51(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ) δ yl)methyl (3',4'-dichloro 7.88(s, 1H), 7.41– fluoro-[1,1'-biphenyl] 7.37(m, 1H), 7.21- yl)carbamate 7.16(m, 1H), 7.08- 7.01(m, 2H), 6.91- 6.88(m, 1H), 177 6.52(s, 1H), 4.24- 4.05(m, 2H), 3.12- 3.07(m, 1H), 2.53- 2.44(m, 1H), 2.38(s, 3H), 2.36- 2.22(m, 1H), 1.94- 1.56(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-cyano 7.86(s, 1H), 7.53– fluoro-[1,1'-biphenyl] 7.49(m, 1H), 7.45- yl)carbamate 7.40(m, 2H), 7.11- 7.05(m, 2H), 6.91- 6.88(m, 1H), 178 6.42(s, 1H), 4.18- 4.02(m, 2H), 3.06- 3.02(m, 1H), 2.45- 2.39(m, 1H), 2.34(s, 3H), 2.28- 2.13(m, 1H), 1.91- 1.53(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-hydroxy 7.85(s, 1H), 7.26– fluoro-[1,1'-biphenyl] 7.19(m, 1H), 7.02- yl)carbamate 6.96(m, 1H), 6.93- 6.90(m, 1H), 6.78- 6.74(m, 3H), 179 6.71(s, 1H), 4.21- 4.18(m, 2H), 3.15- 3.11(m, 1H), 2.62- 2.56(m, 1H), 2.41(s, 3H), 2.34- 2.27(m, 1H), 1.98- 1.62(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (5-fluoro-3'- 7.81(s, 1H), 7.25– (trifluoromethyl)-[1,1'- 7.22(m, 1H), biphenyl]yl)carbamate 7.11(s, 1H), 7.07- 6.91(m, 4H), 180 6.67(s, 1H), 4.30- 4.09(m, 2H), 3.21- 3.13(m, 1H), 2.71- 2.58(m, 1H), 2.39(s, 3H), 2.03- 1.56(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro-4,4',5- 8.02(m, 1H), 7.39- trifluoro-[1,1'-biphenyl]7.38(dd, 1H, yl)carbamate J=4.4Hz), 7.27- 7.25(m, 1H), 7.21- 7.18(m, 1H), 7.01- 6.98(dd, 1H, J=7.2Hz), 6.50(s, 1H), 4.23-4.10(m, 2H), 3.10-3.07(m, 1H), 2.50-2.46(m, 1H), 2.39(s, 3H), 2.28-2.23(m, 1H), 1.95-1.60(m, 4H) (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro-4,5- 8.00(m, 1H), 7.41- difluoro-[1,1'-biphenyl] 7.39(m, 1H), 7.28- yl)carbamate 7.23(m, 1H), 7.20- 7.19(m, 1H), 7.00- 6.96(dd, 1H, 182 J=7.2Hz), 6.61(s, 1H), 4.22-4.10(m, 2H), 3.11-3.09(m, 1H), 2.50-2.46(m, 1H), 2.38(s, 3H), 2.29-2.21(m, 1H), 1.95-1.59(m, 4H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (2',4'-difluoro- 7.96(m, 1H), 7.41- [1,1'-biphenyl] 7.38(m, 1H), 7.30- yl)carbamate 7.26(m, 2H), 7.19- 7.15(m, 2H), 7.01- 6.93(m, 2H), 183 6.38(s, 1H), 4.21- 4.14(m, 2H), 3.35(m, 1H), 3.00- F 2.64(m, 1H), 2.48(s, 3H), 2.26- 2.03(m, 3H), 1.94- 1.67(m, 4H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (2',3'-difluoro- 7.90(m, 1H), 7.44- [1,1'-biphenyl] 7.41(m, 1H), 7.26- yl)carbamate 7.19(m, 4H), 7.09- 7.06(m, 1H), 6.46(s, 1H), 184 N 4.25(m, 2H), 3.80(m, 1H), 2.98(m, 1H), 2.73(s, 3H), 2.29- 2.15(m, 3H), 2.02- 1.57(m, 4H) 1001965344 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (2',6'-difluoro- 7.94(m, 1H), 7.60- [1,1'-biphenyl] 7.37(m, 2H), 7.26- yl)carbamate 7.21(m, 2H), 7.06- 6.99(m, 2H), 6.40(s, 1H), 4.22- 4.20(m, 2H), 3.83(m, 1H), 2.99(m, 1H), 2.73(s, 3H), 2.31- 2.15(m, 3H), 2.02- 1.59(m, 4H) 2-(1-Methylpyrrolidin H NMR(CDCl ): δ yl)ethyl (5'-chloro-2'- 7.92(m, 1H), 7.42- fluoro-[1,1'-biphenyl] 7.39(m, 1H), 7.37- yl)carbamate 7.34(m, 1H), 7.29- 7.28(m, 1H), 7.22- 7.17(m, 2H), 7.14- 7.11(m, 1H), 6.45(s, 1H), 4.22- 4.14(m, 2H), 3.80(m, 1H), 3.47- 3.45(m, 1H), 2.53(s, 3H), 2.16- 2.11(m, 3H), 1.98- 1.72(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (2'-fluoro-[1,1'- 8.00(m, 1H), 7.41- biphenyl]yl)carbamate 7.37(m, 3H), 7.33- 7.27(m, 1H), 7.25- 7.20(m, 1H), 7.19- 7.14(m, 2H), 187 6.61(s, 1H), 4.08- 4.01(m, 2H), 2.88- 2.79(m, 1H), 2.49- 2.45(m, 1H), 2.40(s, 3H), 2.28- 2.14(m, 1H), 1.94- 1.61(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (2',4'-difluoro- 7.98(m, 1H), 7.41- [1,1'-biphenyl] 7.37(m, 1H), 7.29- yl)carbamate 7.23(m, 1H), 7.17- 7.14(m, 2H), 6.99- 6.89(m, 2H), 188 6.44(s, 1H), 4.23- 4.05(m, 2H), 3.10- 3.07(m, 1H), 2.49(m, 1H), 2.38(s, 3H), 2.28- 2.22(m, 3H), 1.93- 1.60(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (2',3'-difluoro- 8.00(m, 1H), 7.38- [1,1'-biphenyl] 7.34(m, 1H), 7.29- yl)carbamate 7.23(m, 2H), 7.20- 7.14(m, 2H), 7.02- 6.89(m, 1H), 189 6.51(s, 1H), 4.20- 4.05(m, 2H), 3.08- 3.05(m, 1H), 2.58- 2.44(m, 1H), 2.39(s, 3H), 2.30- 2.24(m, 3H), 1.99- 1.64(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro-6'- 7.97(m, 1H), 7.43- fluoro-[1,1'-biphenyl] 7.39(m, 1H), 7.23- yl)carbamate 7.08(m, 4H), 7.04- 6.98(m, 1H), 6.52(s, 1H), 4.27- 4.15(m, 2H), 3.17- 3.07(m, 1H), 2.62(m, 1H), 2.44(s, 3H), 2.34- 2.30(m, 3H), 1.95- 1.58(m, 4H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',5'-dimethyl- 8.07-8.05(m, 1H), [1,1'-biphenyl] 7.33-7.30(m, 1H), yl)carbamate 7.18-7.16(m, 1H), 7.10-7.06(m, 1H), 7.03(s, 1H), 6.95(s, 2H), 191 6.69(s, 1H), 4.09- 3.99(m, 2H), 2.69- 2.65(t, 1H, J=17.2Hz), 2.59- 2.40(m, 3H), 2.35- 2.27(m, 4H), 2.01- 1.95(m, 1H), 1.54- 1.48(m, 1H) (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (5-fluoro-3'- 8.07-7.89(bs, 1H), methyl-[1,1'-biphenyl] 7.40-7.29(m, 1H), yl)carbamate 7.29-7.19(m, 1H), 7.19-7.07(m, 2H), 7.07-6.97(m, 1H), 6.97-6.86(m, 1H), 6.61-6.45(bs, 1H), 4.13-3.92(m, 2H), 2.68-2.43(m, 4H), 2.39(s, 3H), 2.36- 2.20(m, 4H), 2.04- 1.88(m, 1H), 1.53- 1.39(m, 1H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (5-fluoro-3',5'- 7.98(m, 1H), 7.89- dimethyl-[1,1'-biphenyl]7.04(m, 6H), yl)carbamate 6.55(s, 1H), 4.08- 3.97(m, 2H), 2.63- 2.59(t, 1H, 193 J=17.2Hz), 2.53- N 2.40(m, 2H), 2.35- 2.31(m, 3H), 2.31(s, 1H), 2.27- 2.23(m, 1H), 1.99- 1.92(m, 1H), 1.51- 1.44(m, 1H) (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',5-difluoro- 7.95(m, 1H), 7.47- [1,1'-biphenyl] 7.41(m, 2H), 7.12- yl)carbamate 7.04(m, 4H), 6.93- 6.91(m, 1H), 6.48(s, 1H), 4.08- 194 3.97(m, 2H), 2.63- 2.59(t, 1H, J=17.2Hz), 2.52- 2.49(m, 3H), 2.34- 2.27(m, 4H), 2.00- 1.93(m, 1H), 1.50- 1.46(m, 1H) 1001965344 (R)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro 7.92(m, 1H), 7.42- fluoro-[1,1'-biphenyl] 7.33(m, 2H), 7.23- yl)carbamate 7.21(m, 2H), 7.07- 7.03(m, 1H), 6.93- 6.90(m, 1H), 6.27(s, 1H), 4.08- 3.97(m, 2H), 2.65- 2.60(t, 1H, J=17.2Hz), 2.53- 2.45(m, 3H), 2.35- 2.29(m, 4H), 2.01- 1.93(m, 1H), 1.53- 1.46(m, 1H) 1001965344 (R)-(1-ethylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro-4',5- 7.87(s, 1H), 7.40- difluoro-[1,1'-biphenyl] 7.38(m, 1H), 7.25- yl)carbamate 7.21(m, 2H), 7.08- 7.03(m, 1H), 6.90(dd, 1H, J=8.8Hz, J=2.8Hz), 6.50(s, 1H), 4.09- 196 3.98(m, 2H), 2.72(t, 1H, J=8.8Hz), 2.64- 2.44(m, 5H), 2.36- 2.33(m, 1H), 2.02- 1.92(m, 1H), 1.55- 1.47(m, 1H), 1.09(t, 3H, J=7.2Hz) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl [1,1'-biphenyl] 8.14-8.01(m, 1H), ylcarbamate 7.51-7.29(m, 6H), 7.23-7.05(m, 2H), 6.75-6.60(bs, 1H), 4.24-4.00(m, 2H), 3.10-2.98(m, 1H) 2.53-2.29(m, 4H), 2.28-2.15(m, 1H), 1.97-1.52(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (4'-fluoro-[1,1'- 8.14-8.01(m, 1H), biphenyl]yl)carbamate 7.51-7.29(m, 5H), 7.23-7.05(m, 2H), 6.75-6.60(bs, 1H), 4.24-4.00(m, 2H), 3.10-2.98(m, 1H) 2.53-2.29(m, 4H), 2.28-2.15(m, 1H), 1.97-1.52(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-methyl-[1,1'- 8.17-8.01(m, 1H), biphenyl]yl)carbamate 7.41-7.27(m, 2H), 7.22-7.02(m, 5H), 6.76-6.63(bs, 1H), 199 4.22-4.00(m, 2H), 3.09-2.98(m, 1H) 2.52-2.30(m, 7H), 2.29-2.12(m, 1H), 1.97-1.80(m, 1H), 1.80-1.50(m, 3H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (5-fluoro-[1,1'- 7.97(s, 1H), 7.45- biphenyl]yl)carbamate 7.37(m, 3H), 7.32- 7.25(m, 3H), 7.05- 7.00(m, 1H), 6.94- 6.91(m, 1H), 200 6.59(s, 1H), 4.19- 4.04(m, 2H), 3.06- 3.04(m, 1H), 2.35(s, 3H), 2.28- 2.18(m, 2H), 1.90- 1.76(m, 2H), 1.61- 1.57(m, 2H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (5-fluoro-3'- 7.82(s, 1H), 7.30- methyl-[1,1'-biphenyl] 7.11(m, 3H), 7.01- yl)carbamate 6.85(m, 3H), 4.30- 4.07(m, 2H), 3.24- 201 3.21(m, 1H), 2.43(s, 3H), 2.35(s, 3H), 1.96- 1.84(m, 2H), 1.79- 1.72(m, 2H), 1.67- 1.51(m, 2H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',5-difluoro- 7.97(s, 1H), 7.43- [1,1'-biphenyl] 7.39(m, 1H), 7.11- yl)carbamate 7.03(m, 4H), 6.91(d, 1H, J=8.4Hz), 6.48(s, 1H), 4.19-4.04(m, 2H), 3.05-3.02(m, 1H), 2.35(s, 3H), 2.26-2.17(m, 2H), 1.88-1.83(m, 2H), 1.71-1.69(m, 2H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (4',5-difluoro- 7.97(s, 1H), 7.31- [1,1'-biphenyl] 7.26(m, 1H), 7.22- yl)carbamate 7.12(m, 2H), 7.06- 7.00(m, 2H), 6.91- 6.88(m, 1H), 203 6.43(s, 1H), 4.21- 4.03(m, 2H), 3.06- 3.02(m, 1H), 2.35(s, 3H), 2.28- 2.15(m, 2H), 1.95- 1.83(m, 2H), 1.70- 1.67(m, 2H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (4-fluoro-[1,1'- 7.96(s, 1H), 7.47- biphenyl]yl)carbamate 7.43(m, 2H), 7.40- 7.36(m, 1H), 7.33- 7.25(m, 2H), 7.18- 7.10(m, 1H), 6.81- 204 H 6.75(m, 2H), 4.18- 4.05(m, 2H), 3.03- 3.01(m, 1H), 2.35(s, 3H), 2.22- 2.17(m, 2H), 1.93- 1.86(m, 2H), 1.61- 1.57(m, 2H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',4-difluoro- 7.96(s, 1H), 7.45- [1,1'-biphenyl] 7.39(m, 2H), 7.25- yl)carbamate 7.23(m, 1H), 7.16- 7.07(m, 2H), 7.03- 7.01(m, 1H), 6.83- 6.78(m, 1H), 6.65(s, 1H), 4.19- 4.06(m, 2H), 3.05- 3.02(m, 1H), 2.36(s, 3H), 2.26- 2.18(m, 2H), 1.93- 1.84(m, 2H), 1.59- 1.50(m, 2H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (5-methyl-[1,1'- 7.92(s, 1H), 7.45- biphenyl]yl)carbamate 7.41(m, 2H), 7.33- 7.25(m, 2H), 7.16- 7.13(m, 1H), 7.02(s, 1H), 6.59(s, 1H), 4.21- 4.05(m, 2H), 3.09- 3.07(m, 1H), 2.38(s, 3H), 2.32(s, 3H), 2.27- 2.23(m, 2H), 1.90- 1.87(m, 2H), 1.78- 1.72(m, 2H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-fluoro 7.88(s, 1H), 7.42- methyl-[1,1'-biphenyl] 7.36(m, 1H), 7.21- yl)carbamate 7.20(m, 1H), 7.17- 7.15(m, 1H), 7.10- 7.03(m, 2H), 7.00(m, 1H), 207 6.55(s, 1H), 4.22- 4.06(m, 2H), 3.10- 3.06(m, 1H), 2.38(s, 3H), 2.31(s, 3H), 2.27- 2.21(m, 2H), 1.94- 1.85(m, 2H), 1.78- 1.69(m, 2H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (5-fluoro-3',5'-7.95(s, 1H), dimethyl-[1,1'-biphenyl] 7.15(m, 2H), 7.04- yl)carbamate 6.98(m, 2H), 6.93- 6.90(m, 2H),, 208 6.72(s, 1H), 4.31- 4.17(m, 2H), 3.14(m, 1H), 2.82(m, 1H), 2.61- 2.03(m, 10H), 1.99- 1.62(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (4'-(tert-butyl)- 7.83(s, 1H), 7.72– -fluoro-[1,1'-biphenyl] 7.70(m, 2H), 7.67- yl)carbamate 7.62(m, 2H), 7.03- 6.91(m, 2H), 6.76(s, 1H), 4.35- 209 4.22(m, 2H), 3.20(m, 1H), 2.96(m, 1H), 2.68- 2.65(m, 1H), 2.48(s, 3H), 1.99- 1.63(m, 4H), 1.51- 1.29(m, 9H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro-5,5'- 7.84(s, 1H), 7.24- difluoro-[1,1'-biphenyl] 7.15(m, 1H), 7.12– yl)carbamate 6.89(m, 4H), 6.64(s, 1H), 4.26- 210 4.10(m, 2H), 3.16- 3.15(m, 1H), 2.62(m, 1H), 2.42(s, 3H), 2.38- F Cl 2.32(m, 1H), 1.99- 1.60(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro-4',5- 8.05(m, 1H), 7.57- difluoro-[1,1'-biphenyl] 7.48(m, 1H), 7.22- yl)carbamate 7.14(m, 2H), 7.12- 7.00(m, 2H), 6.61(s, 1H), 4.23- 4.16(m, 2H), 3.22- 3.10(m, 1H), 2.58- 2.47(m, 1H), 2.38(s, 3H), 2.35- 2.30(m, 3H), 1.98- 1.60(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (4'-chloro-3',5- 7.39-7.31(m, 3H), difluoro-[1,1'-biphenyl] 7.20-7.00(m, 2H), yl)carbamate 6.98-6.88(d, 1H, J=2.8Hz), 4.34- 4.23(m, 2H), 3.45(m, 1H), 3.16(m, 1H), 2.57- 2.54(m, 4H), 2.11- 1.70(m, 4H).
