U.S. patent application number 14/651211 was filed with the patent office on 2016-08-18 for biaryl- or heterocyclic biaryl-substituted cyclohexene derivative compounds as cetp inhibitors.
The applicant listed for this patent is CHONG KUN DANG PHARMACEUTICAL CORP.. Invention is credited to Su Yeal BAE, Il-Hyang KIM, Yun Tae KIM, Jae Kwang LEE, Jae Won LEE, Jae Young LEE, Se Ra LEE, Seo Hee LEE, Jung Taek OH.
Application Number | 20160237046 14/651211 |
Document ID | / |
Family ID | 51745409 |
Filed Date | 2016-08-18 |
United States Patent
Application |
20160237046 |
Kind Code |
A9 |
LEE; Jae Kwang ; et
al. |
August 18, 2016 |
Biaryl- or Heterocyclic Biaryl-Substituted Cyclohexene Derivative
Compounds as CETP Inhibitors
Abstract
The present invention provides biaryl- or heterocyclic
biaryl-substituted cyclohexene derivative compounds, isomers
thereof, or pharmaceutically acceptable salts. The compounds of the
invention show a CETP inhibitory effect that increases
HDL-cholesterol levels and reduces LDL-cholesterol levels.
Pharmaceutical compositions comprising the compounds are useful for
the prevention or treatment of dyslipidemia or dyslipidemia-related
diseases.
Inventors: |
LEE; Jae Kwang;
(Gyeonggi-do, KR) ; OH; Jung Taek; (Gyeonggi-do,
KR) ; LEE; Jae Won; (Gyeonggi-do, KR) ; LEE;
Seo Hee; (Gyeonggi-do, KR) ; KIM; Il-Hyang;
(Gyeonggi-do, KR) ; LEE; Jae Young; (Gyeonggi-do,
KR) ; BAE; Su Yeal; (Gyeonggi-do, KR) ; LEE;
Se Ra; (Gyeonggi-do, KR) ; KIM; Yun Tae;
(Gyeonggi-do, KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CHONG KUN DANG PHARMACEUTICAL CORP. |
Seoul |
|
KR |
|
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20150322023 A1 |
November 12, 2015 |
|
|
Family ID: |
51745409 |
Appl. No.: |
14/651211 |
Filed: |
January 29, 2014 |
PCT Filed: |
January 29, 2014 |
PCT NO: |
PCT/KR2014/000889 PCKC 00 |
371 Date: |
June 10, 2015 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 263/24 20130101;
A61P 9/00 20180101; A61P 3/06 20180101; C07D 413/10 20130101; A61P
9/10 20180101; C07D 413/08 20130101; C07D 263/08 20130101; C07D
263/22 20130101 |
International
Class: |
C07D 263/22 20060101
C07D263/22; C07D 413/08 20060101 C07D413/08; C07D 413/10 20060101
C07D413/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 31, 2013 |
KR |
10-2013-0011206 |
Jan 29, 2014 |
KR |
10-2014-0011555 |
Claims
1. A biaryl-substituted or heterocyclic biaryl-substituted
cyclohexene derivative compounds of Formula I: ##STR00228## or an
isomer or pharmaceutically acceptable salt thereof, wherein:
R.sup.1 is --H or --C.sub.1-C.sub.3 alkyl; R.sup.2 is --H, halogen
or --C.sub.1-C.sub.3 alkyl; R.sup.3, R.sup.4, R.sup.5 and R.sup.6
are each independently --H, halogen, --NO.sub.2, --C.sub.1-C.sub.3
alkyl, or --OC.sub.1-C.sub.3 alkyl; R.sup.7 is --H,
--(C.dbd.O)OR.sup.8, or ##STR00229## R.sup.8 is --H or
--C.sub.1-C.sub.3 alkyl; R.sup.11 and R.sup.12 are each
independently --H or --C.sub.1-C.sub.3 alkyl or may form a 4- to
6-membered non-aromatic ring, wherein the non-aromatic ring may
contain 0 to 2 N or O heteroatoms, and one or more --H in the
non-aromatic ring may substituted with halogen or --OH; A.sup.1,
A.sup.2 and A.sup.3 are each independently N or CR.sup.9, wherein
if A.sup.2 or A.sup.3 is N, A.sup.1 is CR.sup.9; R.sup.9 is --H,
halogen, --C.sub.1--C.sub.3 alkyl or --OC.sub.1-C.sub.3 alkyl; B is
N or CR.sup.10; R.sup.10 is H, halogen, --C.sub.1-C.sub.3 alkyl,
--OC.sub.1-C.sub.3 alkyl, --(C.dbd.O)OR.sup.8, or ##STR00230##
provided that one or more --H atoms in the --C.sub.1-C.sub.3 alkyl
or the --OC.sub.1-C.sub.3 alkyl may be substituted with --F or
--CH.sub.3, and if R.sup.7 is --H, B is CR.sup.10, and R.sup.10 is
--(C.dbd.O)OR.sup.8 or ##STR00231## and if R.sup.7 is not --H,
R.sup.10 cannot be --(C.dbd.O)OR.sup.8 or ##STR00232##
2. The compound of claim 1, wherein: R.sup.1 is --H or --CH.sub.3;
R.sup.2 is --F or --CF.sub.3; R.sup.3, R.sup.4, R.sup.5 and R.sup.6
are each independently --H, --F, --Cl, --NO.sub.2, --CH.sub.3,
--CH(CH.sub.3).sub.2, --CF.sub.3 or --OCH.sub.3; R.sup.7 is --H,
--(C.dbd.O)OR.sup.8, or ##STR00233## R.sup.8 is --H, --CH.sub.3 or
--CH.sub.2CH.sub.3; R.sup.11 and R.sup.12 are each independently
--H, --CH.sub.3 or --CH.sub.2CH.sub.3 or may form 4- to 6-membered
non-aromatic ring, wherein the non-aromatic ring may contain 0 to 2
N or O heteroatoms, and one or more --H atoms in the non-aromatic
ring may be substituted with --F or --OH; A.sup.1, A.sup.2 and
A.sup.3 are each independently N or CR.sup.9, wherein if A.sup.2 or
A.sup.3 is N, A.sup.1 is CR.sup.9; R.sup.9 is --H, --F, --Cl,
--CH.sub.3, --CF.sub.3 or --OCH.sub.3; B is N or CR.sup.10;
R.sup.10 is --H, --F, --Cl, --CH.sub.3, --OCH.sub.3, --CO.sub.2H,
--CO.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.3, or ##STR00234##
provided that if R.sup.7 is --H, B is CR.sup.10, and R.sup.10 is
--CO.sub.2H, --CO.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.3, or
##STR00235## and if R.sup.7 is not --H, R.sup.10 is not
--CO.sub.2H, --CO.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.3, or
##STR00236##
3. The compound of claim 2, wherein: R.sup.1 is --CH.sub.3; R.sup.2
is --CF.sub.3; R.sup.3 is --H, --F, --Cl or --OCH.sub.3; R.sup.4 is
--H, --F, --Cl, --CH.sub.3, --CH(CH.sub.3).sub.2, --CF.sub.3 or
--OCH.sub.3; R.sup.5 is --H, --F or --Cl; R.sup.6 is --H; R.sup.7
is --H, --(C.dbd.O)OH, ##STR00237## A.sup.1, A.sup.2 and A.sup.3
are each independently N or CR.sup.9, wherein if A.sup.2 or A.sup.3
is N, A.sup.1 is CR.sup.9; R.sup.9 is --H, --F, --CH.sub.3,
--CF.sub.3 or --OCH.sub.3; B is CR.sup.10; R.sup.10 is --H, --F or
--CO.sub.2CH.sub.3; provided that if R.sup.7 is --H, B is
CR.sup.10, and R.sup.10 is --CO.sub.2CH.sub.3, and R.sup.7 is not
--H, R.sup.10 is not --CO.sub.2CH.sub.3.
4. The compound of claim 3, wherein: R.sup.3 is --H, --F or
--OCH.sub.3; R.sup.4 is --H, --F, --Cl, --CH.sub.3 or --CF.sub.3;
R.sup.5 is --H or --F; R.sup.7 is --(C.dbd.O)OH; A.sup.1 is N or
CR.sup.9; A.sup.2 and A.sup.3 are each independently CR.sup.9;
R.sup.9 is --H or --F; and B is CH.
5. The compound of claim 1, wherein the compound is selected from
among the following compounds: methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methyl-biphenyl--
4-carboxylate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methyl-biphenyl-
-4-carboxylic acid; methyl
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-me-
thylbenzoate; methyl
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)benzo-
ate;
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)--
3-methyl-benzoic acid;
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)benzo-
ic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxybiphenyl-4-carboxyl-
ate; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-4'-methoxybiphenyl-4-
-carboxylate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-4'-methoxybiphenyl-4-
-carboxylic acid; methyl
5-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxyphenyl)-picolinate-
;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxybiphenyl-4-carboxy-
lic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxybiphenyl-3-carboxyl-
ate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxaz-
olidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxybiphenyl-3-carb-
oxylic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-nitrobiphenyl-4--
carboxylate; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-4'-methoxy-2-methyl-
biphenyl-4-carboxylate; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-4'-methoxy-biphenyl-
-4-carboxylate;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-4'-methoxy-2-methyl-
biphenyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-4'-methoxybiphenyl--
4-carboxylic acid; methyl
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-is-
opropylbenzoate;
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-is-
opropyl-benzoic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)cyclohex-1-enyl)-4'-methoxy-2-methylbiphenyl-4-carboxylate;
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo--
oxazolidin-3-yl)methyl)cyclohex-1-enyl)-2-fluoro-4'-methoxybiphenyl-4-carb-
oxylate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)cyclohex-1-enyl)-4'-methoxy-2-methylbiphenyl-4-carb-
oxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)cyclohex-1-enyl)-2-fluoro-4'-methoxybiphenyl-4-carboxylic
acid; methyl
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-ch-
lorobenzoate;
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-ch-
lorobenzoic acid; methyl
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazo-
lidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-f-
luorobenzoate;
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-fl-
uorobenzoic acid; methyl
3-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)benzo-
ate;
3-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)b-
enzoic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,3-difluoro-4'-methoxy-biphe-
nyl-4-carboxylate; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,6-difluoro-4'-methoxy-biphe-
nyl-4-carboxylate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,3-difluoro-4'-methoxybiphen-
yl-4-carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,6-difluoro-4'-methoxybiphen-
yl-4-carboxylic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,4'-dimethoxybiphenyl-4-carb-
oxylate; methyl
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-2,3--
difluorobenzoate;
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-2,3--
difluoro-benzoic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,4'-dimethoxybiphenyl-4-carb-
oxylic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3,4'-dimethoxybiphenyl-4-carb-
oxylate; methyl
5-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxyphenyl)-3-methylpi-
colinate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-ox-
ooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3,4'-dimethoxybiphen-
yl-4-carboxylic acid;
5-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxyphenyl)-3-methylpi-
colinic acid; methyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidin-2-yl)-3--
methylbenzoate;
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidin-2-yl)-3--
methyl-benzoic acid; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2'-(trifluoromethy-
l)biphenyl-4-carboxylate; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-4'-methoxy-2'-(trifl-
uoromethyl)biphenyl-4-carboxylate; ethyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-fluoro-4'-methoxy-2'-(trif-
luoromethyl)biphenyl-4-carboxylate; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4'-methoxy-2'-(trifl-
uoromethyl)biphenyl-4-carboxylate; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methyl-2'-(trifl-
uoromethyl)biphenyl-4-carboxylate; methyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidin-2-yl)-3--
fluorobenzoate;
5-(5-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxy-2-(trifluoromethy-
l)phenyl)-3-fluoropicolinic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2'-(trifluoromethy-
l)biphenyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-4'-methoxy-2'-(trifl-
uoromethyl)biphenyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-fluoro-4'-methoxy-2'-(trifl-
uoromethyl)biphenyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4'-methoxy-2'-(trifl-
uoromethyl)biphenyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methyl-2'-(trifl-
uoromethyl)biphenyl-4-carboxylic acid;
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidin-2-yl)-3--
fluoro-benzoic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-(trifluoromethyl-
)biphenyl-4-carboxylic acid; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2'-methyl-biphenyl-
-4-carboxylate;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2'-methylbiphenyl--
4-carboxylic acid; methyl
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-yl)-3-me-
thylbenzoate;
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-yl)-3-me-
thylbenzoic acid; methyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidin-2-yl)ben-
zoate; ethyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidin-2-yl)-2--
fluorobenzoate;
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidin-2-yl)ben-
zoic acid;
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-
-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidi-
n-2-yl)-2-fluoro-benzoic acid; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-2'-fluoro-4'-methoxy-
biphenyl-4-carboxylate;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-2'-fluoro-4'-methoxy-
biphenyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-chloro-4'-methoxy-2'-(trifl-
uoromethyl)biphenyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3,4'-dimethoxy-2'-(trifluorom-
ethyl)-biphenyl-4-carboxylic acid;
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-yl)-3-ch-
lorobenzoic acid;
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-yl)-3-fl-
uorobenzoic acid; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-chloro-4'-methoxy-2'-(trifl-
uoromethyl)biphenyl-4-carboxylate; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3,4'-dimethoxy-2'-(trifluorom-
ethyl)-biphenyl-4-carboxylate; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4'-methoxy-biphenyl--
4-carboxylate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4'-methoxybiphenyl-4-
-carboxylic acid;
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl)benzo-
ic acid;
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-o-
xooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2--
yl)-3-methylbenzoic acid;
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl)-3-fl-
uorobenzoic acid;
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl)-3-ch-
lorobenzoic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-fluoro-2-methylbiphenyl-4--
carboxylate; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methylbiphenyl-4-carboxylat-
e;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-fluoro-2-methylbiphenyl--
4-carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methylbiphenyl-4-carboxylic
acid; methyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl)benzo-
ate; methyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl)-3-me-
thylbenzoate; methyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl)-3-fl-
uorobenzoate; methyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl)-3-ch-
lorobenzoate; methyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl)-2,3--
difluorobenzoate; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,2'-difluoro-4'-methoxy-biph-
enyl-4-carboxylate; ethyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2',3-difluoro-4'-methoxy-bip-
henyl-4-carboxylate; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-3,4'-dimethoxybiphe-
nyl-4-carboxylate; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,2',3-trifluoro-4'-methoxy-b-
iphenyl-4-carboxylate;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,2'-difluoro-4'-methoxybiphe-
nyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2',3-difluoro-4'-methoxybiphe-
nyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-3,4'-dimethoxybiphe-
nyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,2',3-trifluoro-4'-methoxybi-
phenyl-4-carboxylic acid; methyl
5-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxyphenyl)-6-methylpi-
colinate;
5-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2--
oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxyphenyl)-6-
-methylpicolinic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-fluoro-2-(trifluoromethyl)-
biphenyl-4-carboxylate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-fluoro-2-(trifluoromethyl)-
biphenyl-4-carboxylic acid; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluorobiphenyl-4-carboxyla-
te; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-o-
xooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,2'-difluorobiphen-
yl-4-carboxylate; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-2-methylbiphenyl-4--
carboxylate; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-methylbiphenyl-4-carboxyla-
te; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-o-
xooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,2'-dimethylbiphen-
yl-4-carboxylate; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-2'-methylbiphenyl-4--
carboxylate;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-methylbiphenyl-4-carboxyli-
c acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoo-
xazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,2'-dimethylbiphenyl--
4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-2'-methylbiphenyl-4--
carboxylic acid,
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluorobiphenyl-4-carboxyli-
c acid,
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoo-
xazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,2'-difluorobiphenyl--
4-carboxylic acid,
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-2-methylbiphenyl-4--
carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methylbiphenyl-4-
-carboxamide; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2,2'-dimethylbiphe-
nyl-4-carboxylate;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2,2'-dimethylbiphe-
nyl-4-carboxylic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-methoxybiphenyl-4-carboxyl-
ate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxaz-
olidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-methoxybiphenyl-4-carb-
oxylic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-methoxy-2-methyl-biphenyl--
4-carboxylate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-methoxy-2-methylbiphenyl-4-
-carboxylic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-5'-methoxybiphenyl-4-
-carboxylate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-5'-methoxybiphenyl-4-
-carb oxylic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-fluoro-2-methylbiphenyl-4--
carboxylate; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-fluoro-2-(trifluoromethyl)-
biphenyl-4-carboxylate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-fluoro-2-methylbiphenyl-4--
carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-fluoro-2-(trifluoromethyl)-
biphenyl-4-carboxylic acid; methyl
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-yl)-3-fl-
uorobenzoate; methyl
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-yl)-3-ch-
lorobenzoate; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,5'-difluorobiphenyl-4-carbo-
xylate; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-fluorobiphenyl-4-carboxyla-
te; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-o-
xooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluorobiphenyl-4--
carboxylate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,5'-difluorobiphenyl-4-carbo-
xylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-fluorobiphenyl-4-carboxyli-
c acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoo-
xazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluorobiphenyl-4-car-
boxylic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-difluorophenyl)-4-methyl-2-oxooxazolidin-3-yl)meth-
yl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methylbiphenyl-4-carboxylate-
;
3'-(2-(((4S,5R)-5-(3,5-difluorophenyl)-4-methyl-2-oxooxazolidin-3-yl)met-
hyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methylbiphenyl-4-carboxylic
acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-fluorobiphenyl-4-carboxyla-
te;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazo-
lidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-fluorobiphenyl-4-carbox-
ylic acid; methyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin
3-yl)methyl)-4,4-dimethyleyclohex-1-enyl)pyridin-2-yl)-3-methylbenzoa-
te;
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxa-
zolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)pyridin-2-yl)-3-methylben-
zoic acid;
3'-(2-(((4S,5S)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-o-
xooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methyl-
biphenyl-4-carboxylic acid;
3'-(2-(((4R,5S)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethyl
cyclohex-1-enyl)-4'-methoxy-2-methylbiphenyl-4-carboxylic acid;
3'-(2-(((4R,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethyl
cyclohex-1-enyl)-4'-methoxy-2-methylbiphenyl-4-carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,4'-difluorobiphenyl-4-carbo-
xylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-2-(trifluoromethyl)-
biphenyl-4-carboxylic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,4'-difluorobiphenyl-4-carbo-
xylate; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethyleyclohex-1-enyl)-2'-fluoro-2-(trifluoromethyl)-
biphenyl-4-carboxylate; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-chloro-2-methylbiphenyl-4--
carboxylate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-chloro-2-methylbiphenyl-4--
carboxylic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-chloro-2-(trifluoromethyl)-
biphenyl-4-carboxylate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-chloro-2-(trifluoromethyl)-
biphenyl-4-carboxylic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4'-fluorobiphenyl-4--
carboxylate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4'-fluorobiphenyl-4--
carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4'-methoxybiphenyl-4-
-carboxamide;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-2-methylbiphenyl-4--
carboxamide;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-fluoro-2-(trifluoromethyl)-
biphenyl-4-carboxamide; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methyl-5'-(trifluoromethyl)-
biphenyl-4-carboxylate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methyl-5'-(trifluoromethyl)-
biphenyl-4-carboxylic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-(trifluoromethyl)biphenyl--
4-carboxylate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-(trifluoromethyl)biphenyl--
4-carboxylic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-5'-(trifluoromethyl)-
biphenyl-4-carboxylate;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-5'-(trifluoromethyl)-
biphenyl-4-carboxylic acid;
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(4'-(3,3-difluoroazetidi-
ne-1-carbonyl)-4-fluoro-2'-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyc-
lohex-1-enyl)methyl)-4-methyloxazolidin-2-one;
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(4-fluoro-4'-(3-hydroxy--
azetidine-1-carbonyl)-2'-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclo-
hex-1-enyl)methyl)-4-methyloxazolidin-2-one;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-N-ethyl-4'-fluoro-2-(trifluor-
omethyl)biphenyl-4-carboxamide;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-N-ethyl-4'-fluoro-N-methyl-2--
(trifluoromethyl)biphenyl-4-carboxamide;
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(4-fluoro-4'-(morpholine-
-4-carbonyl)-2'-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohex-1-eny-
l)methyl)-4-methyloxazolidin-2-one; methyl
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-yl)-3-(t-
rifluoromethyl)benzoate; and
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-yl)-3-(t-
rifluoromethyl)benzoic acid.
6. The compound of claim 5, wherein the compound is selected from
among the following compounds:
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methyl-biphenyl-
-4-carboxylic acid; methyl
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-me-
thylbenzoate;
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazo-
lidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-m-
ethylbenzoic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-4'-methoxybiphenyl-4-
-carboxylic acid; methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxybiphenyl-3-carboxyl-
ate; methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-4'-methoxy-2-methyl-
biphenyl-4-carboxylate;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-4'-methoxy-2-methyl-
biphenyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-4'-methoxybiphenyl--
4-carboxylic acid;
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazo-
lidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-i-
sopropylbenzoic acid;
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-ch-
lorobenzoic acid;
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-fl-
uorobenzoic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,3-difluoro-4'-methoxybiphen-
yl-4-carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,6-difluoro-4'-methoxybiphen-
yl-4-carboxylic acid;
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-2,3--
difluorobenzoic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,4'-dimethoxybiphenyl-4-carb-
oxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2'-(trifluoromethy-
l)biphenyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-4'-methoxy-2'-(trifl-
uoromethyl)biphenyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-fluoro-4'-methoxy-2'-(trifl-
uoromethyl)biphenyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4'-methoxy-2'-(trifl-
uoromethyl)biphenyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methyl-2'-(trifl-
uoromethyl)biphenyl-4-carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-(trifluoromethyl-
)biphenyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2'-methylbiphenyl--
4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-2'-fluoro-4'-methoxy-
biphenyl-4-carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4'-methoxybiphenyl-4-
-carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-fluoro-2-methylbiphenyl-4--
carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methylbiphenyl-4-carboxylic
acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,2'-difluoro-4'-methox-
ybiphenyl-4-carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-fluoro-2-(trifluoromethyl)-
biphenyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,2'-dimethylbiphenyl-4-carbo-
xylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-2-methylbiphenyl-4--
carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2,2'-dimethylbiphe-
nyl-4-carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-methoxy-2-methylbiphenyl-4-
-carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-fluoro-2-(trifluoromethyl)-
biphenyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethyl
cyclohex-1-enyl)-2'-fluoro-2-(trifluoromethyl)biphenyl-4-carboxylic
acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-chloro-2-methylbiphenyl-4--
carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-chloro-2-(trifluoromethyl)-
biphenyl-4-carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4'-fluorobiphenyl-4--
carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-5'-(trifluoromethyl)-
biphenyl-4-carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-N-ethyl-4'-fluoro-2-(trifluor-
omethyl)biphenyl-4-carboxamide;
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(4-fluoro-4'-(morpholine-
-4-carbonyl)-2'-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohex-1-eny-
l)methyl)-4-methyloxazolidin-2-one; and
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-yl)-3-(t-
rifluoromethyl)benzoic.
7. The compound of claim 6, wherein the compound is selected from
among the following compounds:
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methylbiphenyl-4-
-carboxylic acid;
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-me-
thylbenzoic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-4'-methoxy-2-methyl-
-biphenyl-4-carboxylic acid;
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-ch-
lorobenzoic acid;
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazo-
lidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-f-
luorobenzoic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,6-difluoro-4'-methoxybiphenyl-
-4-carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-(trifluoromethyl-
)biphenyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-2'-fluoro-4'-methoxy-
-biphenyl-4-carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4'-methoxybiphenyl-4-
-carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-fluoro-2-methylbiphenyl-4--
carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,2'-difluoro-4'-methoxybiphe-
nyl-4-carboxylic acid;
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-fluoro-2-(trifluoromethyl)-
biphenyl-4-carboxylic acid;
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-2-methylbiphenyl-4--
carboxylic acid; and
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-fluoro-2-(trifluoromethyl)-
biphenyl-4-carboxylic acid.
8. A pharmaceutical composition, comprising: a compound of formula
I of claim 1; and a pharmaceutically acceptable carrier.
9. (canceled)
10. A method for prevention or treatment of dyslipidemia or a
dyslipidemia-related disease, the method comprising administering
to a mammal in need thereof a composition comprising, as an active
ingredient, a compound of formula I of claim 1.
11. The method of claim 10, wherein the dyslipidemia-related
disease is angina pectoris, myocardial infarction or
arteriosclerosis.
12. The method of claim 10, wherein the mammal is a human.
Description
TECHNICAL FIELD
[0001] The present invention relates to novel biaryl- or
heterocyclic biaryl-substituted cyclohexene derivative compounds,
and more particularly to novel biaryl- or heterocyclic
biaryl-substituted cyclohexene derivatives having CETP inhibitory
activity, isomers thereof, pharmaceutically acceptable salts
thereof, the use for preparing pharmaceutical compositions,
pharmaceutical compositions comprising the same, methods of
treating diseases using these compositions, and methods for
preparing novel biaryl- or heterocyclic biaryl-substituted
cyclohexene derivatives.
BACKGROUND ART
[0002] Dyslipidemia generally refers to high blood cholesterol
levels and is asymptomatic. However, dyslipidemia is a very serious
condition, because it causes angina pectoris, myocardial infarction
and arteriosclerosis. Statins, drugs that are commonly used to
treat hyperlipidemia, exhibit therapeutic effects mainly by
lowering LDL-C, but their effects on the prevention of
cardiovascular diseases are still very insufficient. A recent study
reported that not only lowering low-density lipoprotein cholesterol
(LDL-C) levels, but also increasing high-density lipoprotein
cholesterol (HDL-C) levels is very effective in preventing
cardiovascular diseases (Goldbourt et al., 1997, 17, 107-113).
