NZ736557B2 - The Biphenyl Derivative and Method for Preparing Same - Google Patents
The Biphenyl Derivative and Method for Preparing Same Download PDFInfo
- 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
Links
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title claims abstract description 384
- 239000011780 sodium chloride Substances 0.000 claims abstract description 35
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 201000010099 disease Diseases 0.000 claims abstract description 17
- 239000003681 muscarinic M3 receptor antagonist Substances 0.000 claims abstract description 16
- 206010001897 Alzheimer's disease Diseases 0.000 claims abstract description 14
- 208000006673 Asthma Diseases 0.000 claims abstract description 9
- 206010039083 Rhinitis Diseases 0.000 claims abstract description 9
- 206010046543 Urinary incontinence Diseases 0.000 claims abstract description 9
- 206010009887 Colitis Diseases 0.000 claims abstract description 8
- 206010063057 Cystitis noninfective Diseases 0.000 claims abstract description 8
- 208000002551 Irritable Bowel Syndrome Diseases 0.000 claims abstract description 8
- 206010039424 Salivary hypersecretion Diseases 0.000 claims abstract description 8
- 201000003139 chronic cystitis Diseases 0.000 claims abstract description 8
- 206010003119 Arrhythmia Diseases 0.000 claims abstract description 7
- 206010007521 Cardiac arrhythmias Diseases 0.000 claims abstract description 7
- 208000010412 Glaucoma Diseases 0.000 claims abstract description 7
- 206010039966 Senile dementia Diseases 0.000 claims abstract description 7
- 208000008630 Sialorrhea Diseases 0.000 claims abstract description 7
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 7
- 208000009471 Gastroesophageal Reflux Diseases 0.000 claims abstract description 6
- 206010017885 Gastrooesophageal reflux disease Diseases 0.000 claims abstract description 6
- 201000006860 gastroesophageal reflux disease Diseases 0.000 claims abstract description 6
- 235000010290 biphenyl Nutrition 0.000 claims description 409
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 366
- -1 cyano, hydroxy Chemical group 0.000 claims description 358
- 238000003786 synthesis reaction Methods 0.000 claims description 281
- 230000015572 biosynthetic process Effects 0.000 claims description 280
- 230000002194 synthesizing Effects 0.000 claims description 280
- 239000004305 biphenyl Substances 0.000 claims description 265
- 150000001875 compounds Chemical class 0.000 claims description 171
- 239000002253 acid Substances 0.000 claims description 139
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 21
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 102000007202 Muscarinic M3 Receptor Human genes 0.000 claims description 17
- 108010008405 Muscarinic M3 Receptor Proteins 0.000 claims description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 13
- 238000005859 coupling reaction Methods 0.000 claims description 12
- 150000002367 halogens Chemical group 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 239000004480 active ingredient Substances 0.000 claims description 8
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 230000001808 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- CUWCIUNJZHEGTQ-KRWDZBQOSA-N CC=1C=C(C=CC=1)C1=C(C=CC=C1)NC(OC[C@H]1N(CCC1)C)=O Chemical compound CC=1C=C(C=CC=1)C1=C(C=CC=C1)NC(OC[C@H]1N(CCC1)C)=O CUWCIUNJZHEGTQ-KRWDZBQOSA-N 0.000 claims description 5
- 125000006242 amine protecting group Chemical group 0.000 claims description 5
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 4
- CUWCIUNJZHEGTQ-QGZVFWFLSA-N CC=1C=C(C=CC=1)C1=C(C=CC=C1)NC(OC[C@@H]1N(CCC1)C)=O Chemical compound CC=1C=C(C=CC=1)C1=C(C=CC=C1)NC(OC[C@@H]1N(CCC1)C)=O CUWCIUNJZHEGTQ-QGZVFWFLSA-N 0.000 claims description 4
- WBXRAAVXXMXBBR-INIZCTEOSA-N ClC=1C=C(C=CC=1)C1=C(C=CC=C1)NC(OC[C@H]1N(CCC1)C)=O Chemical compound ClC=1C=C(C=CC=1)C1=C(C=CC=C1)NC(OC[C@H]1N(CCC1)C)=O WBXRAAVXXMXBBR-INIZCTEOSA-N 0.000 claims description 4
- ZCZDEHUMQKRBKR-AWEZNQCLSA-N ClC=1C=C(C=CC=1F)C1=C(C=CC=C1)NC(OC[C@H]1N(CCC1)C)=O Chemical compound ClC=1C=C(C=CC=1F)C1=C(C=CC=C1)NC(OC[C@H]1N(CCC1)C)=O ZCZDEHUMQKRBKR-AWEZNQCLSA-N 0.000 claims description 4
- MKRTXPORKIRPDG-UHFFFAOYSA-N Diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 claims description 4
- ZWBGMGWBJURTFR-INIZCTEOSA-N FC1=CC=C(C=C1)C1=C(C=CC(=C1)F)NC(OC[C@H]1N(CCC1)C)=O Chemical compound FC1=CC=C(C=C1)C1=C(C=CC(=C1)F)NC(OC[C@H]1N(CCC1)C)=O ZWBGMGWBJURTFR-INIZCTEOSA-N 0.000 claims description 4