(S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-amino 7.99(s, 1H), 7.23– fluoro-[1,1'-biphenyl] 7.19(m, 1H), 7.03- yl)carbamate 6.98(m, 1H), 6.93- 6.90(m, 1H), 6.74(m, 1H), 6.70- 6.66(m, 1H), 213 6.63(s, 1H), 4.24- 4.07(m, 2H), 3.46(s, 1H), 3.14(m, 1H), 2.59(m, 1H), 2.42(s, 3H), 2.33- 2.29(m, 1H), 1.98- 1.63(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (2',5-difluoro-3'- 7.84(s, 1H), 7.69– (trifluoromethyl)-[1,1'- 7.66(m, 1H), 7.53- biphenyl]yl)carbamate 7.50(m, 1H), 7.37- 7.33(m, 1H), 7.15- 7.10(m, 1H), 6.98- 214 6.95(m, 1H), 6.61(s, 1H), 4.29- 4.15(m, 2H), 3.27(s, 1H), 2.78- 2.70(m, 1H), 2.48- 2.35(m, 4H), 1.98- 1.70(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro7.96(s, 1H), fluoro-5'-(trifluoromethyl)-7.79(s, 1H), [1,1'-biphenyl] 7.61(s, 1H), 7.50- yl)carbamate 7.47(d, 1H, J=11.6Hz), 7.11- 7.06(m, 1H), 6.94- 6.91(m, 1H), 6.58(s, 1H), 4.27- 4.11(m, 2H), 3.22- F C Cl 3.17(m, 1H), 2.67- 2.66(m, 1H), 2.42- 2.32(m, 4H), 2.02- 1.60(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro 7.82(s, 1H), 7.02- fluoro-5'-hydroxy-[1,1'- 6.64(m, 5H), 4.17- biphenyl]yl)carbamate 4.09(m, 2H), 3.10- 3.06(m, 1H), 2.53(m, 1H), 2.37(s, 3H), 2.34- 2.21(m, 1H), 1.96- 1.62(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro 7.94(s, 1H), 7.66- fluoro-5'-methoxy-[1,1'- 7.44(m, 4H), 6.91- biphenyl]yl)carbamate 6.89(d, 1H, J=8.4Hz), 6.62(s, 1H), 4.23-4.08(m, 2H), 3.86-3.85(m, 3H), 3.11(m, 1H), 2.53(m, 1H), H CO Cl 2.34(s, 3H), 2.29- 2.28(m, 1H), 1.93- 1.63(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (5-fluoro-2',4'- 8.11(m, 1H), 7.44- bis(trifluoromethyl)-[1,1'- 7.36(m, 1H), 7.20- biphenyl]yl)carbamate 7.17(m, 2H), 7.10- 6.99(m, 2H), 6.54(s, 1H), 4.27- 4.21(m, 2H), 3.31- F C N 3.15(m, 1H), 2.44- 2.40(m, 1H), F 2.39(s, 3H), 2.30- 2.25(m, 3H), 2.01- 1.55(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-ethoxy 7.58–7.53(m, 1H), fluoro-[1,1'-biphenyl] 7.48-7.44(m, 2H), yl)carbamate 7.29-7.15(m, 2H), 6.95-6.92(m, 1H), 6.84-6.79(m, 1H), 4.27-4.23(m, 2H), 4.14-4.07(q, 2H, J=6.8Hz), 3.28(m, 1H), 2.89(m, 1H), 2.50(m, 4H), 1.98- 1.59(m, 4H), 1.46- 1.40(t, 3H, J=14.0Hz) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (5-fluoro-3',4'- 7.65–7.61(m, 1H), dimethoxy-[1,1'-biphenyl] 7.54-7.52(m, 1H), yl)carbamate 7.47-7.43(m, 2H), 7.33(m, 1H), 6.68- 6.65(m, 1H), 4.29- 4.15(m, 2H), 3.87(s, 6H), 3.28- 3.25(m, 1H), 2.78- 2.70(m, 1H), 2.48- 2.35(m, 4H), 1.98- 1.63(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (5-fluoro-3',5'- 7.93(s, 1H), 7.03– dimethoxy-[1,1'-biphenyl] 6.91(m, 4H), 6.46- yl)carbamate 6.42(m, 1H), 6.38(s, 1H), 4.22- 4.08(m, 2H), 3.77(s, 6H), 3.15(m, 1H), 2.61(m, 1H), CO OC 2.41(s, 3H), 2.36- 2.24(m, 1H), 1.93- 1.58(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (5-methoxy-[1,1'- 7.81(s, 1H), 7.43– biphenyl]yl)carbamate 7.28(m, 4H), 7.20- 7.19(d, 1H, H CO J=4.4Hz), 6.87- 6.86(dd, 1H, J=9.2Hz), 6.76- 6.75(d, 1H, J=2.8Hz), 6.61(s, 1H), 4.20-4.06(m, 2H), 3.77(s, 3H), 3.13-3.10(m, 1H), 2.58-2.43(m, 1H), 2.38(s, 3H), 2.32- 2.25(m, 1H), 1.92- 1.56(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-fluoro 7.74(s, 1H), 7.39– methoxy-[1,1'-biphenyl] 7.33(m, 1H), 7.10- yl)carbamate 7.01(m, 2H), 6.88- 6.85(m, 1H), 6.73- 6.72(m, 1H), 6.59(s, 1H), 4.17- 4.03(m, 2H), 3.76(s, 3H), 3.76(m, 1H), 2.49(m, 1H), 2.36(s, 3H), 2.28- 2.21(m, 1H), 1.99- 1.56(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3'-chloro 7.79(s, 1H), 7.37– methoxy-[1,1'-biphenyl] 7.33(m, 2H), 7.26- yl)carbamate 7.20(m, 2H), 6.91- 6.88(m, 1H), 6.73- H CO 6.72(m, 1H), 6.38(s, 1H), 4.22- 4.05(m, 2H), 3.79(s, 3H), 3.11- 3.07(m, 1H), 2.50- 2.38(m, 1H), 2.33(s, 3H), 2.29- 2.22(m, 1H), 1.94- 1.57(m, 4H) (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',4'-dichloro 7.69(s, 1H), 7.48– methoxy-[1,1'-biphenyl] 7.43(m, 2H), 7.21- yl)carbamate 7.17(m, 1H), 6.90- 6.87(m, 1H), 6.71- H CO 6.70(m, 1H), 6.51(s, 1H), 4.21- 4.05(m, 2H), 3.78(s, 3H), 3.13(m, 1H), 2.52- 2.45(m, 1H), 2.32(s, 3H), 2.30- 2.22(m, 1H), 1.97- 1.59(m, 4H) 1001965344 (S)-(1-methylpyrrolidin H NMR(CDCl ): δ yl)methyl (3',5'-dichloro7.79(s, 1H), methoxy-[1,1'-biphenyl] 7.64(m, 1H), 7.35– yl)carbamate 7.34(m, 1H), 7.23- 7.22(m, 1H), 7.07- H CO 7.02(m, 1H), 6.90- 226 6.87(m, 1H), 6.63(s, 1H), 4.26- 4.05(m, 2H), 3.20- Cl Cl 3.15(m, 1H), 2.66(m, 1H), 2.42- 2.32(m, 4H), 1.99- 1.61(m, 4H) [Example 1] Synthesis of 2-(1-methylpyrrolidinyl)ethyl (4'-fluoro-[1,1'-biphenyl]yl)carbamate 4'-Fluoro-[1,1'-biphenyl]carboxylic acid (747mg, 3.46mmol)(Synthesis Example 1) was dissolved in toluene (20mL), and then biphenylphosphoryl azide (958uL, 4.15mmol) and triethylamine (486uL, 3.46mmol) were added thereto.
The same was stirred at room temperature for 30 minutes, and then stirred again under reflux for 1 hour. The reactant was cooled to room temperature. 2-(2- Hydroxyethyl)methylpyrrolidine (558uL, 4.15mmol) was added thereto and stirred under reflux for 12 hours. The 1001965344 reactant was cooled to room temperature. The solvent was removed by concentrating under reduced pressure, and then the same 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 titled compound (280mg, 24%).
[Examples 2-16] The starting materials in Table 7 were used instead of 4'-fluoro-[1,1'-biphenyl]carboxylic acid (747mg, 3.46mmol)(Synthesis Example 1) to prepare compounds of Examples 2-16 in the same manner as Example 1.
[Table 7] Examples 2-16 Example Chemical Name Starting Material 2-(1-Methylpyrrolidin 3',5'-Difluoro-[1,1'- yl)ethyl (3',5'- biphenyl]carboxylic 2 difluoro-[1,1'- acid (820mg) (Synthesis biphenyl]yl)carbamate Example 2) (290mg, 23%) 2-(1-Methylpyrrolidin 3',4',5'-Trifluoro- yl)ethyl (3',4',5'- [1,1'-biphenyl] 3 trifluoro-[1,1'- carboxylic acid (492mg) biphenyl]yl)carbamate (Synthesis Example 3) (300mg, 41%) 2-(1-Methylpyrrolidin 3'-Fluoro-[1,1'- yl)ethyl (3'-fluoro- biphenyl]carboxylic 4 [1,1'-biphenyl] acid (500mg) (Synthesis yl)carbamate (326mg, Example 4) 41%) 1001965344 2-(1-Methylpyrrolidin 4'-Methoxy-[1,1'- yl)ethyl (4'-methoxy- biphenyl]carboxylic [1,1'-biphenyl] acid (630mg) (Synthesis yl)carbamate (350mg, Example 5) 36%) 2-(1-Methylpyrrolidin yl)ethyl [1,1'- [1,1'-Biphenyl] biphenyl]ylcarbamate carboxylic acid (500mg) (400mg, 50%) 2-(1-Methylpyrrolidin 4'-Chloro-[1,1'- yl)ethyl (4'-chloro- biphenyl]carboxylic 7 [1,1'-biphenyl] acid (500mg) (Synthesis yl)carbamate (230mg, Example 6) %) 2-(1-Methylpyrrolidin 3'-Chloro-[1,1'- yl)ethyl (3'-chloro- biphenyl]carboxylic 8 [1,1'-biphenyl] acid (500mg) (Synthesis yl)carbamate (170mg, Example 7) 22%) 2-(1-Methylpyrrolidin 3',5'-Dichloro-[1,1'- yl)ethyl (3',5'- biphenyl]carboxylic 9 dichloro-[1,1'- acid (300mg) (Synthesis biphenyl]yl)carbamate Example 8) (125mg, 28%) 2-(1-Methylpyrrolidin 4'-Trifluoromethoxy- yl)ethyl (4'- [1,1'-biphenyl] trifluoromethoxy-[1,1'- carboxylic acid (450mg) biphenyl]yl)carbamate (Synthesis Example 9) (370mg, 57%) 1001965344 2-(1-Methylpyrrolidin 4'-Nitro-[1,1'- yl)ethyl (4'-nitro- biphenyl]carboxylic 11 [1,1'-biphenyl] acid (330mg) (Synthesis yl)carbamate (410mg, Example 10) 82%) 2-(1-Methylpyrrolidin 3'-Trifluoromethyl- yl)ethyl (3'- [1,1'-biphenyl] 12 trifluoromethyl-[1,1'- carboxylic acid (500mg) biphenyl]yl)carbamate (Synthesis Example 11) (476mg, 65%) 2-(1-Methylpyrrolidin 4'-Trifluoromethyl- yl)ethyl (4'- [1,1'-biphenyl] 13 trifluoromethyl-[1,1'- carboxylic acid (500mg) biphenyl]yl)carbamate (Synthesis Example 12) (45mg, 6%) 2-(1-Methylpyrrolidin 3'-Fluoro-4'-methyl- yl)ethyl ((3'-fluoro-4'- [1,1'-biphenyl] 14 methyl)-[1,1'-biphenyl]- carboxylic acid (430mg) 2-yl)carbamate (306mg, (Synthesis Example 13) 46%) 2-(1-Methylpyrrolidin 3'-Methyl-[1,1'- yl)ethyl (3'-methyl- biphenyl]carboxylic [1,1'-biphenyl] acid (400mg) (Synthesis yl)carbamate (105mg, Example 14) 16%) 2-(1-Methylpyrrolidin 3'-Ethoxy-[1,1'- yl)ethyl (3'-ethoxy- biphenyl]carboxylic 16 [1,1'-biphenyl] acid (315mg) (Synthesis yl)carbamate (250mg, Example 15) 52%) 1001965344 [Example 17] Synthesis of 2-(1-methylpyrrolidinyl)ethyl (3'-chlorofluoro-[1,1'-biphenyl]yl)carbamate 3'-Chlorofluoro-[1,1'-biphenyl]carboxylic acid (300mg, 1.20mmol)(Synthesis Example 16) was dissolved in toluene (20mL), and then biphenylphosphoryl azide (310uL, 1.44mmol) and triethylamine (202uL, 1.44mmol) was added thereto. The same was stirred at room temperature for 30 minutes, and then stirred again under reflux for 1 hour.
The reactant was cooled to room temperature. 2-(2- Hydroxyethyl)methylpyrrolidine (194uL, 1.44mmol) were added thereto and then stirred under reflux for 12 hours.
The reactant was cooled to room temperature. The solvent was removed by concentrating under reduced pressure, and then the same 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 titled compound (93mg, 21%).
[Examples 18-27] The starting materials in Table 8 were used instead of 3'-chlorofluoro-[1,1'-biphenyl]carboxylic acid (300mg, 1.20mmol)(Synthesis Example 16) to prepare compounds of Examples 18-27 in the same manner as Example 1001965344 [Table 8] Examples 18-27 Example Chemical Name Starting Material 2-(1-Methylpyrrolidin 3',5-Difluoro-[1,1'- yl)ethyl (3',5-difluoro- biphenyl]carboxylic 18 [1,1'-biphenyl] acid (400mg, 1.71mmol) yl)carbamate (465mg, (Synthesis Example 17) 76%) 2-(1-Methylpyrrolidin 4',5-Difluoro-[1,1'- yl)ethyl (4',5-difluoro- biphenyl]carboxylic 19 [1,1'-biphenyl] acid (400mg, 1.71mmol) yl)carbamate (184mg, (Synthesis Example 18) %) 2-(1-Methylpyrrolidin 3',5,5'-Trifluoro- yl)ethyl (3',5,5'- [1,1'-biphenyl] trifluoro-[1,1'- carboxylic acid (500mg, biphenyl]yl)carbamate 1.98mmol) (Synthesis (362mg, 48%) Example 19) 2-(1-Methylpyrrolidin -Fluoro-[1,1'- yl)ethyl (5-fluoro- biphenyl]carboxylic 21 [1,1'-biphenyl] acid (1g, 4.63mmol) yl)carbamate (297mg, (Synthesis Example 20) 19%) -Fluoro-3'-methyl- 2-(1-Methylpyrrolidin yl)ethyl (5-fluoro-3'- [1,1'-biphenyl] 22 methyl-[1,1'-biphenyl]- carboxylic acid (380mg, 2-yl)carbamate (152mg, 1.65mmol) (Synthesis 26%) Example 21) 1001965344 2-(1-Methylpyrrolidin 4-Fluoro-[1,1'- yl)ethyl (4-fluoro- biphenyl]carboxylic 23 [1,1'-biphenyl] acid (500mg, 2.31mmol) yl)carbamate (400mg, (Synthesis Example 22) 51%) 2-(1-Methylpyrrolidin 3',4-Difluoro-[1,1'- yl)ethyl (3',4-difluoro- biphenyl]carboxylic [1,1'-biphenyl] acid (400mg, 1.71mmol) yl)carbamate (84mg, 14%) (Synthesis Example 23) 2-(1-Methylpyrrolidin 4-Methoxy-[1,1'- yl)ethyl (4-methoxy- biphenyl]carboxylic [1,1'-biphenyl] acid (320mg, 1.40mmol) yl)carbamate (170mg, (Synthesis Example 24) 34%) 2-(1-Methylpyrrolidin -Methyl-[1,1'- yl)ethyl (5-methyl- biphenyl]carboxylic 26 [1,1'-biphenyl] acid (300mg, 1.41mmol) yl)carbamate (123mg, (Synthesis Example 25) 26%) 2-(1-Methylpyrrolidin 3'-Fluoromethyl- yl)ethyl (3'-fluoro [1,1'-biphenyl] 27 methyl-[1,1'-biphenyl]- carboxylic acid (200mg, 2-yl)carbamate (279mg, 0.87mmol) (Synthesis 90%) Example 26) [Example 28] Synthesis of 2-(1-methylpyrrolidinyl)ethyl (4'-cyano-[1,1'-biphenyl]yl)carbamate 1001965344 2-(1-Methylpyrrolidinyl)ethyl (2- iodophenyl)carbamate (600mg, 1.6mmol)(Synthesis Example A) was dissolved in a mixed solution of toluene (20mL) and ethanol (4mL). 4-Cyanophenyl boronic acid (259mg, 1.76mmol), potassium carbonate (442mg, 3.2mmol) and tetrakis triphenylphosphine palladium (370mg, 0.32mmol) were added thereto. The reactant was stirred at 110 ℃ for 12 hours and cooled to room temperature. The same was filtered through celite and the solvent was removed by concentrating under reduced pressure. The same 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 titled compound (193mg, 35%).
[Examples 29-32] 2-(1-Methylpyrrolidinyl)ethyl (2- iodophenyl)carbamate of Synthesis Example A as a starting material and reaction materials in Table 9 were used to prepare compounds of Examples 29-32 in the same manner as Example 28.
[Table 9] Examples 29-32 1001965344 Starting Material Example Chemical Name Reacting Material (Synthesis Example A) 2-(1- Methylpyrrolidin- 2-yl)ethyl (3'- 3-(3- (3- 1g, Hydroxypropyl)phenyl hydroxypropyl)- 2.67mmol boronic acid (530mg, [1,1'-biphenyl]- 2.94mmol) 2-yl)carbamate (52mg, 5%) 2-(1- Methylpyrrolidin- 2-yl)ethyl (4'- 200mg, (Dimethylamino)phenyl (dimethylamino)- 0.53mmol boronic acid (131mg, [1,1'-biphenyl]- 0.80mmol) 2-yl)carbamate (71mg, 36%) 2-(1- Methylpyrrolidin- 2-yl)ethyl (4'- 4-Tert-butylphenyl 150mg, 31 (tert-butyl)- boronic acid (110mg, 0.40mmol [1,1'-biphenyl]- 0.60mmol) 2-yl)carbamate (33mg, 22%) 1001965344 2-(1- Methylpyrrolidin- 2-yl)ethyl (2'- 2-Aminophenyl boronic 400mg, 32 amino-[1,1'- acid pinacol ester 1.07mmol biphenyl] (353mg, 1.61mmol) yl)carbamate (37mg, 10%) [Example 33] Synthesis of 2-(1-methylpyrrolidinyl)ethyl (3'-amino-[1,1'-biphenyl]yl)carbamate 2-(1-Methylpyrrolidinyl)ethyl (2- iodophenyl)carbamate (1.36g, 3.63mmol)(Synthesis Example A) was dissolved in a mixed solution of acetonitrile (15mL) and water (15mL). 3-Aminophenyl boronic acid (995mg, 7.26mmol), sodium carbonate (772mg, 7.26mmol) and dichlorobis triphenylphosphine palladium (127mg, 0.18mmol) were added thereto. The reactant was stirred at 110 ℃ in a microwave oven for 10 minutes and cooled to room temperature. The same was filtered through celite and the solvent was removed by concentrating under reduced pressure. The same 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 titled compound (192mg, 16%). 1001965344 [Examples 34-41] 2-(1-Methylpyrrolidinyl)ethyl (2- iodophenyl)carbamate of Synthesis Example A as a starting material and reacting materials in Table 10 were used to prepare compounds of Examples 34-41 in the same manner as Example 33.
[Table 10] Examples 34-41 Starting Material Example Chemical Name Reacting Material (Synthesis Example A) 2-(1- Methylpyrrolidin 2- yl)ethyl (2'-fluoro- 400mg, Fluorophenylboron [1,1'-biphenyl] 1.07mmol ic acid (300mg, yl)carbamate (126mg, 2.14mmol) %) 2-(1- Methylpyrrolidin 2- yl)ethyl (2'-chloro- 400mg, Chlorophenylboron [1,1'-biphenyl] 1.07mmol ic acid (335mg, yl)carbamate (80mg, 2.14mmol) 18%) 2-(1- Methylpyrrolidin 2-Hydroxyphenyl yl)ethyl (2'-hydroxy- 400mg, boronic acid [1,1'-biphenyl] 1.07mmol pinacol ester yl)carbamate (65mg, (471mg, 2.14mmol) 16%) 1001965344 2-(1- Methylpyrrolidin (3-tert-Butyl yl)ethyl (3'-tert- 300mg, methyl)phenylboro 37 butyl-5'-methyl- 0.80mmol nic acid (307mg, [1,1'-biphenyl] 1.60mmol) yl)carbamate (155mg, 49%) 2-(1- Methylpyrrolidin (4-Fluoro yl)ethyl (4'-fluoro- (trifluoromethyl) 297mg, 38 3'-(trifluoromethyl)- phenyl)boronic 0.79mmol [1,1'-biphenyl] acid (330mg, yl)carbamate (66mg, 1.58mmol) %) 2-(1- Methylpyrrolidin (4-Amino yl)ethyl (4'-amino- chlorophenyl)boro 300mg, 39 3'-chloro-[1,1'- nic acid pinacol 0.80mmol biphenyl] ester (406mg, yl)carbamate (81mg, 1.6mmol) 27%) 2-(1- Methylpyrrolidin 3-Hydroxyphenyl yl)ethyl (3'-hydroxy- 300mg, 40 boronic acid [1,1'-biphenyl] 0.80mmol (221mg, 1.6mmol) yl)carbamate (48mg, 1001965344 2-(1- Methylpyrrolidin 3-Chloro yl)ethyl (3'-chloro- 300mg, fluorophenylboron 41 4'-fluoro-[1,1'- 0.80mmol ic acid (240mg, biphenyl] 1.38mmol) yl)carbamate (150mg, 43%) [Example 42] Synthesis of 2-(1-methylpyrrolidinyl)ethyl (3',4',5-trifluoro-[1,1'-biphenyl]yl)carbamate 2-(1-Methylpyrrolidinyl)ethyl (2-bromo fluorophenyl)carbamate (400mg, 1.16mmol)(Synthesis Example B) was dissolved in toluene (20mL). 3,4-Fluorophenyl diboronic acid (280mg, 1.74mmol), potassium carbonate (321mg, 2.32mmol) and tetrakis triphenylphosphine palladium (140mg, 0.12mmol) were added thereto. The reactant was stirred at 120 ℃ for 12 hours and cooled to room temperature. The same was filtered through celite and the solvent was removed by concentrating under reduced pressure. The same 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 titled compound (15mg, 3%). 1001965344 [Examples 43-46] 2-(1-Methylpyrrolidinyl)ethyl (2-bromo fluorophenyl)carbamate of Synthesis Example B as a starting material and reacting materials in Table 11 were used to prepare compounds of Examples 43-46 in the same manner as Example 42.
[Table 11] Examples 43-46 Starting Material Reacting Example Chemical Name (Synthesis Material Example B) 2-(1- Methylpyrrolidin 3,4- yl)ethyl (3',4'- Dichlorophenyl 400mg, 43 dichlorofluoro- boronic acid 1.16mmol [1,1'-biphenyl] (332mg, yl)carbamate (24mg, 1.74mmol) 2-(1- Methylpyrrolidin 3-Ethylphenyl yl)ethyl (3'-ethyl- 300mg, boronic acid 44 5-fluoro-[1,1'- 0.87mmol (200mg, biphenyl] 1.31mmol) yl)carbamate (40mg, 12%) 1001965344 2-(1- Methylpyrrolidin 3,5- yl)ethyl (5-fluoro- Dimethylphenyl 400mg, 45 3',5'-dimethyl- boronic acid 1.16mmol [1,1'-biphenyl] (261mg, yl)carbamate (18mg, 1.74mmol) 2-(1- Methylpyrrolidin 3-Aminophenyl yl)ethyl (3'-amino- 1g, boronic acid 46 5-fluoro-[1,1'- 2.90mmol (600mg, biphenyl] 4.35mmol) yl)carbamate (50mg, [Examples 47-51] 2-(1-Methylpyrrolidinyl)ethyl (2-bromo (trifluoromethyl)phenyl)carbamate of Synthesis Example C as a starting material instead of 2-(1-methylpyrrolidin yl)ethyl (2-bromofluorophenyl)carbamate of Synthesis Example B and reacting materials in Table 12 were used to prepare compounds of Examples 47-51 in the same manner as Example 42.