Among drugs that are used to increase HDL-C levels, the most
effective drug is Niacin. However, this drug needs to be taken in
relatively large doses and causes side effects such as facial
flushing (Taylor et al., Circulation, 2004, 110, 3512-3517).
[0003] Meanwhile, cholesterol ester transfer protein (CETP) is a
protein that participates in reverse cholesterol transport (the
transport of cholesterol from peripheral tissue to the liver). When
CETP is inhibited, HDL-C levels can be effectively increased, thus
preventing cardiovascular diseases. Accordingly, the development of
compounds capable of inhibiting CETP activity is very important
(Barter et al., Arterioscler Thromb Vase Biol, 2003, 23,
160-167).
[0004] CETP inhibitors developed to date include Torcetrapib
(International Patent Publication No. WO 02/088085), Anacetrapib
(International Patent Publication No. WO 2006/014357) and
Evacetrapib (US Patent Publication No. 2010/0331309), which are
structurally similar to each other. In addition, Dalcetrapib
(International Patent Publication No. WO 98/35937), a benzenethiol
derivative, is known as a CETP inhibitor.
[0005] However, among these CETP inhibitors, Torcetrapib (Pfizer)
causes an increase in blood pressure and an increase in mortality
rate, and thus was stopped phase III clinical trial. It was
reported that such side effects occur because Torcetrapib increases
the levels of hormones, such as aldosterone and corticosterone,
associated with an elevation in blood pressure, and increases the
thickness of the vascular wall to cause inflammation, thus
increasing mortality rate (Forrest et al, British Journal of
Pharmacology, 2008, 1-9).
[0006] The other CETP inhibitor Dalcetrapib (Roche) was also
stopped in phase III clinical trial, and it is known that
Dalcetrapib does not have the side effects of Torcetrapib, but has
insufficient effects (Alyse S Goldberg et al, Drug Design
Development and Therapy, 2012, 6, 251-259).
[0007] Recently, the results of phase III DEFINE trial (Determining
the Efficacy and Tolerability of CETP Inhibition with Anacetrapib))
for Anacetrapib (Merck) indicated that, in the case of patients
administered with Anacetrapib, the HDL-c level increased by 138%
and the LDL-c level decreased by 40% (Philip Barter et al, The New
England Journal of Medicine, 2010, 363, 2406-2415). Based on such
results, Merck has performed clinical trials on about 30,000
persons in order to examine whether administration of Anacetrapib
ameliorate cardiovascular diseases (ClinicalTrials.gov,
NCT01252953).
[0008] In addition, the results of phase II clinical trials for
Evacetrapib (Lilly) showed that Evacetrapib increases HDL-c levels
in a dose-dependent manner and does not cause side effects such
blood pressure elevation. Recently, Evacetrapib entered phase III
clinical trials on 10,000 persons (ClinicalTrials.gov,
NCT01687998).
[0009] Efforts have been made to develop novel CETP inhibitors
having more advantages over CETP inhibitors developed to date or
CETP inhibitors being developed. Such advantages may include
excellent efficacy, reduced off-target effects, increased
bioavailability, reduced food effects, etc.
DISCLOSURE OF INVENTION
Technical Problem
[0010] It is an object of the present invention to provide novel
biaryl- or heterocyclic biaryl-substituted cyclohexene derivative
compounds, isomers thereof, or pharmaceutically acceptable salts
thereof.
[0011] Another object of the present invention is to provide
pharmaceutical compositions comprising novel biaryl- or
heterocyclic biaryl-substituted cyclohexene derivatives, which have
less side effects and can effectively inhibit CETP, isomers
thereof, or pharmaceutically acceptable salts thereof.
[0012] Still another object of the present invention is to provide
the use of the above compounds, isomers or pharmaceutically
acceptable salts for preparing pharmaceutical compositions, and
methods of treating diseases using the above compositions, and
methods for preparing the above compounds, isomers or
pharmaceutically acceptable salts.
Solution to Problem
[0013] Novel CETP Inhibitor Compounds
[0014] In accordance with a first embodiment of the present
invention, there are provided novel biaryl- or heterocyclic
biaryl-substituted cyclohexene derivative compounds of the
following formula I, isomers thereof, or pharmaceutically
acceptable salts thereof:
##STR00001##
[0015] wherein
[0016] R.sup.1 is --H or --C.sub.1-C.sub.3 alkyl;
[0017] R.sup.2 is --H, halogen or --C.sub.1-C.sub.3 alkyl;
[0018] R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each independently
--H, halogen, --NO.sub.2, --C.sub.1-C.sub.3 alkyl, or
--OC.sub.1-C.sub.3 alkyl;
[0019] R.sup.7 is --H, --(C.dbd.O)OR.sub.8, or
##STR00002##
[0020] R.sup.8 is --H or --C.sub.1-C.sub.3 alkyl;
[0021] R.sup.11 and R.sup.12 are each independently --H or
--C.sub.1-C.sub.3 alkyl or may form a 4- to 6-membered non-aromatic
ring, wherein the non-aromatic ring may contain 0 to 2 N or O
heteroatoms, and one or more --H in the non-aromatic ring may
substituted with halogen or --OH;
[0022] A.sup.1, A.sup.2 and A.sup.3 are each independently N or
CR.sup.9, wherein if A.sup.2 or A.sup.3 is N, A.sup.1 is
CR.sup.9;
[0023] R.sup.9 is --H, halogen, --C.sub.1-C.sub.3 alkyl or
--OC.sub.1-C.sub.3 alkyl;
[0024] B is N or CR.sup.10;
[0025] R.sup.10 is --H, halogen, --C.sub.1-C.sub.3 alkyl,
--OC.sub.1-C.sub.3 alkyl, --(C.dbd.O)OR.sup.8, or
##STR00003##
[0026] provided that one or more --H atoms in the --C.sub.1-C.sub.3
alkyl or the --OC.sub.1-C.sub.3 alkyl may be substituted with --F
or --CH.sub.3, and if R.sup.7 is --H, B is CR.sup.10, and R.sup.10
is --(C.dbd.O)OR.sup.8 or
##STR00004##
and if R.sup.7 is not --H, R.sup.10 cannot be --(C.dbd.O)OR.sup.8
or
##STR00005##
[0027] In accordance with a second embodiment of the present
invention, there are provided compounds of formula I, isomers
thereof, or pharmaceutically acceptable salts thereof, wherein
[0028] R.sup.1 is --H or --CH.sub.3;
[0029] R.sup.2 is --F or --CF.sub.3;
[0030] R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each independently
--H, --F, --NO.sub.2, --CH.sub.3, --CH(CH.sub.3).sub.2, --CF.sub.3
or --OCH.sub.3;
[0031] R.sup.7 is --H, --(C.dbd.O)OR.sup.8, or
##STR00006##
[0032] R.sup.8 is --H, --CH.sub.3 or --CH.sub.2CH.sub.3;
[0033] R.sup.11 and R.sup.12 are each independently --H, --CH.sub.3
or --CH.sub.2CH.sub.3 or may form 4- to 6-membered non-aromatic
ring, wherein the non-aromatic ring may contain 0 to 2 N or O
heteroatoms, and one or more --H atoms in the non-aromatic ring may
be substituted with --F or --OH;
[0034] A.sup.1, A.sup.2 and A.sup.3 are each independently N or
CR.sup.9, wherein if A.sup.2 or A.sup.3 is N, A' is CR.sup.9;
[0035] R.sup.9 is --H, --F, --Cl, --CH.sub.3, --CF.sub.3 or
--OCH.sub.3;
[0036] B is N or CR.sup.10;
[0037] R.sup.10 is --H, --F, --Cl, --CH.sub.3, --OCH.sub.3,
--CO.sub.2H, --CO.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.3, or
##STR00007##
[0038] provided that if R.sup.7 is --H, B is CR.sup.10, and
R.sup.10 is --CO.sub.2H, --CO.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.3, or
##STR00008##
and if R.sup.7 is not --H, R.sup.10 is not --CO.sub.2H,
--CO.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.3, or
##STR00009##
[0039] In accordance with a third embodiment of the present
invention, there are provided compounds of formula I, isomers
thereof, or pharmaceutically acceptable salts thereof, wherein
[0040] R.sup.1 is --CH.sub.3;
[0041] R.sup.2 is --CF.sub.3;
[0042] R.sup.3 is --H, --F, --Cl or --OCH.sub.3;
[0043] R.sup.4 is --H, --F, --Cl, --CH.sub.3, --CH(CH.sub.3).sub.2,
--CF.sub.3 or --OCH.sub.3;
[0044] R.sup.5 is --H, --F or --Cl;
[0045] R.sup.6 is --H;
[0046] R.sup.7 is --H, --(C.dbd.O)OH,
##STR00010##
[0047] A.sup.1, A.sup.2 and A.sup.3 are each independently N or
CR.sup.9, wherein if A.sup.2 or A.sup.3 is N, A.sup.1 is
CR.sup.9;
[0048] R.sup.9 is --H, --F, --CH.sub.3, --CF.sub.3 or
--OCH.sub.3;
[0049] B is CR.sup.10;
[0050] R.sup.10 is --H, --F or --CO.sub.2CH.sub.3;
[0051] provided that if R.sup.7 is --H, B is CR.sup.10, and
R.sup.10 is --CO.sub.2CH.sub.3, and if R.sup.7 is not --H, R.sup.10
is not --CO.sub.2CH.sub.3.
[0052] In accordance with a forth embodiment of the present
invention, there are provided compounds of formula I, isomers
thereof, or pharmaceutically acceptable salts thereof, wherein
[0053] R.sup.3 is --H, --F or --OCH.sub.3;
[0054] R.sup.4 is --H, --F, --Cl, --CH.sub.3 or --CF.sub.3;
[0055] R.sup.5 is --H or --F;
[0056] R.sup.7 is --(C.dbd.O)OH;
[0057] A.sup.1 is N or CR.sup.9;
[0058] A.sup.2 and A.sup.3 are each independently CR.sup.9;
[0059] R.sup.9 is --H or --F; and
[0060] B is CH.
[0061] Preferred Examples of the compounds of formula I are as
follows:
TABLE-US-00001 No. Name of compound 553 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-4'-methoxy-2-methylbiphenyl-4-carboxylate 554
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4'-methoxy-2-methylbiphenyl-4-carboxylic acid 555 methyl
4-(3-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-
yl)-3-methylbenzoate 556 methyl 4-(3-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-
yl)benzoate 557
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-methoxypyridin-5-yl)-3-methylbenzoic acid 558
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-methoxypyridin-5-yl)benzoic acid 559 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-4'-methoxybiphenyl-4-carboxylate 560 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2-fluoro-4'-methoxybiphenyl-4-carboxylate 561
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-fluoro-4'-methoxybiphenyl-4-carboxylic acid 564 methyl
5-(3-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4- methoxyphenyl)picolinate
565 3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4'-methoxybiphenyl-4-carboxylic acid 567 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-4'-methoxybiphenyl-3-carboxylate 568
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4'-methoxybiphenyl-3-carboxylic acid 569 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-4'-methoxy-2-nitrobiphenyl-4-carboxylate 572 methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2'-fluoro-4'-methoxy-2-methylbiphenyl-4-carboxylate 573
methyl 5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2'-fluoro-4'-methoxybiphenyl-4-carboxylate 574
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2'-fluoro-4'-methoxy-2-methylbiphenyl-4-carboxylic acid 575
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2'-fluoro-4'-methoxybiphenyl-4-carboxylic acid 577 methyl
4-(3-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-
yl)-3-isopropylbenzoate 578
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-methoxypyridin-5-yl)-3-isopropylbenzoic acid 579 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)cyclohex-1-enyl)-4'-
methoxy-2-methylbiphenyl-4-carboxylate 580 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)cyclohex-1-enyl)-2-
fluoro-4'-methoxybiphenyl-4-carboxylate 581
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)cyclohex-1-enyl)-4'-
methoxy-2-methylbiphenyl-4-carboxylic acid 582
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)cyclohex-1-enyl)-2-
fluoro-4'-methoxybiphenyl-4-carboxylic acid 583 methyl
4-(3-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-
yl)-3-chlorobenzoate 584
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-methoxypyridin-5-yl)-3-chlorobenzoic acid 585 methyl
4-(3-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-
yl)-3-fluorobenzoate 586
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-methoxypyridin-5-yl)-3-fluorobenzoic acid 587 methyl
3-(3-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-
yl)benzoate 588
3-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-methoxypyridin-5-yl)benzoic acid 590 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2,3-difluoro-4'-methoxybiphenyl-4-carboxylate 591 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2,6-difluoro-4'-methoxybiphenyl-4-carboxylate 592
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2,3-difluoro-4'-methoxybiphenyl-4-carboxylic acid 593
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2,6-difluoro-4'-methoxybiphenyl-4-carboxylic acid 594 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2,4'-dimethoxybiphenyl-4-carboxylate 595 methyl
4-(3-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-
yl)-2,3-difluorobenzoate 596
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-methoxypyridin-5-yl)-2,3-difluorobenzoic acid 597
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2,4'-dimethoxybiphenyl-4-carboxylic acid 599 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-3,4'-dimethoxybiphenyl-4-carboxylate 600 methyl
5-(3-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxyphenyl)-3-
methylpicolinate 601
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-3,4'-dimethoxybiphenyl-4-carboxylic acid 602
5-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4-methoxyphenyl)-3-methylpicolinic acid 603 methyl
4-(4-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidin-
2-yl)-3-methylbenzoate 604
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-5-methoxypyrimidin-2-yl)-3-methylbenzoic acid 605 methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-4'-methoxy-2'-(trifluoromethyl)biphenyl-4- carboxylate 606
methyl 5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2-fluoro-4'-methoxy-2'-(trifluoromethyl)biphenyl-4-
carboxylate 607 ethyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-3-fluoro-4'-methoxy-2'-(trifluoromethyl)biphenyl-4-
carboxylate 608 methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2-chloro-4'-methoxy-2'-(trifluoromethyl)biphenyl-4-
carboxylate 609 methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-4'-methoxy-2-methyl-2'-(trifluoromethyl)biphenyl-4-
carboxylate 610 methyl 4-(4-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidin-
2-yl)-3-fluorobenzoate 611
5-(5-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4-methoxy-2-(trifluoromethyl)phenyl)-3- fluoropicolinic acid
612 5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4'-methoxy-2'-(trifluoromethyl)biphenyl-4-carboxylic acid 613
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-fluoro-4'-methoxy-2'-(trifluoromethyl)biphenyl-4-
carboxylic acid 614
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-3-fluoro-4'-methoxy-2'-(trifluoromethyl)biphenyl-4-
carboxylic acid 615
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-chloro-4'-methoxy-2'-(trifluoromethyl)biphenyl-4-
carboxylic acid 616
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4'-methoxy-2-methyl-2'-(trifluoromethyl)biphenyl-4-
carboxylic acid 617
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-5-methoxypyrimidin-2-yl)-3-fluorobenzoic acid 618
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4'-methoxy-2-(trifluoromethyl)biphenyl-4-carboxylic acid 619
methyl 5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-4'-methoxy-2'-methylbiphenyl-4-carboxylate 620
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4'-methoxy-2'-methylbiphenyl-4-carboxylic acid 621 methyl
4-(2-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-
yl)-3-methylbenzoate 622
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-3-methoxypyridin-6-yl)-3-methylbenzoic acid 625 methyl
4-(4-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidin-
2-yl)benzoate 626 ethyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-5-methoxypyrimidin-2-yl)-2-fluorobenzoate 628
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-5-methoxypyrimidin-2-yl)benzoic acid 629
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-5-methoxypyrimidin-2-yl)-2-fluorobenzoic acid 630 methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2-chloro-2'-fluoro-4'-methoxybiphenyl-4-carboxylate 631
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-chloro-2'-fluoro-4'-methoxybiphenyl-4-carboxylic acid 632
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-3-chloro-4'-methoxy-2'-(trifluoromethyl)biphenyl-4-
carboxylic acid 633
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-3,4'-dimethoxy-2'-(trifluoromethyl)biphenyl-4- carboxylic
acid 636 4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-3-methoxypyridin-6-yl)-3-chlorobenzoic acid 637
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-3-methoxypyridin-6-yl)-3-fluorobenzoic acid 638 methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-3-chloro-4'-methoxy-2'-(trifluoromethyl)biphenyl-4-
carboxylate 639 methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-3,4'-dimethoxy-2'-(trifluoromethyl)biphenyl-4- carboxylate
642 methyl 3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2-chloro-4'-methoxybiphenyl-4-carboxylate 643
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-chloro-4'-methoxybiphenyl-4-carboxylic acid 644
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-5-methoxypyridin-2-yl)benzoic acid 645
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-5-methoxypyridin-2-yl)-3-methylbenzoic acid 646
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-5-methoxypyridin-2-yl)-3-fluorobenzoic acid 647
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-5-methoxypyridin-2-yl)-3-chlorobenzoic acid 648 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-5'-fluoro-2-methylbiphenyl-4-carboxylate 649 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2-methylbiphenyl-4-carboxylate 650
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-5'-fluoro-2-methylbiphenyl-4-carboxylic acid 651
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-methylbiphenyl-4-carboxylic acid 652 methyl
4-(4-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-
yl)benzoate 653 methyl 4-(4-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-
yl)-3-methylbenzoate 654 methyl 4-(4-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-
yl)-3-fluorobenzoate 655 methyl 4-(4-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-
yl)-3-chlorobenzoate 656 methyl 4-(4-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-
yl)-2,3-difluorobenzoate 657 methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2,2'-difluoro-4'-methoxybiphenyl-4-carboxylate 658 ethyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2',3-difluoro-4'-methoxybiphenyl-4-carboxylate 659 methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2'-fluoro-3,4'-dimethoxybiphenyl-4-carboxylate 660 methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2,2',3-trifluoro-4'-methoxybiphenyl-4-carboxylate 661
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2,2'-difluoro-4'-methoxybiphenyl-4-carboxylic acid 662
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2',3-difluoro-4'-methoxybiphenyl-4-carboxylic acid 663
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2'-fluoro-3,4'-dimethoxybiphenyl-4-carboxylic acid 664
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2,2',3-trifluoro-4'-methoxybiphenyl-4-carboxylic acid 665
methyl 5-(3-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxyphenyl)-6-
methylpicolinate 666
5-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4-methoxyphenyl)-6-methylpicolinic acid 667 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-5'-fluoro-2-(trifluoromethyl)biphenyl-4-carboxylate 668
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-5'-fluoro-2-(trifluoromethyl)biphenyl-4-carboxylic acid 670
methyl 5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2'-fluorobiphenyl-4-carboxylate 671 methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2,2'-difluorobiphenyl-4-carboxylate 672 methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2'-fluoro-2-methylbiphenyl-4-carboxylate 673 methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2'-methylbiphenyl-4-carboxylate 674 methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2,2'-dimethylbiphenyl-4-carboxylate 675 methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2-fluoro-2'-methylbiphenyl-4-carboxylate 676
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2'-methylbiphenyl-4-carboxylic acid 677
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2,2'-dimethylbiphenyl-4-carboxylic acid 678
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-fluoro-2'-methylbiphenyl-4-carboxylic acid 679
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2'-fluorobiphenyl-4-carboxylic acid 680
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2,2'-difluorobiphenyl-4-carboxylic acid 681
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2'-fluoro-2-methylbiphenyl-4-carboxylic acid 682
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4'-methoxy-2-methylbiphenyl-4-carboxamide 683 methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-4'-methoxy-2,2'-dimethylbiphenyl-4-carboxylate 684
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4'-methoxy-2,2'-dimethylbiphenyl-4-carboxylic acid 686 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-5'-methoxybiphenyl-4-carboxylate 687
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-5'-methoxybiphenyl-4-carboxylic acid 688 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-5'-methoxy-2-methylbiphenyl-4-carboxylate 689
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-5'-methoxy-2-methylbiphenyl-4-carboxylic acid 690 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2-fluoro-5'-methoxybiphenyl-4-carboxylate 691
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-fluoro-5'-methoxybiphenyl-4-carboxylic acid 692 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-4'-fluoro-2-methylbiphenyl-4-carboxylate 693 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-4'-fluoro-2-(trifluoromethyl)biphenyl-4-carboxylate 694
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4'-fluoro-2-methylbiphenyl-4-carboxylic acid 695
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4'-fluoro-2-(trifluoromethyl)biphenyl-4-carboxylic acid 696
methyl 4-(2-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-
yl)-3-fluorobenzoate 697 methyl 4-(2-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-
yl)-3-chlorobenzoate 699 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2,5'-difluorobiphenyl-4-carboxylate 700 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-5'-fluorobiphenyl-4-carboxylate 701 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2-fluorobiphenyl-4-carboxylate 702
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2,5'-difluorobiphenyl-4-carboxylic acid 703
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-5'-fluorobiphenyl-4-carboxylic acid 704
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-fluorobiphenyl-4-carboxylic acid 705 methyl
3'-(2-(((4S,5R)-5-(3,5-difluorophenyl)-4-methyl-2-
oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-
methoxy-2-methylbiphenyl-4-carboxylate 706
3'-(2-(((4S,5R)-5-(3,5-difluorophenyl)-4-methyl-2-
oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-
methoxy-2-methylbiphenyl-4-carboxylic acid 708 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-4'-fluorobiphenyl-4-carboxylate 709
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4'-fluorobiphenyl-4-carboxylic acid 714 methyl
4-(4-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)pyridin-2-yl)-3-
methylbenzoate 716
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)pyridin-2-yl)-3-methylbenzoic acid 718
3'-(2-(((4S,5S)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4'-methoxy-2-methylbiphenyl-4-carboxylic acid 719
3'-(2-(((4R,5S)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4'-methoxy-2-methylbiphenyl-4-carboxylic acid 720
3'-(2-(((4R,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4'-methoxy-2-methylbiphenyl-4-carboxylic acid 722
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2,4'-difluorobiphenyl-4-carboxylic acid 723
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2'-fluoro-2-(trifluoromethyl)biphenyl-4-carboxylic acid 724
methyl 3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2,4'-difluorobiphenyl-4-carboxylate 725 methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2'-fluoro-2-(trifluoromethyl)biphenyl-4-carboxylate 726
methyl 3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-4'-chloro-2-methylbiphenyl-4-carboxylate 727
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4'-chloro-2-methylbiphenyl-4-carboxylic acid 728 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-4'-chloro-2-(trifluoromethyl)biphenyl-4-carboxylate 729
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4'-chloro-2-(trifluoromethyl)biphenyl-4-carboxylic acid 738
methyl 3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2-chloro-4'-fluorobiphenyl-4-carboxylate 739
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-chloro-4'-fluorobiphenyl-4-carboxylic acid 740
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-chloro-4'-methoxybiphenyl-4-carboxamide 741
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2'-fluoro-2-methylbiphenyl-4-carboxamide 742
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-4'-fluoro-2-(trifluoromethyl)biphenyl-4-carboxamide 743
methyl 3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2-methyl-5'-(trifluoromethyl)biphenyl-4-carboxylate 744
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-methyl-5'-(trifluoromethyl)biphenyl-4-carboxylic acid 745
methyl 3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-5'-(trifluoromethyl)biphenyl-4-carboxylate 746
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-5'-(trifluoromethyl)biphenyl-4-carboxylic acid 747 methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-
4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-
1-enyl)-2-fluoro-5'-(trifluoromethyl)biphenyl-4-carboxylate 748
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-2-fluoro-5'-(trifluoromethyl)biphenyl-4-carboxylic acid 754
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(4'-(3,3-
difluoroazetidine-1-carbonyl)-4-fluoro-2'-
(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohex-1-
enyl)methyl)-4-methyloxazolidin-2-one 755
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(4-fluoro-
4'-(3-hydroxyazetidine-1-carbonyl)-2'-
(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohex-1-
enyl)methyl)-4-methyloxazolidin-2-one 756
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-N-ethyl-4'-fluoro-2-(trifluoromethyl)biphenyl-4- carboxamide
757 3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-N-ethyl-4'-fluoro-N-methyl-2-
(trifluoromethyl)biphenyl-4-carboxamide 758
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(4-fluoro-
4'-(morpholine-4-carbonyl)-2'-(trifluoromethyl)biphenyl-3-
yl)-4,4-dimethylcyclohex-1-enyl)methyl)-4-methyloxazolidin- 2-one
763 methyl 4-(2-(2-(((4S,5R)-5-(3,5-
bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-
yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-
yl)-3-(trifluoromethyl)benzoate 764
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-
methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-
enyl)-3-methoxypyridin-6-yl)-3-(trifluoromethyl)benzoic acid
Pharmaceutical Compositions Comprising Novel CETP Inhibitor
Compounds
[0062] The present invention provides pharmaceutical compositions
comprising the compounds of formula I, isomers thereof, or
pharmaceutically acceptable salts thereof, together with
pharmaceutically acceptable carriers.
[0063] The carriers that are used in the present invention may be
those that are conventionally used in the art, and Examples thereof
include, but are not limited to, sugar, starch, microcrystalline
cellulose, lactose (lactose hydrate), glucose, di-mannitol,
alginate, alkaline earth metal salts, clay, polyethylene glycol,
anhydrous dibasic calcium phosphate, or mixtures thereof.
[0064] Further, according to another embodiment of the present
invention, the pharmaceutical compositions may contain additives
such as binders, disintegrants, lubricants, pH-adjusting agents,
antioxidants, and the like.