- DFRNURQTAXUXQF-INIZCTEOSA-N FC1=CC=C(C=C1)C1=C(C=CC=C1)NC(OC[C@H]1N(CCC1)C)=O Chemical compound FC1=CC=C(C=C1)C1=C(C=CC=C1)NC(OC[C@H]1N(CCC1)C)=O DFRNURQTAXUXQF-INIZCTEOSA-N 0.000 claims description 4
- OMQUDALDCKOVET-INIZCTEOSA-N FC=1C=C(C=C(C=1)F)C1=C(C=CC(=C1)F)NC(OC[C@H]1N(CCC1)C)=O Chemical compound FC=1C=C(C=C(C=1)F)C1=C(C=CC(=C1)F)NC(OC[C@H]1N(CCC1)C)=O OMQUDALDCKOVET-INIZCTEOSA-N 0.000 claims description 4
- IHNVUNCUNNNVJI-INIZCTEOSA-N FC=1C=C(C=CC=1)C1=C(C=CC(=C1)F)NC(OC[C@H]1N(CCC1)C)=O Chemical compound FC=1C=C(C=CC=1)C1=C(C=CC(=C1)F)NC(OC[C@H]1N(CCC1)C)=O IHNVUNCUNNNVJI-INIZCTEOSA-N 0.000 claims description 4
- OYPGBZSGVFVHBD-INIZCTEOSA-N FC=1C=C(C=CC=1)C1=C(C=CC=C1)NC(OC[C@H]1N(CCC1)C)=O Chemical compound FC=1C=C(C=CC=1)C1=C(C=CC=C1)NC(OC[C@H]1N(CCC1)C)=O OYPGBZSGVFVHBD-INIZCTEOSA-N 0.000 claims description 4
- XGJSKPKXFZDSSG-SFHVURJKSA-N FC=1C=CC(=C(C=1)C1=CC(=CC(=C1)C)C)NC(OC[C@H]1N(CCC1)C)=O Chemical compound FC=1C=CC(=C(C=1)C1=CC(=CC(=C1)C)C)NC(OC[C@H]1N(CCC1)C)=O XGJSKPKXFZDSSG-SFHVURJKSA-N 0.000 claims description 4
- XRSODSMVWHPIFR-KRWDZBQOSA-N FC=1C=CC(=C(C=1)C1=CC(=CC=C1)C)NC(OC[C@H]1N(CCC1)C)=O Chemical compound FC=1C=CC(=C(C=1)C1=CC(=CC=C1)C)NC(OC[C@H]1N(CCC1)C)=O XRSODSMVWHPIFR-KRWDZBQOSA-N 0.000 claims description 4
- KCFDIYZLZIUQKA-INIZCTEOSA-N FC=1C=CC(=C(C=1)C1=CC=CC=C1)NC(OC[C@H]1N(CCC1)C)=O Chemical compound FC=1C=CC(=C(C=1)C1=CC=CC=C1)NC(OC[C@H]1N(CCC1)C)=O KCFDIYZLZIUQKA-INIZCTEOSA-N 0.000 claims description 4
- DHXVGJBLRPWPCS-UHFFFAOYSA-N THP Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- PAQZWJGSJMLPMG-UHFFFAOYSA-N propylphosphonic anhydride Substances CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 claims description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
- MRCAAFFMZODJBP-UHFFFAOYSA-N 1-fluoro-3-phenylbenzene Chemical compound FC1=CC=CC(C=2C=CC=CC=2)=C1 MRCAAFFMZODJBP-UHFFFAOYSA-N 0.000 claims description 3
- NPDIDUXTRAITDE-UHFFFAOYSA-N 1-methyl-3-phenylbenzene Chemical compound CC1=CC=CC(C=2C=CC=CC=2)=C1 NPDIDUXTRAITDE-UHFFFAOYSA-N 0.000 claims description 3
- HVUAXGMASOBPQH-UHFFFAOYSA-N C(#N)C1=CC=C(C=C1)C1=C(C=CC=C1)NC(OCCC1N(CCC1)C)=O Chemical compound C(#N)C1=CC=C(C=C1)C1=C(C=CC=C1)NC(OCCC1N(CCC1)C)=O HVUAXGMASOBPQH-UHFFFAOYSA-N 0.000 claims description 3
- DODOUMJGJWNOBZ-UHFFFAOYSA-N ClC=1C=C(C=C(C=1)F)C1=C(C=CC(=C1)F)NC(OCCC1N(CCC1)C)=O Chemical compound ClC=1C=C(C=C(C=1)F)C1=C(C=CC(=C1)F)NC(OCCC1N(CCC1)C)=O DODOUMJGJWNOBZ-UHFFFAOYSA-N 0.000 claims description 3
- PCJWXOPQGIELNK-INIZCTEOSA-N FC=1C=C(C=C(C=1)F)C1=C(C=CC=C1)NC(OC[C@H]1N(CCC1)C)=O Chemical compound FC=1C=C(C=C(C=1)F)C1=C(C=CC=C1)NC(OC[C@H]1N(CCC1)C)=O PCJWXOPQGIELNK-INIZCTEOSA-N 0.000 claims description 3
- XRSODSMVWHPIFR-QGZVFWFLSA-N FC=1C=CC(=C(C=1)C1=CC(=CC=C1)C)NC(OC[C@@H]1N(CCC1)C)=O Chemical compound FC=1C=CC(=C(C=1)C1=CC(=CC=C1)C)NC(OC[C@@H]1N(CCC1)C)=O XRSODSMVWHPIFR-QGZVFWFLSA-N 0.000 claims description 3
- 125000006244 carboxylic acid protecting group Chemical group 0.000 claims description 3
- RUYZJEIKQYLEGZ-UHFFFAOYSA-N 1-fluoro-4-phenylbenzene Chemical compound C1=CC(F)=CC=C1C1=CC=CC=C1 RUYZJEIKQYLEGZ-UHFFFAOYSA-N 0.000 claims description 2
- VVUKIWRQNCORFL-KRWDZBQOSA-N C(#N)C=1C=C(C=CC=1)C1=C(C=CC=C1)NC(OC[C@H]1N(CCC1)C)=O Chemical compound C(#N)C=1C=C(C=CC=1)C1=C(C=CC=C1)NC(OC[C@H]1N(CCC1)C)=O VVUKIWRQNCORFL-KRWDZBQOSA-N 0.000 claims description 2
- VZERCFSMAKGUQB-UHFFFAOYSA-N C(C)(C)(C)C1=CC=C(C=C1)C1=C(C=CC=C1)NC(OCCC1N(CCC1)C)=O Chemical compound C(C)(C)(C)C1=CC=C(C=C1)C1=C(C=CC=C1)NC(OCCC1N(CCC1)C)=O VZERCFSMAKGUQB-UHFFFAOYSA-N 0.000 claims description 2
- ADDLJMRWTOPDCH-SFHVURJKSA-N C1(=C(C=CC=C1)NC(OC[C@H]1N(CCC1)C(C)C)=O)C1=CC=CC=C1 Chemical compound C1(=C(C=CC=C1)NC(OC[C@H]1N(CCC1)C(C)C)=O)C1=CC=CC=C1 ADDLJMRWTOPDCH-SFHVURJKSA-N 0.000 claims description 2
- AMYOCGSOFQXMOR-UHFFFAOYSA-N CC=1C=C(C=CC=1)C1=C(C=CC=C1)NC(OCCC1N(CCC1)C)=O Chemical compound CC=1C=C(C=CC=1)C1=C(C=CC=C1)NC(OCCC1N(CCC1)C)=O AMYOCGSOFQXMOR-UHFFFAOYSA-N 0.000 claims description 2
- ODGBYJBVIOASEG-UHFFFAOYSA-N CC=1C=CC(=C(C=1)C1=CC=CC=C1)NC(OCCC1N(CCC1)C)=O Chemical compound CC=1C=CC(=C(C=1)C1=CC=CC=C1)NC(OCCC1N(CCC1)C)=O ODGBYJBVIOASEG-UHFFFAOYSA-N 0.000 claims description 2
- MWEVFUJKZFFKLC-UHFFFAOYSA-N CN(C1=CC=C(C=C1)C1=C(C=CC=C1)NC(OCCC1N(CCC1)C)=O)C Chemical compound CN(C1=CC=C(C=C1)C1=C(C=CC=C1)NC(OCCC1N(CCC1)C)=O)C MWEVFUJKZFFKLC-UHFFFAOYSA-N 0.000 claims description 2