[Table 12] Examples 47-51 Starting Material Example Chemical Name Reacting Material (Synthesis Example C) 1001965344 2-(1- Methylpyrrolidin- 2-yl)ethyl (5- 300mg, Phenylboronic acid 47 (trifluoromethyl)- 0.76mmol (102mg, 0.84mmol) [1,1'-biphenyl] yl)carbamate (26mg, 9%) 2-(1- Methylpyrrolidin- 2-yl)ethyl (4'- 4-Fluorophenylboronic fluoro 300mg, 48 acid (118mg, (trifluoromethyl)- 0.76mmol 0.84mmol) [1,1'-biphenyl] yl)carbamate (14mg, 4%) 2-(1- Methylpyrrolidin- 2-yl)ethyl (3'- 3-Fluorophenylboronic fluoro 300mg, 49 acid (118mg, (trifluoromethyl)- 0.76mmol 0.84mmol) [1,1'-biphenyl] yl)carbamate (19mg, 6%) 1001965344 2-(1- Methylpyrrolidin- 2-yl)ethyl (3',5'- 3,5- difluoro 260mg, Difluorophenylboronic (trifluoromethyl)- 0.66mmol acid (115mg, [1,1'-biphenyl] 0.73mmol) yl)carbamate (12mg, 4%) 2-(1- Methylpyrrolidin- 2-yl)ethyl (3'- 3-Chlorophenylboronic chloro 300mg, 51 acid (131mg, (trifluoromethyl)- 0.76mmol 0.84mmol) [1,1'-biphenyl] yl)carbamate (14mg, 4%) [Example 52] Synthesis of 2-(1-methylpyrrolidinyl)ethyl (3'-chloro-5,5'-difluoro-[1,1'-biphenyl]yl)carbamate F Cl 2-(1-Methylpyrrolidinyl)ethyl (2-bromo fluorophenyl)carbamate (300mg, 0.87mmol)(Synthesis Example B) was dissolved in a mixed solution of acetonitrile (10mL) and water (10mL). (3-Chlorofluorophenyl)boronic acid (303mg, 1.74mmol), sodium carbonate (184mg, 1.74mmol) and dichlorobis triphenylphosphine palladium (31mg, 0.04mmol) 1001965344 were added thereto. The reactant was stirred at 110 ℃ in a microwave oven for 10 minutes and cooled to room temperature. The same was filtered through celite and the solvent was removed by concentrating under reduced pressure. The same 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 titled compound (51mg, 15%).
[Examples 53-59] 2-(1-Methylpyrrolidinyl)ethyl (2-bromo fluorophenyl)carbamate of Synthesis Example B as a starting material and reacting materials in Table 13 were used to used to prepare compounds of Examples 53-59 in the same manner as Example 52.
[Table 13] Examples 53-59 Starting Material Example Chemical Name Reacting Material (Synthesis Example B) 2-(1- Methylpyrrolidin- 2-yl)ethyl (3'- (3-Chloro chloro-4',5- 300mg, 53 fluorophenyl)boronic difluoro-[1,1'- 0.87mmol acid (303mg, 1.74mmol) biphenyl] yl)carbamate (81mg, 24%) 1001965344 2-(1- Methylpyrrolidin- 2-yl)ethyl (4'- (3-Fluoro chloro-3',5- 400mg, 54 chlorophenyl)boronic difluoro-[1,1'- 1.16mmol acid (405mg, 2.32mmol) biphenyl] yl)carbamate (173mg, 38%) 2-(1- Methylpyrrolidin- 2-yl)ethyl 3,5-Dichlorophenyl (3',5'-dichloro- 400mg, 55 boronic acid (443mg, -fluoro-[1,1'- 1.16mmol 2.32mmol) biphenyl] yl)carbamate (71mg, 15%) 2-(1- Methylpyrrolidin- 2-yl)ethyl 3,5-Dichloro (3',5'-dichloro- 400mg, 56 fluorophenyl boronic 4',5-difluoro- 1.16mmol acid (484mg, 2.32mmol) [1,1'-biphenyl]- 2-yl)carbamate (99mg, 20%) 1001965344 2-(1- Methylpyrrolidin- 2-yl)ethyl (3'- (3-Chloro chlorofluoro- 300mg, 57 hydroxyphenyl)boronic '-hydroxy-[1,1'- 0.87mmol acid (300mg, 1.74mmol) biphenyl] yl)carbamate (97mg, 28%) 2-(1- Methylpyrrolidin- 2-yl)ethyl (3'- (3-Chloro chlorofluoro- 400mg, 58 hydroxyphenyl)boronic 4'-hydroxy-[1,1'- 1.16mmol acid (400mg, 2.32mmol) biphenyl] yl)carbamate (176mg, 39%) 2-(1- Methylpyrrolidin- 2-yl)ethyl (5- (3,4- fluoro-3',4'- 400mg, 59 Dimethylphenyl)boronic dimethyl-[1,1'- 1.16mmol acid (348mg, 2.32mmol) biphenyl] yl)carbamate (129mg, 30%) [Examples 60-65] 2-(1-Methylpyrrolidinyl)ethyl (2-bromo methoxyphenyl)carbamate of Synthesis Example D instead of 2-(1-methylpyrrolidinyl)ethyl (2-bromo fluorophenyl)carbamate of Synthesis Example B as a starting material and reacting materials in Table 14 were used to 1001965344 prepare compounds of Examples 60-65 in the same manner as Example 52.
[Table 14] Examples 60-65 Starting Material Example Chemical Name Reacting Material (Synthesis Example D) 2-(1- Methylpyrrolidin- 2-yl)ethyl (5- 300mg, Phenylboronic acid 60 methoxy-[1,1'- 0.84mmol (154mg, 1.26mmol) biphenyl] yl)carbamate (25mg, 8%) 2-(1- Methylpyrrolidin- 2-yl)ethyl (3'- 3-Fluorophenylboronic 300mg, 61 fluoromethoxy- acid (176mg, 0.84mmol [1,1'-biphenyl]- 1.26mmol) 2-yl)carbamate (112mg, 36%) 2-(1- Methylpyrrolidin- 2-yl)ethyl 3,5- (3',5'-difluoro- 400mg, Difluorophenylboronic -methoxy-[1,1'- 1.12mmol acid (354mg, biphenyl] 2.24mmol) yl)carbamate (161mg, 37%) 1001965344 2-(1- Methylpyrrolidin- 2-yl)ethyl (3'- 3-Chlorophenylboronic 330mg, 63 chloromethoxy- acid (289mg, 0.92mmol [1,1'-biphenyl]- 1.85mmol) 2-yl)carbamate (112mg, 31%) 2-(1- Methylpyrrolidin- 2-yl)ethyl 3,5- (3',5'-dichloro- 400mg, Dichlorophenylboronic -methoxy-[1,1'- 1.12mmol acid (427mg, biphenyl] 2.24mmol) yl)carbamate (92mg, 19%) 2-(1- Methylpyrrolidin- 2-yl)ethyl (3'- (3-Chloro chloro-4'-fluoro- 400mg, fluoro)phenylboronic -methoxy-[1,1'- 1.12mmol acid (390mg, biphenyl] 2.24mmol) yl)carbamate (155mg, 34%) [Examples 66-73] 2-(1-Methylpyrrolidinyl)ethyl (2-bromo chlorophenyl)carbamate of Synthesis Example E instead of 2- (1-methylpyrrolidinyl)ethyl (2-bromo fluorophenyl)carbamate of Synthesis Example B as a starting material and reacting materials in Table 15 were used to 1001965344 prepare compounds of Examples 66-73 in the same manner as Example 52.
[Table 15] Examples 66-73 Starting Material Example Chemical Name Reacting Material (Synthesis Example E) 2-(1- Methylpyrrolidin- 2-yl)ethyl (5- 400mg, Phenylboronic acid 66 chloro-[1,1'- 1.11mmol (271mg, 2.22mmol) biphenyl] yl)carbamate (94mg, 24%) 2-(1- Methylpyrrolidin- 2-yl)ethyl (5- 400mg, Fluorophenylboronic 67 chloro-3'-fluoro- 1.11mmol acid (311mg, [1,1'-biphenyl]- 2.22mmol) 2-yl)carbamate (187mg, 45%) 2-(1- Methylpyrrolidin- 2-yl)ethyl (5- 400mg, Fluorophenylboronic 68 chloro-4'-fluoro- 1.11mmol acid (311mg, [1,1'-biphenyl]- 2.22mmol) 2-yl)carbamate (38mg, 9%) 1001965344 2-(1- Methylpyrrolidin- 2-yl)ethyl (5- 3,5-Difluorophenyl chloro-3',5'- 400mg, 69 boronic acid (351mg, difluoro-[1,1'- 1.11mmol 2.22mmol) biphenyl] yl)carbamate (162mg, 37%) 2-(1- Methylpyrrolidin- 2-yl)ethyl (3',5- 400mg, Chlorophenylboronic 70 dichloro-[1,1'- 1.11mmol acid (347mg, biphenyl] 2.22mmol) yl)carbamate (111mg, 25%) 2-(1- Methylpyrrolidin- 2-yl)ethyl 3,5-Dichlorophenyl (3',5,5'- 400mg, 71 boronic acid (424mg, trichloro-[1,1'- 1.11mmol 2.22mmol) biphenyl] yl)carbamate (58mg, 12%) 1001965344 2-(1- Methylpyrrolidin- 2-yl)ethyl (3',5- (3-Chloro dichloro-5'- 400mg, fluorophenyl)boronic fluoro-[1,1'- 1.11mmol acid (387mg, biphenyl] 2.22mmol) yl)carbamate (119mg, 26%) 2-(1- Methylpyrrolidin- 2-yl)ethyl (3',5- (3-Chloro dichloro-4'- 400mg, fluorophenyl)boronic fluoro-[1,1'- 1.11mmol acid (387mg, biphenyl] 2.22mmol) yl)carbamate (88mg, 19%) [Example 74] Synthesis of (R)-(1-methylpyrrolidin yl)methyl (3'-fluoro-4'-formyl-[1,1'-biphenyl] yl)carbamate (R)-(1-methylpyrrolidinyl)methyl (2- bromophenyl)carbamate (220mg, 0.70mmol)(Synthesis Example F) and 3-fluoroformylphenylboronic acid (237mg, 1.41mmol) were used as starting materials to prepare titled compound (124mg, 50%) in the same manner as Example 52.
[Example 75] Synthesis of 2-(1-methylpyrrolidinyl)ethyl (3',5'-difluorohydroxy-[1,1'-biphenyl]yl)carbamate 1001965344 2-(1-Methylpyrrolidinyl)ethyl (3',5'-difluoro methoxy-[1,1'-biphenyl]yl)carbamate (130mg, 0.33mmol)(Example 62) was dissolved in dichloromethane (10mL). A boron trichloride solution (1.0M dichloromethane, 0.99ml, 0.99mmol) was added thereto and stirred at room temperature for 2 hours. After reaction was terminated, the reactant 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 titled compound (68mg, 55%).
[Example 76] Synthesis of 2-(1-methylpyrrolidinyl)ethyl (3',5'-dichlorohydroxy-[1,1'-biphenyl]yl)carbamate 2-(1-Methylpyrrolidinyl)ethyl (3',5'-dichloro methoxy-[1,1'-biphenyl]yl)carbamate (90mg, 0.21mmol)(Example 64) was used instead of Example 62 to prepare titled compound (10mg, 12%) in the same manner as Example 75.
[Example 77] Synthesis of 2-(1-methylpyrrolidinyl)ethyl (3'-chloro-4'-fluorohydroxy-[1,1'-biphenyl] yl)carbamate 2-(1-Methylpyrrolidinyl)ethyl (3'-chloro-4'- fluoromethoxy-[1,1'-biphenyl]yl)carbamate (140mg, 1001965344 0.34mmol)(Example 65) was used instead of Example 62 to prepare titled compound (130mg, 96%) in the same manner as Example 75.
[Example 78] Synthesis of (R)-pyrrolidinylmethyl [1,1'- biphenyl]ylcarbamate [Step 1] (R)-tert-butyl 3-((([1,1'-biphenyl] ylcarbamoyl)oxy)methyl)pyrrolidinecarboxylate [1,1'-Biphenyl]carboxylic acid (2g, 10.09mmol) was dissolved in toluene (50mL), and then biphenylphosphoryl azide (2.61mL, 12.11mmol) and triethylamine (1.42mL, .09mmol) were added thereto. The same was stirred at room temperature for 30 minutes and then stirred again under reflux for 1 hour. The reactant was cooled to room temperature. (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine- 1-carboxylate (2.44g, 12.11mmol) was added thereto and stirred under reflux for 12 hours. The reactant was cooled to room temperature. The solvent was removed by concentrating under reduced pressure, and then the same was extracted with water and dichloromethane. The organic 1001965344 layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the titled compound (3g, 75%).
H NMR(CDCl ): 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)-pyrrolidinylmethyl [1,1'- biphenyl]ylcarbamate (R)-tert-butyl 3-((([1,1'-biphenyl] ylcarbamoyl)oxy)methyl)pyrrolidinecarboxylate (3g, 7.57mmol) was dissolved in dichloromethane (80mL).
Trifluoroacetic acid (40mL) was added thereto and stirred at room temperature for 2 hours. The solvent was removed by concentrating the reactant under reduced pressure and the same 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 titled compound (1.73g, 77%).
[Examples 79-88] Starting materials and reacting materials in Table 16 were used to prepare compounds of Examples 79-88 in the same manner as Example 78. 1001965344 [Table 16] Examples 79-88 Example Chemical Name Starting Material Reacting Material (S)- pyrrolidin (S)-tert-butyl 3- ylmethyl [1,1'-Biphenyl] (hydroxymethyl)pyr 79 [1,1'- carboxylic acid rolidine biphenyl] (2g, 10.09mmol) carboxylate ylcarbamate (2.44g, 12.11mmol) (1.53g, 51%) (R)- pyrrolidin 3',5'-Difluoro- ylmethyl (R)-tert-butyl 3- [1,1'-biphenyl] (3',5'- (hydroxymethyl)pyr carboxylic acid 80 difluoro- rolidine (500mg, 2.13mmol) [1,1'- carboxylate (Synthesis Example biphenyl] (516mg, 2.56mmol) yl)carbamate (435mg, 63%) (S)- pyrrolidin 3',5'-Difluoro- ylmethyl (S)-tert-butyl 3- [1,1'-biphenyl] (3',5'- (hydroxymethyl)pyr carboxylic acid 81 difluoro- rolidine (500mg, 2.13mmol) [1,1'- carboxylate (Synthesis Example biphenyl] (516mg, 2.56mmol) yl)carbamate (416mg, 59%) 1001965344 (S)- -Fluoro-[1,1'- pyrrolidin (S)-tert-butyl 3- biphenyl] ylmethyl (5- (hydroxymethyl)pyr carboxylic acid 82 fluoro-[1,1'- rolidine (1g, 4.63mmol) biphenyl] carboxylate (Synthesis Example yl)carbamate (1,12g, 5.56mmol) (712mg, 51%) (S)- -Fluoro-3'- pyrrolidin methyl-[1,1'- (S)-tert-butyl 3- ylmethyl (5- biphenyl] (hydroxymethyl)pyr fluoro-3'- 83 carboxylic acid rolidine methyl-[1,1'- (1g, 4.34mmol) carboxylate biphenyl] (Synthesis Example (1,05g, 5.21mmol) yl)carbamate (260mg, 18%) (R)- pyrrolidin 3',5,5'-Trifluoro- ylmethyl (R)-tert-butyl 3- [1,1'-biphenyl] (3',5,5'- (hydroxymethyl)pyr carboxylic acid 84 trifluoro- rolidine (500mg, 1.98mmol) [1,1'- carboxylate (Synthesis Example biphenyl] (479mg, 2.38mmol) yl)carbamate (470mg, 67%) 1001965344 (S)- pyrrolidin 3',5,5'-Trifluoro- ylmethyl (S)-tert-butyl 3- [1,1'-biphenyl] (3',5,5'- (hydroxymethyl)pyr carboxylic acid 85 trifluoro- rolidine (500mg, 1.98mmol) [1,1'- carboxylate (Synthesis Example biphenyl] (479mg, 2.38mmol) yl)carbamate (400mg, 58%) (R)- -Methyl-[1,1'- pyrrolidin (R)-tert-butyl 3- biphenyl] ylmethyl (5- (hydroxymethyl)pyr carboxylic acid 86 methyl-[1,1'- rolidine (600mg, 2.83mmol) biphenyl] carboxylate (Synthesis Example yl)carbamate (684mg, 3.40mmol) (222mg, 25%) (R)- 3'-Fluoro pyrrolidin methyl-[1,1'- (R)-tert-butyl 3- ylmethyl (3'- biphenyl] (hydroxymethyl)pyr fluoro 87 carboxylic acid rolidine methyl-[1,1'- (400mg, 1.74mmol) carboxylate biphenyl] (Synthesis Example (420mg, 2.09mmol) yl)carbamate (346mg, 61%) 1001965344 (S)- 4'-Fluoro-[1,1'- pyrrolidin (S)-tert-butyl 2- biphenyl] ylmethyl (4'- (hydroxymethyl)pyr carboxylic acid 88 fluoro-[1,1'- rolidine (750mg, 3.47mmol) biphenyl] carboxylate (Synthesis Example yl)carbamate (837mg, 4.16mmol) (915mg, 84%) [Example 89] Synthesis of (R)-(1-methylpyrrolidin yl)methyl [1,1'-biphenyl]ylcarbamate (R)-pyrrolidinylmethyl [1,1'-biphenyl] ylcarbamate (727mg, 2.45mmol)(Example 78) was dissolved in water (50mL). Acetic acid (1mL), formaldehyde solution (3mL) and zinc powder (300mg) were sequentially added thereto and stirred at room temperature for 12 hours. The reactant was filtered, neutralized with 2N-sodium hydroxide and extracted with water and dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the titled compound (209mg, 28%).
[Examples 90-99] Starting materials in Table 17 were used instead of (R)-pyrrolidinylmethyl [1,1'-biphenyl]ylcarbamate to 1001965344 prepare compounds of Examples 90-99 in the same manner as Example 89.
[Table 17] Examples 90-99 Example Chemical Name Starting Material (S)-pyrrolidin (S)-(1-methylpyrrolidin- ylmethyl [1,1'- 3-yl)methyl [1,1'- 90 biphenyl]ylcarbamate biphenyl]ylcarbamate (523mg, 1.76mmol) (285mg, 52%) (Example 79) (R)-pyrrolidin (R)-(1-methylpyrrolidin- ylmethyl (3',5'- 3-yl)methyl (3',5'- difluoro-[1,1'- 91 difluoro-[1,1'- biphenyl] biphenyl]yl)carbamate yl)carbamate (400mg, (138mg, 33%) 1.2mmol) (Example 80) (S)-pyrrolidin (S)-(1-methylpyrrolidin- ylmethyl (3',5'- 3-yl)methyl (3',5'- difluoro-[1,1'- 92 difluoro-[1,1'- biphenyl] biphenyl]yl)carbamate yl)carbamate (377mg, (78mg, 19%) 1.13mmol) (Example 81) (S)-(1-methylpyrrolidin- (S)-pyrrolidin 3-yl)methyl (5-fluoro-ylmethyl (5-fluoro- 93 [1,1'-biphenyl] [1,1'-biphenyl] yl)carbamate (230mg, yl)carbamate (330mg, 67%) 1.05mmol) (Example 82) 1001965344 (S)-(1-methylpyrrolidin- (S)-pyrrolidin 3-yl)methyl (5-fluoro- ylmethyl (5-fluoro-3'- 94 3'-methyl-[1,1'- methyl-[1,1'-biphenyl]- biphenyl]yl)carbamate 2-yl)carbamate (260mg, (24mg, 9%) 0.79mmol) (Example 83) (R)-pyrrolidin (R)-(1-methylpyrrolidin- ylmethyl (3',5,5'- 3-yl)methyl (3',5,5'- trifluoro-[1,1'- 95 trifluoro-[1,1'- biphenyl] biphenyl]yl)carbamate yl)carbamate (400mg, (58mg, 14%) 1.14mmol) (Example 84) (S)-pyrrolidin (S)-(1-methylpyrrolidin- ylmethyl (3',5,5'- 3-yl)methyl (3',5,5'- trifluoro-[1,1'- 96 trifluoro-[1,1'- biphenyl] biphenyl]yl)carbamate yl)carbamate (400mg, (144mg, 35%) 1.14mmol) (Example 85) (R)-pyrrolidin (R)-(1-methylpyrrolidin- ylmethyl (5-methyl- 3-yl)methyl (5-methyl- 97 [1,1'-biphenyl] [1,1'-biphenyl] yl)carbamate (145mg, yl)carbamate (24mg, 16%) 0.47mmol) (Example 86) (R)-(1-methylpyrrolidin- (R)-pyrrolidin 3-yl)methyl (3'-fluoro- ylmethyl (3'-fluoro 98 5-methyl-[1,1'- methyl-[1,1'-biphenyl]- biphenyl]yl)carbamate 2-yl)carbamate (320mg, (15mg, 5%) 0.97mmol) (Example 87) 1001965344 (S)-pyrrolidin (S)-(1-methylpyrrolidin- ylmethyl (4'-fluoro- 2-yl)methyl (4'-fluoro- 99 [1,1'-biphenyl] [1,1'-biphenyl] yl)carbamate (850mg, yl)carbamate (87mg, 10%) 2.70mmol) (Example 88) [Example 100] Synthesis of (R)-(1-methylpyrrolidin yl)methyl (3'-methyl-[1,1'-biphenyl]yl)carbamate [Step 1] Synthesis of (R)-pyrrolidinylmethyl (3'-methyl- [1,1'-biphenyl]yl)carbamate 3'-Methyl-[1,1'-biphenyl]carboxylic acid (Synthesis Example 14) and (R)-tert-butyl 3- (hydroxymethyl)pyrrolidinecarboxylate were used as starting materials to prepare the titled compound in the same manner as Example 78.