[0065] Examples of the binders that may be used in the present
invention include, but are not limited to, starch, microcrystalline
cellulose, highly dispersed silica, mannitol, di-mannitol, sucrose,
lactose hydrate, polyethylene glycol, polyvinylpyrrolidone
(povidone), polyvinylpyrrolidone copolymer (copovidone),
hypromellose, hydroxypropyl cellulose, natural gum, synthetic gum,
copovidone, gelatin, or mixtures thereof.
[0066] Examples of the disintegrants that may be used in the
present invention include, but are not limited to, starches or
modified starches such as sodium starch glyconate, maize starch,
potato starch or pregelatinized starch; clays such as bentonite,
montmorillonite, or veegum; celluloses such as microcrystalline
cellulose, hydroxypropylcellulose or carboxymethylcellulose; algins
such as sodium alginate or alginic acid; crosslinked celluloses
such as croscarmellose sodium; gums such as guar gum or xanthan
gum; crosslinked polymers such as crosslinked polyvinylpyrrolidone
(crospovidone); effervescent formulations such as sodium
bicarbonate or citric acid; or mixtures thereof.
[0067] Examples of the lubricants that may be used in the present
invention include, but are not limited to, talc, stearic acid,
magnesium stearate, calcium stearate, sodium lauryl sulfate,
hydrogenated vegetable oil, sodium benzoate, sodium stearyl
fumarate, glyceryl behenate, glyceryl monooleate, glyceryl
monostearate, glyceryl palmitostearate, colloidal silicon dioxide,
or mixtures thereof.
[0068] Examples of the pH-adjusting agents that may be used in the
present invention include, but are not limited to, acidifying
agents such as acetic acid, adipic acid, ascorbic acid, sodium
ascorbate, sodium etherate, malic acid, succinic acid, tartaric
acid, fumaric acid or citric acid, and basifying agents such as
precipitated calcium carbonate, ammonia water, meglumine, sodium
carbonate, magnesium oxide, magnesium carbonate, sodium citrate, or
tribasic calcium phosphate.
[0069] Examples of the antioxidants that may be used in the present
invention include, but are not limited to, dibutyl hydroxytoluene,
butylated hydroxyanisole, tocopherol acetate, tocopherol, propyl
gallate, sodium hydrogen sulfite, sodium pyrosulfite, and the
like.
[0070] The compounds of formula I according to the present
invention exhibit the effect of inhibiting CETP activity to
increase high-density lipoprotein cholesterol (HDL-C) levels and
reduce low-density lipoprotein cholesterol (LDL-C) levels. Thus,
pharmaceutical compositions containing the compounds of formula I
according to the present invention, isomers thereof, or
pharmaceutically acceptable salts thereof, can be used for the
prevention or treatment of dyslipidemia or dyslipidemia-related
vascular diseases.
[0071] The dyslipidemia-related vascular diseases may include
angina pectoris, myocardial infarction, and atherosclerosis.
[0072] Method for Prevention or Treatment of Dyslipidemia or
Dyslipidemia-Related Vascular Diseases
[0073] The present invention also provides a method for preventing
or treating dyslipidemia or dyslipidemia-related vascular diseases,
the method comprising administering a composition, which contains
the compound of formula I as an active ingredient, to a subject in
need thereof.
[0074] The composition that is used in the inventive method for
preventing or treating dyslipidemia or dyslipidemia-related
vascular diseases includes the pharmaceutical composition described
in the specification.
[0075] In addition, the subject in the prevention or treatment
method of the present invention includes mammals, particularly
humans.
[0076] Methods for Preparing Novel CETP Inhibitor Compounds
[0077] The compounds of formula I according to the present
invention can be prepared according to methods described in various
literatures, but are not limited thereto.
[0078] Hereinafter, methods for preparing the compounds of formula
I will be described in detail with reference to the following
reaction schemes 1 and 2.
##STR00011##
[0079] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, A.sup.1, A.sup.2, A.sup.3 and B are each as
defined in formula I. In addition, X, Y, Z and Q may each
independently be halogen,
##STR00012##
and the halogen is preferably chloride (--Cl) or bromide
(--Br).
[0080] First, a compound of formula III as a starting material may
be reacted with phosphorus tribromide (PBr.sub.3) or phosphorous
oxychloride (POCl.sub.3) in dimethylformamide (DMF) [Vilsmeier
reaction] to prepare a halogenated compound of formula IV.
[0081] In the Vilsmeier reaction, methylene chloride may be used as
a solvent, and the reaction temperature is 0.about.70.degree. C.,
and preferably 0.about.45.degree. C.
[0082] The prepared compound of formula IV may be reacted with a
compound of formula V according to the Suzuki reaction (Morris, G.
A., et al., Tetrahedron Lett., 2001, 42, 2093) or the Ullman
reaction (Martin G. Banwell et al. Org. Lett. 2004, 6, 2741) to
prepare a compound of formula VI.
[0083] A solvent that is used in the Suzuki reaction or the Ullman
reaction is dimethoxyethane (DME), dimethylsulfoxide (DMSO), water,
or a mixture thereof, and the reaction temperature is
80.about.150.degree. C., and preferably 80.about.100.degree. C.
[0084] The prepared compound of formula VI may be subjected to
reductive amination with a compound of formula VII to prepare a
compound of formula VIII. The compound of formula VII that is used
in the reductive amination reaction can be prepared with reference
to the literature (International Patent Publication No. WO
2006/014357; Jingjun Yin et al., J. Org. Chem. 2006, 840).
[0085] The prepared compound of formula VIII may be subjected to
cyclization with triphosgene to prepare a desired compound of
formula II.
[0086] The Suzuki or Ullman reaction step and the reductive
amination/cyclization reaction step are not limited to the
above-described order and may be carried out in a reverse
order.
[0087] The prepared compound of formula II may be subjected to the
Suzuki reaction according to the following reaction scheme 2 to
prepare a compound of formula I.
##STR00013##
[0088] The compound of formula I according to the present invention
can be prepared according to reaction schemes 1 and 2 above, and
compounds of more specific Examples of the present invention can be
prepared according to the following reaction schemes 3 to 18.
##STR00014## ##STR00015##
TABLE-US-00002 Compounds R.sup.1 R.sup.4 R.sup.5 R.sup.6 R.sup.7 B
553 CH.sub.3 CH.sub.3 H H CO.sub.2CH.sub.3 CH 554 CH.sub.3 CH.sub.3
H H CO.sub.2H CH 559 CH.sub.3 H H H CO.sub.2CH.sub.3 CH 565
CH.sub.3 H H H CO.sub.2H CH 560 CH.sub.3 F H H CO.sub.2CH.sub.3 CH
561 CH.sub.3 F H H CO.sub.2H CH 564 CH.sub.3 H H H CO.sub.2CH.sub.3
N 567 CH.sub.3 H H H H CCO.sub.2CH.sub.3 568 CH.sub.3 H H H H
CCO.sub.2H 569 CH.sub.3 NO.sub.2 H H CO.sub.2CH.sub.3 CH 579 H
CH.sub.3 H H CO.sub.2CH.sub.3 CH 581 H CH.sub.3 H H CO.sub.2H CH
580 H F H H CO.sub.2CH.sub.3 CH 582 H F H H CO.sub.2H CH 590
CH.sub.3 F H H CO.sub.2CH.sub.3 CF 592 CH.sub.3 F H H CO.sub.2H CF
591 CH.sub.3 F F H CO.sub.2CH.sub.3 CH 593 CH.sub.3 F F H CO.sub.2H
CH 599 CH.sub.3 H H H CO.sub.2CH.sub.3 COCH.sub.3 601 CH.sub.3 H H
H CO.sub.2H COCH.sub.3 600 CH.sub.3 H H CH.sub.3 CO.sub.2CH.sub.3 N
602 CH.sub.3 H H CH.sub.3 CO.sub.2H N 665 CH.sub.3 CH.sub.3 H H
CO.sub.2CH.sub.3 N 666 CH.sub.3 CH.sub.3 H H CO.sub.2H N
[0089] Reaction scheme 3 above shows a general process for
synthesizing compounds 553, 554, 559, 560, 561, 564, 565, 567, 568,
569, 579, 580, 581, 582, 590, 591, 592, 593, 599, 600, 601, 602,
665 and 666 of the present invention, and other compounds of the
present invention can also be prepared according to reaction scheme
3 above. In the above reaction scheme, R.sup.1, R.sup.4, R.sup.5,
R.sup.6, R.sup.7 and B are each as defined above, and Q may be
##STR00016##
[0090] Compound 1 synthesized according to a known method is
subjected to the Suzuki reaction with
5-chloro-2-methoxyphenylboronic acid in the presence of a palladium
catalyst to synthesize compounds 3a and 3b, which are then reacted
with compound 4 prepared according to a method described in the
literature (International Patent Publication No. WO 2006/014357 A1;
Jingjun Yin et al., J. Org. Chem. 2006, 840), thereby preparing
compounds 5a and 5b. The prepared compounds 5a and 5b are reacted
with triphosgene to synthesize compounds 6a and 6b, which are then
subjected to the Suzuki reaction with various boronic acid
derivatives in the presence of a palladium catalyst, thereby
synthesizing ester compounds 553, 559, 560, 564, 567, 569, 579,
580, 590, 591, 599, 600 and 665. In addition, these ester compounds
may be hydrolyzed with lithium hydroxide to obtain desired
carboxylic acid compounds 554, 561, 565, 568, 581, 582, 592, 593,
601, 602 and 666.
##STR00017## ##STR00018##
TABLE-US-00003 Compounds R.sup.4 R.sup.7 B 555 CH.sub.3
CO.sub.2CH.sub.3 CH 557 CH.sub.3 CO.sub.2H CH 556 H
CO.sub.2CH.sub.3 CH 558 H CO.sub.2H CH 583 Cl CO.sub.2CH.sub.3 CH
584 Cl CO.sub.2H CH 585 F CO.sub.2CH.sub.3 CH 586 F CO.sub.2H CH
587 H H CCO.sub.2CH.sub.3 588 H H CCO.sub.2H 595 F CO.sub.2CH.sub.3
CF 596 F CO.sub.2H CF
[0091] Reaction scheme 4 above shows a general process for
synthesizing compounds 555, 556, 557, 558, 583, 584, 585, 586, 587,
588, 595 and 596 of the present invention, and other compounds can
also be prepared according to reaction scheme 4. In reaction scheme
4, R.sup.4, R.sup.7 and B are each as defined above, and Q may
be
##STR00019##
[0092] Compound 8 synthesized according to a known method is
subjected to the Suzuki reaction with
5-bromo-3-iodo-2-methoxypyridine (9) in the presence of a palladium
catalyst to synthesize compound 10, which is then subjected to an
oxidation/reduction reaction to synthesize compound 11.
[0093] The obtained compound 11 is reacted with compound 4 prepared
according to a known method, thereby preparing compound 12. The
prepared compound 12 is reacted with triphosgene to synthesize
compound 13, which is then subjected to the Suzuki reaction with
various boronic acid derivatives in the presence of a palladium
catalyst to synthesize ester compounds 555, 556, 583, 585, 587 and
595. The ester compounds may be hydrolyzed with lithium hydroxide
to obtain desired carboxylic acid compounds 557, 558, 584, 586, 588
and 596.
##STR00020## ##STR00021##
TABLE-US-00004 Compounds R.sup.3 R.sup.4 R.sup.7 B A.sup.2 A.sup.3
603 OCH.sub.3 CH.sub.3 CO.sub.2CH.sub.3 CH N N 604 OCH.sub.3
CH.sub.3 CO.sub.2H CH N N 610 OCH.sub.3 F CO.sub.2CH.sub.3 CH N N
617 OCH.sub.3 F CO.sub.2H CH N N 625 OCH.sub.3 H CO.sub.2CH.sub.3
CH N N 628 OCH.sub.3 H CO.sub.2H CH N N 626 OCH.sub.3 H
CO.sub.2CH.sub.2CH.sub.3 CF N N 629 OCH.sub.3 H CO.sub.2H CF N N
673 H H CO.sub.2CH.sub.3 CH CCH.sub.3 CH 676 H H CO.sub.2H CH
CCH.sub.3 CH 674 H CH.sub.3 CO.sub.2CH.sub.3 CH CCH.sub.3 CH 677 H
CH.sub.3 CO.sub.2H CH CCH.sub.3 CH 675 H F CO.sub.2CH.sub.3 CH
CCH.sub.3 CH 678 H F CO.sub.2H CH CCH.sub.3 CH 763 OCH.sub.3
CF.sub.3 CO.sub.2CH.sub.3 CH CH N 764 OCH.sub.3 CF.sub.3 CO.sub.2H
CH CH N
[0094] Reaction scheme 5 above shows a general process for
synthesizing compounds 603, 604, 610, 617, 625, 626, 628, 629, 673,
674, 675, 676, 677, 678, 763 and 764 of the present invention, and
other compounds of the present invention can also be synthesized
according to reaction scheme 5. In reaction scheme 5, R.sup.3,
R.sup.4, R.sup.7, B, A.sup.2 and A.sup.3
##STR00022##
[0095] Compound 1 synthesized according to a known method is
reacted with compound 4 to synthesize compound 15, which is then
reacted with triphosgene to synthesize compound 16, which is then
subjected to Suzuki reaction with various boronic acid derivatives
in the presence of a palladium catalyst to synthesize pinacolate
compound 17, which is then subjected to the Suzuki reaction with
various boronic acid derivatives in the presence of a palladium
catalyst to synthesize ester compounds 603, 610, 625, 626, 673,
674, 675 and 763. The ester compounds may be hydrolyzed with
lithium hydroxide to obtain desired carboxylic acid compounds 604,
617, 628, 629, 676, 677, 678 and 764.
##STR00023## ##STR00024##
TABLE-US-00005 Compounds R.sup.4 R.sup.7 B 572 CH.sub.3
CO.sub.2CH.sub.3 CH 574 CH.sub.3 CO.sub.2H CH 573 H
CO.sub.2CH.sub.3 CH 575 H CO.sub.2H CH 630 Cl CO.sub.2CH.sub.3 CH
631 Cl CO.sub.2H CH 657 F CO.sub.2CH.sub.3 CH 661 F CO.sub.2H CH
658 H CO.sub.2CH.sub.2CH.sub.3 CF 662 H CO.sub.2H CF 659 H
CO.sub.2CH.sub.3 COCH.sub.3 663 H CO.sub.2H COCH.sub.3 660 F
CO.sub.2CH.sub.3 CF 664 F CO.sub.2H CF
[0096] Reaction scheme 6 above shows a general process for
synthesizing compounds 572, 573, 574, 575, 630, 631, 657, 658, 659,
660, 661, 662, 663 and 664 of the present invention, and other
compounds of the present invention can also be prepared according
to reaction scheme 6. In reaction scheme 6, R.sup.4, R.sup.7 and B
are each as defined above, and Q may be
##STR00025##
[0097] Compound 20 as a starting material is subjected to the
Suzuki reaction with compound 8 to prepare compound 21, which is
then subjected to an oxidation/reduction reaction to synthesize
compound 22. The obtained compound 22 is reacted with compound 4
prepared according to a known method, thereby preparing compound
23. The prepared compound 23 is reacted with triphosgene to
synthesize compound 24, which is then hydrogenated in the presence
of a nickel catalyst to synthesize compound 25, which is then
subjected to the Sandmeyer reaction to synthesize iodine-containing
compound 26. The synthesized compound 26 is subjected to the Suzuki
reaction with various boronic acid derivatives in the presence of a
palladium catalyst to synthesize ester compounds 572, 573, 630,
657, 658, 659 and 660. The ester compounds may be hydrolyzed with
lithium hydroxide to obtain desired carboxylic acid compounds 574,
575, 631, 661, 662, 663 and 664.
##STR00026## ##STR00027##
TABLE-US-00006 Compounds R.sup.4 R.sup.7 B 652 H CO.sub.2CH.sub.3
CH 644 H CO.sub.2H CH 653 CH.sub.3 CO.sub.2CH.sub.3 CH 645 CH.sub.3
CO.sub.2H CH 654 F CO.sub.2CH.sub.3 CH 646 F CO.sub.2H CH 655 Cl
CO.sub.2CH.sub.3 CH 647 Cl CO.sub.2H CH 656 F CO.sub.2CH.sub.3
CF
[0098] Reaction scheme 7 above shows a general process for
synthesizing compounds 644, 645, 646, 647, 652, 653, 654, 655 and
656 of the present invention, and other compounds of the present
invention can also be synthesized according to reaction scheme 7.
In reaction scheme 7, R.sup.4, R.sup.7 and B are each as defined
above, and Q may be
##STR00028##
[0099] Compound 1 synthesized according to a known method is
subjected to the Suzuki reaction with
2-bromo-5-methoxypyridin-4-ylboronic acid in the presence of a
palladium catalyst to synthesize compound 29, which is then reacted
with compound 4 prepared according to a known method, thereby
preparing compound 30. The prepared compound 30 is reacted with
triphosgene to synthesize compound 31, which is then subjected to
the Suzuki reaction with various boronic acid derivatives in the
presence of a palladium catalyst to synthesize ester compounds 652,
653, 654, 655 and 656. The ester compounds may be hydrolyzed with
lithium hydroxide to obtain desired carboxylic acid compounds 644,
645, 646 and 647.
##STR00029##
TABLE-US-00007 Compounds R.sup.4 R.sup.7 621 CH.sub.3
CO.sub.2CH.sub.3 622 CH.sub.3 CO.sub.2H 696 F CO.sub.2CH.sub.3 637
F CO.sub.2H 697 Cl CO.sub.2CH.sub.3 636 Cl CO.sub.2H
[0100] Reaction scheme 8 above shows a general process for
synthesizing compounds 621, 622, 636, 637, 696 and 697 of the
present invention, and other compounds of the present invention can
also be synthesized according to reaction scheme 8. In reaction
scheme 8, R.sup.4 and R.sup.7 are each as defined above, and Q may
be
##STR00030##
[0101] 2-bromo-6-iodo-3-methoxypyridine as a starting material is
subjected to the Suzuki reaction with various boronic acid
derivatives to synthesize compounds 33a to 33c. The synthesized
compounds are subjected to the Suzuki reaction with compound 17,
synthesized as shown in reaction scheme 5, in the presence of a
palladium catalyst, to synthesize ester compounds 621, 696 and 697,
which may then be hydrolyzed with lithium hydroxide to obtain
desired carboxylic acid compounds 622, 636 and 637.
##STR00031## ##STR00032##
[0102] Reaction scheme 9 above shows a general process for
synthesizing compounds 577 and 578 of the present invention, and
other compounds of the present invention can also be prepared
according to reaction scheme 9.
[0103] Compound 583 as a starting material is subjected to the
Suzuki reaction with propen-2-ylboronic acid in the presence of a
palladium catalyst to synthesize compound 35. The synthesized
compound is hydrogenated in the presence of a palladium catalyst to
obtain ester compound 577, which may then be hydrolyzed with
lithium hydroxide to obtain desired carboxylic acid compound
578.
##STR00033## ##STR00034##
TABLE-US-00008 Compounds R.sup.4 R.sup.5 R.sup.6 R.sup.7 A.sup.2 B
605 H H H CO.sub.2CH.sub.3 CCF.sub.3 CH 612 H H H CO.sub.2H
CCF.sub.3 CH 606 F H H CO.sub.2CH.sub.3 CCF.sub.3 CH 613 F H H
CO.sub.2H CCF.sub.3 CH 607 H H H CO.sub.2Et CCF.sub.3 CF 614 H H H
CO.sub.2H CCF.sub.3 CF 608 Cl H H CO.sub.2CH.sub.3 CCF.sub.3 CH 615
Cl H H CO.sub.2H CCF.sub.3 CH 609 CH.sub.3 H H CO.sub.2CH.sub.3
CCF.sub.3 CH 616 CH.sub.3 H H CO.sub.2H CCF.sub.3 CH 611 H H F
CO.sub.2H CCF.sub.3 N 619 H H H CO.sub.2CH.sub.3 CCH.sub.3 CH 620 H
H H CO.sub.2H CCH.sub.3 CH 638 H H H CO.sub.2CH.sub.3 CCF.sub.3 CCl
632 H H H CO.sub.2H CCF.sub.3 CCl 639 H H H CO.sub.2CH.sub.3
CCF.sub.3 COCH.sub.3 633 H H H CO.sub.2H CCF.sub.3 COCH.sub.3 683
CH.sub.3 H H CO.sub.2CH.sub.3 CCH.sub.3 CH 684 CH.sub.3 H H
CO.sub.2H CCH.sub.3 CH
[0104] Reaction scheme 10 above shows a general process
synthesizing compounds 605, 606, 607, 608, 609, 611, 612, 613, 614,
615, 616, 619, 620, 632, 633, 638, 639, 683 and 684 of the present
invention, and other compounds of the present invention can also be
prepared according to reaction scheme 10. In reaction scheme 10,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, B and A.sup.2 are each as
defined above, and Q may be
##STR00035##
[0105] Compound 36 as a starting material is reacted with
N-iodosuccinimide in a sulfuric acid solvent to synthesize
compounds 37a and 37b, which are then subjected to the Ullman
reaction (Martin G. Banwell et al. Org. Lett. 2004, 6, 2741) with
compound 1 to synthesize compounds 38a and 38b. The synthesized
compounds 38a and 38b are subjected to a reductive amination
reaction with compound 4 prepared according to a known method,
thereby synthesizing compounds 39a and 39b. The synthesized
compounds 39a and 39b are reacted with triphosgene to synthesize
compounds 40a and 40b. The synthesized compounds 40a and 40b are
hydrogenated in the presence of a nickel catalyst to synthesize
compounds 41a and 41b, which are then subjected to the Sandmeyer
reaction to synthesize iodine-containing compounds 42a and 42b. The
synthesized compounds 42a and 42b are subjected to the Suzuki
reaction with various boronic acid derivatives in the presence of a
palladium catalyst to synthesize ester compounds 605, 606, 607,
608, 609, 619, 638, 639 and 683. The ester compounds may be
hydrolyzed with lithium hydroxide to obtain desired carboxylic acid
compounds 612, 613, 614, 615, 616, 620, 632, 633 and 684. Compound
611 is converted to a desired carboxylic acid compound by the
Suzuki reaction.
##STR00036##
TABLE-US-00009 Compounds R.sup.3 R.sup.4 R.sup.7 A.sup.1 A.sup.2
594 OCH.sub.3 OCH.sub.3 CO.sub.2CH.sub.3 CH CH 597 OCH.sub.3
OCH.sub.3 CO.sub.2H CH CH 667 H CF.sub.3 CO.sub.2CH.sub.3 CF CH 668
H CF.sub.3 CO.sub.2H CF CH 692 F CH.sub.3 CO.sub.2CH.sub.3 CH CH
694 F CH.sub.3 CO.sub.2H CH CH 693 F CF.sub.3 CO.sub.2CH.sub.3 CH
CH 695 F CF.sub.3 CO.sub.2H CH CH 699 H F CO.sub.2CH.sub.3 CF CH
702 H F CO.sub.2H CF CH 700 H H CO.sub.2CH.sub.3 CF CH 703 H H
CO.sub.2H CF CH 701 H F CO.sub.2CH.sub.3 CH CH 704 H F CO.sub.2H CH
CH 708 F H CO.sub.2CH.sub.3 CH CH 709 F H CO.sub.2H CH CH 714 H
CH.sub.3 CO.sub.2CH.sub.3 CH N 716 H CH.sub.3 CO.sub.2H CH N 726 Cl
CH.sub.3 CO.sub.2CH.sub.3 CH CH 727 Cl CH.sub.3 CO.sub.2H CH CH
[0106] Reaction scheme 11 above shows a general process for
synthesizing compounds of 594, 597, 667, 668, 692, 693, 694, 695,
699, 700, 701, 702, 703, 704, 708, 709, 714, 716, 726 and 727 of
the present invention, and other compounds of the present invention
can also be prepared according to reaction scheme 11. In reaction
scheme 11, R.sup.3, R.sup.4, R.sup.7, A.sup.1 and A.sup.2 are each
as defined above, and Y, Z and Q may each independently be
halogen,
##STR00037##
[0107] Compound 43 as a starting material is subjected to the
Suzuki reaction with compound 44 in the presence of a palladium
catalyst to synthesize compound 45, which is then subjected to the
Suzuki reaction with compound 17 to synthesize ester compounds 594,
667, 692, 693, 699, 700, 701, 708, 714 and 726. The ester compounds
may be hydrolyzed with lithium hydroxide to obtain desired
carboxylic acid compounds 597, 668, 694, 695, 702, 703, 704, 709,
716 and 727.
##STR00038## ##STR00039##
[0108] Reaction scheme 12 above shows a general process for
synthesizing compound 618 of the present invention, and other
compounds of the present invention can also be prepared according
to reaction scheme 12.
[0109] 4-methoxyphenylboronic acid as a starting material is
subjected to the Suzuki reaction with methyl
4-bromo-3-(trifluoromethyl)benzoate in the presence of a palladium
catalyst to synthesize compound 48, which is then reacted with
iodine and silver sulfate to synthesize compound 49. The
synthesized compound 49 is subjected to the Suzuki reaction in the
presence of a palladium catalyst to synthesize pinacolate compound
50, which is then subjected to the Suzuki reaction with compound 16
in the presence of a palladium catalyst to synthesize ester
compound 51. The ester compound may be hydrolyzed with lithium
hydroxide to obtain desired carboxylic acid compound 618.
##STR00040## ##STR00041##
[0110] Reaction scheme 13 above shows a general process for
synthesizing compounds 648, 649, 650 and 651 of the present
invention, and other compounds of the present invention can also be
prepared according to reaction scheme 13.