- DFRNURQTAXUXQF-MRXNPFEDSA-N CN1CCC[C@@H]1COC(=O)NC1=CC=CC=C1C1=CC=C(F)C=C1 Chemical compound CN1CCC[C@@H]1COC(=O)NC1=CC=CC=C1C1=CC=C(F)C=C1 DFRNURQTAXUXQF-MRXNPFEDSA-N 0.000 claims description 2
- SKQFHNDLVFDMAY-UHFFFAOYSA-N COC1=CC(=C(C=C1)C1=CC=CC=C1)NC(OCCC1N(CCC1)C)=O Chemical compound COC1=CC(=C(C=C1)C1=CC=CC=C1)NC(OCCC1N(CCC1)C)=O SKQFHNDLVFDMAY-UHFFFAOYSA-N 0.000 claims description 2
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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.
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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
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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.
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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;
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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;
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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;
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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;
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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;
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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;
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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;
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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;
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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
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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
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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]
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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
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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
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[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
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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]
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[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]
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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.
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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.
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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
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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
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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
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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
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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
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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
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-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%)
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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%)
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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
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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%)
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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
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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%)
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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%)
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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)
- 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.
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 |
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NZ736557A NZ736557A (en) | 2021-05-28 |
NZ736557B2 true NZ736557B2 (en) | 2021-08-31 |
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