H NMR(CDCl ): 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) 1001965344 [Step 2] Synthesis of (R)-(1-methylpyrrolidinyl)methyl (3'-methyl-[1,1'-biphenyl]yl)carbamate (R)-pyrrolidinylmethyl (3'-methyl-[1,1'-biphenyl]- 2-yl)carbamate (600mg, 1.93mmol) prepared in Step 1 was used to prepare the titled coumpound (30mg, 5%) in the same manner as Example 89.
[Example 101] Synthesis of (S)-(1-methylpyrrolidin yl)methyl (3'-methyl-[1,1'-biphenyl]yl)carbamate [Step 1] Synthesis of (S)-pyrrolidinylmethyl (3'-methyl- [1,1'-biphenyl]yl)carbamate 3'-Methyl-[1,1'-biphenyl]carboxylic acid (Synthesis Example 14) and (S)-tert-butyl 3- (hydroxymethyl)pyrrolidinecarboxylate were used as starting materials to prepare the titled compound in the same manner as Example 78. 1001965344 H NMR(CDCl ): 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-methylpyrrolidinyl)methyl (3'-methyl-[1,1'-biphenyl]yl)carbamate (S)-pyrrolidinylmethyl (3'-methyl-[1,1'-biphenyl]- 2-yl)carbamate (900mg, 2.90mmol) prepared in Step 1 was used to prepare the titled compound (208mg, 22%) in the same manner as Example 89.
[Example 102] Synthesis of (R)-(1-ethylpyrrolidin yl)methyl [1,1'-biphenyl]ylcarbamate (R)-pyrrolidinylmethyl [1,1'-biphenyl] ylcarbamate (1g, 3.37mmol)(Example 78) was dissolved in dimethylformamide (20mL). Potassium carbamate (652mg, 4.72mmol), potassium iodide (112mg, 0.67mmol), triethylamine (1.42mL, 10.11mmol) and iodoethane (323uL, 4.04mmol) were sequentially added thereto and stirred at 120 ℃ for 12 hours. The reactant was cooled to room temperature and extracted with water and ethyl acetate. 1001965344 The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified with column chromatography to prepare the titled compound (142mg, 13%).
[Examples 103-105] Starting materials in Table 18 were used instead of (R)-pyrrolidinylmethyl [1,1'-biphenyl]ylcarbamate to prepare compounds of Examples 103-105 in the same manner as Example 102.
[Table 18] Examples 103-105 Example Chemical Name Starting Material (S)-pyrrolidin (S)-(1-ethylpyrrolidin- ylmethyl [1,1'- 3-yl)methyl [1,1'- 103 biphenyl]ylcarbamate biphenyl]ylcarbamate (1g, 3.37mmol) (Example (89mg, 8%) (R)-pyrrolidin (R)-(1-ethylpyrrolidin- ylmethyl (3'-methyl- 3-yl)methyl (3'-methyl- [1,1'-biphenyl] 104 [1,1'-biphenyl] yl)carbamate (623mg, yl)carbamate (109mg, 2.01mmol) (Example 100, 16%) Step 1) (S)-pyrrolidin (S)-(1-ethylpyrrolidin- ylmethyl (3'-methyl- 3-yl)methyl (3'-methyl- [1,1'-biphenyl] [1,1'-biphenyl] yl)carbamate (600mg, yl)carbamate (40mg, 6%) 1.93mmol) (Example 101, Step 1) 1001965344 [Example 106] Synthesis of (S)-(1-ethylpyrrolidin yl)methyl [1,1'-biphenyl]ylcarbamate (S)-pyrrolidinylmethyl [1,1'-biphenyl] ylcarbamate (1g, 3.37mmol) and 2-iodoethane (323uL, 4.04mmol) were used as starting materials to prepare titled compound (385mg, 35%) in the same manner as Example 102.
[Example 107] Synthesis of (S)-(1-isobutylpyrrolidin yl)methyl [1,1'-biphenyl]ylcarbamate (S)-pyrrolidinylmethyl [1,1'-biphenyl] ylcarbamate (940mg, 3.17mmol) and 1-iodomethylpropane (438uL, 3.08mmol) were used as starting materials to prepare titled compound (47mg, 4%) in the same manner as Example 102.
[Example 108] Synthesis of (S)-(1-methylpyrrolidin yl)methyl (3',5-difluoro-[1,1'-biphenyl]yl)carbamate 1001965344 3',5-Difluoro-[1,1'-biphenyl]carboxylic acid (800mg, 3.42mmol) (Synthesis Example 17) and (S)-tert-butyl 3-(hydroxymethyl)pyrrolidinecarboxylate (825mg, 4.10mmol) were used as starting materials to prepare titled compound (50mg, 5%) in the same manner as Example 78 and Example 89.
[Example 109] Synthesis of (R)-(1-methylpyrrolidin yl)methyl [1,1'-biphenyl]ylcarbamate [Step 1] Synthesis of (R)-pyrrolidinylmethyl [1,1'- biphenyl]ylcarbamate [1,1'-Biphenyl]carboxylic acid (821mg, 4.14mmol) and (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine carboxylate (1g, 4.97mmol) were used as starting materials 1001965344 to prepare titled compound (730mg, 60%) in the same manner as Example 78.
H NMR (CDCl ): 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-methylpyrrolidinyl)methyl [1,1'-biphenyl]ylcarbamate (R)-pyrrolidinylmethyl [1,1'-biphenyl] ylcarbamate (730mg, 2.46mmol) was used as a starting material to prepare titled compound (183mg, 24%) in the same manner as Example 89.
[Example 110] Synthesis of (R)-(1-methylpyrrolidin yl)methyl (3'-methyl-[1,1'-biphenyl]yl)carbamate 3'-Methyl-[1,1'-biphenyl]carboxylic acid (700mg, 3.3mmol)(Synthesis Example 14) and (R)-tert-butyl 2- (hydroxymethyl)pyrrolidinecarboxylate (797mg, 3.96mmol) were used as starting materials to prepare titled compound 1001965344 (258mg, 24%) in the same manner as Example 78 and Example [Example 111] Synthesis of (R)-(1-methylpyrrolidin yl)methyl (5-fluoro-3'-methyl-[1,1'-biphenyl] yl)carbamate -Fluoro-3'-methyl-[1,1'-biphenyl]carboxylic acid (1g, 4.34mmol)(Synthesis Example 21) and (R)-tert-butyl 2- (hydroxymethyl)pyrrolidinecarboxylate (1.05g, 5.21mmol) were used as starting materials to prepare titled compound (52mg, 4%) in the same manner as Example 78 and Example 89.
[Example 112] Synthesis of (S)-(1-isopropylpyrrolidin yl)methyl [1,1'-biphenyl]ylcarbamate [Step 1] Synthesis of (S)-pyrrolidinylmethyl [1,1'- biphenyl]ylcarbamate 1001965344 [1,1'-Biphenyl]carboxylic acid (2.5g, 12.61mmol) and (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine carboxylate (3.05g, 15.14mmol) were used as starting materials to prepare titled compound (3.06g, 82%) in the same manner as Example 78.
H NMR (CDCl ) 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), 4.78-4.76(m, 1H), 3.23-3.21(m, 1H), 2.87-2.73(m, 4H), 2.06-2.05(m, 3H), 2.04-1.67(m, 1H), 1.66-1.54(m, 1H), 1.53-1.35(m, 1H) [Step 2] Synthesis of (S)-(1-isopropylpyrrolidin yl)methyl [1,1'-biphenyl]ylcarbamate (S)-pyrrolidinylmethyl [1,1'-biphenyl] ylcarbamate (1g, 3.37mmol) and 2-iodopropyl (404uL, 4.04mmol) were used as starting materials to prepare titled compound (78mg, 7%) in the same manner as Example 102.
[Example 113] Synthesis of (R)-(1-methylpyrrolidin yl)methyl (3'-fluoro-[1,1'-biphenyl]yl)carbamate (R)-(1-methylpyrrolidinyl)methyl (2- bromophenyl)carbamate (230mg, 0.73mmol)(Synthesis Example F) was dissolved in a mixed solution of ethanol (5mL) and 1001965344 water (5mL). 3-Fluorophenylboronic acid (123mg, 0.88mmol), potassium carbonate (203mg, 1.47mmol), di(acetato)dicyclohexylphenylphosphine palladium(II) and Polymer-bound FibreCat (30mg) were added thereto. The reactant was stirred at 110 ℃ for 12 hours and then cooled to room temperature. The same was filtered through celite and the solvent was removed by concentrating under reduced pressure. The same 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 titled compound (60mg, 25%).
[Examples 114-115] Reacting materials in Table 19 was used instead of 3-fluorophenylboronic acid to prepare compounds of Examples 114-115.
[Table 19] Example 114-115 Starting Material Example Chemical Name Reacting Material (Synthesis Example F) (R)-(1- methylpyrrolidin- 3-yl)methyl (4'- 4-Fluorophenylboronic 230mg, 114 fluoro-[1,1'- acid (123mg, 0.73mmol biphenyl] 0.88mmol) yl)carbamate (58mg, 24%) 1001965344 (R)-(1- methylpyrrolidin- 3,4- 3-yl)methyl 220mg, Difluorophenylboronic 115 (3',4'-difluoro- 0.70mmol acid (222mg, [1,1'-biphenyl]- 1.40mmol) 2-yl)carbamate (132mg, 55%) [Examples 116] Synthesis of (S)-(1-methylpyrrolidin yl)methyl (3'-fluoro-[1,1'-biphenyl]yl)carbamate (S)-(1-methylpyrrolidinyl)methyl (2- bromophenyl)carbamate (200mg, 0.64mmol)(Synthesis Example G) was dissolved in toluene (10mL). 3-Fluorophenylboronic acid (179mg, 1.28mmol), potassium carbonate (177mg, 1.28mmol) and tetrakis triphenylphosphine palladium (74mg, 0.064mmol) were added thereto. The reactant was stirred at 110 ℃ for 12 hours and cooled to room temperature. The same was filtered through celite and the solvent was removed by concentrating under reduced pressure. The same was extracted with water and dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered 1001965344 and concentrated. The resulting residue was purified with column chromatography to prepare the titled compound (102mg, 49%).
[Examples 117-129] Starting materials and reacting materials in Table were used to prepare compounds of Examples 117-129 in the same manner as Example 116.
[Table 20] Examples 117-129 Reacting Example Chemical Name Starting Material Material (R)-(1- (R)-(1- methylpyrrolidin- methylpyrrolidin 3-yl)methyl (2- 3- yl)methyl bromophenyl)carbam Chlorophenylboro 117 (3'-chloro- ate (230mg, nic acid (138mg, [1,1'-biphenyl]- 0.73mmol) 0.88mmol) 2-yl)carbamate (Synthesis Example (160mg, 63%) (S)-(1- (S)-(1- methylpyrrolidin- methylpyrrolidin 3-yl)methyl (2- 3- yl)methyl bromophenyl)carbam Chlorophenylboro 118 (3'-chloro- ate (305mg, nic acid (305mg, [1,1'-biphenyl]- 0.97mmol) 1.95mmol) 2-yl)carbamate (Synthesis Example (130mg, 39%) 1001965344 (S)-(1- (S)-(1- methylpyrrolidin- methylpyrrolidin 3,5- 3-yl)methyl (2- yl)methyl Dichlorophenylbo bromophenyl)carbam 119 (3',5'-dichloro- ronic acid ate (274mg, [1,1'-biphenyl]- (334mg, 0.88mmol) 2-yl)carbamate 1.75mmol) (Synthesis Example (170mg, 51%) (S)-(1- (S)-(1- methylpyrrolidin methylpyrrolidin- yl)methyl 3-yl)methyl (2- 3-Chloro (3'-chloro-5'- bromophenyl)carbam fluorophenylboro fluoro-[1,1'- ate (312mg, nic acid (348mg, biphenyl] 1.00mmol) 1.99mmol) yl)carbamate (Synthesis Example (66mg, 18%) G) (S)-(1- (S)-(1- methylpyrrolidin methylpyrrolidin- (3-Chloro yl)methyl 3-yl)methyl (2- fluoro)phenylbor (3'-chloro-4'- bromophenyl)carbam 121 onic acid fluoro-[1,1'- ate (200mg, (223mg, biphenyl] 0.63mmol) 1.28mmol) yl)carbamate (Synthesis Example (107mg, 47%) G) 1001965344 (S)-(1- (S)-(1- methylpyrrolidin- methylpyrrolidin 3-yl)methyl (2- 3,5- yl)methyl (5- bromo Dimethylphenylbo fluoro-3',5'- 122 fluorophenyl)carbaronic acid dimethyl-[1,1'- mate (190mg, (172mg, biphenyl] 0.57mmol) 1.15mmol) yl)carbamate (Synthesis Example (160mg, 73%) (S)-(1- (S)-(1- methylpyrrolidin methylpyrrolidin- yl)methyl 3-yl)methyl (2- (3-Chloro (3'-chloro bromo hydroxyphenyl)bo 123 fluoro-5'- fluorophenyl)carbaronic acid hydroxy-[1,1'- mate (205mg, (213mg, biphenyl] 0.62mmol) 1.24mmol) yl)carbamate (Synthesis Example (150mg, 64%) I) (S)-(1- (S)-(1- methylpyrrolidin- methylpyrrolidin 3-yl)methyl (2- yl)methyl bromo Fluorophenylboro 124 (4',5-difluoro- fluorophenyl)carba nic acid (114mg, [1,1'-biphenyl]- mate (225mg, 0.82mmol) 2-yl)carbamate 0.68mmol) (78mg, 33%) (Synthesis Example 1001965344 (S)-(1- (S)-(1- methylpyrrolidin- methylpyrrolidin 3-yl)methyl (2- yl)methyl 3- bromo (3'-chloro Chlorophenylboro 125 fluorophenyl)carba fluoro-[1,1'- nic acid (125mg, mate (220mg, biphenyl] 0.80mmol) 0.66mmol) yl)carbamate (Synthesis Example (153mg, 64%) (S)-(1- (S)-(1- methylpyrrolidin- methylpyrrolidin 3-yl)methyl (2- 3,5- yl)methyl bromo Dichlorophenylbo (3',5'-dichloro- 126 fluorophenyl)carbaronic acid -fluoro-[1,1'- mate (280mg, (460mg, biphenyl] 0.85mmol) 1.69mmol) yl)carbamate (Synthesis Example (74mg, 22%) (S)-(1- (S)-(1- methylpyrrolidin- methylpyrrolidin 3-yl)methyl (2- yl)methyl 4- bromo (4'-chloro Chlorophenylboro 127 fluorophenyl)carba fluoro-[1,1'- nic acid (111mg, mate (195mg, biphenyl] 0.71mmol) 0.59mmol) yl)carbamate (Synthesis Example (37mg, 17%) 1001965344 (S)-(1- (S)-(1- methylpyrrolidin- methylpyrrolidin 3-yl)methyl (2- 3,4- yl)methyl bromo Dichlorophenylbo (3',4'-dichloro- 128 fluorophenyl)carbaronic acid -fluoro-[1,1'- mate (220mg, (152mg, biphenyl] 0.66mmol) 0.80mmol) yl)carbamate (Synthesis Example (50mg, 19%) (S)-(1- (S)-(1- methylpyrrolidin- methylpyrrolidin 3-yl)methyl (2- (3-Chloro yl)methyl bromo fluorophenyl)bor (3'-chloro-5,5'- 129 fluorophenyl)carbaonic acid difluoro-[1,1'- mate (210mg, (221mg, biphenyl] 0.63mmol) 1.27mmol) yl)carbamate (Synthesis Example (130mg, 54%) [Example 130] Synthesis of (R)-(1-methylpyrrolidin yl)methyl (3',4'-dichloro-[1,1'-biphenyl]yl)carbamate (R)-(1-methylpyrrolidinyl)methyl (2- bromophenyl)carbamate (225mg, 0.72mmol)(Synthesis Example F) was dissolved in a mixed solution of ethanol (5mL) and 1001965344 water (5mL). 3,4-Dichlorophenylboronic acid (274mg, 1.44mmol), potassium carbonate (199mg, 1.44mmol) and tetrakis triphenylphosphine palladium (83mg, 0.072mmol) were added thereto. The reactant was stirred at 110 ℃ for 6 hours and cooled to room temperature. The same was filtered through celite and the solvent was removed by concentrating under reduced pressure. The same 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 titled compound (151mg, 56%).
[Examples 131-135] Starting materials and reacting materials in Table 21 were used to prepare compounds of Examples 131-135 in the same manner as Example 130.
[Table 21] Examples 131-135 Example Chemical Name Starting Material Reacting Material 1001965344 (R)-(1- (R)-(1- methylpyrrolidin- methylpyrrolidin- 3-yl)methyl (2- 3,5- 3-yl)methyl bromophenyl)carbam Dichlorophenylbor 131 (3',5'-dichloro- ate (206mg, onic acid (251mg, [1,1'-biphenyl]- 0.66mmol) 1.32mmol) 2-yl)carbamate (Synthesis Example (101mg, 40%) (R)-(1- (R)-(1- methylpyrrolidin- methylpyrrolidin- 3-yl)methyl (2- 3-Chloro 3-yl)methyl (3'- bromophenyl)carbam fluorophenylboron chloro-5'-fluoro- ate (206mg, ic acid (251mg, [1,1'-biphenyl]- 0.66mmol) 1.32mmol) 2-yl)carbamate (Synthesis Example (R)-(1- (R)-(1- methylpyrrolidin- methylpyrrolidin- 3-yl)methyl (2- 3-yl)methyl (5- bromo Aminophenylboroni 133 fluoro-3'-amino- fluorophenyl)carba c acid (178mg, [1,1'-biphenyl]- mate (215mg, 1.30mmol) 2-yl)carbamate 0.65mmol) (63mg, 28%) (Synthesis Example 1001965344 (R)-(1- (R)-(1- methylpyrrolidin- methylpyrrolidin- 3-yl)methyl (2- 3-yl)methyl (3'- (3-Chloro bromo chlorofluoro- hydroxyphenyl)bor 134 fluorophenyl)carba '-hydroxy-[1,1'- onic acid (246mg, mate (236mg, biphenyl] 1.43mmol) 0.71mmol) yl)carbamate (Synthesis Example (143mg, 53%) (R)-(1- (R)-(1- methylpyrrolidin- methylpyrrolidin- 3-yl)methyl (2- 3-yl)methyl 3,5- bromo (3',5'-dichloro- Dichlorophenylbor 135 fluorophenyl)carba -fluoro-[1,1'- onic acid (254mg, mate (220mg, biphenyl] 1.33mmol) 0.66mmol) yl)carbamate (Synthesis Example (65mg, 25%) [Example 136] Synthesis of (R)-(1-methylpyrrolidin yl)methyl (3'-chloro-4'-fluoro-[1,1'-biphenyl] yl)carbamate (R)-(1-methylpyrrolidinyl)methyl (2- bromophenyl)carbamate (250mg, 0.80mmol)(Synthesis Example 1001965344 F) was dissolved in a mixed solution of acetonitrile (6mL) and water (6mL). (3-Chlorofluorophenyl)boronic acid (279mg, 1.60mmol), sodium carbonate (170mg, 1.60mmol) and dichlorobistriphenylphosphine palladium (28mg, 0.04mmol) were added thereto. The reactant was stirred in a microwave oven at 110 ℃ for 30 minutes and cooled to room temperature. The same was filtered through celite and the solvent was removed by concentrating under reduced pressure. The same 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 titled compound (23mg, 70%).