[0111] Compound 52 as a starting material is subjected to the
Suzuki reaction with compound 8 in the presence of a palladium
catalyst to synthesize compounds 53a and 53b, which are than
subjected to an oxidation/reduction reaction to synthesize aldehyde
compounds 54a and 54b. The synthesized compounds 54a and 54b are
reacted with compound 4 prepared according to a known method,
thereby preparing compounds 55a and 55b. The synthesized compounds
55a and 55b are reacted with triphosgene to synthesize compounds
56a and 56b, which are then subjected to the Suzuki reaction with
boronic acid to synthesize ester compounds 648 and 649. The ester
compounds may be hydrolyzed with lithium hydroxide to obtain
desired carboxylic acid compounds 650 and 651.
##STR00042##
TABLE-US-00010 Compounds R.sup.3 R.sup.4 R.sup.7 642 OCH.sub.3 Cl
CO.sub.2CH.sub.3 643 OCH.sub.3 Cl CO.sub.2H 728 Cl CF.sub.3
CO.sub.2CH.sub.3 729 Cl CF.sub.3 CO.sub.2H 738 F Cl
CO.sub.2CH.sub.3 739 F Cl CO.sub.2H
[0112] Reaction scheme 14 above shows a general process for
synthesizing compounds 642, 643, 728, 729, 738 and 739 of the
present invention, and other compounds of the present invention can
also be prepared according to reaction scheme 14. In reaction
scheme 14, R.sup.3, R.sup.4 and R.sup.7 are each as defined above,
and Q may be
##STR00043##
[0113] Compound 58 as a starting material is subjected to the
Sandmeyer reaction to synthesize iodine-containing compound 59,
which is then subjected to the Suzuki reaction with boronic acid
compound 59 in the presence of a palladium catalyst to synthesize
ester compounds 642, 728 and 738. The ester compounds may be
hydrolyzed with lithium hydroxide to obtained desired carboxylic
acid compounds 643, 729 and 739.
##STR00044##
TABLE-US-00011 Compounds R.sup.3 R.sup.4 R.sup.7 A.sup.1 A.sup.2
670 H H CO.sub.2CH.sub.3 CH CF 679 H H CO.sub.2H CH CF 671 H F
CO.sub.2CH.sub.3 CH CF 680 H F CO.sub.2H CH CF 672 H CH.sub.3
CO.sub.2CH.sub.3 CH CF 681 H CH.sub.3 CO.sub.2H CH CF 686 H H
CO.sub.2CH.sub.3 COCH.sub.3 CH 687 H H CO.sub.2H COCH.sub.3 CH 688
H CH.sub.3 CO.sub.2CH.sub.3 COCH.sub.3 CH 689 H CH.sub.3 CO.sub.2H
COCH.sub.3 CH 690 H F CO.sub.2CH.sub.3 COCH.sub.3 CH 691 H F
CO.sub.2H COCH.sub.3 CH 724 F F CO.sub.2CH.sub.3 CH CH 722 F F
CO.sub.2H CH CH 725 H CF.sub.3 CO.sub.2CH.sub.3 CH CF 723 H
CF.sub.3 CO.sub.2H CH CF 743 H CH.sub.3 CO.sub.2CH.sub.3 CCF.sub.3
CH 744 H CH.sub.3 CO.sub.2H CCF.sub.3 CH 745 H H CO.sub.2CH.sub.3
CCF.sub.3 CH 746 H H CO.sub.2H CCF.sub.3 CH 747 H F
CO.sub.2CH.sub.3 CCF.sub.3 CH 748 H F CO.sub.2H CCF.sub.3 CH
[0114] Reaction scheme 15 above shows a general process for
synthesizing compounds 670, 671, 672, 679, 680, 681, 686, 687, 688,
689, 690, 691, 722, 723, 724, 725, 743, 744, 745, 746, 747 and 748
of the present invention, and other compounds of the present
invention can also be prepared according to reaction scheme 15. In
reaction scheme 15,
##STR00045##
[0115] Compound 16 synthesized according to a known method is
subjected to the Suzuki reaction with various boronic acid
derivatives (61) in the presence of a palladium catalyst to
synthesize compounds 62a to 62d, which are then subjected to the
Suzuki reaction with various boronic acid derivatives (63) in the
presence of a palladium catalyst to synthesize ester compounds 670,
671, 672, 686, 688, 690, 724, 725, 743, 745 and 747. The ester
compounds may be hydrolyzed with lithium hydroxide to obtain
desired carboxylic acid compounds 679, 680, 681, 687, 689, 691,
722, 723, 744, 746 and 748.
##STR00046##
TABLE-US-00012 Compounds Stating material Condition R.sup.3 R.sup.4
A.sup.2 ##STR00047## 682 554 1 OCH.sub.3 CH.sub.3 CH NH.sub.2 740
643 1 OCH.sub.3 Cl CH NH.sub.2 741 681 1 H CH.sub.3 CF NH.sub.2 742
695 1 F CF.sub.3 CH NH.sub.2 754 695 2 F CF.sub.3 CH ##STR00048##
755 695 2 F CF.sub.3 CH ##STR00049## 756 695 2 F CF.sub.3 CH
##STR00050## 757 695 2 F CF.sub.3 CH ##STR00051## 758 695 2 F
CF.sub.3 CH ##STR00052##
[0116] Reaction scheme 16 above shows a general process for
synthesizing compounds 682, 740, 741, 742, 754, 755, 756, 757 and
758 of the present invention, and other compounds of the present
invention can also be prepared according to reaction scheme 16. In
reaction scheme 16, starting materials, conditions, R.sup.3,
R.sup.4, A.sup.2 and
##STR00053##
are as defined above.
[0117] Compounds 554, 643, 681 and 695 that are starting materials
are converted to compounds 682, 740, 741 and 742 using thionyl
chloride, dimethylformamide, and ammonia water. In addition,
compound 695 as a starting material is reacted with compound 64 and
EDC to synthesize 754, 755, 756, 757 and 758.
##STR00054## ##STR00055## ##STR00056##
[0118] Reaction scheme 17 above shows a general process for
synthesizing compounds 718, 719 and 720 of the present invention,
and other compounds of the present invention can also be prepared
according to reaction scheme 17.
[0119] Compound 65 as a starting material is subjected to a
reduction reaction to synthesize alcohol compound 66. The obtained
compound 66 is subjected to the Suzuki reaction with boronic acid
to synthesize ester compound 67, which is then reacted with thionyl
chloride to synthesize chlorinated compound 68. The synthesized
compound 68 is reacted with compounds 69, 71 and 73, prepared
according to a known method (International Patent Publication No.
WO 2007/081571), in the presence of sodium hydride, to synthesize
compounds 70, 72 and 74. The synthesized compounds 70, 72 and 74
may be hydrolyzed with lithium hydroxide to obtain desired
carboxylic acid compounds 718, 719 and 720.
##STR00057## ##STR00058##
[0120] Reaction scheme 18 above shows a general process for
synthesizing compounds 705 and 706 of the present invention, and
other compounds of the present invention can also be prepared
according to reaction scheme 18.
[0121] Compound 3b is reacted with compound 75, prepared according
to a known method (International Patent Publication No. WO
2010/056849), to prepare compound 76. The prepared compound 76 is
reacted with triphosgene to synthesize compound 77, which is then
subjected to the Suzuki reaction with boronic acid compound 57 in
the presence of a palladium catalyst to synthesize ester compound
705. The ester compound may be hydrolyzed with lithium hydroxide to
obtain desired carboxylic acid compound 706.
[0122] The biaryl- or heterocyclic biaryl-substituted cyclohexene
derivative compounds of formula I may contain one or more
asymmetric carbon atoms, and thus can be present as racemates,
racemic mixtures, single enantiomers, diastereomeric mixtures, and
single diastereomers. Such isomers, for Example, biaryl- or
heterocyclic biaryl-substituted cyclohexene derivative compounds of
formula I, can be separated by column chromatography or HPLC.
Alternatively, stereoisomers of the compounds of formula I can be
stereospecifically synthesized using optically pure starting
materials or reagents having a known configuration.
[0123] In the present invention, some compounds are observed as
atropisomers (rotamers) in NMR spectra. Single atropisomers and
mixtures thereof are included in the scope of the compounds of the
present invention.
[0124] The compounds of formula I according to the present
invention may be used in the form of pharmaceutically acceptable
salts derived from inorganic or organic acids, and preferred
cations for the salts include sodium, potassium, magnesium,
calcium, zinc or tetrabutyl ammonium.
Advantageous Effects of Invention
[0125] Novel biaryl- or heterocyclic biaryl-substituted cyclohexene
derivative compounds according to the present invention, isomers
thereof, or pharmaceutically acceptable salts thereof, have less
side effects and exhibit the effect of effectively inhibiting
CETP.
[0126] Novel biaryl- or heterocyclic biaryl-substituted cyclohexene
derivative compounds according to the present invention, isomers
thereof, or pharmaceutically acceptable salts thereof, can be used
for the prevention or treatment of dyslipidemia or
dyslipidemia-related diseases.
MODE FOR THE INVENTION
[0127] Hereinafter, the present invention will be described in
further detail with reference to Examples, preparation Examples and
experimental Examples. It is to be understood, however, that these
Examples are for illustrative purposes only and are not intended to
limit the scope of the present invention.
Preparation of Novel Compounds According to Reaction Scheme 3
Intermediate Compound 3b:
2-(5-chloro-2-methoxyphenyl)-5,5-dimethylcyclohex-1-enecarbaldehyde
[0128] Starting material 1 (3.5 g, 20.3 mmol), compound 2 (4.2 g,
22.3 mmol), sodium carbonate (6.4 g, 60.8 mmol) and
Pd(dbpf)Cl.sub.2 (0.7 g, 1.0 mmol) were dissolved in
dimethoxyethane (3 mL)/water (1 mL) at room temperature, and the
reaction mixture was stirred at 100.degree. C. for 18 hours. Then,
water was poured into the reaction mixture and extracted with ethyl
acetate. The organic layer was dried with anhydrous magnesium
sulfate, and then concentrated under reduced pressure to remove the
solvent. The residue was purified by MPLC (Sift,
EtOAc/hexane=0%.about.5%) to obtain compound 3b (3.2 g, 56.6%) as
yellow oil.
Intermediate compound 5b:
(1R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((2-(5-chloro-2-methoxypheny-
l)-5,5-dimethylcyclohex-1-enyl)methylamino)propan-1-ol
[0129] Starting material 3b (3.1 g, 11.1 mmol), compound 4 (3.5 g,
12.2 mmol) and acetic acid (0.7 mL, 12.2 mmol) were dissolved in
methylene chloride (20 mL), and the reaction mixture was stirred at
the same temperature for 1 hour, and then sodium cyanoborohydride
(NaBH.sub.3CN) (0.8 g, 12.2 mmol) was added thereto at room
temperature, followed by stiffing at the same temperature for 3
hours. Then, aqueous solution of saturated sodium bicarbonate was
poured into the reaction mixture, which was then extracted with
ethyl acetate. The organic layer was dried with anhydrous magnesium
sulfate to remove water, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by MPLC
(SiO.sub.2, EtOAc/hexane=0%.about.20%) to obtain compound 5b (3.5
g, 57.2%) as yellow oil.
Intermediate compound 6a:
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(5-chloro-2-methoxypheny-
l)cyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
[0130] Starting material 5a (0.8 g, 1.65 mmol) and
5-chloro-2-methoxyphenylboronic acid (0.37 g, 2.0 mmol) were
dissolved in dimethoxyethane/water (v/v=3:1, 1 mL), and then
degassed. Then, Pd(dbpf)Cl.sub.2 (54 mg, 0.08 mmol) and sodium
carbonate (0.35 g, 3.3 mmol) were added to the reaction mixture,
which was then stirred with microwave irradiation at 120.degree. C.
for 30 minutes. After completion of the reaction, the reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and then washed with water and brine. The organic layer was dried
with anhydrous magnesium sulfate, filtered, and then concentrated
under reduced pressure to remove the solvent. The residue was
purified by MPLC (SiO.sub.2 40 g, hexane/EtOAc=10%.about.20%) to
obtain compound 6a (0.68 g, 75%) as brown oil.
Intermediate compound 6b:
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(5-chloro-2-methoxypheny-
l)-5,5-dim
ethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
[0131] Starting material 5b (3.5 g, 6.4 mmol) and
diisopropylethylamine (3.3 mL, 19.1 mmol) were dissolved in
methylene chloride (200 mL) at room temperature, and the reaction
mixture was cooled to 0.degree. C., and triphosgene (1.9 g, 6.4
mmol) was slowly added thereto. The reaction mixture was warmed to
room temperature and stirred for 3 hours. Then, water was poured
into the reaction mixture and the reaction mixture was extracted
with ethyl acetate. The organic layer was washed with aqueous
solution of saturated sodium bicarbonate, dried with anhydrous
magnesium sulfate, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (Sift,
EtOAc/hexane=0%.about.20%) to obtain compound 6b (3.0 g, 81.8%) as
a white foam solid.
EXAMPLE 1
Compound 553
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methylbiph-
enyl-4-carboxylate
[0132] Starting material 6b (0.53 g, 0.92 mmol), boronic acid 7
(0.38 g, 1.38 mmol), Pd(dbpf)Cl.sub.2 (0.03 g, 0.05 mmol) and
sodium carbonate (0.29 g, 2.76 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 1.2 mL), and the reaction mixture
was stirred with microwave irradiation at 120.degree. C. for 30
minutes. After completion of the reaction, the reaction mixture was
cooled to room temperature, diluted with ethyl acetate and then
washed with water. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by MPLC
(SiO.sub.2, EtOAc/hexane=0%.about.10%) to obtain compound 553 (0.3
g, 47.3%) as a white foam solid.
[0133] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.3 atropisomeric
mixture; .delta. 7.94-7.82 (m, 3H), 7.73 (d, 2H, J=11.2 Hz),
7.27-7.17 (m, 2H), 6.96-6.89 (m, 2H), 5.62-5.59 (m, 1H), 4.05-3.91
(m, 5H), 3.83-3.79 (m, 3H), 3.67-3.50 (m, 1H), 2.60-2.10 (m, 5H),
2.00-1.90 (m, 2H), 1.51-1.47 (m, 2H), 1.07-0.89 (m, 6H), 0.44-0.35
(m, 3H)
[0134] MS (ESI) m/z 690.2 (M.sup.++H).
EXAMPLE 2
Compound 554
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methylbiphenyl-4--
carboxylic acid
[0135] Starting material 553 (2.4 g, 3.48 mmol) and lithium
hydroxide monohydrate (0.44 g, 10.44 mmol) were dissolved in
dioxane (0.8 mL)/water (0.2 mL), and then stirred at 50.degree. C.
for 4 hours. 1M hydrochloric acid was poured into the reaction
mixture and extracted with ethyl acetate, and the resulting organic
layer was washed with brine, after which it was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=0%.about.20%) to obtain compound 554
(1.8 g, 76.6%) as a white foam solid.
[0136] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.30 atropisomeric
mixture; .delta. 8.02-7.75 (m, 3H), 7.75 (d, 2H, J=10.8 Hz),
7.31-7.19 (m, 2H), 6.98-6.90 (m, 2H), 5.64-5.61 (m, 1H), 4.15-3.91
(m, 2H), 3.84 (d, 3H, J=10.3 Hz), 3.68-3.52 (m, 1H), 2.60-2.01 (m,
5H), 2.00-1.93 (m, 2H), 1.54-1.46 (m, 2H), 1.07-0.88 (m, 6H),
0.45-0.37 (m, 3H)
[0137] MS (ESI) m/z 676.2 (M.sup.++H).
EXAMPLE 3
Compound 559
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxybiphenyl-4-ca-
rboxylate
[0138] Starting material 6b (0.15 g, 0.26 mmol) and
4-(methoxycarbonyl)phenylboronic acid (94 mg, 0.52 mmol) were added
to dimethoxyethane/water (v/v=3:1, 1 mL), and then degassed.
Pd(dbpf)Cl.sub.2 (17 mg, 0.03 mmol) and sodium carbonate (55 mg,
0.52 mmol) were added to the reaction mixture, which was then
stirred with microwave irradiation at 120.degree. C. for 30
minutes. After completion of the reaction, the reaction mixture was
cooled to room temperature, diluted with ethyl acetate and then
washed with water and brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=0%.about.10%.fwdarw.CH.sub.2Cl.sub.2
100%) to obtain compound 559 (89 mg, 51%) as a white solid.
[0139] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.3 atropisomeric
mixture; .delta. 8.08-8.02 (m, 2H), 7.84 (br s, 1H), 7.73 (br s,
2H), 7.60-7.58 (m, 1H), 7.54-7.48 (m, 2H), 7.25-7.24 (m, 1H),
6.97-6.90 (m, 1H), 5.60-5.56 (m, 1H), 4.09-3.98 (m, 2H), 3.93 (d,
3H, J=7.0 Hz), 3.81 (d, 3H, J=7.0 Hz), 3.64-3.47 (m, 1H), 2.60-2.04
(br m, 2H), 2.02-1.93 (br m, 2H), 1.54-1.47 (m, 2H), 1.27-1.24 (m,
6H), 0.42-0.34 (m, 3H)
[0140] MS (ESI) m/z 676.2 (M.sup.++H).
EXAMPLE 4
Compound 560
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-4'-methoxybiph-
enyl-4-carboxylate
[0141] Starting material 6b (0.1 g, 0.17 mmol) and
2-fluoro-4-(methoxycarbonyl)phenylboronic acid (69 mg, 0.35 mmol)
were dissolved in dimethoxyethane/water (v/v=3:1, 0.8 mL), and then
degassed. Pd(dbpf)Cl.sub.2 (11 mg, 0.02 mmol) and sodium carbonate
(37 mg, 0.35 mmol) were added to the reaction mixture, which was
then stirred with microwave irradiation at 120.degree. C. for 30
minutes. After completion of the reaction, the reaction mixture was
cooled to room temperature, diluted with ethyl acetate, and then
washed with water and brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentration under
reduced pressure to remove the solvent. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=10%.about.30%) to obtain compound 560
(63 mg, 52%) as colorless oil.
[0142] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.3 atropisomeric
mixture; .delta. 7.87-7.82 (m, 2H), 7.79-7.70 (m, 3H), 7.48-7.40
(m, 2H), 7.25-7.20 (m, 1H), 6.96, 6.92 (2d, 1H, J=8.6 Hz), 5.61,
5.54 (2d, 1H, J=8.0 Hz), 4.02-3.92 (m, 5H), 3.81 (d, 3H, J=7.0 Hz),
3.66-3.45 (m, 1H), 2.60-2.02 (br m, 2H), 2.01-1.92 (br m, 2H),
1.52-1.48 (m, 2H), 1.05-1.01 (m, 6H), 0.37 (2d, 3H, J=6.5 Hz)
[0143] MS (ESI) m/z 694.2 (M.sup.++H).
EXAMPLE 5
Compound 561
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-4'-methoxybiphenyl-4--
carboxylic acid
[0144] Starting material 560 (60 mg, 0.09 mmol) was dissolved in
dioxane (4 mL), and a solution of lithium hydroxide monohydrate (18
mg, 0.43 mmol) in water (1 mL) was added dropwise thereto. Then,
the reaction mixture was stirred overnight at 50.degree. C. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with
water, saturated ammonium chloride and brine. The organic layer was
dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (Sift,
CH.sub.3OH/CH.sub.2Cl.sub.2=0%.about.10%) to obtain compound 561
(27 mg, 46%) as a yellow solid.
[0145] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.95-7.90 (m,
1H), 7.87-7.80 (m, 2H), 7.74 (d, 2H, J=7.0 Hz), 7.53-7.42 (m, 2H),
7.28-7.23 (m, 1H), 6.98, 6.94 (2d, 1H, J=8.6 Hz), 5.62, 5.55 (2d,
1H, J=8.0 Hz), 4.05-3.92 (m, 2H), 3.83-3.80 (m, 3H), 3.71-3.46 (m,
1H), 2.28-2.03 (br m, 2H), 2.02-1.93 (br m, 2H), 1.53-1.47 (m, 2H),
1.06-1.02 (m, 6H), 0.39, 0.37 (2d, 3H, J=6.5 Hz)
[0146] MS (ESI) m/z 680.2 (M.sup.++H).
EXAMPLE 6
Compound 564
methyl
5-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxyphenyl)picol-
inate
[0147] Starting material 6b (0.1 g, 0.17 mmol) and methyl
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (78 mg,
0.3 mmol) were dissolved in dimethoxyethane/water (v/v=3:1, 1 mL),
followed by degassing. Pd(dbpf)Cl.sub.2 (11 mg, 0.02 mmol) and
sodium carbonate (37 mg, 0.35 mmol) were added to the reaction
mixture, which was then stirred with microwave irradiation at
120.degree. C. for 30 minutes. After completion of the reaction,
the reaction mixture was cooled to room temperature, diluted with
ethyl acetate, and then washed with water and brine. The organic
layer was dried with anhydrous magnesium sulfate, filtered, and
then concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (Sift, EtOAc/hexane=20%.about.50%) to
obtain compound 564 (14 mg, 12%) as yellow oil.
[0148] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.3 atropisomeric
mixture; .delta. 8.89, 8.82 (2d, 1H, J=2.2 Hz), 8.17, 8.13 (2d, 1H,
J=8.1 Hz), 7.97-7.91 (m, 1H), 7.85 (s, 1H), 7.71 (d, 2H, J=7.0 Hz),
7.53-7.50 (m, 1H), 7.23 (d, 1H, J=7.0 Hz), 7.01-6.95 (m, 1H),
5.61-5.58 (m, 1H), 4.04-3.96 (m, 5H), 3.82 (d, 3H, J=7.0 Hz),
3.61-3.43 (m, 1H), 2.60-1.96 (br m, 2H), 1.94-1.92 (br m, 2H),
1.53-1.48 (br m, 2H), 1.07-1.01 (m, 6H), 0.45-0.36 (m, 3H)
[0149] MS (ESI) m/z 677.2 (M.sup.++H).
EXAMPLE 7
Compound 565
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxybiphenyl-4-carboxyli-
c acid
[0150] Starting material 559 (68 mg, 0.1 mmol) was dissolved in
dioxane (4 mL), and a solution of lithium hydroxide monohydrate (21
mg, 0.5 mmol) in water (1 mL) was added dropwise thereto, followed
by stirring overnight at 50.degree. C. After completion of the
reaction, the reaction mixture was cooled to room temperature,
diluted with ethyl acetate, and then washed with saturated ammonium
chloride and brine. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by MPLC
(SiO.sub.2, EtOAc/hexane=30%-50%) to obtain compound 565 (34 mg,
51%) as a white solid.
[0151] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.4 atropisomeric
mixture; .delta. 8.15, 8.11 (2d, 2H, J=8.2 Hz), 7.85 (br s, 1H),
7.72 (br s, 2H), 7.64 (d, 1H, J=8.2 Hz), 7.57 (d, 1H, J=8.2 Hz),
7.54-7.50 (m, 1H), 7.27-7.26 (m, 1H), 6.97, 6.93 (2d, 1H, J=8.6
Hz), 5.61-5.57 (m, 1H), 4.06-3.91 (m, 2H), 3.82 (d, 3H, J=7.0 Hz),
3.65-3.48 (m, 1H), 2.55-1.99 (br m, 2H), 1.96-1.90 (br m, 2H),
1.55-1.46 (m, 2H), 1.07-1.02 (m, 6H), 0.43-0.36 (m, 3H)
[0152] MS (ESI) m/z 662.2 (M.sup.++H).
EXAMPLE 8
Compound 567
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxybiphenyl-3-ca-
rboxylate
[0153] Starting material 6b (80 mg, 0.14 mmol) and
3-(methoxycarbonyl)phenylboronic acid (38 mg, 0.21 mmol) were
dissolved in dimethoxyethane/water (v/v=4:1, 0.5 mL), followed by
degassing. Pd(dbpf)Cl.sub.2 (9 mg, 0.01 mmol) and sodium carbonate
(29 mg, 0.28 mmol) were added to the reaction mixture, which was
then stirred with microwave irradiation at 120.degree. C. for 30
minutes. After completion of the reaction, the reaction mixture was
cooled to room temperature, diluted with ethyl acetate, and then
washed with water and brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (Sift, EtOAc/hexane=10%-15%) to obtain compound 567 (75 mg,
80%) as colorless oil.
[0154] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.4 atropisomeric
mixture; .delta. 8.20-8.13 (m, 1H), 7.98-7.92 (m, 1H), 7.84 (d, 1H,
J=6.8 Hz), 7.72-7.65 (m, 3H), 7.50-7.42 (m, 2H), 7.24 (dd, 1H,
J=5.4, 2.4 Hz), 6.96, 6.91 (2d, 1H, J=8.6 Hz), 5.63-5.56 (m, 1H),
4.03-3.89 (m, 5H), 3.81, 3.79 (2s, 3H), 3.65-3.46 (m, 1H),
2.16-1.93 (br m, 2H), 1.98-1.63 (br m, 2H), 1.50-1.45 (m, 2H),
1.06-1.02 (m, 6H), 0.42-0.35 (m, 3H)
[0155] MS (ESI) m/z 676.2 (M.sup.++H).
EXAMPLE 9
Compound 568
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxybiphenyl-3-carboxyli-
c acid
[0156] Stating material 567 (50 mg, 0.07 mmol) was dissolved in
dioxane (4 mL), and a solution of lithium hydroxide monohydrate (16
mg, 0.37 mmol) in water (1 mL) was added dropwise thereto, followed
by stirring overnight at 50.degree. C. After completion of the
reaction, the reaction mixture was cooled to room temperature,
diluted with ethyl acetate, and then washed with water, saturated
ammonium chloride and brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (Sift, EtOAc/hexane=10%-70%) to obtain compound 568 (40 mg,
82%) as a white solid.