[Examples 137-149] Starting materials and reacting materials in Table 22 were used to prepare compounds of Examples 137-149 in the same manner as Example 136.
[Table 22] Examples 137-149 Example Chemical Name Starting Material Reacting Material 1001965344 (R)-(1- (R)-(1- methylpyrrolidi methylpyrrolidin- nyl)methyl 3-yl)methyl (2- 3- (3'-hydroxy- bromophenyl)carba Hydroxyphenylboro [1,1'- mate (230mg, nic acid (111mg, biphenyl] 0.73mmol) 0.81mmol) yl)carbamate (Synthesis (156mg, 65%) Example F) (R)-(1- (R)-(1- methylpyrrolidi methylpyrrolidin- nyl)methyl (3-Chloro 3-yl)methyl (2- (3'-chloro-5'- (trifluoromethyl) bromophenyl)carba 138 (trifluoromethy phenyl)boronic mate (365mg, l)-[1,1'- acid (523mg, 0.17mmol) biphenyl] 2.33mmol) (Synthesis yl)carbamate Example F) (208mg, 43%) (R)-(1- (R)-(1- methylpyrrolidi methylpyrrolidin- nyl)methyl 3-yl)methyl (2- (3-Chloro (3'-chloro bromo methoxyphenyl)bor 139 fluoro-5'- fluorophenyl)carb onic acid (240mg, methoxy-[1,1'- amate (213mg, 1.29mmol) biphenyl] 0.64mmol) yl)carbamate (Synthesis (184mg, 73%) Example H) 1001965344 (R)-(1- (R)-(1- methylpyrrolidi methylpyrrolidin- nyl)methyl 3-yl)methyl (2- (3-Chloro (3'-chloro bromo (trifluoromethyl) fluoro-5'- 140 fluorophenyl)carb phenyl)boronic (trifluoromethy amate (227mg, acid (307mg, l)-[1,1'- 0.69mmol) 1.37mmol) biphenyl] (Synthesis yl)carbamate Example H) (135mg, 47%) (R)-(1- (R)-(1- methylpyrrolidin- methylpyrrolidi 3-yl)methyl (2- nyl)methyl 4- bromo (4',5-difluoro- Fluorophenylboron 141 fluorophenyl)carb [1,1'- ic acid (270mg, amate (320mg, biphenyl] 1.93mmol) 0.97mmol) yl)carbamate (Synthesis (208mg, 62%) Example H) (R)-(1- (R)-(1- methylpyrrolidi methylpyrrolidin- nyl)methyl 3-yl)methyl (2- (3-Chloro (3'-chloro- bromo fluorophenyl)boro 142 5,5'-difluoro- fluorophenyl)carb nic acid (238mg, [1,1'- amate (226mg, 1.37mmol) biphenyl] 0.68mmol) yl)carbamate (Synthesis (108mg, 42%) Example H) 1001965344 (R)-(1- (R)-(1- methylpyrrolidi methylpyrrolidin- nyl)methyl 3-yl)methyl (2- (3-Chloro (3'-chloro-4', bromo fluorophenyl)boro 143 5-difluoro- fluorophenyl)carb nic acid (253mg, [1,1'- amate (240mg, 1.45mmol) biphenyl] 0.73mmol) yl)carbamate (Synthesis (150mg, 54%) Example H) (R)-(1- (R)-(1- methylpyrrolidin- methylpyrrolidi 3-yl)methyl (2- nyl)methyl 2-Fluorophenyl bromo (2',5-difluoro- boronic acid 144 fluorophenyl)carb [1,1'- (254mg, amate (300mg, biphenyl] 1.812mmol) 0.91mmol) yl)carbamate (Synthesis (134mg, 43%) Example H) (R)-(1- (R)-(1- methylpyrrolidin- methylpyrrolidi 3-yl)methyl (2- nyl)methyl 3- bromo (3',5-dichloro- Chlorophenylboron 145 chlorophenyl)carb [1,1'- ic acid (197mg, amate (290mg, biphenyl] 1.26mmol) 0.84mmol) yl)carbamate (Synthesis (69mg, 22%) Example J) 1001965344 (R)-(1- (R)-(1- methylpyrrolidin- methylpyrrolidi 3-yl)methyl (2- nyl)methyl (3-Chloro bromo (3',5-dichloro- fluorophenyl)boro 146 chlorophenyl)carb 4'-fluoro- nic acid (300mg, amate (300mg, [1,1'- 1.72mmol) 0.84mmol) biphenyl] (Synthesis yl)carbamate Example J) (R)-(1- (R)-(1- methylpyrrolidin- methylpyrrolidi 3-yl)methyl (2- nyl)methyl (3-Chloro bromo (3'-chloro-4'- fluorophenyl)boro 147 methoxyphenyl)car fluoro nic acid (274mg, bamate (270mg, methoxy-[1,1'- 1.57mmol) 0.78mmol) biphenyl] (Synthesis yl)carbamate Example K) (S)-(1- (S)-(1- methylpyrrolidi methylpyrrolidin- nyl)methyl 2-yl)methyl (2- (3-Chloro (3'-chloro-5'- bromophenyl)carba fluorophenyl)boro fluoro-[1,1'- mate (200mg, nic acid (223mg, biphenyl] 0.64mmol) 1.28) yl)carbamate (Synthesis (150mg, 65%) Example M) 1001965344 (S)-(1- (S)-(1- methylpyrrolidi methylpyrrolidin- nyl)methyl 2-yl)methyl (2- (3-Chloro (3'-chloro-4'- bromophenyl)carba fluorophenyl)boro fluoro-[1,1'- mate (500mg, nic acid (555mg, biphenyl] 1.59mmol) 3.18mmol) yl)carbamate (Synthesis (151mg, 26%) Example M) [Example 150] Synthesis of (R)-(1-ethylpyrrolidin yl)methyl (3'-chloro-4'-fluoro-[1,1'-biphenyl] yl)carbamate [Step 1] Synthesis of (R)-tert-butyl 3-((((3'-chloro-4'- fluoro-[1,1'-biphenyl] yl)carbamoyl)oxy)methyl)pyrrolidinecarboxylate Cl O (R)-tert-butyl 3-((((2- bromophenyl)carbamoyl)oxy)methyl)pyrrolidinecarboxylate (4g, 10.02mmol)(Synthesis Example F, Step 1) and (3-chloro- 4-fluoro)phenylboronic acid (3.5g, 20.04mmol) were used as 1001965344 starting materials to prepare titled compound (3.4g, 76%) in the same manner as Example 42.
H NMR (CDCl ): 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)-pyrrolidinylmethyl (3'-chloro- 4'-fluoro-[1,1'-biphenyl]yl)carbamate (R)-tert-butyl 3-((((3'-chloro-4'-fluoro-[1,1'- biphenyl]yl)carbamoyl)oxy)methyl)pyrrolidine carboxylate (3.4g, 7.57mmol) prepared in Step 1 was used as a starting material to prepare titled compound (2.3g, 87%) in the same manner as Example 78.
H NMR (CDCl ): 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)-pyrrolidinylmethyl (3'-chloro- 4'-fluoro-[1,1'-biphenyl]yl)carbamate (R)-pyrrolidinylmethyl (3'-chloro-4'-fluoro-[1,1'- biphenyl]yl)carbamate (345mg, 0.99mmol) prepared in Step 2 was dissolved in tetrahydrofuran (20mL). Triethylamine (150uL, 1.09mmol) and bromoethane (118uL, 1.58mmol) were sequentially added thereto and stirred at room temperature for 3 days. The reactant was concentrated under reduced 1001965344 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 titled compound (74mg, 20%).
[Example 151] Synthesis of (R)-(1-isopropyl pyrrolidin yl)methyl (3'-chloro-4'-fluoro-[1,1'-biphenyl] yl)carbamate (R)-pyrrolidinylmethyl (3'-chloro-4'-fluoro-[1,1'- biphenyl]yl)carbamate (347mg, 1.00mmol)(Example 150, Step 2) was dissolved in tetrahydrofuran (20mL).
Triethylamine (150uL, 1.10mmol) and 2-bromopropane (100uL, 1.10mmol) were sequentially added thereto and stirred at room temperature for 3 days. The reactant 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 titled compound (17mg, 4%).
[Example 152] Synthesis of (R)-(1-methylpyrrolidin yl)methyl (3'-(hydroxymethyl)-[1,1'-biphenyl] yl)carbamate 1001965344 (R)-(1-methylpyrrolidinyl)methyl (2- bromophenyl)carbamate (395mg, 1.26mmol)(Synthesis Example F) was dissolved in a mixed solution of toluene (15mL) and ethanol (2mL). 3-(Hydroxymethyl)phenylboronic acid (211mg, 1.39mmol), potassium carbonate (348mg, 2.52mmol) and tetrakis triphenylphosphine palladium (146mg, 0.13mmol) were added thereto. The reactant was stirred at 110 ℃ for 12 hours and cooled to room temperature. The same was filtered through celite and the solvent was removed by concentrating under reduced pressure. The same 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 titled compound (126mg, 29%).
[Examples 153-190] Starting materials and reacting materials in Table 23 were used to prepare compounds of Examples 153-190 in the same manner as Example 152.
[Table 23] Examples 153-190 Example Chemical Name Starting Material Reacting Material 1001965344 (R)-(1- (R)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2- (3- (3'-carbamoyl- bromophenyl)carbama Carbamoylphenyl)b [1,1'- te (395mg, oronic acid biphenyl] 1.26mmol) (229mg, 1.39mmol) yl)carbamate (Synthesis Example (125mg, 28%) F) (R)-(1- (R)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2- 3- (3'-amino- bromophenyl)carbama Aminophenylboroni [1,1'- te (220mg, c acid (115mg, biphenyl] 0.70mmol) 0.84mmol) yl)carbamate (Synthesis Example (102mg, 45%) F) (R)-(1- (R)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2- 3- (3'-cyano- bromophenyl)carbama Cyanophenylboroni [1,1'- te (210mg, c acid (118mg, biphenyl] 0.67mmol) 0.80mmol) yl)carbamate (Synthesis Example (77mg, 34%) F) 1001965344 (R)-(1- (R)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2- 2-Fluorophenyl (2'-fluoro- bromophenyl)carbama boronic acid [1,1'- te (300mg, (201mg, biphenyl] 0.958mmol) 1.437mmol) yl)carbamate (Synthesis Example (210mg, 67%) F) (R)-(1- (R)-(1- methylpyrrolid methylpyrrolidin inyl)methyl 2,4- yl)methyl (2- (2',4'- Difluorophenyl bromophenyl)carbama 157 difluoro- boronic acid te (200mg, [1,1'- (202mg, 0.639mmol) biphenyl] 1.277mmol) (Synthesis Example yl)carbamate (115mg, 52%) (R)-(1- (R)-(1- methylpyrrolid methylpyrrolidin inyl)methyl 2,3- yl)methyl (2- (2',3'- Difluorophenyl bromophenyl)carbama 158 difluoro- boronic acid te (200mg, [1,1'- (202mg, 0.639mmol) biphenyl] 1.277mmol) (Synthesis Example yl)carbamate (145mg, 66%) 1001965344 (R)-(1- (R)-(1- methylpyrrolid methylpyrrolidin 3-Chloro inyl)methyl yl)methyl (2- fluorophenyl (3'-chloro-6'- bromophenyl)carbama 159 boronic acid fluoro-[1,1'- te (200mg, (223mg, biphenyl] 0.639mmol) 1.277mmol) yl)carbamate (Synthesis Example (130mg, 56%) F) (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2- 3- (3'-fluoro- bromophenyl)carbama Fluorophenylboron [1,1'- te (200mg, ic acid (107mg, biphenyl] 0.64mmol) 0.77mmol) yl)carbamate (Synthesis Example (183mg, 87%) M) (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2- 3,5- (3',5'- bromophenyl)carbama Difluorophenylbor 161 difluoro- te (200mg, onic acid (121mg, [1,1'- 0.64mmol) 0.77mmol) biphenyl] (Synthesis Example yl)carbamate (163mg, 74%) 1001965344 (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2- 3,4- (3',4'- bromophenyl)carbama Difluorophenylbor 162 difluoro- te (100mg, onic acid (101mg, [1,1'- 0.32mmol) 0.64mmol) biphenyl] (Synthesis Example yl)carbamate (105mg, 95%) (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2- 2,4,5- (2',4',5'- bromophenyl)carbama Trifluorophenylbo 163 trifluoro- te (100mg, ronic acid [1,1'- 0.32mmol) (113mg, 0.64mmol) biphenyl] (Synthesis Example yl)carbamate (79mg, 68%) (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2- 4- (4'-chloro- bromophenyl)carbama Chlorophenylboron [1,1'- te (100mg, ic acid (100mg, biphenyl] 0.32mmol) 0.64mmol) yl)carbamate (Synthesis Example (103mg, 94%) M) 1001965344 (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2- 3- (3'-chloro- bromophenyl)carbama Chlorophenylboron [1,1'- te (100mg, ic acid (100mg, biphenyl] 0.32mmol) 0.64mmol) yl)carbamate (Synthesis Example (70mg, 64%) M) (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2- 3,4- (3',4'- bromophenyl)carbama Dichlorophenylbor 166 dichloro- te (100mg, onic acid (122mg, [1,1'- 0.32mmol) 0.64mmol) biphenyl] (Synthesis Example yl)carbamate (96mg, 79%) (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2- 2,4- (2',4'- bromophenyl)carbama Dichlorophenylbor 167 dichloro- te (100mg, onic acid (122mg, [1,1'- 0.32mmol) 0.64mmol) biphenyl] (Synthesis Example yl)carbamate (83mg, 69%) 1001965344 (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2- 3- (3'-hydroxy- bromophenyl)carbama Hydroxyphenylboro [1,1'- te (200mg, nic acid (106mg, biphenyl] 0.64mmol) 0.77mmol) yl)carbamate (Synthesis Example (160mg, 77%) M) (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2- 3- (3'-cyano- bromophenyl)carbama Cyanophenylboroni [1,1'- te (200mg, c acid (113mg, biphenyl] 0.64mmol) 0.77mmol) yl)carbamate (Synthesis Example (17mg, 13%) M) (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2- 3- (3'-amino- bromophenyl)carbama Aminophenylboroni [1,1'- te (200mg, c acid (105mg, biphenyl] 0.64mmol) 0.77mmol) yl)carbamate (Synthesis Example (78mg, 38%) M) 1001965344 (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2-bromo- 3,4- (3',4',5- 4- Difluorophenylbor 171 trifluoro- fluorophenyl)carbam onic acid (95mg, [1,1'- ate (100mg, 0.60mmol) biphenyl] 0.30mmol) yl)carbamate (Synthesis Example (88mg, 81%) N) (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2-bromo- 3,5- (3',5,5'- 4- Difluorophenylbor 172 trifluoro- fluorophenyl)carbam onic acid (190mg, [1,1'- ate (200mg, 1.20mmol) biphenyl] 0.60mmol) yl)carbamate (Synthesis Example (180mg, 83%) N) (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2-bromo- 2,4,5- (2',4',5,5'- 4- Trifluorophenylbo 173 tetrafluoro- fluorophenyl)carbam ronic acid [1,1'- ate (200mg, (211mg, 1.20mmol) biphenyl] 0.60mmol) yl)carbamate (Synthesis Example (188mg, 82%) N) 1001965344 (S)-(1- (S)-(1- methylpyrrolidin methylpyrrolid yl)methyl (2-bromo- inyl)methyl 3- (3'-chloro Chlorophenylboron 174 fluorophenyl)carbam fluoro-[1,1'- ic acid (188mg, ate (200mg, biphenyl] 1.20mmol) 0.60mmol) yl)carbamate (Synthesis Example (171mg, 79%) (S)-(1- (S)-(1- methylpyrrolidin methylpyrrolid yl)methyl (2-bromo- inyl)methyl 4- (4'-chloro Chlorophenylboron 175 fluorophenyl)carbam fluoro-[1,1'- ic acid (188mg, ate (200mg, biphenyl] 1.20mmol) 0.60mmol) yl)carbamate (Synthesis Example (198mg, 91%) (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2-bromo- 2,4- (2',4'- 4- Dichlorophenylbor 176 dichloro fluorophenyl)carbam onic acid (230mg, fluoro-[1,1'- ate (200mg, 1.20mmol) biphenyl] 0.60mmol) yl)carbamate (Synthesis Example (146mg, 61%) N) 1001965344 (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2-bromo- 3,4- (3',4'- 4- Dichlorophenylbor 177 dichloro fluorophenyl)carbam onic acid (115mg, fluoro-[1,1'- ate (100mg, 0.60mmol) biphenyl] 0.30mmol) yl)carbamate (Synthesis Example (76mg, 64%) N) (S)-(1- (S)-(1- methylpyrrolidin methylpyrrolid yl)methyl (2-bromo- inyl)methyl 3- (3'-cyano Cyanophenylboroni 178 fluorophenyl)carbam fluoro-[1,1'- c acid (176mg, ate (200mg, biphenyl] 1.20mmol) 0.60mmol) yl)carbamate (Synthesis Example (117mg, 55%) (S)-(1- (S)-(1- methylpyrrolidin methylpyrrolid yl)methyl (2-bromo- inyl)methyl 3- (3'-hydroxy Hydroxyphenylboro 179 fluorophenyl)carbam fluoro-[1,1'- nic acid (83mg, ate(100mg, biphenyl] 0.60mmol) 0.30mmol) yl)carbamate (Synthesis Example (66mg, 64%) 1001965344 (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2-bromo- 3- (5-fluoro-3'- 4- (Trifluoromethyl) 180 (trifluorometh fluorophenyl)carbam phenylboronic yl)-[1,1'- ate (100mg, acid (115mg, biphenyl] 0.30mmol) 0.60mmol) yl)carbamate (Synthesis Example (43mg, 36%) N) (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2-bromo- (3'-chloro- 3-Chloro 4,5- 4,4',5- fluorophenyl 181 difluorophenyl)carb trifluoro- boronic acid amate (200mg, [1,1'- (200mg, 1.15mmol) 0.57mmol) biphenyl] (Synthesis Example yl)carbamate (57mg, 25%) (R)-(1- (R)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2-bromo- (3'-chloro- 4,5- 3-Chlorophenyl 182 4,5-difluoro- difluorophenyl)carb boronic acid [1,1'- amate (180mg, (161mg, 1.03mmol) biphenyl] 1.52mmol) yl)carbamate (Synthesis Example (50mg, 25%) L) 1001965344 2-(1- 2-(1- Methylpyrrolid Methylpyrrolidin inyl)ethyl 2,4- yl)ethyl (2- (2',4'- Difluorophenyl iodophenyl)carbamat 183 difluoro- boronic acid e (300mg, [1,1'- (290mg, 0.917mmol) biphenyl] 1.834mmol) (Synthesis Example yl)carbamate (50mg, 15%) 2-(1- 2-(1- Methylpyrrolid Methylpyrrolidin inyl)ethyl 2,3- yl)ethyl (2- (2',3'- Difluorophenyl iodophenyl)carbamat 184 difluoro- boronic acid e (300mg, [1,1'- (290mg, 0.917mmol) biphenyl] 1.834mmol) (Synthesis Example yl)carbamate (50mg, 15%) 2-(1- 2-(1- Methylpyrrolid Methylpyrrolidin inyl)ethyl 2,6- yl)ethyl (2- (2',6'- Difluorophenyl iodophenyl)carbamat 185 difluoro- boronic acid e (300mg, [1,1'- (290mg, 0.917mmol) biphenyl] 1.834mmol) (Synthesis Example yl)carbamate (50mg, 15%) 1001965344 2-(1- 2-(1- Methylpyrrolid Methylpyrrolidin -Chloro inyl)ethyl yl)ethyl (2- fluorophenyl (5'-chloro-2'- iodophenyl)carbamat 186 boronic acid fluoro-[1,1'- e (300mg, (320mg, biphenyl] 0.917mmol) 1.834mmol) yl)carbamate (Synthesis Example (160mg, 46%) A) (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl yl)methyl (2- 2-Fluorophenyl (2'-fluoro- bromophenyl)carbama boronic acid [1,1'- te (300mg, (268mg, biphenyl] 0.958mmol) 1.916mmol) yl)carbamate (Synthesis Example (205mg, 65%) M) (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl 2,4- yl)methyl (2- (2',4'- Difluorophenyl bromophenyl)carbama 188 difluoro- boronic acid te (300mg, [1,1'- (303mg, 0.958mmol) biphenyl] 1.916mmol) (Synthesis Example yl)carbamate (250mg, 75%) 1003490018 (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin inyl)methyl 2,3- yl)methyl (2- (2',3'- Difluorophenyl bromophenyl)carbama 189 difluoro- boronic acid te (300mg, [1,1'- (303mg, 0.958mmol) biphenyl] 1.916mmol) (Synthesis Example yl)carbamate (100mg, 30%) (S)-(1- (S)-(1- methylpyrrolid methylpyrrolidin 3-Chloro inyl)methyl yl)methyl (2- fluorophenyl (3'-chloro-6'- bromophenyl)carbama 190 boronic acid fluoro-[1,1'- te (300mg, (334mg, biphenyl] 0.958mmol) 1.916mmol) yl)carbamate (Synthesis Example (150mg, 43%) M) [Example 191] Synthesis of (R)-(1-methylpyrrolidin yl)methyl (3',5'-dimethyl-[1,1'-biphenyl]yl)carbamate (R)-(1-methylpyrrolidinyl)methyl (2- bromophenyl)carbamate (220mg, 0.70mmol)(Synthesis Example F) was dissolved in a mixed solution of ethanol (5mL) and water (5mL). 3,5-Dimethylboronic acid (211mg, 1.41mmol), potassium carbonate (194mg, 1.41mmol), di(acetato)dicyclohexylphenylphosphine palladium(II) and 1001965344 Polymer-bound FibreCat (28mg) were added thereto. The reactant was stirred in a microwave oven at 110 ℃ for 30 minutes and cooled to room temperature. The same was filtering through celite and the solvent was removed by concentrating under reduced pressure. The same 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 titled compound (134mg, 56%).
[Examples 192-195] Starting materials and reacting materials in Table 24 were used to prepare compounds of Examples 192-195 in the same manner as Example 191.
[Table 24] Examples 192-195 Example Chemical Name Starting Material Reacting Material 1001965344 (R)-(1- (R)-(1- methylpyrrolidin- methylpyrrolid 3-yl)methyl (2- inyl)methyl 3- bromo (5-fluoro-3'- Methylphenylboron 192 fluorophenyl)carb methyl-[1,1'- ic acid (172mg, amate (210mg, biphenyl] 1.27mmol) 0.63mmol) yl)carbamate (Synthesis (158mg, 73%) Example H) (R)-(1- (R)-(1- methylpyrrolid methylpyrrolidin- inyl)methyl 3-yl)methyl (2- (5-fluoro- 3,5- bromo 3',5'- Dimethylphenylbor 193 fluorophenyl)carb dimethyl- onic acid (187mg, amate (206mg, [1,1'- 1.24mmol) 0.62mmol) biphenyl] (Synthesis yl)carbamate Example H) (82mg, 39%) (R)-(1- (R)-(1- methylpyrrolid methylpyrrolidin- inyl)methyl 3-yl)methyl (2- (3',5- bromo Fluorophenylboron 194 difluoro- fluorophenyl)carb ic acid (182mg, [1,1'- amate (215mg, 1.30mmol) biphenyl] 0.65mmol) yl)carbamate (Synthesis (124mg, 55%) Example H) 1001965344 (R)-(1- (R)-(1- methylpyrrolidin- methylpyrrolid 3-yl)methyl (2- inyl)methyl 3- bromo (3'-chloro Chlorophenylboron 195 fluorophenyl)carb fluoro-[1,1'- ic acid (198mg, amate (210mg, biphenyl] 1.27mmol) 0.63mmol) yl)carbamate (Synthesis (151mg, 66%) Example H) [Example 196] Synthesis of (R)-(1-ethylpyrrolidin yl)methyl (3'-chloro-4',5-difluoro-[1,1'-biphenyl] yl)carbamate [Step 1] Synthesis of (R)-(1-ethylpyrrolidinyl)methyl (2-bromofluorophenyl)carbamate 2-Bromofluorobenzoic acid (3g, 13.70mmol) and (R)-tert-butyl 3-(hydroxymethyl)pyrrolidinecarbaxylate (3.31g, 16.44mmol) were used as starting materials to prepare titled compound (4.5g, 79%) in the same manner as Synthesis Example F. 1001965344 H NMR (CDCl ): 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=7.2Hz) [Step 2] Synthesis of (R)-(1-ethylpyrrolidinyl)methyl (3'-chloro-4',5-difluoro-[1,1'-biphenyl]yl)carbamate (R)-(1-ethylpyrrolidinyl)methyl (2-bromo fluorophenyl)carbamate (165mg, 0.48mmol) and (3-chloro fluorophenyl)boronic acid (167mg, 0.96mmol) were used as starting materials to prepare titled compound (143mg, 76%) in the same manner as Example 136.
[Example 197] Synthesis of (S)-(1-methylpyrrolidin yl)methyl [1,1'-biphenyl]ylcarbamate [1,1'-Biphenyl]carboxylic acid (1g, 5.05mmol) was dissolved in toluene (20mL). Biphenylphosphoryl azide (1.4mL, 6.05mmol) and triethylamine (0.71mL, 5.05mmol) were added thereto. The same was stirred at room temperature 1001965344 for 30 minutes, and then stirred again under reflux at room temperature for 1 hour. The reactant was cooled to room temperature and (S)-(1-methylpyrrolidinyl)methanol (0.72mL, 6.05mmol) was added thereto, and then stirred under reflux for 12 hours. The reactant was cooled to room temperature. The solvent was removed by concentrating under reduced pressure. The same 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 titled compound (458mg, 29%).
[Examples 198-207] Starting materials and reacting materials in Table 25 were used to prepare compounds of Examples 198-207 in the same manner as Example 197.
[Table 25] Examples 198-207 Example Chemical Name Starting Material Reacting Material 1001965344 (S)-(1- methylpyrrolid 4'-Fluoro-[1,1'- inyl)methyl biphenyl] (S)-(1- (4'-fluoro- carboxylic acid methylpyrrolidin- [1,1'- (482mg, 2.23mmol) 2-yl)methanol biphenyl] (Synthesis (318uL, 2.68mmol) yl)carbamate Example 1) (97mg, 13%) (S)-(1- methylpyrrolid 3'-Methyl-[1,1'- inyl)methyl biphenyl] (S)-(1- (3'-methyl- carboxylic acid methylpyrrolidin- [1,1'- (488mg, 2.3mmol) 2-yl)methanol biphenyl] (Synthesis (328uL, 2.76mmol) yl)carbamate Example 14) (379mg, 51%) (S)-(1- methylpyrrolid 5-Fluoro-[1,1'- (S)-(1- inyl)methyl biphenyl] methylpyrrolidin- (5-fluoro- carboxylic acid 200 2-yl)methanol [1,1'- (400mg, 1.85mmol) (0.26mL, biphenyl] (Synthesis 2.22mmol) yl)carbamate Example 20) (42mg, 7%) 1001965344 (S)-(1- -Fluoro-3'- methylpyrrolid methyl-[1,1'- inyl)methyl (S)-(1- biphenyl] (5-fluoro-3'- methylpyrrolidin- 201 carboxylic acid methyl-[1,1'- 2-yl)methanol (460mg, 2.0mmol) biphenyl] (0.29mL, 2.4mmol) (Synthesis yl)carbamate Example 21) (98mg, 14%) (S)-(1- methylpyrrolid 3',5-Difluoro- inyl)methyl (S)-(1- [1,1'-biphenyl]- (3',5- methylpyrrolidin- 2-carboxylic acid 202 difluoro- 2-yl)methanol (400mg, 1.71mmol) [1,1'- (0.24mL, (Synthesis biphenyl] 2.05mmol) Example 17) yl)carbamate (280mg, 47%) (S)-(1- methylpyrrolid 4',5-Difluoro- inyl)methyl (S)-(1- [1,1'-biphenyl]- (4',5- methylpyrrolidin- 2-carboxylic acid 203 difluoro- 2-yl)methanol (400mg, 1.71mmol) [1,1'- (0.24mL, (Synthesis biphenyl] 2.05mmol) Example 18) yl)carbamate (312mg, 53%) 1001965344 (S)-(1- methylpyrrolid 4-Fluoro-[1,1'- inyl)methyl biphenyl] (S)-(1- (4-fluoro- carboxylic acid methylpyrrolidin- [1,1'- (180mg, 0.83mmol) 2-yl)methanol biphenyl] (Synthesis (0.12mL, 1.0mmol) yl)carbamate Example 22) (140mg, 51%) (S)-(1- methylpyrrolid 3',4-Difluoro- inyl)methyl (S)-(1- [1,1'-biphenyl]- (3',4- methylpyrrolidin- 2-carboxylic acid 205 difluoro- 2-yl)methanol (400mg, 1.71mmol) [1,1'- (0.24mL, (Synthesis biphenyl] 2.05mmol) Example 23) yl)carbamate (200mg, 34%) (S)-(1- methylpyrrolid 5-Methyl-[1,1'- inyl)methyl biphenyl] (S)-(1- (5-methyl- carboxylic acid methylpyrrolidin- [1,1'- (300mg, 1.41mmol) 2-yl)methanol biphenyl] (Synthesis (201uL, 1.7mmol) yl)carbamate Example 25) (189mg, 41%) 1001965344 (S)-(1- 3'-Fluoro methylpyrrolid methyl-[1,1'- inyl)methyl (S)-(1- biphenyl] (3'-fluoro methylpyrrolidin- 207 carboxylic acid methyl-[1,1'- 2-yl)methanol (200mg, 0.87mmol) biphenyl] (124uL, 1.04mmol) (Synthesis yl)carbamate Example 26) (265mg, 89%) [Example 208] Synthesis of (S)-(1-methylpyrrolidin yl)methyl (5-fluoro-3',5'-dimethyl-[1,1'-biphenyl] yl)carbamate (S)-(1-methylpyrrolidinyl)methyl (2-bromo fluorophenyl)carbamate (200mg, 0.60mmol)(Synthesis Example N) was dissolved in a mixed solution of acetonitrile (3mL) and water (3mL). 3,5-Dimethylphenylboronic acid (181mg, 1.20mmol), sodium carbonate (95mg, 0.90mmol) and dichlorobistriphenylphosphine palladium (2mg, 0.003mmol) were added thereto. The reactant was stirred in a microwave oven at 150 ℃ for 10 minutes and cooled to room temperature. The same was filtered through celite and the solvent was removed by concentrating under reduced 1001965344 pressure. The same 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 titled compound (98mg, 46%).
[Examples 209-226] Starting materials and reacting materials in Table 26 were used to prepare compounds of Examples 209-226 in the same manner as Example 208.
[Table 26] Examples 209-226 Example Chemical Name Starting Material Reacting Material (S)-(1- (S)-(1- methylpyrroli methylpyrrolidin- din 2-yl)methyl (2- yl)methyl 4-tert- bromo (4'-(tert- Butylphenylboroni 209 fluorophenyl)carb butyl) c acid (213mg, amate (200mg, fluoro-[1,1'- 1.20mmol) 0.60mmol) biphenyl] (Synthesis yl)carbamate Example N) (68mg, 30%) 1001965344 (S)-(1- methylpyrroli (S)-(1- din methylpyrrolidin- yl)methyl 2-yl)methyl (2- (3-Chloro (3'-chloro- bromo fluoro)phenylboro 210 5,5'- fluorophenyl)carb nic acid (158mg, difluoro- amate (150mg, 0.90mmol) [1,1'- 0.45mmol) biphenyl] (Synthesis yl)carbamate Example N) (55mg, 32%) (S)-(1- methylpyrroli (S)-(1- din methylpyrrolidin- yl)methyl 2-yl)methyl (2- (3-Chloro (3'-chloro- bromo fluoro)phenylboro 211 4',5- fluorophenyl)carb nic acid (316mg, difluoro- amate (300mg, 1.81mmol) [1,1'- 0.91mmol) biphenyl] (Synthesis yl)carbamate Example N) (56mg, 16%) 1001965344 (S)-(1- methylpyrroli (S)-(1- din methylpyrrolidin- yl)methyl 2-yl)methyl (2- (3-Fluoro (4'-chloro- bromo chloro)phenylboro 212 3',5- fluorophenyl)carb nic acid (316mg, difluoro- amate (300mg, 1.81mmol) [1,1'- 0.91mmol) biphenyl] (Synthesis yl)carbamate Example N) (140mg, 40%) (S)-(1- (S)-(1- methylpyrroli methylpyrrolidin- din 2-yl)methyl (2- yl)methyl bromo Aminophenylboroni 213 (3'-amino fluorophenyl)carb c acid (68mg, fluoro-[1,1'- amate (150mg, 0.50mmol) biphenyl] 0.45mmol) yl)carbamate (Synthesis (46mg, 45%) Example N) 1001965344 (S)-(1- methylpyrroli (S)-(1- din methylpyrrolidin- yl)methyl 2-yl)methyl (2- (2-Fluoro (2',5- bromo (trifluoromethyl) 214 difluoro-3'- fluorophenyl)carb phenyl)boronic (trifluoromet amate (150mg, acid (187mg, hyl)-[1,1'- 0.45mmol) 0.90mmol) biphenyl] (Synthesis yl)carbamate Example N) (17mg, 10%) (S)-(1- methylpyrroli (S)-(1- din methylpyrrolidin- yl)methyl 2-yl)methyl (2- (3-Chloro (3'-chloro bromo (trifluoromethyl) 215 fluoro-5'- fluorophenyl)carb phenyl)boronic (trifluoromet amate (150mg, acid (202mg, hyl)-[1,1'- 0.45mmol) 0.90mmol) biphenyl] (Synthesis yl)carbamate Example N) (80mg, 41%) 1001965344 (S)-(1- methylpyrroli (S)-(1- din methylpyrrolidin- yl)methyl 2-yl)methyl (2- (3-Chloro (3'-chloro bromo hydroxyphenyl)bor 216 fluoro-5'- fluorophenyl)carb onic acid (135mg, hydroxy- amate (130mg, 0.79mmol) [1,1'- 0.39mmol) biphenyl] (Synthesis yl)carbamate Example N) (35mg, 24%) (S)-(1- methylpyrroli (S)-(1- din methylpyrrolidin- yl)methyl 2-yl)methyl (2- (3-Chloro (3'-chloro bromo methoxyphenyl)bor 217 fluoro-5'- fluorophenyl)carb onic acid (168mg, methoxy- amate (150mg, 0.90mmol) [1,1'- 0.45mmol) biphenyl] (Synthesis yl)carbamate Example N) (55mg, 31%) 1001965344 (S)-(1- methylpyrroli (S)-(1- din methylpyrrolidin- yl)methyl (5- 2-yl)methyl (2- (2,4- fluoro-2',4'- bromo Bis(trifluorometh 218 bis(trifluoro fluorophenyl)carb yl)phenyl)boronic methyl)- amate (150mg, acid (230mg, [1,1'- 0.45mmol) 0.90mmol) biphenyl] (Synthesis yl)carbamate Example N) (85mg, 41%) (S)-(1- (S)-(1- methylpyrroli methylpyrrolidin- din 2-yl)methyl (2- yl)methyl bromo Ethoxyphenylboron 219 (3'-ethoxy fluorophenyl)carb ic acid (200mg, fluoro-[1,1'- amate (200mg, 1.20mmol) biphenyl] 0.60mmol) yl)carbamate (Synthesis (94mg, 42%) Example N) (S)-(1- (S)-(1- methylpyrroli methylpyrrolidin- din 2-yl)methyl (2- yl)methyl (5- 3,4- bromo fluoro-3', Dimethoxyphenylbo 220 fluorophenyl)carb 4'-dimethoxy- ronic acid amate (200mg, [1,1'- (218mg, 1.20mmol) 0.60mmol) biphenyl] (Synthesis yl)carbamate Example N) (54mg, 23%) 1001965344 (S)-(1- (S)-(1- methylpyrroli methylpyrrolidin- din 2-yl)methyl (2- yl)methyl (5- 3,5- bromo fluoro-3',5'- Dimethoxyphenylbo 221 fluorophenyl)carb dimethoxy- ronic acid amate (200mg, [1,1'- (218mg, 1.20mmol) 0.60mmol) biphenyl] (Synthesis yl)carbamate Example N) (140mg, 60%) (S)-(1- (S)-(1- methylpyrroli methylpyrrolidin- din 2-yl)methyl (2- yl)methyl (5- bromo Phenylboronic 222 methoxy- methoxyphenyl)car acid (142mg, [1,1'- bamate (200mg, 1.16mmol) biphenyl] 0.58mmol) yl)carbamate (Synthesis (66mg, 34%) Example O) (S)-(1- (S)-(1- methylpyrroli methylpyrrolidin- din 2-yl)methyl (2- yl)methyl 3- bromo (3'-fluoro Fluorophenylboron 223 methoxyphenyl)car methoxy- ic acid (162mg, bamate (200mg, [1,1'- 1.16mmol) 0.58mmol) biphenyl] (Synthesis yl)carbamate Example O) (99mg, 55%) 1001965344 (S)-(1- (S)-(1- methylpyrroli methylpyrrolidin- din 2-yl)methyl (2- yl)methyl 3- bromo (3'-chloro Chlorophenylboron 224 methoxyphenyl)car methoxy- ic acid (181mg, bamate (200mg, [1,1'- 1.16mmol) 0.58mmol) biphenyl] (Synthesis yl)carbamate Example O) (117mg, 54%) (S)-(1- methylpyrroli (S)-(1- din methylpyrrolidin- yl)methyl 2-yl)methyl (2- 3,4- (3',4'- bromo Dichlorophenylbor 225 dichloro methoxyphenyl)car onic acid (221mg, methoxy- bamate (200mg, 1.16mmol) [1,1'- 0.58mmol) biphenyl] (Synthesis yl)carbamate Example O) (90mg, 38%) 1001965344 (S)-(1- methylpyrroli (S)-(1- din methylpyrrolidin- yl)methyl 2-yl)methyl (2- 3,5- (3',5'- bromo Dichlorophenylbor 226 dichloro methoxyphenyl)car onic acid (221mg, methoxy- bamate (200mg, 1.16mmol) [1,1'- 0.58mmol) biphenyl] (Synthesis yl)carbamate Example O) (110mg, 46%) [Experimental Example 1] Binding assay on human muscarinic M3 receptor Cell membrane proteins (Perkin Elmer) wherein human muscarinic M3 receptor was overexpressed, [ H]-methyl scopolamine and test compounds in various concentration were cultured in 0.2 ml of Tris-HCl buffer at 25 ℃ for 120 minutes. The same was filtered under suction through glass fiber filter (Whatman GF/B), and then the filter was washed 5 times with 1ml of Tris-HCl buffer. The radioactivity of [ H]-methyl scopolamine adsorbed on the filter was measured by a liquid scintillation counter. Non-specific binding was evaluated under existence of 5 uM of atropine.
Affinity of the compound of the present invention to muscarinic M3 receptor was calculated as the dissociation 1001965344 constant (K ), which can be calculated from concentration (IC ) of test compounds inhibiting 50% of binding of [ H]- methyl scopolamine (i.e. labeled ligand) according to Cheng and Prusoff [Cheng and Prusoff, Biochem. Pharmacol., 22, 3099, 1973]. In following Table, compounds having stronger binding affinity to human muscarinic M3 receptor have lower dissociation constant (K ).
[Table 27] Binding affinity to human muscarine M3 receptor Binding Affinity to Binding Affinity to Example Example M3 Receptor, K (nM) M3 Receptor, K (nM) 1 4.42 115 7.49 2 8.69 116 12.60 3 11.58 117 1.60 4 2.93 118 2.42 1101.45 119 42.34 6 2.47 120 9.70 7 31.84 121 1.75 8 1.33 122 87.80 9 9.10 123 52.84 401.05 124 8.12 11 467.04 125 2.67 12 88.00 126 24.79 13 80.10 127 69.36 14 12.39 128 3.41 2.27 129 12.56 16 1056.28 130 2.10 17 1.00 131 12.01 1001965344 18 6.98 132 4.64 19 4.17 133 34.48 20.72 134 46.90 21 2.25 135 24.15 22 3.79 136 1.59 23 6.40 137 27.02 24 31.01 138 >1000 115.46 139 82.67 26 18.52 140 >1000 27 56.72 141 7.57 28 844.79 142 4.88 29 931.06 143 1.12 830.16 144 17.16 31 311.47 145 14.27 32 >1000 146 6.85 33 16.84 147 77.41 34 19.64 148 10.20 434.72 149 1.57 36 >1000 150 5.60 37 >1000 151 14.95 38 574.03 152 147.11 39 28.04 153 >1000 40 118.89 154 16.67 41 2.45 155 >1000 42 9.21 156 10.63 43 1.48 157 29.63 44 95.47 158 119.82 45 69.57 159 5.13 46 37.51 160 4.29 47 136.47 161 8.92 1001965344 48 257.54 162 5.34 49 303.01 163 16.13 50 >1000 164 36.92 51 101.48 165 0.63 52 10.02 166 9.04 53 1.34 167 67.35 54 125.95 168 22.86 55 38.76 169 282.30 56 12.52 170 9.23 57 34.83 171 16.93 58 26.31 172 6.15 59 6.42 173 42.74 60 118.72 174 0.61 61 217.94 175 22.49 62 >1000 176 >1000 63 58.09 177 6.32 64 >1000 178 >1000 65 71.32 179 241.05 66 6.98 180 9.15 67 16.32 181 3.29 68 13.23 182 >1000 69 108.98 183 18.91 70 8.17 184 63.46 71 134.09 185 46.09 72 58.83 186 4.68 73 4.84 187 10.66 74 >1000 188 13.73 75 471.30 189 65.59 76 >1000 190 2.17 77 22.00 191 30.78 1001965344 78 4.62 192 4.60 80 27.38 193 45.83 81 30.35 194 6.30 82 18.89 195 1.08 83 18.29 196 7.67 84 34.94 197 0.78 86 111.04 198 1.87 87 94.38 199 0.80 88 99.67 200 2.03 89 2.43 201 2.70 90 1.97 202 2.18 91 4.50 203 2.36 92 10.66 204 3.53 93 4.12 205 7.95 94 6.18 206 7.32 95 6.27 207 13.45 96 17.57 208 110.05 97 35.17 209 >1000 98 46.18 210 4.60 99 8.10 211 9.91 100 2.43 212 >1000 101 3.79 213 53.03 102 12.86 214 >1000 103 12.96 215 >1000 104 14.18 216 60.13 105 19.55 217 222.89 106 0.80 218 >1000 107 752.18 219 >1000 108 3.95 220 >1000 109 5.33 221 >1000 1001965344 110 9.13 222 28.27 111 10.79 223 120.66 112 3.77 224 15.14 113 1.92 225 53.65 114 4.23 226 16.71 [Experimental Example 2] Antagonism assay on human muscarinic M3 receptor The antagonism assay for various compounds of the present invention was conducted on antagonism to human M3 receptor in Cos-7 cells that was transfected with plasmid coding human muscarinic M3 receptor. Test compounds in various concentrations were pre-treated to the cells for 3 minutes, and then the changes of intracellular calcium were measured after treating the same with carbachol (i.e. muscarinic receptor agonist). The FLIPR Calcium 5 assay (Molecular Devices) and Flex3 device (Molecular Devices) were used to measure concentration of calcium. Amounts of calcium before and after carbachol treatment were set as 0% and 100% respectively. Inhibition rates (%) by the compounds for increase in intracellular calcium by carbachol were calculated. The antagonistic potency of the test compounds on human muscarinic M3 receptor was calculated as the functional inhibitory constant (K ), 1001965344 which can be calculated from concentration (IC ) of compound inhibiting 50% of activity of carbachol according to Cheng and Prusoff equation. The compounds used in the experiment were identified as antagonists for human muscarinic M3 receptor, and lower K value means superior antagonistic potency.