[0157] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.4 atropisomeric
mixture; .delta. 8.27-8.21 (m, 1H), 8.06-8.01 (m, 1H), 7.84-7.72
(m, 4H), 7.54-7.47 (m, 2H), 7.26-7.22 (m, 1H), 6.97, 6.92 (2d, 1H,
J=8.5 Hz), 5.63-5.56 (m, 1H), 4.06-3.93 (m, 2H), 3.82, 3.80 (2S,
3H), 3.66-3.47 (m, 1H), 2.56-2.04 (br m, 2H), 2.00-1.90 (br m, 2H),
1.57-1.47 (m, 2H), 1.07-0.98 (m, 6H), 0.42-0.36 (m, 3H)
[0158] MS (ESI) m/z 662.2 (M.sup.++H).
EXAMPLE 10
Compound 569
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-nitrobiphe-
nyl-4-carboxylate
[0159] Starting material 6b (0.13 g, 0.23 mmol) and
4-(methoxycarbonyl)-2-nitrophenylboronic acid (76 mg, 0.34 mmol)
were dissolved in dimethoxyethane/water (v/v=3:1, 0.5 mL), followed
by degassing. Pd(dbpf)Cl.sub.2 (7 mg, 0.01 mmol) and sodium
carbonate (48 mg, 0.45 mmol) were added to the reaction mixture,
which was then stirred with microwave irradiation at 120.degree. C.
for 30 minutes. After completion of the reaction, the reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and then washed with water and brine. The organic layer was dried
with anhydrous magnesium sulfate, filtered, and then concentrated
under reduced pressure to remove the solvent. The residue was
purified by MPLC (SiO.sub.2, EtOAc/hexane=5%.about.50%) to obtain
compound 569 (15 mg, 9%) as yellow oil.
[0160] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.45, 8.40 (2d,
1H, J=1.6 Hz), 8.24-8.17 (m, 1H), 7.85-7.79 (m, 1H), 7.75-7.71 (m,
2H), 7.53, 7.47 (2d, 1H, J=8.0 Hz), 7.23-7.20 (m, 1H), 6.97-6.92
(m, 2H), 5.59 (d, 1H, J=8.0 Hz), 4.02-3.97 (m, 4H), 3.85-3.71 (m,
4H), 3.69-3.49 (m, 1H), 2.55-2.20 (m, 2H), 1.96-1.85 (m, 2H),
1.50-1.43 (m, 2H), 1.04-0.98 (m, 6H), 0.43-0.39 (m, 3H)
[0161] MS (ESI) m/z 721.1 (M.sup.++H).
EXAMPLE 11
Compound 579
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)cyclohex-1-enyl)-4'-methoxy-2-methylbiphenyl-4-carbox-
ylate
[0162] Starting material 6a (0.1 g, 0.18 mmol) and methyl
3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
(55 mg, 0.2 mmol) were dissolved in dimethoxyethane/water (v/v=4:1,
0.3 mL), followed by degassing. Pd(dbpf)Cl.sub.2 (6 mg, 0.009 mmol)
and sodium carbonate (39 mg, 0.37 mmol) were added to the reaction
mixture, which was then stirred with microwave irradiation at
120.degree. C. for 15 minutes. After completion of the reaction,
the reaction mixture was cooled to room temperature, diluted with
ethyl acetate, and then washed with water and brine. The organic
layer was dried with anhydrous magnesium sulfate, filtered, and
then concentrated under reduce pressure to remove the solvent. The
residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=10%.about.20%) to obtain compound 579 (50 mg, 41%) as
colorless oil.
[0163] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.3 atropisomeric
mixture; .delta. 7.90-7.81 (m, 3H), 7.72 (d, 2H, J=13.4 Hz),
7.24-7.16 (m, 2H), 6.97-6.87 (m, 2H), 5.62-5.57 (m, 1H), 4.09-3.90
(m, 5H), 3.82, 3.79 (2s, 3H), 3.65-3.49 (m, 1H), 2.57-2.09 (m, 7H),
1.79-1.74 (br m, 4H), 0.43-0.36 (m, 3H)
[0164] MS (ESI) m/z 662.2 (M.sup.++H).
EXAMPLE 12
Compound 580
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)cyclohex-1-enyl)-2-fluoro-4'-methoxybiphenyl-4-carbox-
ylate
[0165] Starting material 6a (0.1 g, 0.18 mmol) and
2-fluoro-4-(methoxycarbonyl)phenylboronic acid (54 mg, 0.27 mmol)
were dissolved in dimethoxyethane/water (v/v=4:1, 0.3 mL), followed
by degassing. Pd(dbpf)Cl.sub.2 (6 mg, 0.009 mmol) and sodium
carbonate (39 mg, 0.37 mmol) were added to the reaction mixture,
which was then stirred with microwave irradiation at 120.degree. C.
for 15 minutes. After completion of the reaction, the reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and then washed with water and brine. The organic layer was dried
with anhydrous magnesium sulfate, filtered, and then concentrated
under reduced pressure to remove the solvent. The residue was
purified by MPLC (SiO.sub.2, EtOAc/hexane=10%.about.20%) to obtain
compound 580 (50 mg, 41%) as brown oil.
[0166] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.1 atropisomeric
mixture; .delta. 7.87-7.73 (m, 5H), 7.51-7.40 (m, 2H), 7.27-7.23
(m, 1H), 6.98-6.91 (m, 1H), 5.61, 5.54 (2d, 1H, J=8.0 Hz),
4.03-3.90 (m, 5H), 3.83, 3.80 (2s, 3H), 3.66-3.45 (m, 1H),
2.42-2.11 (br m, 4H), 1.82-1.74 (br m, 4H), 0.41-0.34 (m, 3H)
[0167] MS (ESI) m/z 666.2 (M.sup.++H).
EXAMPLE 13
Compound 581
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)cyclohex-1-enyl)-4'-methoxy-2-methylbiphenyl-4-carboxylic
acid
[0168] Starting material 579 (46 mg, 0.07 mmol) was dissolved in
dioxane (4 mL), and a solution of lithium hydroxide monohydrate (15
mg, 0.35 mmol) in water (1 mL) was added dropwise thereto, followed
by stirring at 50.degree. C. for 3 hours. After completion of the
reaction, the reaction mixture was cooled to room temperature,
diluted with ethyl acetate, and then washed with water, saturated
ammonium chloride and brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=20%.about.50%) to obtain compound 581
(21 mg, 47%) as a white solid.
[0169] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.4 atropisomeric
mixture; .delta. 7.97-7.90 (m, 2H), 7.85 (s, 1H), 7.73 (d, 2H,
J=13.0 Hz), 7.30-7.18 (m, 2H), 6.99-6.89 (m, 2H), 5.63-5.58 (m,
1H), 4.06-3.85 (m, 2H), 3.83-3.79 (m, 3H), 3.66-3.50 (m, 1H),
2.46-2.04 (m, 7H), 1.81-1.74 (br m, 4H), 0.44, 0.38 (2d, 3H, J=6.5
Hz)
[0170] MS (ESI) m/z 648.2 (M.sup.++H).
EXAMPLE 14
Compound 582
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)cyclohex-1-enyl)-2-fluoro-4'-methoxybiphenyl-4-carboxylic
acid
[0171] Starting material 580 (45 mg, 0.07 mmol) was dissolved in
dioxane (2 mL), and a solution of lithium hydroxide monohydrate (14
mg, 0.34 mmol) in water (0.5 mL) was added dropwise thereto,
followed by stirring at 50.degree. C. for 3 hours. After completion
of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with
water, saturated ammonium chloride and brine. The organic layer was
dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=20%.about.50%) to obtain compound 582 (10 mg, 23%) as
a yellow solid.
[0172] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.1 atropisomeric
mixture; .delta. 7.92-7.78 (m, 3H), 7.73 (s, 2H), 7.51-7.32 (m,
2H), 7.28-7.09 (m, 1H), 6.98-6.92 (m, 1H), 5.62-5.53 (m, 1H),
4.03-3.89 (m, 2H), 3.92-3.79 (m, 3H), 3.66-3.46 (m, 1H), 2.43-2.17
(br m, 4H), 1.80-1.74 (br m, 4H), 0.42-0.35 (m, 3H)
[0173] MS (ESI) m/z 650.2 (M.sup.+-H).
EXAMPLE 15
Compound 590
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,3-difluoro-4'-methoxy-
biphenyl-4-carboxylate
[0174] Starting material 6b (0.105 g, 0.18 mmol) and
2,3-difluoro-4-(methoxycarbonyl)phenylboronic acid (51 mg, 0.24
mmol) were dissolved in dimethoxyethane/water (v/v=3:1, 0.4 mL),
and then degassed. Pd(dbpf)Cl.sub.2 (6 mg, 0.009 mmol) and sodium
carbonate (39 mg, 0.37 mmol) were added to the reaction mixture,
which was then stirred with microwave irradiation at 120.degree. C.
for 20 minutes. After completion of the reaction, the reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and then washed with water and brine. The organic layer was dried
with anhydrous magnesium sulfate, filtered, and then concentrated
under reduced pressure to remove the solvent. The residue was
purified by MPLC (SiO.sub.2, EtOAc/hexane=10%.about.15%) to obtain
compound 590 (28 mg, 22%) as colorless oil.
[0175] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.85 (s, 1H),
7.75-7.69 (m, 3H), 7.47-7.40 (m, 1H), 7.25-7.16 (m, 2H), 6.97, 6.93
(2d, 1H, J=8.6 Hz), 5.62-5.55 (m, 1H), 4.02-3.92 (m, 5H), 3.82 (d,
3H, J=10.0 Hz), 3.64-3.44 (m, 1H), 2.58-1.98 (br m, 2H), 1.96-1.90
(br m, 2H), 1.54-1.42 (m, 2H), 1.05-1.01 (m, 6H), 0.42-0.37 (m,
3H)
[0176] MS (ESI) m/z 712.2 (M.sup.++H).
EXAMPLE 16
Compound 591
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,6-difluoro-4'-methoxy-
biphenyl-4-carboxylate
[0177] Starting material 6b (0.31 g, 0.53 mmol) and methyl
3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
(0.19 g, 0.64 mmol) were dissolved in dimethoxyethane/water
(v/v=3:1, 0.6 mL), followed by degassing. Pd(dbpf)Cl.sub.2 (17 mg,
0.03 mmol) and sodium carbonate (0.11 g, 1.06 mmol) were added to
the reaction mixture, which was then stirred with microwave
irradiation at 120.degree. C. for 30 minutes. After completion of
the reaction, the reaction mixture was cooled to room temperature,
diluted with ethyl acetate, and then washed with water and brine.
The organic layer was dried with anhydrous magnesium sulfate,
filtered, and then concentrated under reduced pressure to remove
the solvent. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=10%.about.15%) to obtain compound 591 (31 mg, 8%) as
yellow oil.
[0178] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.1 atropisomeric
mixture; .delta. 7.84 (s, 1H), 7.73 (d, 2H, J=6.7 Hz), 7.63, 7.60
(2d, 2H, J=7.5 Hz), 7.39-7.34 (m, 1H), 7.13-7.12 (m, 1H), 6.98-6.92
(m, 1H), 5.62-5.52 (m, 1H), 4.00-3.87 (m, 5H), 3.82 (d, 3H, J=7.6
Hz), 3.68-3.45 (m, 1H), 2.60-2.20 (br m, 2H), 2.04-1.94 (br m, 2H),
1.53-1.43 (m, 2H), 1.06-1.00 (m, 6H), 0.38-0.32 (m, 3H)
[0179] MS (ESI) m/z 712.3 (M.sup.++H).
EXAMPLE 17
Compound 592
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,3-difluoro-4'-methoxybipheny-
l-4-carboxylic acid
[0180] Starting material 590 (25 mg, 0.04 mmol) was dissolved in
dioxane (2 mL), and a solution of lithium hydroxide monohydrate (7
mg, 0.18 mmol) in water (0.5 mL) was added dropwise thereto,
followed by stirring at 50.degree. C. for 4 hours. After completion
of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with
water, saturated ammonium chloride and brine. The organic layer was
dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=10%.about.60%) to obtain compound 592 (15 mg, 61%) as
a yellow solid.
[0181] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.92-7.76 (m,
2H), 7.73 (br s, 2H), 7.54-7.42 (m, 1H), 7.22-7.17 (m, 2H), 6.99,
6.95 (2d, 1H, J=8.6 Hz), 5.66-5.58 (m, 1H), 4.03-3.92 (m, 2H),
3.84-3.80 (m, 3H), 3.65-3.45 (m, 1H), 2.60-2.04 (br m, 2H),
1.96-1.93 (br m, 2H), 1.54-1.46 (m, 2H), 1.06-1.02 (m, 6H),
0.41-0.38 (m, 3H)
[0182] MS (ESI) m/z 698.2 (M.sup.++H).
EXAMPLE 18
Compound 593
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,6-difluoro-4'-methoxybipheny-
l-4-carboxylic acid
[0183] Starting material 591 (31 mg, 0.04 mmol) was dissolved in
dioxane (2 mL), and a solution of lithium hydroxide monohydrate (9
mg, 0.22 mmol) in water (0.5 mL) was added dropwise thereto,
followed by stirring at 50.degree. C. for 6 hours. After completion
of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with
water, saturated ammonium chloride and brine. The organic layer was
dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=10%.about.70%) to obtain compound 593 (10 mg, 33%) as
a white solid.
[0184] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.2 atropisomeric
mixture; .delta. 7.85 (s, 1H), 7.74 (d, 2H, J=6.8 Hz), 7.70-7.65
(m, 2H), 7.40-7.36 (m, 1H), 7.15 (d, 1H, J=5.0 Hz), 6.99-6.93 (m,
1H), 5.63-5.53 (m, 1H), 4.01-3.90 (m, 2H), 3.83-3.79 (m, 3H), 3.67,
3.47 (2d, 1H, J=14.8 Hz), 2.60-2.13 (br m, 2H), 2.04-1.94 (br m,
2H), 1.52-1.46 (m, 2H), 1.05-1.00 (m, 6H), 0.39-0.33 (m, 3H)
[0185] MS (ESI) m/z 698.2 (M.sup.++H).
EXAMPLE 19
Compound 599
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3,4'-dimethoxybiphenyl--
4-carboxylate
[0186] Starting material 6b (0.08 g, 0.13 mmol), methyl
2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
(0.06 g, 0.2 mmol), Pd(dbpf)Cl.sub.2 (8.0 mg, 0.01 mmol) and sodium
carbonate (0.04 g, 0.39 mmol) were dissolved in dimethoxyethane (3
mL)/water (1 mL) and heated by microwave irradiation at 120.degree.
C. for 30 minutes. After completion of the reaction, the reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and then washed with brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (SiO.sub.2, hexane/EtOAc=10%.about.50%) to obtain compound 599
(64 mg, 69.7%) as colorless oil.
[0187] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 7.88-7.80 (m, 2H), 7.71 (2s, 2H), 7.47 (2t, 1H, J=2.6 Hz),
7.21 (t, 1H, J=2.0 Hz), 7.15-7.04 (m, 2H), 6.93 (2d, 1H, J=8.6 Hz),
5.58 (2d, 1H, J=4.4 Hz), 4.02-3.79 (m, 11H), 3.56 (2d, 1H, J=14.6
Hz), 2.56-1.94 (m, 4H), 1.51 (m, 2H), 1.04 (2d, 6H, J=12.3 Hz),
0.40 (2d, 3H, J=6.6 Hz)
[0188] MS (ESI) m/z 706.2 (M.sup.++H).
EXAMPLE 20
Compound 600
methyl
5-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxyphenyl)-3-me-
thylpicolinate
[0189] Starting material 6b (0.08 g, 0.14 mmol), methyl
3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate
(0.06 g, 0.21 mmol), Pd(dbpf)Cl.sub.2 (9.0 mg, 0.01 mmol) and
sodium carbonate (0.05 g, 0.43 mmol) were dissolved in
dimethoxyethane (3 mL)/water (1 mL) and heated by microwave
irradiation at 120.degree. C. for 30 minutes. After completion of
the reaction, the reaction mixture was cooled to room temperature,
diluted with ethyl acetate, and then washed with brine. The organic
layer was dried with anhydrous magnesium sulfate, filtered, and
then concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (SiO.sub.2,
hexane/EtOAc=10%.about.50%) to obtain compound 600 (15 mg, 15.3%)
as colorless oil.
[0190] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.67 (2d, 1H, J=2.1 Hz), 7.85 (s, 1H), 7.72-7.66 (m, 3H),
7.52-7.47 (m, 1H), 7.21 (d, 1H, J=2.4 Hz), 6.97 (2d, 1H, J=8.6 Hz),
5.59 (d, 1H, J=8.1 Hz), 4.06-3.91 (m, 5H), 3.87 (2s, 3H), 3.54 (2d,
1H, J=13.5 Hz), 2.65 (2s, 3H), 2.54-1.93 (m, 4H), 1.51 (m, 2H),
1.05 (2d, 6H, J=15.9 Hz), 0.41 (2d, 3H, J=6.6 Hz)
[0191] MS (ESI) m/z 691.2 (M.sup.++H).
EXAMPLE 21
Compound 601
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3,4'-dimethoxybiphenyl-4-carbo-
xylic acid
[0192] Starting material 599 (0.06 g, 0.08 mmol) and lithium
hydroxide monohydrate (0.01 g, 0.41 mmol) were dissolved in dioxane
(3 mL)/water (1 mL) at room temperature and stirred overnight at
50.degree. C. After completion of the reaction, a solution of 1 M
hydrochloric acid was added dropwise to the reaction mixture until
a pH of 6.5 was reached, after which water was poured into the
reaction mixture and the reaction mixture was extracted with ethyl
acetate. The organic layer was washed with brine, dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
preparative TLC (SiO.sub.2, hexane/EtOAc=0%.about.30%) to obtain
compound 601 (30 mg, 52.9%) as colorless oil.
[0193] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.17 (2d, 1H, J=8.20 Hz), 7.85 (s, 1H), 7.71 (2s, 2H), 7.49
(2t, 1H, J=2.6 Hz), 7.30-7.21 (m, 2H), 7.15 (2s, 1H), 6.95 (2d, 1H,
J=8.6 Hz), 5.57 (2d, 1H, J=8.1 Hz), 4.12 (2s, 3H), 4.05-3.93 (m,
2H), 3.81 (2s, 3H), 3.54 (2d, 1H, J=14.6 Hz), 2.55-1.93 (m, 4H),
1.51 (m, 2H), 1.04 (2d, 6H, J=12.2 Hz), 0.42 (2d, 3H, J=6.5 Hz)
[0194] MS (ESI) m/z 692.3 (M.sup.++H).
EXAMPLE 22
Compound 602
5-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxyphenyl)-3-methylpic-
olinic acid
[0195] Staring material 600 (13 mg, 0.02 mmol) and lithium
hydroxide monohydrate (2 mg, 0.09 mmol) were dissolved in dioxane
(3 mL)/water (1 mL) at room temperature and stirred overnight at
50.degree. C. After completion of the reaction, a solution of 1 M
hydrochloric acid was added dropwise to the reaction mixture until
a pH of 6.5 was reached, after which water was poured into the
reaction mixture and the reaction mixture was extracted with ethyl
acetate. The organic layer was washed with brine, dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
preparative TLC (SiO.sub.2, hexane/EtOAc=0%.about.30%) to obtain
compound 602 (2.5 mg, 23.6%) as colorless oil.
[0196] MS (ESI) m/z 677.3 (M.sup.++H)
EXAMPLE 23
Compound 665
methyl
5-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxyphenyl)-6-me-
thylpicolinate
[0197] Starting material 6b (0.190 g, 0.686 mmol), boronic acid 7
(0.474 g, 0.823 mmol), Pd(dbpf)Cl.sub.2 (0.022 g, 0.034 mmol) and
sodium carbonate (0.218 g, 2.057 mmol) were dissolved in
dimethoxyethane (0.9 mL)/water (0.3 mL) and heated by microwave
irradiation at 120.degree. C. for 30 minutes. Then, the reaction
mixture was cooled to room temperature, after which water was
poured into the reaction mixture and the reaction mixture was
extracted with ethyl acetate. The organic layer was dried with
anhydrous magnesium sulfate to remove water, and then concentrated
under reduced pressure. The residue was purified by MPLC
(SiO.sub.2, EtOAc/hexane=0%.about.100%) to obtain desired compound
665 (0.160 g, 33.8%) as clear oil.
[0198] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.00 (2d, 1H,
J=7.9 Hz), 7.86 (s, 1H), 7.73 (2s, 2H), 7.61 (2d, 1H, J=7.9 Hz),
7.23 (m, 1H), 6.97 (m, 2H), 5.61 (2d, 1H, J=8.2 Hz), 4.06-3.95 (m,
5H), 3.94 (2s, 3H), 3.56 (2d, 1H, J=14.7 Hz), 2.59 (2s, 3H),
2.20-2.00 (m, 2H), 1.95-1.92 (m, 2H), 1.52 (m, 2H), 1.07-0.97 (m,
6H), 0.29 (m, 3H)
[0199] MS (ESI) m/z 691.2 (M.sup.++H).
EXAMPLE 24
Compound 666
5-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxyphenyl)-6-methylpic-
olinic acid
[0200] Starting material 665 (0.160 g, 0.232 mmol) and lithium
hydroxide monohydrate (0.029 g, 0.695 mmol) were dissolved in
dioxane (8 ml)/water (2 ml) at room temperature, and the reaction
mixture was stirred for 16 hours at the same temperature. 1M
hydrochloric acid was added to the reaction mixture and the
reaction mixture was extracted with ethyl acetate. The organic
layer was washed with brine, dried with anhydrous magnesium sulfate
to remove water, and then concentrated under reduced pressure. The
residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=0%.about.100%) to obtain desired compound 666 (0.020
g, 12.8%) as a white foam solid.
[0201] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.00 (m, 5H),
7.22 (m, 1H), 7.08 (m, 2H), 5.80 (m, 1H), 4.20 (m, 1H), 3.82 (m,
4H), 3.60 (m, 1H), 2.6 (m, 3H), 2.40-1.80 (m, 4H), 1.45 (m, 2H),
1.0 (m, 6H), 0.4 (m, 3H)
[0202] MS (ESI) m/z 677.2 (M.sup.++H).
Preparation of Novel Compounds According to Reaction Scheme 4
Intermediate compound 10: ethyl
2-(5-bromo-2-methoxypyridin-3-yl)-5,5-dimethylcyclohex-1-enecarboxylate
[0203] Starting material 8 (1.14 g, 3.70 mmol),
5-bromo-3-iodo-2-methoxypyridine (1.40 g, 4.44 mmol),
Pd(PPh.sub.3).sub.4 (0.85 g, 0.74 mmol) and cesium carbonate (2.41
g, 7.40 mmol) were dissolved in dioxane/water (v/v 9:1, 10 mL), and
then reacted by microwave irradiation at 120.degree. C. for 30
minutes. After completion of the reaction, the reaction mixture was
cooled to room temperature, diluted with ethyl acetate, and then
washed with a saturated ammonium chloride solution. The organic
layer was dried with anhydrous magnesium sulfate, filtered, and
then concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (SiO.sub.2, EtOAc/hexane=1:9) to
obtain compound 10 (0.37 g, 27%) as colorless oil.
[0204] MS (ESI) m/z 368.0 (M.sup.++H).
Intermediate compound 11:
2-(5-bromo-2-methoxypyridin-2-yl)-5,5-dimethylcyclohex-1-enecarbaldehyde
[0205] Starting material 10 (0.32 g, 0.87 mmol) was dissolved in
tetrahydrofuran (THF) (10 mL), and lithium aluminum hydride (1.73
mL, 1.73 mmol) was added dropwise thereto at 0.degree. C., followed
by stirring at 0.degree. C. for 1 hour. Water was added dropwise to
stop the reaction, and the reaction mixture was extracted with
ethyl acetate. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (Sift,
EtOAc/hexane=10%) to obtain an alcohol compound (0.17 g, 61%) as
colorless oil. The obtained alcohol compound (0.17 g, 0.53 mmol)
was dissolved in methylene chloride (5 mL), and then DMP (0.25 g,
0.58 mmol) was slowly added dropwise thereto at 0.degree. C.,
followed by stirring at room temperature for 30 minutes. After
completion of the reaction, the reaction mixture was diluted with
methylene chloride, and then washed with water. The organic solvent
was dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (SiO.sub.2, EtOAc/hexane=10%) to
aldehyde obtain 11 (0.12 g, 71%) as colorless oil.
[0206] MS (ESI) m/z 324.0 (M.sup.++H).
Intermediate compound 12:
(1R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((2-(5-bromo-2-methoxypyridi-
n-3-yl)-5,5-dimethylcyclohex-1-enyl)methylamino)propan-1-ol
[0207] Starting material 11 (0.12 g, 0.36 mmol), amino alcohol
compound 4 (0.12 g, 0.43 mmol) and sodium cyanoborohydride (26.7
mg, 0.43 mmol) were dissolved in methylene chloride (5 mL), and
acetic acid (0.02 mL, 0.43 mmol) was slowly added dropwise thereto
at room temperature. The reaction mixture was stirred at room
temperature for 2 hours, diluted with methylene chloride, and then
washed with water. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent. The obtained product (197 mg,
93.3%) was used in the next reaction.
[0208] MS (ESI) m/z 595.2 (M.sup.++H).