[Table 28] Antagonistic potency for human muscarinic M3 receptor Antagonism for M3 Antagonism for M3 Example Example receptor, K (nM) receptor, K (nM) 2 6.02 128 1.20 4 3.41 129 6.24 8 3.02 130 1.14 4.10 131 1.86 19 1.90 132 0.75 21 0.49 135 16.53 22 2.39 136 0.25 34 2.64 141 0.35 41 0.18 142 1.04 42 1.19 143 0.68 52 1.22 144 1.42 53 0.57 145 2.97 56 10.00 146 1.57 58 4.70 148 2.22 59 2.38 149 0.10 66 3.06 150 1.34 67 11.85 151 2.67 1001965344 68 13.22 156 1.15 70 1.95 157 3.25 73 4.75 159 0.46 77 10.00 166 1.33 89 0.16 181 0.29 90 0.17 183 2.57 91 1.32 186 0.34 95 0.75 187 0.48 100 0.64 188 2.23 114 0.58 190 0.95 115 0.32 194 0.58 116 1.21 195 0.43 117 0.34 196 1.54 118 0.77 199 0.26 120 1.03 207 3.52 124 2.86 211 10.00 125 0.33 224 7.5 126 17.47 226 4.99 [Experimental Example 3] Experiment on rhythmic bladder contractions in rats (in vivo) Female Sprague-Dawley rat was halothane- anesthetized, and a polyethylene catheter was inserted through urethra lay down straight and fixed. Urine in bladder was excreted through the catheter by gently massaging abdomen of the rat, and then removed. A three- way stopcock was connected to the catheter and a pressure 1001965344 transducer was connected to one side of the three-way stopcock to measure pressure, and a syringe was installed at the other side to inject 37 ℃ of saline solution. The saline solution was slowly injected until regular bladder contractions occurred repeatedly. When regular bladder contractions occurred stably, test compounds were administered intravenously through the tail vein.
Inhibitory effect of the test compounds was evaluated by measuring degree of amplitude reduction of bladder contractions. The compounds of the present invention significantly reduced amplitude of bladder contractions when the compounds were administered at least 0.3 mg/kg or more.
[Table 29] Rhythmic bladder contraction in rats Inhibition of Inhibition of Rhythmic bladder Rhythmic bladder Example Example contraction in rats contraction in rats (%, 0.3 mpk) (%, 0.3 mpk) 1 26.1±5.1 117 15.4±0.1 2 20.1±3.1 121 31.4±6.1 3 15.9±0.9 124 21.2±0.7 4 22.3±4.9 125 22.6±5.8 6 28.5±4.6 128 15.1±3.4 8 23.2±2.3 129 15.7±1.4 9 9.6±1.6 131 17.8±2.5 25.6±2.2 136 33.2±4.0 1001965344 17 27.9±6.1 142 15.1±3.4 19 12.8±3.0 143 24.3±5.5 22 16.7±1.7 145 13.1±3.0 26 11.0±2.5 146 8.2±2.9 34 20.1±1.8 150 25.1±2.5 43 8.9±2.3 160 15.5±2.4 52 10.8±0.8 165 34.5±2.5 53 28.0±5.0 166 10.2±1.7 59 11.6±1.9 172 12.4±2.7 66 12.0±1.4 177 11.3±2.2 70 9.7±4.1 180 6.3±1.3 73 10.0±1.0 181 18.1±2.6 78 17.9±2.1 192 18.6±3.6 89 33.9±3.5 194 24.6±2.6 90 27.4±1.9 195 20.3±2.6 91 25.2±2.5 197 32.8±9.7 93 27.3±1.9 198 26.3±2.4 95 15.7±0.8 199 27.8±4.5 99 16.3±1.0 201 9.1±3.0 100 26.0±6.0 202 17.3±1.3 101 20.1±1.7 203 19.4±4.0 108 18.1±1.4 204 23.3±6.6 109 18.1±1.7 205 11.9±3.7 106 32.7±5.2 207 18.2±3.7 112 34.8±2.9 [Experimental Example 4] Acute toxicity test for oral administration on rats 1001965344 In order to confirm acute toxicity of the compounds of the present invention, following experiment was conducted. A low-dose group, a medi-dose group and a high- dose group, wherein the compounds of Examples were administered 100 mg/kg, 300 mg/kg and 1000 mg/kg respectively, were prepared. Methyl cellulose solution (0.5%) was prepared and orally administered to 3 rats of each group (i.e. both sexes of 6-week old Sprague-Dawley (SD) rats; male rats in 142-143 g; female rats in 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 discovered approximate lethal dose (ALD) therefrom were explained in Table 30 below. As shown in Table 30, approximate lethal dose of the test compounds were 1000 mg/kg or more, therefore the compounds were determined as safe drugs.
[Table 30] Approximate lethal dose Example Approximate Lethal Example Approximate Lethal Dose (ALD) Dose (ALD) >1000 100 >1000 53 >1000 136 >1000 89 >1000 143 >1000 90 >1000 150 >1000 91 >1000 199 >1000 1001965344 【Industrial Applicability 】 The novel biphenyl derivatives, the isomers or pharmaceutically acceptable salts thereof according to the present invention acts as a muscarinic M3 receptor antagonist, and thus can be useful 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, gastroesophogeal reflux disease, cardiac arrhythmia, and hyper salivation syndrome. 1003490018 【

Claims (1)

  1. CLAIMS 】 【Claim 1 】 A biphenyl derivative represented by the following formula 1, a stereoisomer thereof, or a pharmaceutically 5 acceptable salt thereof: [Formula 1] wherein R is hydrogen, halogen, hydroxy, C -C alkoxy, 1 1 6 10 unsubstituted C -C alkyl, or C -C alkyl substituted with 1 6 1 6 halogen; R, R and R are each independently hydrogen, halogen, 2 3 4 unsubstituted amino, nitro, cyano, hydroxy, -C(O)R , unsubstituted C -C alkyl, unsubstituted C -C alkoxy, C -C 1 6 1 6 1 6 15 alkoxy substituted with halogen, amino substituted with C - C alkyl, C -C alkyl substituted with halogen, or C -C 6 1 6 1 6 alkyl substituted with hydroxyl; R is hydrogen or C -C alkyl; 5 1 6 n is 0 or 1; and 20 R is amino, wherein the biphenyl derivative is selected from the group consisting of the following compounds: 1) 2-(1-methylpyrrolidinyl)ethyl (4'-fluoro-[1,1'- biphenyl]yl)carbamate; 1003490018 2) 2-(1-methylpyrrolidinyl)ethyl (3',5'-difluoro-[1,1'- biphenyl]yl)carbamate; 3) 2-(1-methylpyrrolidinyl)ethyl (3',4',5'-trifluoro- [1,1'-biphenyl]yl)carbamate; 5 4) 2-(1-methylpyrrolidinyl)ethyl (3'-fluoro-[1,1'- biphenyl]yl)carbamate; 6) 2-(1-methylpyrrolidinyl)ethyl [1,1'-biphenyl] ylcarbamate; 7) 2-(1-methylpyrrolidinyl)ethyl (4'-chloro-[1,1'- 10 biphenyl]yl)carbamate; 8) 2-(1-methylpyrrolidinyl)ethyl (3'-chloro-[1,1'- biphenyl]yl)carbamate; 9) 2-(1-methylpyrrolidinyl)ethyl (3',5'-dichloro-[1,1'- biphenyl]yl)carbamate; 15 10) 2-(1-methylpyrrolidinyl)ethyl (4'-trifluoromethoxy- [1,1'-biphenyl]yl)carbamate; 11) 2-(1-methylpyrrolidinyl)ethyl (4'-nitro-[1,1'- biphenyl]yl)carbamate; 12) 2-(1-methylpyrrolidinyl)ethyl (3'-trifluoromethyl- 20 [1,1'-biphenyl]yl)carbamate; 13) 2-(1-methylpyrrolidinyl)ethyl (4'-trifluoromethyl- [1,1'-biphenyl]yl)carbamate; 14) 2-(1-methylpyrrolidinyl)ethyl ((3'-fluoro-4'- methyl)-[1,1'-biphenyl]yl)carbamate; 25 15) 2-(1-methylpyrrolidinyl)ethyl (3'-methyl-[1,1'- biphenyl]yl)carbamate; 17) 2-(1-methylpyrrolidinyl)ethyl (3'-chlorofluoro- [1,1'-biphenyl]yl)carbamate; 1003490018 18) 2-(1-methylpyrrolidinyl)ethyl (3',5-difluoro-[1,1'- biphenyl]yl)carbamate; 19) 2-(1-methylpyrrolidinyl)ethyl (4',5-difluoro-[1,1'- biphenyl]yl)carbamate; 5 20) 2-(1-methylpyrrolidinyl)ethyl (3',5,5'-trifluoro- [1,1'-biphenyl]yl)carbamate; 21) 2-(1-methylpyrrolidinyl)ethyl (5-fluoro-[1,1'- biphenyl]yl)carbamate; 22) 2-(1-methylpyrrolidinyl)ethyl (5-fluoro-3'-methyl- 10 [1,1'-biphenyl]yl)carbamate; 23) 2-(1-methylpyrrolidinyl)ethyl (4-fluoro-[1,1'- biphenyl]yl)carbamate; 24) 2-(1-methylpyrrolidinyl)ethyl (3',4-difluoro-[1,1'- biphenyl]yl)carbamate; 15 25) 2-(1-methylpyrrolidinyl)ethyl (4-methoxy-[1,1'- biphenyl]yl)carbamate; 26) 2-(1-methylpyrrolidinyl)ethyl (5-methyl-[1,1'- biphenyl]yl)carbamate; 27) 2-(1-methylpyrrolidinyl)ethyl (3'-fluoromethyl- 20 [1,1'-biphenyl]yl)carbamate; 28) 2-(1-methylpyrrolidinyl)ethyl (4'-cyano-[1,1'- biphenyl]yl)carbamate; 29) 2-(1-methylpyrrolidinyl)ethyl (3'-(3-hydroxypropyl)- [1,1'-biphenyl]yl)carbamate; 25 30) 2-(1-methylpyrrolidinyl)ethyl (4'-(dimethylamino)- [1,1'-biphenyl]yl)carbamate; 31) 2-(1-methylpyrrolidinyl)ethyl (4'-(tert-butyl)- [1,1'-biphenyl]yl)carbamate; 1003490018 33) 2-(1-methylpyrrolidinyl)ethyl (3'-amino-[1,1'- biphenyl]yl)carbamate; 34) 2-(1-methylpyrrolidinyl)ethyl (2'-fluoro-[1,1'- biphenyl]yl)carbamate; 5 35) 2-(1-methylpyrrolidinyl)ethyl (2'-chloro-[1,1'- biphenyl]yl)carbamate; 38) 2-(1-methylpyrrolidinyl)ethyl (4'-fluoro-3'- (trifluoromethyl)-[1,1'-biphenyl]yl)carbamate; 39) 2-(1-methylpyrrolidinyl)ethyl (4'-amino-3'-chloro- 10 [1,1'-biphenyl]yl)carbamate; 40) 2-(1-methylpyrrolidinyl)ethyl (3'-hydroxy-[1,1'- biphenyl]yl)carbamate; 41) 2-(1-methylpyrrolidinyl)ethyl (3'-chloro-4’-fluoro- [1,1'-biphenyl]yl)carbamate; 15 42) 2-(1-methylpyrrolidinyl)ethyl (3',4',5-trifluoro- [1,1'-biphenyl]yl)carbamate; 43) 2-(1-methylpyrrolidinyl)ethyl (3',4'-dichloro fluoro-[1,1'-biphenyl]yl)carbamate; 44) 2-(1-methylpyrrolidinyl)ethyl (3'-ethylfluoro- 20 [1,1'-biphenyl]yl)carbamate; 45) 2-(1-methylpyrrolidinyl)ethyl (5-fluoro-3',5'- dimethyl-[1,1'-biphenyl]yl)carbamate; 46) 2-(1-methylpyrrolidinyl)ethyl (3'-aminofluoro- [1,1'-biphenyl]yl)carbamate; 25 47) 2-(1-methylpyrrolidinyl)ethyl (5-(trifluoromethyl)- [1,1'-biphenyl]yl)carbamate; 48) 2-(1-methylpyrrolidinyl)ethyl (4'-fluoro (trifluoromethyl)-[1,1'-biphenyl]yl)carbamate; 1003490018 49) 2-(1-methylpyrrolidinyl)ethyl (3'-fluoro (trifluoromethyl)-[1,1'-biphenyl]yl)carbamate; 51) 2-(1-methylpyrrolidinyl)ethyl (3'-chloro (trifluoromethyl)-[1,1'-biphenyl]yl)carbamate; 5 52) 2-(1-methylpyrrolidinyl)ethyl (3'-chloro-5,5'- difluoro-[1,1'-biphenyl]yl)carbamate; 53) 2-(1-methylpyrrolidinyl)ethyl (3'-chloro-4',5- difluoro-[1,1'-biphenyl]yl)carbamate; 54) 2-(1-methylpyrrolidinyl)ethyl (4'-chloro-3',5- 10 difluoro-[1,1'-biphenyl]yl)carbamate; 55) 2-(1-methylpyrrolidinyl)ethyl (3',5'-dichloro fluoro-[1,1'-biphenyl]yl)carbamate; 56) 2-(1-methylpyrrolidinyl)ethyl (3',5'-dichloro-4',5- difluoro-[1,1'-biphenyl]yl)carbamate; 15 57) 2-(1-methylpyrrolidinyl)ethyl (3'-chlorofluoro- 5'-hydroxy-[1,1'-biphenyl]yl)carbamate; 58) 2-(1-methylpyrrolidinyl)ethyl (3'-chlorofluoro- 4'-hydroxy-[1,1'-biphenyl]yl)carbamate; 59) 2-(1-methylpyrrolidinyl)ethyl (5-fluoro-3',4'- 20 dimethyl-[1,1'-biphenyl]yl)carbamate; 60) 2-(1-methylpyrrolidinyl)ethyl (5-methoxy-[1,1'- biphenyl]yl)carbamate; 61) 2-(1-methylpyrrolidinyl)ethyl (3'-fluoromethoxy- [1,1'-biphenyl]yl)carbamate; 25 63) 2-(1-methylpyrrolidinyl)ethyl (3'-chloromethoxy- [1,1'-biphenyl]yl)carbamate; 65) 2-(1-methylpyrrolidinyl)ethyl (3'-chloro-4'-fluoro- 5-methoxy-[1,1'-biphenyl]yl)carbamate; 1003490018 66) 2-(1-methylpyrrolidinyl)ethyl (5-chloro-[1,1'- biphenyl]yl)carbamate; 67) 2-(1-methylpyrrolidinyl)ethyl (5-chloro-3'-fluoro- [1,1'-biphenyl]yl)carbamate; 5 68) 2-(1-methylpyrrolidinyl)ethyl (5-chloro-4'-fluoro- [1,1'-biphenyl]yl)carbamate; 69) 2-(1-methylpyrrolidinyl)ethyl (5-chloro-3',5'- difluoro-[1,1'-biphenyl]yl)carbamate; 70) 2-(1-methylpyrrolidinyl)ethyl (3',5-dichloro-[1,1'- 10 biphenyl]yl)carbamate; 71) 2-(1-methylpyrrolidinyl)ethyl (3',5,5'-trichloro- [1,1'-biphenyl]yl)carbamate; 72) 2-(1-methylpyrrolidinyl)ethyl (3',5-dichloro-5'- fluoro-[1,1'-biphenyl]yl)carbamate; 15 73) 2-(1-methylpyrrolidinyl)ethyl (3',5-dichloro-4'- fluoro-[1,1'-biphenyl]yl)carbamate; 75) 2-(1-methylpyrrolidinyl)ethyl (3',5'-difluoro hydroxy-[1,1'-biphenyl]yl)carbamate; 77) 2-(1-methylpyrrolidinyl)ethyl (3'-chloro-4'-fluoro- 20 5-hydroxy-[1,1'-biphenyl]yl)carbamate; 78) (R)-pyrrolidinylmethyl [1,1'-biphenyl] ylcarbamate; 79) (S)-pyrrolidinylmethyl [1,1'-biphenyl] ylcarbamate; 25 80) (R)-pyrrolidinylmethyl (3',5'-difluoro-[1,1'- biphenyl]yl)carbamate; 81) (S)-pyrrolidinylmethyl (3',5'-difluoro-[1,1'- biphenyl]yl)carbamate; 1003490018 82) (S)-pyrrolidinylmethyl (5-fluoro-[1,1'-biphenyl] yl)carbamate; 83) (S)-pyrrolidinylmethyl (5-fluoro-3'-methyl-[1,1'- biphenyl]yl)carbamate; 5 84) (R)-pyrrolidinylmethyl (3',5,5'-trifluoro-[1,1'- biphenyl]yl)carbamate; 85) (S)-pyrrolidinylmethyl (3',5,5'-trifluoro-[1,1'- biphenyl]yl)carbamate; 86) (R)-pyrrolidinylmethyl (5-methyl-[1,1'-biphenyl] 10 yl)carbamate; 87) (R)-pyrrolidinylmethyl (3'-fluoromethyl-[1,1'- biphenyl]yl)carbamate; 88) (S)-pyrrolidinylmethyl (4'-fluoro-[1,1'-biphenyl] yl)carbamate; 15 89) (R)-(1-methylpyrrolidinyl)methyl [1,1'-biphenyl] ylcarbamate; 90) (S)-(1-methylpyrrolidinyl)methyl [1,1'-biphenyl] ylcarbamate; 91) (R)-(1-methylpyrrolidinyl)methyl (3',5'-difluoro- 20 [1,1'-biphenyl]yl)carbamate; 92) (S)-(1-methylpyrrolidinyl)methyl (3',5'-difluoro- [1,1'-biphenyl]yl)carbamate; 93) (S)-(1-methylpyrrolidinyl)methyl (5-fluoro-[1,1'- biphenyl]yl)carbamate; 25 94) (S)-(1-methylpyrrolidinyl)methyl (5-fluoro-3'- methyl-[1,1'-biphenyl]yl)carbamate; 95) (R)-(1-methylpyrrolidinyl)methyl (3',5,5'-trifluoro- [1,1'-biphenyl]yl)carbamate; 1003490018 96) (S)-(1-methylpyrrolidinyl)methyl (3',5,5'-trifluoro- [1,1'-biphenyl]yl)carbamate; 97) (R)-(1-methylpyrrolidinyl)methyl (5-methyl-[1,1'- biphenyl]yl)carbamate; 5 98) (R)-(1-methylpyrrolidinyl)methyl (3'-fluoro methyl-[1,1'-biphenyl]yl)carbamate; 99) (S)-(1-methylpyrrolidinyl)methyl (4'-fluoro-[1,1'- biphenyl]yl)carbamate; 100) (R)-(1-methylpyrrolidinyl)methyl (3'-methyl-[1,1'- 10 biphenyl]yl)carbamate; 101) (S)-(1-methylpyrrolidinyl)methyl (3'-methyl-[1,1'- biphenyl]yl)carbamate; 102) (R)-(1-ethylpyrrolidinyl)methyl [1,1'-biphenyl] ylcarbamate; 15 103) (S)-(1-ethylpyrrolidinyl)methyl [1,1'-biphenyl] ylcarbamate; 104) (R)-(1-ethylpyrrolidinyl)methyl (3'-methyl-[1,1'- biphenyl]yl)carbamate; 105) (S)-(1-ethylpyrrolidinyl)methyl (3'-methyl-[1,1'- 20 biphenyl]yl)carbamate; 106) (S)-(1-ethylpyrrolidinyl)methyl [1,1'-biphenyl] ylcarbamate; 108) (S)-(1-methylpyrrolidinyl)methyl (3',5-difluoro- [1,1'-biphenyl]yl)carbamate; 25 109) (R)-(1-methylpyrrolidinyl)methyl [1,1'-biphenyl] ylcarbamate; 110) (R)-(1-methylpyrrolidinyl)methyl (3'-methyl-[1,1'- biphenyl]yl)carbamate; 1003490018 111) (R)-(1-methylpyrrolidinyl)methyl (5-fluoro-3'- methyl-[1,1'-biphenyl]yl)carbamate; 112) (S)-(1-isopropylpyrrolidinyl)methyl [1,1'- biphenyl]ylcarbamate; 5 113) (R)-(1-methylpyrrolidinyl)methyl (3'-fluoro-[1,1'- biphenyl]yl)carbamate; 114) (R)-(1-methylpyrrolidinyl)methyl (4'-fluoro-[1,1'- biphenyl]yl)carbamate; 115) (R)-(1-methylpyrrolidinyl)methyl (3',4'-difluoro- 10 [1,1'-biphenyl]yl)carbamate; 116) (S)-(1-methylpyrrolidinyl)methyl (3'-fluoro-[1,1'- biphenyl]yl)carbamate; 117) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro-[1,1'- biphenyl]yl)carbamate; 15 118) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro-[1,1'- biphenyl]yl)carbamate; 119) (S)-(1-methylpyrrolidinyl)methyl (3',5'-dichloro- [1,1'-biphenyl]yl)carbamate; 120) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro-5'- 20 fluoro-[1,1'-biphenyl]yl)carbamate; 121) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro-4'- fluoro-[1,1'-biphenyl]yl)carbamate; 122) (S)-(1-methylpyrrolidinyl)methyl (5-fluoro-3',5'- dimethyl-[1,1'-biphenyl]yl)carbamate; 25 123) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro fluoro-5'-hydroxy-[1,1'-biphenyl]yl)carbamate; 124) (S)-(1-methylpyrrolidinyl)methyl (4',5-difluoro- [1,1'-biphenyl]yl)carbamate; 1003490018 125) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro fluoro-[1,1'-biphenyl]yl)carbamate; 126) (S)-(1-methylpyrrolidinyl)methyl (3',5'-dichloro