Intermediate compound 13:
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(5-bromo-2-methoxypyridi-
n-3-yl)-5,5-dimethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
[0209] Starting material 12 (0.2 g, 0.33 mmol) and triphosgene
(0.12 g, 0.4 mmol) were dissolved in methylene chloride (5 mL), and
diisopropylethylamine (0.35 mL, 2.0 mmol) was slowly added dropwise
thereto. The reaction mixture was stirred at room temperature for 1
hour, diluted with methylene chloride, and then washed with water.
The organic solvent was dried with anhydrous magnesium sulfate,
filtered, and then concentrated under reduced pressure to remove
the solvent. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=10%) to obtain compound 13 (0.15 g, 73%) as colorless
oil.
[0210] MS (ESI) m/z 621.1 (M.sup.++H).
EXAMPLE 25
Compound 555
methyl
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl-
)-3-methylbenzoate
[0211] Starting material 13 (0.07 g, 0.11 mmol),
2-methyl-4-methoxycarbonylphenylboronic acid, pinacol ester (0.04
g, 0.13 mmol), Pd(dbpf)Cl.sub.2 (4 mg, 0.005 mmol) and sodium
carbonate (0.03 g, 0.32 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 1.6 mL), and the reaction mixture
was stirred with microwave irradiation at 120.degree. C. for 30
minutes. After completion of the reaction, the reaction mixture was
cooled to room temperature, diluted with ethyl acetate, and then
washed with water and brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=1:4) to obtain compound 555 (42 mg,
56%) as a white solid.
[0212] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.5 atropisomeric
mixture; .delta. 8.06-8.04 (m, 1H), 7.96-7.86 (m, 3H), 7.74-7.71
(m, 2H), 7.31-7.19 (m, 2H), 5.64 (d, 0.6H, J=7.7 Hz), 5.57 (d,
0.4H, J=7.7 Hz), 4.07-4.00 (m, 2H), 3.98-3.92 (m, 6H), 3.59-3.51
(m, 1H), 2.58-2.03 (m, 5H), 1.98-1.87 (m, 2H), 1.57-1.43 (m, 2H),
1.06-1.00 (m, 6H), 0.51 (d, 1.2H, J=6.3 Hz), 0.36 (d, 1.8H, J=6.3
Hz)
[0213] MS (ESI) m/z 691.2 (M.sup.++H).
EXAMPLE 26
Compound 556
methyl
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl-
)benzoate
[0214] Starting material 13 (0.06 g, 0.1 mmol),
4-methoxycarbonylphenylboronic acid (0.02 g, 0.12 mmol),
Pd(dbpf)Cl.sub.2 (3 mg, 0.005 mmol) and sodium carbonate (0.03 g,
0.3 mmol) were dissolved in dimethoxyethane/water (v/v=3:1, 1.6
mL), and then stirred with microwave irradiation at 120.degree. C.
for 30 minutes. After completion of the reaction, the reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and then washed with water and brine. The organic layer was dried
with anhydrous magnesium sulfate, filtered, and then concentrated
under reduced pressure to remove the solvent. The residue was
purified by MPLC (SiO.sub.2, EtOAc/hexane=1:4) to obtain compound
556 (12 mg, 18%) as a white solid.
[0215] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.6 atropisomeric
mixture; .delta. 8.37-8.35 (m, 1H), 8.16-8.11 (m, 2H), 7.88-7.87
(m, 1H), 7.74-7.72 (m, 2H), 7.61-7.54 (m, 3H), 5.64 (d, 0.6H, J=8.2
Hz), 5.57 (d, 0.4H, J=8.2 Hz), 4.10-4.03 (m, 2H), 3.99-3.94 (m,
6H), 3.58-3.52 (m, 1H), 2.58-2.18 (m, 2H), 2.02-1.98 (m, 2H),
1.60-1.48 (m, 2H), 1.08-1.02 (m, 6H), 0.53 (d, 1.2H, J=6.4 Hz),
0.39 (d, 1.8H, J=6.4 Hz)
[0216] MS (ESI) m/z 677.2 (M.sup.++H).
EXAMPLE 27
Compound 557
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-met-
hylbenzoic acid
[0217] Starting material 555 (36 mg, 0.05 mmol) was dissolved in
dioxane (0.4 mL), and a solution of lithium hydroxide monohydrate
(0.01 g, 0.26 mmol) in water (0.1 mL) was added dropwise thereto.
The reaction mixture was stirred overnight at 50.degree. C. After
completion of the reaction, the reaction mixture was cooled to room
temperature, and a solution of 1M hydrochloric acid solution was
added dropwise thereto until a pH of 2 was reached. Then, the
reaction mixture was extracted with ethyl acetate, and the organic
layer was dried with anhydrous magnesium sulfate, filtered, and
then concentrated under reduced pressure to remove the solvent,
thereby obtaining compound 557 (28 mg, 79%) as a white solid.
[0218] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.6 atropisomeric
mixture; .delta. 8.08-8.07 (m, 1H), 8.02-7.92 (m, 2H), 7.87-7.86
(m, 1H), 7.74-7.71 (m, 2H), 7.31-7.25 (m, 2H), 5.64 (d, 0.6H, J=8.2
Hz), 5.57 (d, 0.4H, J=8.2 Hz), 4.07-3.92 (m, 5H), 3.59-3.51 (m,
1H), 2.59-2.04 (m, 5H), 1.99-1.88 (m, 2H), 1.58-1.45 (m, 2H),
1.07-1.01 (m, 6H), 0.52 (d, 1.2H, J=6.5 Hz), 0.38 (d, 1.8H, J=6.5
Hz)
[0219] MS (ESI) m/z 677.2 (M.sup.++H).
EXAMPLE 28
Compound 558
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)benzoi-
c acid
[0220] Starting material 556 (10 mg, 0.02 mmol) was dissolved in
dioxane (0.4 mL), and a solution of lithium hydroxide monohydrate
(3 mg, 0.07 mmol) in water (0.1 mL) was added dropwise thereto. The
reaction mixture was stirred overnight at 50.degree. C. After
completion of the reaction, the reaction mixture was cooled to room
temperature, and a solution of 1M hydrochloric acid was added
dropwise thereto until a pH of 2 was reached. Then, the reaction
mixture was extracted with ethyl acetate, and the organic layer was
dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent, thereby
obtaining compound 558 (8 mg, 77%) as a white solid.
[0221] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.6 atropisomeric
mixture; .delta. 8.31-8.29 (m, 1H), 8.11-8.06 (m, 2H), 7.80-7.79
(m, 1H), 7.74-7.72 (m, 2H), 7.66-7.50 (m, 3H), 5.58-5.48 (m, 1H),
3.99-3.95 (m, 2H), 3.92-3.87 (m, 3H), 3.51-3.44 (m, 1H), 2.51-2.04
(m, 2H), 1.90-1.88 (m, 2H), 1.49-1.44 (m, 2H), 1.01-0.95 (m, 6H),
0.46 (d, 1.1H, J=6.5 Hz), 0.39 (d, 1.9H, J=6.5 Hz)
[0222] MS (ESI) m/z 663.2 (M.sup.++H).
EXAMPLE 29
Compound 583
methyl
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl-
)-3-chlorobenzoate
[0223] Starting material 13 (0.15 g, 0.24 mmol), boronic acid 14
(0.06 g, 0.27 mmol), Pd(dbpf)Cl.sub.2 (8.0 mg, 0.01 mmol) and
sodium carbonate (0.05 g, 0.48 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 4 mL), and then stirred with
microwave irradiation at 120.degree. C. for 30 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=0%-20%) to obtain compound 583 (0.12 g, 68.7%) as
colorless oil.
[0224] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.13-8.16 (m, 2H), 7.95-8.00 (m, 1H), 7.87 (s, 1H), 7.74
(d, 2H, J=6.6 Hz), 7.37-7.47 (m, 2H), 5.59-5.64 (m, 1H), 3.84-4.06
(m, 8H), 3.53-3.66 (m, 1H), 2.00-2.56 (m, 2H), 2.00-1.97 (m, 2H),
1.50-1.55 (m, 2H), 1.02-1.07 (m, 6H), 0.52 (d, 1.3H, J=6.6 Hz),
0.36 (d, 1.7H, J=6.6 Hz)
[0225] MS (ESI) m/z 710.2 (M.sup.++H).
EXAMPLE 30
Compound 584
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-chl-
orobenzoic acid
[0226] Starting material 583 (0.07 g, 0.10 mmol) and anhydrous
lithium hydroxide (12 mg, 0.49 mmol) were dissolved in
dioxane/water (v/v=4:1, 1.25 mL), and then stirred overnight at
40.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and then washed with 1M hydrochloric acid solution and brine. The
organic layer was dried with anhydrous magnesium sulfate, filtered,
and then concentrated under reduced pressure to remove the solvent.
The residue was purified by MPLC (SiO.sub.2, EtOAc/hexane=0%-50%)
to obtain compound 584 (2 mg, 2.5%) as colorless oil.
[0227] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.16-8.23 (m, 2H), 8.02-8.07 (m, 1H), 7.87 (s, 1H), 7.74
(d, 2H, J=9.0 Hz), 7.41-7.49 (m, 2H), 5.65 (d, 0.6H, J=8.2 Hz),
5.59 (d, 0.4H, J=8.3 Hz), 3.93-4.06 (m, 5H), 3.65 (d, 0.6H, J=14.6
Hz), 3.57 (d, 0.4H, J=15.0 Hz), 2.05-2.60 (m, 2H), 1.96-1.98 (m,
2H), 1.51-1.57 (m, 2H), 1.02-1.08 (m, 6H), 0.53 (d, 1.2H, J=6.6
Hz), 0.38 (d, 1.8H, J=6.6 Hz)
[0228] MS (ESI) m/z 697.1 (M.sup.++H).
EXAMPLE 31
Compound 585
methyl
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl-
)-3-fluorobenzoate
[0229] Starting material 13 (0.15 g, 0.24 mmol), boronic acid 14
(0.05 g, 0.27 mmol), Pd(dbpf)Cl.sub.2 (8.0 mg, 0.01 mmol) and
sodium carbonate (0.05 g, 0.48 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 4 mL), and the reaction mixture was
stirred with microwave irradiation at 120.degree. C. for 30
minutes. After completion of the reaction, the reaction mixture was
cooled to room temperature, diluted with ethyl acetate, and then
washed with water and brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=0%.about.20%) to obtain compound 585
(0.14 g, 82.9%) as colorless oil.
[0230] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.27-8.30 (m, 1H), 7.81-7.92 (m, 3H), 7.80 (s, 2H),
7.56-7.45 (m, 2H), 5.59-5.63 (m, 1H), 3.94-4.14 (m, 8H), 3.48-3.62
(m, 1H), 2.05-2.53 (m, 2H), 1.97 (m, 2H), 1.48-1.52 (m, 2H),
1.03-1.07 (m, 6H), 0.48 (d, 1.3H, J=6.6 Hz), 0.37 (d, 1.7H, J=6.5
Hz)
[0231] MS (ESI) m/z 694.2 (M.sup.++H)
EXAMPLE 32
Compound 586
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-flu-
orobenzoic acid
[0232] Starting material 585 (0.06 g, 0.09 mmol) and anhydrous
lithium hydroxide (11 mg, 0.46 mmol) were dissolved in
dioxane/water (v/v=4:1, 1.25 mL), and then stirred overnight at
40.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and then washed with 1M hydrochloric acid solution and brine. The
organic layer was dried with anhydrous magnesium sulfate, filtered,
and then concentrated under reduced pressure to remove the solvent.
The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=0%.about.50%) to obtain compound 586 (15 mg, 23.9%) as
colorless oil.
[0233] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.30-8.32 (s, 1H), 7.90-7.99 (m, 1H), 7.83-7.87 (m, 2H),
7.75 (s, 2H), 7.51-7.58 (m, 2H), 5.60-5.64 (m, 1H), 3.95-4.05 (m,
5H), 3.50-3.62 (m, 1H), 2.00-2.60 (m, 2H), 1.97 (s, 2H), 1.50-1.54
(m, 2H), 1.03-1.08 (m, 6H), 0.49 (d, 1.3H, J=6.5 Hz), 0.41 (d,
1.7H, J=6.5 Hz)
[0234] MS (ESI) m/z 681.2 (M.sup.++H).
EXAMPLE 33
Compound 587
methyl
3-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl-
)benzoate
[0235] Starting material 13 (0.14 g, 0.22 mmol), boronic acid 14
(0.04 g, 0.24 mmol), Pd(dbpf)Cl.sub.2 (7.0 mg, 0.01 mmol) and
sodium carbonate (0.05 g, 0.43 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 4 mL), and the reaction mixture was
stirred with microwave irradiation at 120.degree. C. for 20
minutes. After completion of the reaction, the reaction mixture was
cooled to room temperature, diluted with ethyl acetate, and then
washed with water and brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=0%.about.20%) to obtain compound 587
(0.12 g, 79.7%) as colorless oil.
[0236] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.33-8.34 (m, 1H), 8.14-8.20 (m, 1H), 8.01-8.05 (m, 1H),
7.99 (s, 1H), 7.68-7.87 (m, 3H), 7.48-7.56 (m, 2H), 5.58-5.65 (m,
1H), 3.99-4.14 (m, 2H), 3.96-3.97 (m, 3H), 3.92-3.93 (m, 3H),
3.50-3.60 (m, 1H), 2.00-2.60 (m, 2H), 1.96-1.98 (m, 2H), 1.51-1.58
(m, 2H), 1.03-1.08 (m, 6H), 0.37-0.52 (m, 3H)
[0237] MS (ESI) m/z 677.2 (M.sup.++H).
EXAMPLE 34
Compound 588
3-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)benzoi-
c acid
[0238] Starting material 587 (0.08 g, 0.11 mmol) and anhydrous
lithium hydroxide (14 mg, 0.57 mmol) were dissolved in
dioxane/water (v/v=4:1, 1.25 mL), and then stirred overnight at
40.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and then washed with 1M hydrochloric acid solution and brine. The
organic layer was dried with anhydrous magnesium sulfate, filtered,
and then concentrated under reduced pressure to remove the solvent.
The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=0%.about.50%) to obtain compound 588 (10 mg, 13.3%) as
colorless oil.
[0239] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.35-8.37 (m, 1H), 8.21-8.26 (m, 1H), 8.07-8.12 (m, 1H),
7.85-7.87 (m, 1H), 7.73-7.79 (m, 3H), 7.52-7.59 (m, 2H), 5.65 (d,
0.6H, J=8.1 Hz), 5.60 (d, 0.4H, J=8.2 Hz), 3.96-4.09 (m, 5H),
3.51-3.60 (m, 1H), 2.21-2.58 (m, 2H), 2.05 (s, 2H), 1.50-1.58 (m,
2H), 1.00-1.08 (m, 6H), 0.53 (d, 1.1H, J=6.6 Hz), 0.39 (d, 1.9H,
J=6.5 Hz)
[0240] MS (ESI) m/z 663.2 (M.sup.++H).
EXAMPLE 35
Compound 595
methyl
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl-
)-2,3-difluorobenzoate
[0241] Starting material 13 (6 mg, 0.009 mmol), difluorophenyl
pinacol ester (3 mg, 0.01 mmol), Pd(dbpf)Cl.sub.2 (0.3 mg) and
sodium carbonate (3.0 mg, 0.03 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 2 mL), and the reaction mixture was
stirred with microwave irradiation at 120.degree. C. for 30
minutes. After completion of the reaction, the reaction mixture was
cooled to room temperature, diluted with ethyl acetate, and then
washed with water and saturated ammonium chloride solution. The
organic layer was dried with anhydrous magnesium sulfate, filtered,
and then concentrated under reduced pressure to remove the solvent.
The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=10%.about.20%) to obtain compound 595 (6 mg, 91.8%) as
a solid.
[0242] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.3 atropisomeric
mixture; .delta. 8.29-8.27 (m, 1H), 7.86 (s, 1H), 7.79-7.74 (m,
1H), 7.73 (brs, 2H), 7.54-7.49 (m, 1H), 7.25-7.18 (m, 1H),
5.62-5.57 (m, 1H), 4.04-3.90 (m, 8H), 3.58-3.46 (m, 1H), 2.55-1.99
(m, 2H), 1.69-1.68 (m, 2H), 1.56-1.48 (m, 2H), 1.06-1.01 (m, 6H),
0.49 (d, 1.3H, J=6.5 Hz), 0.39 (d, 1.7H, J=6.5 Hz)
[0243] MS (ESI) m/z 713.2 (M.sup.++H).
EXAMPLE 36
Compound 596
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-2,3-d-
ifluorobenzoic acid
[0244] Starting material 595 (5.0 mg, 0.007 mmol) and lithium
hydroxide monohydrate (1 mg, 0.04 mmol) were dissolved in
dioxane/water (v/v=3:1, 0.8 mL), and then stirred overnight at
50.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, and 1M hydrochloric acid
solution was added dropwise thereto until a pH of 2 was reached,
followed by extraction with ethyl acetate. The organic layer was
washed with water, dried with anhydrous magnesium sulfate,
filtered, and then concentrated under reduced pressure to remove
the solvent, thereby obtaining compound 596 (1.4 mg, 28.6%) as a
solid.
[0245] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.4 atropisomeric
mixture; .delta. 8.30-8.29 (m, 1H), 7.86-7.79 (m, 2H), 7.73-7.72
(m, 2H), 7.55-7.52 (m, 1H), 7.33-7.21 (m, 1H), 5.63-5.57 (m, 1H),
4.07-3.94 (m, 5H), 3.57 (d, 0.5H, J=14.7 Hz), 3.49 (d, 0.5H, J=14.7
Hz), 2.55-2.04 (m, 2H), 1.96-1.95 (m, 2H), 1.54-1.46 (m, 2H),
1.06-1.01 (m, 6H), 0.50 (d, 1.2H, J=6.6 Hz), 0.40 (d, 1.8H, J=6.6
Hz)
[0246] MS (ESI) m/z 699.1 (M.sup.++H).
Preparation of Novel Compounds According to Reaction Scheme 5
Intermediate compound 19:
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(2-chloro-5-methoxypyrim-
idin-4-yl)-5,5-dimethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
[0247] Starting material 17 (0.21 g, 0.37 mmol),
2,4-dichloro-5-methoxypyrimidine 18 (0.07 g, 0.37 mmol), sodium
carbonate (0.09 g, 0.86 mmol) and Pd(dppf)Cl.sub.2 (3.0 mg, 0.004
mmol) were dissolved in dimethoxyethane/water (v/v=3:1, 4 mL), and
the reaction mixture was stirred with microwave irradiation at
120.degree. C. for 40 minutes. After completion of the reaction,
the reaction mixture was cooled to room temperature, poured into
water and extracted with ethyl acetate. The organic layer was
washed with brine, dried with anhydrous magnesium sulfate, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by preparative TLC (SiO.sub.2,
hexane/EtOAc=3:1) to obtain compound 19 (43 mg, 20%) as colorless
oil.
[0248] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.20 (s, 1H),
7.87 (s, 1H), 7.75 (s, 1H), 5.53 (d, 1H, J=8.0 Hz), 4.11 (m, 2H),
3.92 (s, 3H), 3.32 (d, 1H, J=15.1 Hz), 2.31 (m, 2H), 1.96 (s, 2H),
1.51 (t, 2H, J=6.4 Hz), 1.02 (d, 6H, J=9.4 Hz), 0.57 (d, 3H, J=6.6
Hz)
[0249] MS (ESI) m/z 578.1 (M.sup.++H).
EXAMPLE 37
Compound 603
methyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidin-2--
yl)-3-methylbenzoate
[0250] Starting material 19 (0.04 g, 0.074 mmol), boronic acid
pinacol ester 14 (0.03 g, 0.09 mmol), sodium carbonate (0.02 g,
0.17 mmol) and Pd(dppf)Cl.sub.2 (3.0 mg, 0.004 mmol) were dissolved
in dimethoxyethane/water (v/v=3:1, 4 mL), and the reaction mixture
was stirred with microwave irradiation at 120.degree. C. for 30
minutes. After completion of the reaction, the reaction mixture was
cooled to room temperature, poured into water and extracted with
ethyl acetate. The organic layer was washed with brine, dried with
anhydrous magnesium sulfate, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by MPLC
(SiO.sub.2, hexane/EtOAc=10%.about.50%) to obtain compound 603 (27
mg, 52.5%) as colorless oil.
[0251] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.45 (s, 1H),
7.93-7.76 (m, 4H), 7.61 (s, 2H), 5.40 (d, 1H, J=8.0 Hz), 4.09 (m,
1H), 4.00 (m, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.39 (d, 1H, J=15.1
Hz), 2.52 (s, 3H), 2.39 (m, 2H), 2.01 (s, 2H), 1.54 (t, 2H, J=6.4
Hz), 1.03 (d, 6H, J=9.3 Hz), 0.35 (d, 3H, J=6.5 Hz)
[0252] MS (ESI) m/z 692.2 (M.sup.++H).
EXAMPLE 38
Compound 604
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidin-2-yl)-3-m-
ethylbenzoic acid
[0253] Starting material 603 (0.03 g, 0.04 mmol) and lithium
hydroxide monohydrate (5.0 mg, 0.2 mmol) were dissolved in
dioxane/water (v/v=3:1, 4 mL), and then stirred overnight at
50.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and then washed with water and brine. The organic layer was dried
with anhydrous magnesium sulfate, filtered, and then concentrated
under reduced pressure to remove the solvent. The residue was
purified by preparative TLC (SiO.sub.2,
CH.sub.2Cl.sub.2/CH.sub.3OH=20:1) to obtain compound 604 (17 mg,
64.3%) as colorless oil.
[0254] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.48 (s, 1H), 8.0
(s, 1H), 7.95 (d, 1H, J=8.6 Hz), 7.82 (s, 1H), 7.79 (d, 1H, J=8.1
Hz), 7.62 (s, 2H), 5.41 (d, 1H, J=7.8 Hz), 4.13-3.98 (m, 5H), 3.41
(d, 1H, J=15.1 Hz), 2.54-2.34 (m, 5H), 1.98 (s, 2H), 1.55 (t, 2H,
J=6.2 Hz), 1.04 (d, 6H, J=9.8 Hz), 0.37 (d, 3H, J=6.4 Hz)
[0255] MS (ESI) m/z 678.2 (M.sup.++H).
EXAMPLE 39
Compound 610
methyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidin-2--
yl)-3-fluorobenzoate
[0256] Starting material 19 (0.05 g, 0.09 mmol), boronic acid
pinacol ester 14 (0.02 g, 0.1 mmol), sodium carbonate (0.02 g, 0.2
mmol) and Pd(dppf)Cl.sub.2 (4.0 mg, 0.004 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 4 mL), and the reaction mixture was
stirred with microwave irradiation at 120.degree. C. for 30
minutes. After completion of the reaction, the reaction mixture was
cooled to room temperature, poured into water, and extracted with
ethyl acetate. The organic layer was washed with brine, dried with
anhydrous magnesium sulfate, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by
preparative TLC (SiO.sub.2, hexane/EtOAc=1:1) to obtain compound
610 (3.3 mg, 5.5%) as colorless oil.
[0257] MS (ESI) m/z 696.2 (M.sup.++H).
EXAMPLE 40
Compound 617
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidin-2-yl)-3-f-
luorobenzoic acid
[0258] Starting material 610 (0.04 g, 0.06 mmol) and lithium
hydroxide monohydrate (8.0 mg, 0.32 mmol) were dissolved in
dioxane/water (v/v=3:1, 4 mL), and then stirred overnight at
50.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, and 1M hydrochloric acid
solution was added dropwise thereto until a pH of 6 was reached.
Then, the reaction mixture was diluted with ethyl acetate, and then
washed with water and brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
preparative TLC (Sift, hexane/EtOAc=1:2) to obtain compound 617 (26
mg, 60.3%) as colorless oil.
[0259] MS (ESI) m/z 682.3 (M.sup.++H).
EXAMPLE 41
Compound 625
methyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidin-2--
yl)benzoate
[0260] Starting material 19 (0.06 g, 0.1 mmol), phenylboronic acid
(0.02 g, 0.12 mmol),
[0261] Pd(dbpf)Cl.sub.2 (3.0 mg, 0.005 mmol) and sodium carbonate
(0.03 g, 0.3 mmol) were dissolved in dimethoxyethane/water
(v/v=3:1, 0.5 mL), and the reaction mixture was stirred with
microwave irradiation at 120.degree. C. for 30 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and saturated ammonium chloride. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=30%) to obtain compound 625 (36 mg,
53.9%) as a solid.
[0262] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.42 (s, 1H),
8.42-8.38 (m, 2H), 8.09-8.07 (m, 2H), 7.82-7.81 (m, 1H), 7.62-7.61
(m, 2H), 5.42-5.40 (m, 1H), 4.09-4.05 (m, 2H), 3.96 (s, 3H), 3.93
(s, 3H), 3.40 (d, 1H, J=15.1 Hz), 2.48-2.30 (m, 2H), 2.01-1.99 (m,
2H), 1.56-1.49 (m, 2H), 1.07 (s, 3H), 1.04 (s, 3H), 0.41 (d, 3H,
J=6.4 Hz)
[0263] MS (ESI) m/z 678.2 (M.sup.++H).
EXAMPLE 42
Compound 626
ethyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoo-
xazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidin-2-y-
l)-2-fluorobenzoate
[0264] Starting material 19 (0.06 g, 0.1 mmol), 3-fluorophenyl
boronic acid (0.03 g, 0.12 mmol), Pd(dbpf)Cl.sub.2 (3.0 mg, 0.005
mmol) and sodium carbonate (0.03 g, 0.3 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 0.5 mL), and the reaction mixture
was stirred with microwave irradiation at 120.degree. C. for 30
minutes. After completion of the reaction, the reaction mixture was
cooled to room temperature, diluted with ethyl acetate, and then
washed with water and saturated ammonium chloride. The organic
layer was dried with anhydrous magnesium sulfate, filtered, and
then concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (SiO.sub.2, EtOAc/hexane=30%) to
obtain compound 626 (59 mg, 84.3%) as a solid.