fluoro-[1,1'-biphenyl]yl)carbamate; 5 127) (S)-(1-methylpyrrolidinyl)methyl (4'-chloro fluoro-[1,1'-biphenyl]yl)carbamate; 128) (S)-(1-methylpyrrolidinyl)methyl (3',4'-dichloro fluoro-[1,1'-biphenyl]yl)carbamate; 129) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro-5,5'- 10 difluoro-[1,1'-biphenyl]yl)carbamate; 130) (R)-(1-methylpyrrolidinyl)methyl (3',4'-dichloro- [1,1'-biphenyl]yl)carbamate; 131) (R)-(1-methylpyrrolidinyl)methyl (3',5'-dichloro- [1,1'-biphenyl]yl)carbamate; 15 132) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro-5'- fluoro-[1,1'-biphenyl]yl)carbamate; 133) (R)-(1-methylpyrrolidinyl)methyl (5-fluoro-3'- amino-[1,1'-biphenyl]yl)carbamate; 134) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro 20 fluoro-5'-hydroxy-[1,1'-biphenyl]yl)carbamate; 135) (R)-(1-methylpyrrolidinyl)methyl (3',5'-dichloro fluoro-[1,1'-biphenyl]yl)carbamate; 136) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro-4'- fluoro-[1,1'-biphenyl]yl)carbamate; 25 137) (R)-(1-methylpyrrolidinyl)methyl (3'-hydroxy-[1,1'- biphenyl]yl)carbamate; 139) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro fluoro-5'-methoxy-[1,1'-biphenyl]yl)carbamate; 1003490018 141) (R)-(1-methylpyrrolidinyl)methyl (4',5-difluoro- [1,1'-biphenyl]yl)carbamate; 142) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro-5,5'- difluoro-[1,1'-biphenyl]yl)carbamate; 5 143) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro-4',5- dlfluoro-[1,1'-biphenyl]yl)carbamate; 144) (R)-(1-methylpyrrolidinyl)methyl (2',5-difluoro- [1,1'-biphenyl]yl)carbamate; 145) (R)-(1-methylpyrrolidinyl)methyl (3',5-dichloro- 10 [1,1'-biphenyl]yl)carbamate; 146) (R)-(1-methylpyrrolidinyl)methyl (3',5-dichloro-4'- fluoro-[1,1'-biphenyl]yl)carbamate; 147) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro-4'- fluoromethoxy-[1,1'-biphenyl]yl)carbamate; 15 148) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro-5'- fluoro-[1,1'-biphenyl]yl)carbamate; 149) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro-4'- fluoro-[1,1'-biphenyl]yl)carbamate; 150) (R)-(1-ethylpyrrolidinyl)methyl (3'-chloro-4'- 20 fluoro-[1,1'-biphenyl]yl)carbamate; 151) (R)-(1-isopropylpyrrolidinyl)methyl (3'-chloro-4'- fluoro-[1,1'-biphenyl]yl)carbamate; 152) (R)-(1-methylpyrrolidinyl)methyl (3'- (hydroxymethyl)-[1,1'-biphenyl]yl)carbamate; 25 154) (R)-(1-methylpyrrolidinyl)methyl (3'-amino-[1,1'- biphenyl]yl)carbamate; 156) (R)-(1-methylpyrrolidinyl)methyl (2'-fluoro-[1,1'- biphenyl]yl)carbamate; 1003490018 157) (R)-(1-methylpyrrolidinyl)methyl (2',4'-difluoro- [1,1'-biphenyl]yl)carbamate; 158) (R)-(1-methylpyrrolidinyl)methyl (2',3'-difluoro- [1,1'-biphenyl]yl)carbamate; 5 159) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro-6'- fluoro-[1,1'-biphenyl]yl)carbamate; 160) (S)-(1-methylpyrrolidinyl)methyl (3'-fluoro-[1,1'- biphenyl]yl)carbamate; 161) (S)-(1-methylpyrrolidinyl)methyl (3',5'-difluoro- 10 [1,1'-biphenyl]yl)carbamate; 162) (S)-(1-methylpyrrolidinyl)methyl (3',4'-difluoro- [1,1'-biphenyl]yl)carbamate; 163) (S)-(1-methylpyrrolidinyl)methyl (2',4',5'- trifluoro-[1,1'-biphenyl]yl)carbamate; 15 164) (S)-(1-methylpyrrolidinyl)methyl (4'-chloro-[1,1'- biphenyl]yl)carbamate; 165) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro-[1,1'- biphenyl]yl)carbamate; 166) (S)-(1-methylpyrrolidinyl)methyl (3',4'-dichloro- 20 [1,1'-biphenyl]yl)carbamate; 167) (S)-(1-methylpyrrolidinyl)methyl (2',4'-dichloro- [1,1'-biphenyl]yl)carbamate; 168) (S)-(1-methylpyrrolidinyl)methyl (3'-hydroxy-[1,1'- biphenyl]yl)carbamate; 25 169) (S)-(1-methylpyrrolidinyl)methyl (3'-cyano-[1,1'- biphenyl]yl)carbamate; 170) (S)-(1-methylpyrrolidinyl)methyl (3'-amino-[1,1'- biphenyl]yl)carbamate; 1003490018 171) (S)-(1-methylpyrrolidinyl)methyl (3',4',5- trifluoro-[1,1'-biphenyl]yl)carbamate; 172) (S)-(1-methylpyrrolidinyl)methyl (3',5,5'- trifluoro-[1,1'-biphenyl]yl)carbamate; 5 173) (S)-(1-methylpyrrolidinyl)methyl (2',4',5,5'- tetrafluoro-[1,1'-biphenyl]yl)carbamate; 174) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro fluoro-[1,1'-biphenyl]yl)carbamate; 175) (S)-(1-methylpyrrolidinyl)methyl (4'-chloro 10 fluoro-[1,1'-biphenyl]yl)carbamate; 177) (S)-(1-methylpyrrolidinyl)methyl (3',4'-dichloro fluoro-[1,1'-biphenyl]yl)carbamate; 179) (S)-(1-methylpyrrolidinyl)methyl (3'-hydroxy fluoro-[1,1'-biphenyl]yl)carbamate; 15 180) (S)-(1-methylpyrrolidinyl)methyl (5-fluoro-3'- (trifluoromethyl)-[1,1'-biphenyl]yl)carbamate; 181) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro-4,4',5- trifluoro-[1,1'-biphenyl]yl)carbamate; 183) 2-(1-methylpyrrolidinyl)ethyl (2',4'-difluoro- 20 [1,1'-biphenyl]yl)carbamate; 184) 2-(1-methylpyrrolidinyl)ethyl (2',3'-difluoro- [1,1'-biphenyl]yl)carbamate; 185) 2-(1-methylpyrrolidinyl)ethyl (2',6'-difluoro- [1,1'-biphenyl]yl)carbamate; 25 186) 2-(1-methylpyrrolidinyl)ethyl (5'-chloro-2'-fluoro- [1,1'-biphenyl]yl)carbamate; 187) (S)-(1-methylpyrrolidinyl)methyl (2'-fluoro-[1,1'- biphenyl]yl)carbamate; 1003490018 188) (S)-(1-methylpyrrolidinyl)methyl (2',4'-difluoro- [1,1'-biphenyl]yl)carbamate; 189) (S)-(1-methylpyrrolidinyl)methyl (2',3'-difluoro- [1,1'-biphenyl]yl)carbamate; 5 190) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro-6'- fluoro-[1,1'-biphenyl]yl)carbamate; 191) (R)-(1-methylpyrrolidinyl)methyl (3',5'-dimethyl- [1,1'-biphenyl]yl)carbamate; 192) (R)-(1-methylpyrrolidinyl)methyl (5-fluoro-3'- 10 methyl-[1,1'-biphenyl]yl)carbamate; 193) (R)-(1-methylpyrrolidinyl)methyl (5-fluoro-3',5'- dimethyl-[1,1'-biphenyl]yl)carbamate; 194) (R)-(1-methylpyrrolidinyl)methyl (3',5-difluoro- [1,1'-biphenyl]yl)carbamate; 15 195) (R)-(1-methylpyrrolidinyl)methyl (3'-chloro fluoro-[1,1'-biphenyl]yl)carbamate; 196) (R)-(1-ethylpyrrolidinyl)methyl (3'-chloro-4',5- difluoro-[1,1'-biphenyl]yl)carbamate; 197) (S)-(1-methylpyrrolidinyl)methyl [1,1'-biphenyl] 20 ylcarbamate; 198) (S)-(1-methylpyrrolidinyl)methyl (4'-fluoro-[1,1'- biphenyl]yl)carbamate; 199) (S)-(1-methylpyrrolidinyl)methyl (3'-methyl-[1,1'- biphenyl]yl)carbamate; 25 200) (S)-(1-methylpyrrolidinyl)methyl (5-fluoro-[1,1'- biphenyl]yl)carbamate; 201) (S)-(1-methylpyrrolidinyl)methyl (5-fluoro-3'- methyl-[1,1'-biphenyl]yl)carbamate; 1003490018 202) (S)-(1-methylpyrrolidinyl)methyl (3',5-difluoro- [1,1'-biphenyl]yl)carbamate; 203) (S)-(1-methylpyrrolidinyl)methyl (4',5-difluoro- [1,1'-biphenyl]yl)carbamate; 5 204) (S)-(1-methylpyrrolidinyl)methyl (4-fluoro-[1,1'- biphenyl]yl)carbamate; 205) (S)-(1-methylpyrrolidinyl)methyl (3',4-difluoro- [1,1'-biphenyl]yl)carbamate; 206) (S)-(1-methylpyrrolidinyl)methyl (5-methyl-[1,1'- 10 biphenyl]yl)carbamate; 207) (S)-(1-methylpyrrolidinyl)methyl (3'-fluoro methyl-[1,1'-biphenyl]yl)carbamate; 208) (S)-(1-methylpyrrolidinyl)methyl (5-fluoro-3',5'- dimethyl-[1,1'-biphenyl]yl)carbamate; 15 210) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro-5,5'- difluoro-[1,1'-biphenyl]yl)carbamate; 211) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro-4',5- difluoro-[1,1'-biphenyl]yl)carbamate; 213) (S)-(1-methylpyrrolidinyl)methyl (3'-amino 20 fluoro-[1,1'-biphenyl]yl)carbamate; 216) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro fluoro-5'-hydroxy-[1,1'-biphenyl]yl)carbamate; 217) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro fluoro-5'-methoxy-[1,1'-biphenyl]yl)carbamate; 25 222) (S)-(1-methylpyrrolidinyl)methyl (5-methoxy-[1,1'- biphenyl]yl)carbamate; 223) (S)-(1-methylpyrrolidinyl)methyl (3'-fluoro methoxy-[1,1'-biphenyl]yl)carbamate; 1003490018 224) (S)-(1-methylpyrrolidinyl)methyl (3'-chloro methoxy-[1,1'-biphenyl]yl)carbamate; 225) (S)-(1-methylpyrrolidinyl)methyl (3',4'-dichloro methoxy-[1,1'-biphenyl]yl)carbamate; and 5 226) (S)-(1-methylpyrrolidinyl)methyl (3',5'-dichloro methoxy-[1,1'-biphenyl]yl)carbamate. 【Claim 2 】 A method for preparing the biphenyl derivative, stereoisomer thereof or pharmaceutically acceptable salt 10 thereof of claim 1, the method comprising a step of reacting a compound of the following formula 2 with a compound of the following formula 3 in the presence of a carbamate synthesis reagent: [Formula 2] [Formula 3] wherein R to R and n are the same as defined in claim 1. 20 【Claim 3 】 1003490018 A method for preparing the biphenyl derivative, stereoisomer thereof or pharmaceutically acceptable salt thereof of claim 1, the method comprising the steps of: reacting a compound of the following formula 2 with a 5 compound of the following formula 3a in the presence of a carbamate synthesis reagent to prepare a compound of the following formula 4; removing an amine protecting group from the compound of formula 4 to prepare a compound of the following formula 10 1a; and introducing an R substituent into the compound of formula 1a: [Formula 2] 15 [Formula 3a] [Formula 4] [Formula 1a] 1003490018 wherein R to R and n are the same as defined in claim 1, and PG is an amine protecting group selected from the 5 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). 10 【Claim 4 】 The method of claim 2 or 3, wherein 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 15 formula 6, which has a carboxylic acid protecting group introduced therein; coupling the compound of formula 6 with a compound of the following formula 7 to prepare a compound of the following formula 8; and 20 de-esterifying the compound of formula 8 in the presence of a base: [Formula 5] 1003490018 [Formula 6] [Formula 7] [Formula 8] wherein R to R are the same as defined in claim 1; X is halogen; and PG is a protecting group selected from the 10 group consisting of a C -C alkyl group, benzyl, PMB (4- methoxybenzyl), THP (tetrahydropyranyl), TBDMS (tert- butyldimethylsilyl), and TBDPS (tert-butyldiphenylsilyl). 【Claim 5 】 A method for preparing the biphenyl derivative, 15 stereoisomer thereof or pharmaceutically acceptable salt thereof of claim 1, the method comprising the steps of: 1003490018 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 the following formula 9; and 5 coupling a compound of the following formula 7 to the compound of formula 9: [Formula 5] [Formula 3] [Formula 9] [Formula 7] wherein R to R and n are the same as defined in claim 1, and X is halogen. 【Claim 6 】 1003490018 A method for preparing the biphenyl derivative, stereoisomer thereof or pharmaceutically acceptable salt thereof of claim 1, the method comprising the steps of: reacting a compound of the following formula 5 with a 5 compound of the following formula 3a in the presence of a carbamate synthesis reagent to prepare a compound of the following formula 9a; deprotecting the compound of formula 9a to prepare a compound of the following formula 9b; 10 introducing an R substituent into the compound of formula 9b to prepare a compound of the following formula 9; and coupling a compound of the following formula 7 to the compound of formula 9: 15 [Formula 5] [Formula 3a] [Formula 9a] [Formula 9b] 1003490018 [Formula 9] [Formula 7] wherein R to R and n are the same as defined in claim 1; X is halogen; and PG is the same as defined in claim 3. 【Claim 7 】 10 The method of any one of claims 2, 3, 5 and 6, wherein the carbamate synthesis reagent comprises an azide compound. 【Claim 8 】 The method of claim 7, wherein the carbamate 15 synthesis reagent is a mixture of diphenylphosphoryl azide (DPPA) and triethylamine, a mixture of propylphosphonic anhydride (T3P), trimethylsilyl azide (TMSN) and triethylamine, or a mixture of sodium azide (NaN ), tetrabutylammonium bromide and zinc(II) triflate. 1003490018 【Claim 9 】 A muscarinic M3 receptor antagonist containing the compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active 5 ingredient. 【Claim 10 】 The muscarinic M3 receptor antagonist of claim 9, which is for preventing or treating a disease selected from the group consisting of chronic obstructive pulmonary 10 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 hyper-salivation syndromes. 15 【Claim 11 】 Use of the compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient for preparation of a medicament for preventing or treating a muscarinic M3 receptor-related 20 disease. 【Claim 12 】 The biphenyl derivative, stereoisomer thereof or pharmaceutically acceptable salt thereof according to claim 1, substantially as herein described with reference to any 25 one of tables 28 to 30.
NZ736557A 2013-07-30 2014-07-17 The Biphenyl Derivative and Method for Preparing Same NZ736557B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
KR10-2013-0090175 2013-07-30
KR1020130090175A KR101538846B1 (en) 2013-07-30 2013-07-30 Novel Biphenyl Derivatives and the Method for Preparing the same
NZ71674314 2014-07-17

Publications (2)

Publication Number Publication Date
NZ736557A NZ736557A (en) 2021-05-28
NZ736557B2 true NZ736557B2 (en) 2021-08-31

Family

ID=

Similar Documents

Publication Publication Date Title
TWI707683B (en) Glp-1 receptor agonists and uses thereof
EP2427425B1 (en) Tetracycline compounds
WO2019241231A1 (en) Antiestrogen compounds
CN106414408A (en) Ring-contracted morphinans and the use thereof
KR20220063192A (en) BRD9 bifunctional disintegrant and method of use thereof
EP3029026B1 (en) Novel biphenyl derivative and method for preparing same
EP1847535A1 (en) 1-(piperidin-4-yl)-1h-indole derivative
WO2017165822A1 (en) Small molecule inhibitor of the nuclear translocation of androgen receptor for the treatment of castration-resistant prostate cancer
TWI784199B (en) DP antagonist
WO2010090304A1 (en) Acylguanidine derivative
KR101592280B1 (en) Biaryl or Heterocyclic Biaryl Substituted Cyclohexene Derivatives Compound for Inhibitor
EP4167986A1 (en) Thyromimetics
CN115397412A (en) Modulators of MAS-related G protein receptor X4 and related products and methods
EP1966218A1 (en) Novel, cyclic substituted furopyrimidine derivatives and use thereof for treating cardiovascular diseases
SG188415A1 (en) Cyclohexane derivative compound
NZ736557B2 (en) The Biphenyl Derivative and Method for Preparing Same
NZ736557A (en) The biphenyl derivative and method for preparing same
CN110372638A (en) Piperazines AMPK agonist and its medical usage
RU2769715C9 (en) Glp-1 receptor agonists and use thereof
BR112016001746B1 (en) BIPHENYL DERIVATIVE, METHOD FOR ITS PREPARATION AND USE OF A COMPOSITION CONTAINING THE COMPOUND
CN114761025A (en) PDIA4 inhibitor and application thereof in inhibiting beta cell pathology and treating diabetes
TW202239756A (en) 1,3,4-oxadiazole thiocarbonyl compounds as histone deacetylase 6 inhibitor, and pharmaceutical composition comprising the same
EA040816B1 (en) GLP-1 RECEPTOR AGONISTS AND THEIR USE
JP2002193880A (en) Bicyclooctane derivative
MXPA00002133A (en) Cyano containing oxamic acids and derivatives as thyroid receptor ligands