[0265] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.2 atropisomeric
mixture; .delta. 8.41 (s, 0.6H), 8.20 (s, 0.4H), 8.16 (dd, 1H,
J=8.2 Hz, 1.6 Hz), 8.10 (dd, 1H, J=12.2 Hz, 1.5 Hz), 7.99-7.95 (m,
1H), 7.86-7.64 (m, 3H), 5.53 (d, 0.4H, J=8.0 Hz), 5.44-5.42 (m,
0.6H), 5.53 (q, 1.3H, J=7.1 Hz), 4.13 (q, 0.7H, J=7.1 Hz),
4.11-4.04 (m, 2H), 3.96 (s, 1.8H), 3.92 (s, 1.2H), 3.38 (d, 0.6H,
J=15.1 Hz), 3.32 (d, 0.4H, J=15.1 Hz), 2.38-2.30 (m, 2H), 1.99-1.96
(m, 2H), 1.56-1.54 (m, 2H), 1.52-1.49 (m, 1H), 1.41 (t, 2H, J=7.1
Hz), 1.07-1.01 (m, 6H), 0.57 (d, 1.3H, J=6.5 Hz), 0.37 (d, 1.7H,
J=6.5 Hz)
[0266] MS (ESI) m/z 710.2 (M.sup.++H).
EXAMPLE 43
Compound 628
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidin-2-yl)benz-
oic acid
[0267] Starting material 625 (0.03 g, 0.05 mmol) and lithium
hydroxide monohydrate (10 mg, 0.2 mmol) were dissolved in
dioxane/water (v/v=4:1, 0.5 mL), and then stirred overnight at
45.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, and 1M hydrochloric acid
solution was added dropwise thereto until a pH of 2 was reached,
followed by extraction with ethyl acetate. The organic layer was
washed with water, dried with anhydrous magnesium sulfate,
filtered, and then concentrated under reduced pressure to remove
the solvent. The residue was purified by MPLC (Sift,
CH.sub.3OH/CH.sub.2Cl.sub.2=10%) to obtain compound 628 (15 mg,
49.7%) as a solid.
[0268] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.44 (s, 1H),
8.43 (d, 2H, J=8.4 Hz), 8.17 (d, 2H, J=8.4 Hz), 7.82 (brs, 1H),
7.63 (brs, 2H), 5.41 (d, 1H, J=7.6 Hz), 4.13-4.03 (m, 2H), 3.97 (s,
3H), 3.41 (d, 1H, J=14.8 Hz), 2.45-2.32 (m, 2H), 2.00-1.99 (m, 2H),
1.58-1.55 (m, 2H), 1.08 (s, 3H), 1.04 (s, 3H), 0.43 (d, 3H, J=6.5
Hz)
[0269] MS (ESI) m/z 664.2 (M.sup.++H).
EXAMPLE 44
Compound 629
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyrimidin-2-yl)-2-f-
luorobenzoic acid
[0270] Starting material 626 (0.06 g, 0.08 mmol) and lithium
hydroxide monohydrate (16 mg, 0.39 mmol) were dissolved in
dioxane/water (v/v=4:1, 0.5 mL), and then stirred overnight at
45.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, and 1M hydrochloric acid
solution was added dropwise thereto until a pH of 2 was reached,
followed by extraction with ethyl acetate. The organic layer was
washed with water, dried with anhydrous magnesium sulfate,
filtered, and then concentrated under reduced pressure to remove
the solvent. The residue was purified by MPLC (Sift,
CH.sub.3OH/CH.sub.2Cl.sub.2=10%) to obtain compound 629 (22 mg,
41.6%) as a solid.
[0271] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.44 (s, 1H),
8.20-8.18 (m, 1H), 8.15-8.12 (m, 1H), 8.09-8.05 (m, 1H), 7.82 (brs,
1H), 7.65 (brs, 2H), 5.45 (d, 1H, J=7.2 Hz), 4.10-4.02 (m, 2H),
3.98 (s, 3H), 3.42-3.38 (m, 1H), 2.44-2.31 (m, 2H), 2.00-1.99 (m,
2H), 1.57-1.54 (m, 2H), 1.08 (s, 3H), 1.04 (s, 3H), 0.45 (d, 3H,
J=6.3 Hz)
[0272] MS (ESI) m/z 682.2 (M.sup.++H).
EXAMPLE 45
Compound 673
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-methylbiphenyl-4-car-
boxylate
[0273] Starting material 19 (0.090 g, 0.161 mmol),
4-(methoxycarbonyl)phenylboronic acid (0.038 g, 0.209 mmol),
Pd(dbpf)Cl.sub.2 (0.005 g, 0.008 mmol) and sodium carbonate (0.051
g, 0.482 mmol) were dissolved in dimethoxyethane/water (v/v=3:1, 1
ml) and heated by microwave irradiation at 120.degree. C. for 30
minutes. Then, the reaction mixture was cooled to room temperature,
and water was poured into the reaction mixture, which was then
extracted with ethyl acetate. The organic layer was washed with
aqueous solution of saturated ammonium chloride, dried with
anhydrous magnesium sulfate, and then concentrated under reduced
pressure. The residue was purified by MPLC (Sift,
EtOAc/hexane=5%.about.10%) to obtain compound 673 (0.052 g, 49.0%)
as a white solid.
[0274] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.07-8.04 (m, 2H), 7.85 (s, 1H), 7.71 (s, 2H), 7.33-7.31
(m, 2H), 7.22 (d, 1H, J=7.8 Hz), 7.01 (dd, 1H, J=7.7, 1.9 Hz), 6.94
(d, 1H, J=1.8 Hz), 5.58 (d, 1H, J=8.2 Hz), 4.06-4.02 (m, 1H), 3.94
(s, 3H), 3.91-3.87 (m, 1H), 3.75 (d, 1H, J=14.7 Hz), 2.44-2.36 (m,
2H), 2.21 (s, 3H), 1.95-1.91 (m, 2H), 1.49 (t, 2H, J=6.5 Hz), 1.02
(s, 3H), 0.99 (s, 3H), 0.39 (d, 3H, J=6.6 Hz)
[0275] MS (ESI) m/z 660.2 (M.sup.++H).
EXAMPLE 46
Compound 674
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,2'-dimethylbiphenyl-4-
-carboxylate
[0276] Starting material 19 (0.090 g, 0.161 mmol),
4-(methoxycarbonyl)2-methylphenylboronic acid (0.058 g, 0.209
mmol), Pd(dbpf)Cl.sub.2 (0.005 g, 0.008 mmol) and sodium carbonate
(0.051 g, 0.482 mmol) were dissolved in dimethoxyethane/water
(v/v=3:1, 1 ml) and heated by microwave irradiation at 120.degree.
C. for 30 minutes. Then, the reaction mixture was cooled to room
temperature, and water was poured into the reaction mixture, which
was then extracted with ethyl acetate. The organic layer was washed
with aqueous solution of saturated ammonium chloride, dried with
anhydrous magnesium sulfate to remove water, and then concentrated
under reduced pressure. The residue was purified by MPLC
(SiO.sub.2, EtOAc/hexane=10%) to obtain compound 674 (0.053 g,
49.2%) as a white solid.
[0277] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 7.94-7.91 (m, 1H), 7.89-7.83 (m, 2H), 7.72 (m, 2H), 7.22
(dd, 1H, J=7.8, 2.7 Hz), 7.15 (d, 0.5H, J=7.8 Hz), 7.07 (d, 0.5H,
J=7.9 Hz), 7.02-6.98 (m, 1H), 6.82 (dd, 1H, J=6.8, 1.8 Hz), 5.60
(d, 1H, J=8.2 Hz), 4.06-4.00 (m, 1H), 3.92 (s, 3H), 3.91-3.85 (m,
1H), 3.82-3.74 (m, 1H), 2.43-2.25 (m, 2H), 2.07-2.04 (m, 3H),
1.99-1.98 (m, 3H), 1.94-1.90 (m, 2H), 1.49-1.46 (m, 2H), 1.02-0.98
(m, 6H), 0.39-0.35 (m, 3H)
[0278] MS (ESI) m/z 674.2 (M.sup.++H).
EXAMPLE 47
Compound 675
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-2'-methylbiphe-
nyl-4-carboxylate
[0279] Starting material 19 (0.090 g, 0.161 mmol),
2-fluoro-4-(methoxycarbonyl)phenylboronic acid (0.059 g, 0.209
mmol), Pd(dbpf)Cl.sub.2 (0.005 g, 0.008 mmol) and sodium carbonate
(0.051 g, 0.482 mmol) were dissolved in dimethoxyethane/water
(v/v=3:1, 1 ml) and heated by microwave irradiation at 120.degree.
C. for 30 minutes. Then, the reaction mixture was cooled to room
temperature, and water was poured into the reaction mixture, which
was then extracted with ethyl acetate. The organic layer was washed
with aqueous solution of saturated ammonium chloride, dried with
anhydrous magnesium sulfate, and then concentrated under reduced
pressure. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=10%) to obtain compound 675 (0.034 g, 31.1%) as a
white solid.
[0280] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 7.88-7.85 (m, 2H), 7.77 (dd, 1H, J=10.0, 1.5 Hz), 7.72 (s,
2H), 7.30-7.23 (m, 2H), 7.06 (dd, 1H, J=7.7, 1.8 Hz), 7.95 (d, 1H,
J=1.5 Hz), 5.56 (d, 1H, J=8.1 Hz), 4.04-4.00 (m, 1H), 3.95 (s, 3H),
3.90-3.83 (m, 1H), 3.76 (d, 1H, J=14.8 Hz), 2.45-2.36 (m, 2H), 2.14
(s, 3H), 1.96-1.92 (m, 2H), 1.50-1.47 (m, 2H), 1.02 (s, 3H), 0.99
(s, 3H), 0.35 (d, 3H, J=6.5 Hz)
[0281] MS (ESI) m/z 678.2 (M.sup.++H).
EXAMPLE 48
Compound 676
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-methylbiphenyl-4-carboxylic
acid
[0282] Starting material 673 (0.048 g, 0.074 mmol) and lithium
hydroxide monohydrate (0.016 g, 0.372 mmol) were dissolved in
dioxane/water (v/v=4:1, 1 ml) at 50.degree. C., and the reaction
mixture was stirred at the same temperature for 4 hours. The
reaction mixture was concentrated, and water was poured into the
reaction mixture, which was then extracted with ethyl acetate. The
organic layer was washed with aqueous solution of 1M hydrochloric
acid, dried with anhydrous magnesium sulfate, and then concentrated
under reduced pressure. The residue was purified by MPLC
(SiO.sub.2, CH.sub.3OH/CH.sub.2Cl.sub.2=2%) to obtain compound 676
(0.033 g, 69.2%) as a white solid.
[0283] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.14 (d, 2H, J=8.3 Hz), 7.85 (s, 1H), 7.72 (s, 2H), 7.37
(d, 2H, J=8.4 Hz), 7.24 (d, 1H, J=8.0 Hz), 7.02 (dd, 1H, J=7.7, 1.8
Hz), 6.96 (d, 1H, J=1.7 Hz), 5.59 (d, 1H, J=8.2 Hz), 4.04-4.00 (m,
1H), 3.95-3.88 (m, 1H), 3.77-3.74 (m, 1H), 2.43-2.27 (m, 2H), 2.23
(s, 3H), 1.95-1.91 (m, 2H), 1.51-1.48 (m, 2H), 1.03 (s, 3H), 0.99
(s, 3H), 0.40 (d, 3H, J=6.6 Hz)
[0284] MS (ESI) m/z 646.2 (M.sup.++H).
EXAMPLE 49
Compound 677
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,2'-dimethylbiphenyl-4-carbox-
ylic acid
[0285] Starting material 674 (0.053 g, 0.079 mmol) and lithium
hydroxide monohydrate (0.017 g, 0.396 mmol) were dissolved in
dioxane/water (v/v=4:1, 1 ml) at 50.degree. C., and the reaction
mixture was stirred at the same temperature for 4 hours. The
reaction mixture was concentrated, and water was poured into the
reaction mixture, which was then extracted with ethyl acetate. The
organic layer was washed with aqueous solution of 1M hydrochloric
acid, dried with anhydrous magnesium sulfate, and then concentrated
under reduced pressure. The residue was purified by MPLC
(SiO.sub.2, CH.sub.3OH/CH.sub.2Cl.sub.2=5%) to obtain compound 677
(0.037 g, 71.3%) as a white solid.
[0286] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.01-7.98 (m, 1H), 7.97-7.91 (m, 1H), 7.86 (s, 1H), 7.72
(s, 2H), 7.24-7.21 (m, 1H), 7.20 (d, 0.5H, J=7.8 Hz), 7.11 (d,
0.5H, J=7.7 Hz), 7.04-6.99 (m, 1H), 6.83 (dd, 1H, J=6.5, 1.8 Hz),
5.60 (d, 1H, J=8.3 Hz), 4.03-4.01 (m, 1H), 3.91-3.82 (m, 1H),
3.78-3.74 (m, 1H), 2.45-2.28 (m, 2H), 2.10 (s, 1.5H), 2.04 (s,
1.5H), 2.01-2.00 (m, 3H), 1.95-1.91 (m, 2H), 1.50-1.47 (m, 2H),
1.02 (s, 3H), 0.99 (s, 3H), 0.40-0.36 (m, 3H)
[0287] MS (ESI) m/z 660.2 (M.sup.++H).
EXAMPLE 50
Compound 678
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-2'-methylbiphenyl-4-c-
arboxylic acid
[0288] Starting material 675 (0.030 g, 0.044 mmol) and lithium
hydroxide monohydrate (0.009 g, 0.221 mmol) were dissolved in
dioxane/water (v/v=4:1, 1 ml) at 50.degree. C., and the reaction
mixture was stirred at the same temperature for 4 hours. The
reaction mixture was concentrated, and water was poured into the
reaction mixture, which was then extracted with ethyl acetate. The
organic layer was washed with aqueous solution of 1M hydrochloric
acid, dried with anhydrous magnesium sulfate, and then concentrated
under reduced pressure. The residue was purified by MPLC
(SiO.sub.2, CH.sub.3OH/CH.sub.2Cl.sub.2=5%) to obtain compound 678
(0.022 g, 74.9%) as a white solid.
[0289] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 7.95-7.93 (m, 1H), 7.85-7.80 (m, 2H), 7.72 (s, 2H),
7.35-7.31 (m, 1H), 7.26-7.25 (m, 1H), 7.07 (dd, 1H, J=7.7, 1.8 Hz),
6.96 (d, 1H, J=1.4 Hz), 5.57 (d, 1H, J=8.1 Hz), 4.05-4.01 (m, 1H),
3.91-3.84 (m, 1H), 3.79-3.75 (m, 1H), 2.43-2.25 (m, 2H), 2.16 (s,
3H), 1.95-1.94 (m, 2H), 1.50-1.47 (m, 2H), 1.02 (s, 3H), 0.99 (s,
3H), 0.36 (d, 3H, J=6.5 Hz)
[0290] MS (ESI) m/z 664.2 (M.sup.++H).
EXAMPLE 51
Compound 763
methyl
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-yl-
)-3-(trifluoromethyl)benzoate
[0291] Starting material 19 (0.100 g, 0.173 mmol),
methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl-
)benzoate compound (0.086 g, 0.260 mmol), potassium acetate (0.049
g, 0.520 mmol) and Pd(dbpf)Cl.sub.2 (0.006 g, 0.009 mmol) were
added to N,N-dimethylformamide (0.8 mL)/water (0.4 mL) and heated
by microwave irradiation at 120.degree. C. for 20 minutes, and then
the temperature was lowered to room temperature to stop the
reaction. Water was poured into the reaction mixture, which was
then extracted with ethyl acetate. The organic layer was dried with
anhydrous magnesium sulfate to remove water, filtered, and then
concentrated under pressure. The residue was purified by MPLC
(SiO.sub.2, EtOAc/hexane=0%.about.20%) to obtain desired compound
763 (0.020 g, 15.5%) as a brown solid.
[0292] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.42 (s, 1H),
8.22 (d, 1H, J=6.9 Hz), 7.84 (s, 1H), 7.68 (m, 2H), 7.54 (m, 1H),
7.34-7.29 (m, 2H), 5.58 (m, 1H), 4.12-4.05 (m, 2H), 3.98 (s, 3H),
3.91 (s, 3H), 3.40 (m, 1H), 2.47-2.33 (m, 2H), 1.95 (m, 2H), 1.55
(t, 2H, J=6.3 Hz), 1.06 (d, 6H, J=6.6 Hz), 0.32 (m, 3H)
[0293] MS (ESI) m/z 745.1 (M.sup.++H).
EXAMPLE 52
Compounds 764
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-yl)-3-(tr-
ifluoromethyl)benzoic acid
[0294] Starting material 763 (0.010 g, 0.014 mmol) and lithium
hydroxide monohydrate (0.006 g, 0.144 mmol) were dissolved in
1,4-dioxane (4 mL)/water (1 mL) at room temperature, and the
reaction mixture was stirred at the same temperature for 16 hours.
An aqueous solution of 1M hydrochloric acid was poured into the
reaction mixture, which was then extracted with ethyl acetate. The
organic layer was washed, dried with anhydrous magnesium sulfate,
filtered, and then concentrated under reduced pressure. The residue
was purified by MPLC (SiO.sub.2, EtOAc/hexane=20%.about.50%) to
obtain compound 764 (0.005 g, 47.6%) as a white solid.
[0295] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.41 (s, 1H),
8.19 (d, 1H, J=8.0 Hz), 7.84 (s, 1H), 7.72 (s, 2H), 7.54 (d, 1H,
J=7.8 Hz), 7.37-7.29 (m, 2H), 5.55 (m, 1H), 4.12-4.05 (m, 2H), 3.90
(s, 3H), 3.47-3.43 (m, 1H), 2.60-2.23 (m, 2H), 1.98 (m, 2H), 1.55
(m, 2H), 1.06 (m, 6H), 0.32 (m, 3H)
[0296] MS (ESI) m/z 731.1 (M.sup.++H).
Preparation of Novel Compounds According to Reaction Scheme 6
Intermediate compound 23:
(1R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((2-(4-fluoro-2-methoxy-5-ni-
trophenyl)-5,5-dimethylcyclohex-1-enyl)methylamino)propan-1-ol
[0297] Starting material 22 (0.2 g, 0.65 mmol), aminoalcohol
compound 4 (0.2 g, 0.78 mmol) and sodium cyanoborohydride (49 mg,
0.78 mmol) were dissolved in methylene chloride (10 mL), and acetic
acid (0.05 mL, 0.78 mmol) was slowly added dropwise thereto at room
temperature. The reaction mixture was stirred at room temperature
for 1 hour, diluted with methylene chloride, and then washed with
water. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The obtained compound 23 (369 mg, 98%) as a
white solid was used in the next reaction.
[0298] MS (ESI) m/z 579.2 (M.sup.++H).
Intermediate compound 24:
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(4-fluoro-2-methoxy-5-ni-
trophenyl-5,5-dimethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
[0299] Starting material 23 (0.37 g, 0.64 mmol) and triphosgene
(0.23 g, 0.77 mmol) were dissolved in methylene chloride (10 mL),
and diisopropylethylamine (0.67 mL, 3.83 mmol) was slowly added
dropwise thereto. The reaction mixture was stirred at room
temperature for 1 hour, diluted with methylene chloride, and then
washed with water. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by MPLC
(SiO.sub.2 12 g, EtOAc/hexane=10%) to obtain compound 24 (0.29 g,
75%) as a yellow solid.
[0300] MS (ESI) m/z 605.1 (M.sup.++H).
Intermediate compound 25:
(4S,5R)-3-((2-(5-amino-4-fluoro-2-methoxyphenyl)-5,5-dimethylcyclohex-1-e-
nyl)methyl)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one
[0301] Starting material 24 (0.29 g, 0.47 mmol) was dissolved in
methanol (3 mL), and Raney Ni (1 spoon) was added dropwise thereto,
and the reaction mixture was hydrogenated overnight. After
completion of the reaction, the reaction mixture was filtered
through celite under reduced pressure, and then concentrated under
reduced pressure to remove the solvent. The obtained yellow solid
compound 25 (0.27 g, 103.3%) was used in the next reaction.
[0302] MS (ESI) m/z 575.3 (M.sup.++H).
Intermediate compound 26:
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(4-fluoro-5-iodo-2-metho-
xyphenyl)-5,5-dimethylcyclohex-1-enyl)methyl-4-methyloxazolidin-2-one
[0303] Starting material 25 (0.28 g, 0.48 mmol) was dissolved in
acetonitrile (5 mL), and para-toluenesulfonic acid monohydrate
(0.27 g, 1.4 mmol) and a solution of sodium nitrite (0.03 g, 0.5
mmol) in water (2 mL) were sequentially added dropwise thereto,
followed by stirring at room temperature for 2 hours. Potassium
iodide (0.09 g, 0.53 mmol) was added dropwise to the reaction
mixture, which was then stirred at room temperature for 1 hour.
After completion of the reaction, the reaction mixture was diluted
with ethyl acetate, and then washed with water and sodium
thiosulfate solution. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by MPLC
(Sift, EtOAc/hexane=1:9) to obtain compound 26 (0.17 g, 51%).
[0304] MS (ESI) m/z 686.1 (M.sup.++H).
EXAMPLE 53
Compound 572
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-4'-methoxy-2--
methylbiphenyl-4-carboxylate
[0305] Starting material 26 (0.05 g, 0.07 mmol),
2-methyl-4-methoxycarbonylphenylboronic acid pinacol ester (0.02 g,
0.09 mmol), Pd(dbpf)Cl.sub.2 (2.4 mg, 0.004 mmol) and sodium
carbonate (23.2 mg, 0.22 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 1 mL), and then stirred with
microwave irradiation at 120.degree. C. for 30 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and saturated ammonium chloride solution. The organic layer was
dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (Sift, EtOAc/hexane=1:4) to obtain
compound 572 (28 mg, 55%) as a solid.
[0306] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.2 atropisomeric
mixture; .delta. 7.94-7.83 (m, 3H), 7.74-7.71 (m, 2H), 7.23-7.12
(m, 1H), 6.86-6.82 (m, 1H), 6.70-6.64 (m, 1H), 5.62-5.59 (m, 1H),
4.04-3.86 (m, 5H), 3.78 (s, 1.4H), 3.75 (s, 1.6H), 3.63-3.45 (m,
1H), 2.52-2.04 (m, 5H), 1.97-1.85 (m, 2H), 1.55-1.42 (m, 2H),
1.05-0.98 (m, 6H), 0.45 (d, 1.4H, J=6.5 Hz), 0.39 (d, 1.6H, J=6.5
Hz)
[0307] MS (ESI) m/z 708.2 (M.sup.++H).
EXAMPLE 54
Compound 573
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-4'-methoxybip-
henyl-4-carboxylate
[0308] Starting material 26 (0.05 g, 0.07 mmol),
4-methoxycarbonylphenylboronic acid (0.02 g, 0.09 mmol),
Pd(dbpf)Cl.sub.2 (2.4 mg, 0.004 mmol) and sodium carbonate (23.2
mg, 0.22 mmol) were dissolved in dimethoxyethane/water (v/v=3:1, 1
mL), and then stirred with microwave irradiation at 120.degree. C.
for 30 minutes. After completion of the reaction, the reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and then washed with water and saturated ammonium chloride
solution. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (Sift,
EtOAc/hexane=1:4) to obtain compound 573 (17 mg, 33%) as a
solid.
[0309] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.3 atropisomeric
mixture; .delta. 8.09-8.01 (m, 2H), 7.86 (brs, 1H), 7.72-7.71 (m,
2H), 7.58-7.50 (m, 2H), 7.08-7.05 (m, 1H), 6.72-6.66 (m, 1H),
5.61-5.58 (m, 1H), 4.04-3.97 (m, 2H), 3.93-3.92 (m, 3H), 3.81-3.78
(m, 3H), 3.62-3.46 (m, 1H), 2.17-2.04 (m, 2H), 1.97-1.87 (m, 2H),
1.55-1.43 (m, 2H), 1.05-1.00 (m, 6H), 0.45 (d, 1.3H, J=6.5 Hz),
0.40 (d, 1.7H, J=6.5 Hz)
[0310] MS (ESI) m/z 694.2 (M.sup.++H).
EXAMPLE 55
Compound 574
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-4'-methoxy-2-methylb-
iphenyl-4-carboxylic acid
[0311] Starting material 572 (23 mg, 0.03 mmol) was dissolved in
dioxane (1 mL), and a solution of lithium hydroxide monohydrate
(6.8 mg, 0.16 mmol) in water (1 mL) was added dropwise thereto,
followed by stirring overnight at 50.degree. C. After completion of
the reaction, the reaction mixture was cooled to room temperature,
and 1M hydrochloric acid solution was added dropwise thereto until
a pH of 2 was reached, followed by extraction with ethyl acetate.
The organic layer was washed with water, dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure, thereby obtaining compound 574 (19 mg, 83%) as a
solid.
[0312] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.2 atropisomeric
mixture; .delta. 8.01-7.98 (m, 1H), 7.97-7.90 (m, 1H), 7.87-7.86
(m, 1H), 7.74-7.71 (m, 2H), 7.28 (d, 0.6H, J=7.9 Hz), 7.19 (d,
0.4H, J=7.9 Hz), 6.85 (t, 1H, J=8.2 Hz), 6.71-6.65 (m, 1H),
5.63-5.59 (m, 1H), 4.03-3.89 (m, 2H), 3.82 (s, 1.4H), 3.78 (s,
1.6H), 3.64-3.46 (m, 1H), 2.53-2.09 (m, 5H), 1.97-1.85 (m, 2H),
1.53-1.42 (m, 2H), 1.05-0.99 (m, 6H), 0.46 (d, 1.4H, J=6.5 Hz),
0.40 (d, 1.6H, J=6.5 Hz)
[0313] MS (ESI) m/z 694.2 (M.sup.++H).
EXAMPLE 56
Compound 575
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-4'-methoxybiphenyl-4-
-carboxylic acid
[0314] Starting material 573 (23 mg, 0.03 mmol) was dissolved in
dioxane (1 mL), a solution of lithium hydroxide monohydrate (6.8
mg, 0.16 mmol) in water (1 mL) was added dropwise thereto, followed
by stirring overnight at 50.degree. C. After completion of the
reaction, the reaction mixture was cooled to room temperature, and
1M hydrochloric acid solution was added dropwise thereto until a pH
of 2 was reached, followed by extraction with ethyl acetate. The
organic layer was washed with water, dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure,
thereby obtaining compound 575 (7 mg, 62%) as a solid.
[0315] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.3 atropisomeric
mixture; .delta. 8.16-8.10 (m, 2H), 7.86-7.85 (m, 1H), 7.73-7.71
(m, 2H), 7.62-7.53 (m, 2H), 7.08 (dd, 1H, J=8.9 Hz, 1.5 Hz),
6.74-6.67 (m, 1H), 5.61 (dd, 1H, J=8.2, 2.8 Hz), 4.03-3.92 (m, 2H),
3.81-3.78 (m, 3H), 3.63-3.46 (m, 1H), 2.51-2.04 (m, 2H), 1.98-1.92
(m, 2H), 1.54-1.42 (m, 2H), 1.05-1.01 (m, 6H), 0.46 (d, 1.3H, J=6.5
Hz), 0.41 (d, 1.7H, J=6.5 Hz)
[0316] MS (ESI) m/z 680.2 (M.sup.++H).
EXAMPLE 57
Compound 630
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-2'-fluoro-4'-m-
ethoxybiphenyl-4-carboxylate
[0317] Starting material 26 (0.10 g, 0.14 mmol), methyl
3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
(0.04 g, 0.17 mmol), Pd(dppf)Cl.sub.2 (6.0 mg, 0.007 mmol) and
sodium carbonate (34 mg, 0.32 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 4 mL), and then stirred with
microwave irradiation at 120.degree. C. for 30 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by preparative TLC
(SiO.sub.2, hexane/EtOAc=4:1) to obtain compound 630 (39 mg, 39%)
as colorless oil.
[0318] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.12 (2d, 1H, J=1.6 Hz), 7.94 (2dd, 1H, J=8.0, 1.7 Hz),
7.86 (s, 1H), 7.72 (2s, 2H), 7.36 (2d, 1H, J=8.0 Hz), 6.93 (2d, 1H,
J=2.0 Hz), 6.69 (2d, 1H, J=11.6 Hz), 5.60 (2d, 1H, J=3.6 Hz),
4.04-3.88 (m, 5H), 3.80 (2s, 3H), 3.49 (2d, 1H, J=14.6 Hz),
2.56-1.89 (m, 4H), 1.49 (m, 2H), 1.01 (2d, 6H, J=11.2 Hz), 0.42
(2d, 3H, J=6.6 Hz)
[0319] MS (ESI) m/z 728.2 (M.sup.++H).
EXAMPLE 58
Compound 631
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-2'-fluoro-4'-methoxyb-
iphenyl-4-carboxylic acid
[0320] Starting material 630 (25 mg, 0.03 mmol) and lithium
hydroxide monohydrate (4 mg, 0.17 mmol) were dissolved in
dioxane/water (v/v=3:1, 4 mL), and then stirred overnight at
45.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and then washed with water. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
preparative TLC (SiO.sub.2, hexane/EtOAc=1:2) to obtain compound
631 (13 mg, 53%) as colorless oil.
[0321] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.19 (2d, 1H, J=1.5 Hz), 8.01 (2dd, 1H, J=8.0, 1.5 Hz),
7.87 (s, 1H), 7.72 (2s, 2H), 7.40 (2d, 1H, J=8.0 Hz), 6.95 (2d, 1H,
J=2.8 Hz), 6.70 (2d, 1H, J=11.7 Hz), 5.60 (2d, 1H, J=4.1 Hz),
4.05-3.85 (m, 2H), 3.81 (2s, 3H), 3.57 (2d, 1H, J=14.8 Hz),
2.54-1.87 (m, 4H), 1.48 (m, 2H), 1.01 (2d, 6H, J=11.1 Hz), 0.43
(2d, 3H, J=6.5 Hz)
[0322] MS (ESI) m/z 714.2 (M.sup.++H).
EXAMPLE 59
Compound 657
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,2'-difluoro-4'-methox-
ybiphenyl-4-carboxylate
[0323] Starting material 26 (0.100 g, 0.146 mmol),
methyl-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
(27, 0.049 g, 0.175 mmol), Pd(dbpf)Cl.sub.2 (0.005 g, 0.007 mmol)
and sodium carbonate (0.046 g, 0.438 mmol) were added to
dimethoxyethane/water (v/v=3:1, 1 ml) and heated by microwave
irradiation at 120.degree. C. for 20 minutes. Then, the temperature
was lowered to room temperature, and water was poured into the
reaction mixture, which was then extracted with ethyl acetate. The
organic layer was washed with aqueous solution of saturated
ammonium chloride, dried with anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=20%) to obtain compound 657 (0.049 g,
47.2%) as a white solid.
[0324] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 7.88-7.83 (m, 2H), 7.81-7.74 (m, 3H), 7.44-7.40 (m, 1H),
7.05-7.00 (m, 1H), 6.74-6.67 (m, 1H), 5.62-5.56 (m, 1H), 4.01-3.92
(m, 5H), 3.81 (s, 1.5H), 3.78 (s, 1.5H), 3.63 (d, 0.5H, J=14.7 Hz),
3.46 (d, 0.5H, J=14.8 Hz), 2.52-2.03 (m, 2H), 1.96-1.90 (m, 2H),
1.49-1.47 (m, 2H), 1.04-0.99 (m, 6H), 0.42-0.40 (m, 3H)
[0325] MS (ESI) m/z 712.3 (M.sup.++H).
EXAMPLE 60
Compound 658
ethyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxa-
zolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,3'-difluoro-4'-methoxy-
biphenyl-4-carboxylate
[0326] Starting material 26 (0.050 g, 0.073 mmol),
4-(ethoxycarbonyl)-3-fluorophenyl boronic acid (0.019 g, 0.088
mmol), Pd(dbpf)Cl.sub.2 (0.002 g, 0.004 mmol) and sodium carbonate
(0.023 g, 0.219 mmol) were added to dimethoxyethane/water (v/v=3:1,
0.5 ml) and heated by microwave irradiation at 120.degree. C. for
20 minutes. Then, the temperature was lowered to room temperature,
and water was poured into the reaction mixture, which was then
extracted with ethyl acetate. The organic layer was washed with
aqueous solution of saturated ammonium chloride, dried with
anhydrous magnesium sulfate, and then concentrated under reduced
pressure. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=20%) to obtain compound 658 (0.021 g, 39.7%) as a
white solid.
[0327] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.31 atropisomeric
mixture; .delta. 7.99-7.91 (m, 1H), 7.86-7.85 (m, 1H), 7.72-7.71
(m, 2H), 7.35-7.21 (m, 2H), 7.06 (d, 1H, J=8.9 Hz), 6.72-6.66 (m,
1H), 5.61 (dd, 1H, J=8.1, 3.3 Hz), 4.43-4.36 (m, 2H), 4.02-3.91 (m,
2H), 3.81-3.78 (m, 3H), 3.58 (d, 0.5H, J=14.6 Hz), 3.46 (d, 0.5H,
J=15.0 Hz), 2.48-2.04 (m, 2H), 1.97-1.87 (m, 2H), 1.50-1.45 (m,
2H), 1.41-1.37 (m, 3H), 1.05-1.00 (m, 6H), 0.45 (d, 1.3H, J=6.6
Hz), 0.41 (d, 1.7H, J=6.4 Hz)
[0328] MS (ESI) m/z 726.3 (M.sup.++H).
EXAMPLE 61
Compound 659
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-3,4'-dimethox-
ybiphenyl-4-carboxylate
[0329] Starting material 26 (0.100 g, 0.146 mmol),
methyl-2-methoxy-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
(0.051 g, 0.175 mmol), Pd(dbpf)Cl.sub.2 (0.005 g, 0.007 mmol) and
sodium carbonate (0.046 g, 0.438 mmol) were added to
dimethoxyethane/water (v/v=3:1, 1 ml) and heated by microwave
irradiation at 120.degree. C. for 20 minutes. Then, the temperature
was lowered to room temperature, and water was poured into the
reaction mixture, which was then extracted with ethyl acetate. The
organic layer was washed with aqueous solution of saturated
ammonium chloride, dried with anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=20%) to obtain compound 659 (0.047 g,
44.5%) as a white solid.
[0330] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.36 atropisomeric
mixture; .delta. 7.86-7.80 (m, 2H), 7.72-7.71 (m, 2H), 7.11-6.98
(m, 3H), 6.72-6.65 (m, 1H), 5.61-5.58 (m, 1H), 4.03-3.89 (m, 8H),
3.81-3.77 (m, 3H), 3.60 (d, 0.5H, J=14.6 Hz), 3.48 (d, 0.5H, J=15.0
Hz), 2.50-2.03 (m, 2H), 1.99-1.87 (m, 2H), 1.52-1.47 (m, 2H),
1.05-1.00 (m, 6H), 0.47 (d, 1.3H, J=6.6 Hz), 0.41 (d, 1.7H, J=6.5
Hz).
[0331] MS (ESI) m/z 724.3 (M.sup.++H).
EXAMPLE 62
Compound 660
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,2',3-trifluoro-4'-met-
hoxybiphenyl-4-carboxylate
[0332] Starting material 26 (0.100 g, 0.146 mmol),
2,3-difluoro-4-(methoxycarbonyl)phenylboronic acid (0.038 g, 0.175
mmol), Pd(dbpf)Cl.sub.2 (0.005 g, 0.007 mmol) and sodium carbonate
(0.046 g, 0.438 mmol) were added to dimethoxyethane/water (v/v=3:1,
1 ml) and heated by microwave irradiation at 120.degree. C. for 20
minutes. Then, the temperature was lowered to room temperature, and
water was poured into the reaction mixture, which was then
extracted with ethyl acetate. The organic layer was washed with
aqueous solution of saturated ammonium chloride, dried with
anhydrous magnesium sulfate, and then concentrated under reduced
pressure. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=20%) to obtain compound 660 (0.031 g, 29.1%) as a
white solid.
[0333] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 7.86-7.85 (m, 1H), 7.74-7.70 (m, 3H), 7.22-7.12 (m, 1H),
7.04-7.00 (m, 1H), 6.75-6.68 (m, 1H), 5.62-5.57 (m, 1H), 3.99-3.95
(m, 5H), 3.82-3.79 (m, 3H), 3.61 (d, 0.5H, J=14.8 Hz), 3.45 (d,
0.5H, J=14.9 Hz), 2.51-2.06 (m, 2H), 1.99-1.87 (m, 2H), 1.49-1.47
(m, 2H), 1.04-0.99 (m, 6H), 0.44-0.41 (m, 3H)
[0334] MS (ESI) m/z 730.3 (M.sup.++H).
EXAMPLE 63
Compound 661
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,2'-difluoro-4'-methoxybiphen-
yl-4-carboxylic acid
[0335] Starting material 657 (0.046 g, 0.064 mmol) and lithium
hydroxide monohydrate (0.013 g, 0.320 mmol) were dissolved in
dioxane/water (v/v=4:1, 1 ml) at 50.degree. C., and the reaction
mixture was stirred overnight at the same temperature. Then, the
reaction mixture was concentrated, and water was added thereto,
followed by extraction with ethyl acetate. The organic layer was
washed with aqueous solution of 1M hydrochloric acid, dried with
anhydrous magnesium sulfate, and then concentrated under reduced
pressure, thereby obtaining compound 661 (0.035 g, 78.7%) as a
white solid.
[0336] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 7.95-7.80 (m, 3H), 7.74-7.73 (m, 2H), 7.48-7.44 (m, 1H),
7.07-7.02 (m, 1H), 6.75-6.69 (m, 1H), 5.62-5.57 (m, 1H), 4.00-3.94
(m, 2H), 3.82 (s, 1.5H), 3.79 (s, 1.5H), 3.63 (d, 0.6H, J=15.1 Hz),
3.47 (d, 0.4H, J=14.9 Hz), 2.50-2.05 (m, 2H), 1.95-1.91 (m, 2H),
1.50-1.48 (m, 2H), 1.05-1.00 (m, 6H), 0.43-0.41 (m, 3H)
[0337] MS (ESI) m/z 698.2 (M.sup.++H).
EXAMPLE 64
Compound 662
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2',3-difluoro-4'-methoxybiphen-
yl-4-carboxylic acid
[0338] Starting material 658 (0.021 g, 0.029 mmol) and lithium
hydroxide monohydrate (0.006 g, 0.145 mmol) were dissolved in
dioxane/water (v/v=4:1, 1 ml) at 50.degree. C., and the reaction
mixture was stirred overnight at the same temperature. Then, the
reaction mixture was concentrated, and water was added thereto,
followed by extraction with ethyl acetate. The organic layer was
washed with aqueous solution of 1M hydrochloric acid, dried with
anhydrous magnesium sulfate, and then concentrated under reduced
pressure, thereby obtaining compound 662 (0.016 g, 80.2%) as a
white solid.
[0339] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.38 atropisomeric
mixture; .delta. 8.08-8.02 (m, 1H), 7.86-7.85 (m, 1H), 7.73-7.71
(m, 2H), 7.39-7.29 (m, 2H), 7.09-7.07 (m, 1H), 6.74-6.67 (m, 1H),
5.62-5.60 (m, 1H), 4.02-3.97 (m, 2H), 3.82-3.78 (m, 3H), 3.59 (d,
0.6H, J=14.4 Hz), 3.46 (d, 0.4H, J=15.4 Hz), 2.50-2.05 (m, 2H),
1.94-1.92 (m, 2H), 1.50-1.47 (m, 2H), 1.05-1.00 (m, 6H), 0.46 (d,
1.3H, J=6.5 Hz), 0.42 (d, 1.7H, J=6.5 Hz)
[0340] MS (ESI) m/z 698.2 (M.sup.++H).
EXAMPLE 65
Compound 663
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-3,4'-dimethoxybiphen-
yl-4-carboxylic acid
[0341] Starting material 659 (0.043 g, 0.059 mmol) and lithium
hydroxide monohydrate (0.012 g, 0.297 mmol) were dissolved in
dioxane/water (v/v=4:1, 1 ml) at 50.degree. C., and the reaction
mixture was stirred overnight at the same temperature. Then, the
reaction mixture was concentrated, and water was added thereto,
followed by extraction with ethyl acetate. The organic layer was
washed with aqueous solution of 1M hydrochloric acid, dried with
anhydrous magnesium sulfate, and then concentrated under reduced
pressure, thereby obtaining compound 663 (0.017 g, 40.8%) as a
white solid.
[0342] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.44 atropisomeric
mixture; .delta. 8.23-8.16 (m, 1H), 7.87-7.86 (m, 1H), 7.73-7.70
(m, 2H), 7.24-7.07 (m, 3H), 6.74-6.67 (m, 1H), 5.63-5.60 (m, 1H),
4.12-4.08 (m, 3H), 4.02-3.95 (m, 2H), 3.82-3.79 (m, 3H), 3.58-3.46
(m, 1H), 2.50-2.04 (m, 2H), 1.94-1.92 (m, 2H), 1.51-1.49 (m, 2H),
1.06-1.00 (m, 6H), 0.49 (d, 1.2H, J=6.6 Hz), 0.43 (d, 1.8H, J=6.6
Hz)
[0343] MS (ESI) m/z 710.2 (M.sup.++H).
EXAMPLE 66
Compound 664
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-22',3-trifluoro-4'-methoxybiph-
enyl-4-carboxylic acid
[0344] Starting material 660 (0.026 g, 0.036 mmol) and lithium
hydroxide monohydrate (0.007 g, 0.178 mmol) were dissolved in
dioxane/water (v/v=4:1, 1 ml) at 50.degree. C., and the reaction
mixture was stirred overnight at the same temperature. Then, the
reaction mixture was concentrated, and water was added thereto,
followed by extraction with ethyl acetate. The organic layer was
washed with aqueous solution of 1M hydrochloric acid, dried with
anhydrous magnesium sulfate, and then concentrated under reduced
pressure, thereby obtaining compound 664 (0.023 g, 89.9%) as a
white solid.
[0345] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 7.86-7.73 (m, 4H), 7.22-7.18 (m, 1H), 7.06-7.01 (m, 1H),
6.76-6.69 (m, 1H), 5.63-5.58 (m, 1H), 4.03-3.91 (m, 2H), 3.83-3.80
(m, 3H), 3.61 (d, 0.5H, J=14.8 Hz), 3.46 (d, 0.5H, J=15.0 Hz),
2.50-2.05 (m, 2H), 1.95-1.91 (m, 2H), 1.51-1.46 (m, 2H), 1.05-1.00
(m, 6H), 0.45-0.42 (m, 3H)
[0346] MS (ESI) m/z 716.2 (M.sup.++H).
Preparation of Novel Compounds According to Reaction Scheme 7
Intermediate compound 29:
2-(2-bromo-5-methoxypyridin-4-yl)-5,5-dimethylcyclohex-1-enecarboaldehyde
[0347] Starting material 1 (0.05 g, 0.22 mmol), boronic acid 28
(0.07 g, 0.22 mmol), Pd(PPh.sub.3).sub.4 (0.03 g, 0.03 mmol) and
cesium carbonate (0.14 g, 0.43 mmol) were dissolved in
dimethylformamide/water (v/v=2:1, 3 mL), and then stirred at
80.degree. C. for 3 hours. After completion of the reaction, the
reaction mixture was cooled to room temperature, diluted with ethyl
acetate, and then washed with water and brine. The organic layer
was dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (SiO.sub.2, EtOAc/hexane=0%.about.15%)
to obtain compound 29 (0.06 g, 75.8%) as colorless oil.
Intermediate compound 30:
(1R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((2-(2-bromo-5-methoxypyridi-
n-4-yl)-5,5-dimethylcyclohex-1-enyl)methylamino)propan-1-ol
[0348] Starting material 29 (0.68 g, 2.09 mmol), aminoalcohol
compound 4 (0.51 g, 2.09 mmol) and acetic acid (0.14 mL, 2.30 mmol)
were dissolved in methylene chloride (5 mL), and then stirred at
room temperature for 30 minutes, and sodium cyanoborohydride (0.14
g, 2.30 mmol) was added dropwise thereto, followed by stirring for
2 hours. After completion of the reaction, the reaction mixture was
diluted with methylene chloride, and then washed with water and
brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (Sift,
CH.sub.3OH/CH.sub.2Cl.sub.2=0%.about.10%) to obtain compound 30
(1.06 g, 85.3%) as colorless oil.
Intermediate compound 31:
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-2-((2-(2-bromo-5-methoxypyridi-
n-4-yl)-5,5-dimethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
[0349] Starting material 30 (1.06 g, 1.78 mmol) was dissolved in
methylene chloride (10 mL), and diisopropylethylamine (1.38 mL,
10.68 mmol) was added dropwise thereto at 0.degree. C., followed by
stirring for 30 minutes. Then, triphosgene (0.79 g, 2.67 mmol) was
added dropwise to the reaction mixture, followed by stirring for 2
hours. After completion of the reaction, the reaction mixture was
diluted with methylene chloride, and then washed with water and
brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=0%.about.30%) to obtain compound 31 (0.6 g, 54.2%) as
colorless oil.
EXAMPLE 67
Compound 652
methyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl-
)benzoate
[0350] Starting material 31 (0.07 g, 0.11 mmol), boronic acid 26
(0.02 g, 0.12 mmol),
[0351] Pd(dbpf)Cl.sub.2 (3.7 mg, 0.006 mmol) and sodium carbonate
(24 mg, 0.23 mmol) were dissolved in dimethoxyethane/water (v/v
4:1, 1.25 mL), and then stirred with microwave irradiation at
120.degree. C. for 15 minutes. After completion of the reaction,
the reaction mixture was cooled to room temperature, diluted with
ethyl acetate, and then washed with water and brine. The organic
layer was dried with anhydrous magnesium sulfate, filtered, and
then concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (SiO.sub.2, EtOAc/hexane=0%.about.20%)
to obtain compound 652 (35 mg, 45.9%) as colorless oil.
[0352] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.35 (d, 1H, J=13.7 Hz), 8.01-8.09 (m, 2H), 7.94-8.01 (m,
2H), 7.85 (s, 1H), 7.71 (s, 2H), 7.44 (s, 1H), 5.59-5.63 (m, 1H),
3.95-4.04 (m, 2H), 3.86-3.94 (m, 6H), 3.46-3.57 (m, 1H), 2.00-2.60
(m, 2H), 1.96 (s, 2H), 1.50-1.56 (m, 2H), 1.01-1.12 (m, 6H),
0.42-0.49 (m, 3H)
[0353] MS (ESI) m/z 677.2 (M.sup.++H).
EXAMPLE 68
Compound 644
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl)benzoi-
c acid
[0354] Starting material 652 (0.04 g, 0.05 mmol) and lithium
hydroxide monohydrate (6 mg, 0.27 mmol) were dissolved in
dioxane/water (v/v=4:1, 1.25 mL), and then stirred at 50.degree. C.
for 8 hours. After completion of the reaction, the reaction mixture
was cooled to room temperature, diluted with ethyl acetate, and
then washed with 1M hydrochloric acid solution and brine. The
organic layer was dried with anhydrous magnesium sulfate, filtered,
and then concentrated under reduced pressure to remove the solvent.
The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=0%.about.50%) to obtain compound 644 (20 mg, 56.7%) as
a white foam solid.
[0355] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.39-8.44 (m, 1H), 8.23-8.30 (m, 2H), 8.04-8.17 (m, 2H),
7.87 (s, 1H), 7.60-7.80 (m, 2H), 7.47-7.52 (m, 2H), 5.60-5.67 (m,
1H), 3.50-3.59 (m, 5H), 2.00-2.60 (m, 2H), 1.80-2.00 (m, 2H),
1.20-1.40 (m, 2H), 1.00-1.20 (m, 6H), 0.45-0.60 (m, 3H)
[0356] MS (ESI) m/z 663.2 (M.sup.++H).
EXAMPLE 69
Compound 653
methyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl-
)-3-methylbenzoate
[0357] Starting material 31 (0.07 g, 0.11 mmol), boronic acid 26
(0.03 g, 0.12 mmol), Pd(dbpf)Cl.sub.2 (4.0 mg, 0.006 mmol) and
sodium carbonate (24 mg, 0.23 mmol) were added to
dimethoxyethane/water (v/v 4:1, 1.25 mL), and then stirred with
microwave irradiation at 120.degree. C. for 15 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=0%.about.20%) to obtain compound 653 (51 mg, 65.6%) as
colorless oil.
[0358] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.35 (d, 1H, J=11.9 Hz), 7.86-7.95 (m, 3H), 7.69-7.74 (m,
2H), 7.44 (d, 0.5H, J=7.9 Hz), 7.35 (d, 0.5H, J=8.0 Hz), 7.07 (s,
1H), 5.60-5.63 (m, 1H), 3.87-4.02 (m, 8H), 3.58 (d, 0.5H, J=14.8
Hz), 3.49 (d, 0.5H, J=15.1 Hz), 2.00-2.60 (m, 5H), 1.94-1.95 (m,
2H), 1.52-1.56 (m, 2H), 1.01-1.06 (m, 6H), 0.42-0.48 (m, 3H)
[0359] MS (ESI) m/z 691.2 (M.sup.++H).
EXAMPLE 70
Compound 645
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl)-3-met-
hylbenzoic acid
[0360] Starting material 653 (0.05 g, 0.07 mmol) and lithium
hydroxide monohydrate (8 mg, 0.34 mmol) were dissolved in
dioxane/water (v/v=4:1, 1.25 mL), and then stirred at 50.degree. C.
for 8 hours. After completion of the reaction, the reaction mixture
was cooled to room temperature, diluted with ethyl acetate, and
then washed with 1M hydrochloric acid solution and brine. The
organic layer was dried with anhydrous magnesium sulfate, filtered,
and then concentrated under reduced pressure to remove the solvent.
The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=0%.about.50%) to obtain compound 645 (20 mg, 43.4%) as
a white foam solid.
[0361] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.42 (d, 1H, J=7.9 Hz), 7.92-7.98 (m, 2H), 7.88 (s, 1H),
7.74 (d, 2H, J=6.4 Hz), 7.44 (dd, 1H, J=27.4, 5.8 Hz), 7.10 (s,
1H), 5.61-5.64 (m, 1H), 3.94-4.07 (m, 5H), 3.48-3.67 (m, 1H),
2.19-2.60 (m, 5H), 1.80-2.01 (m, 2H), 1.50-1.60 (m, 2H), 0.82-1.05
(m, 6H), 0.33-0.50 (m, 3H)
[0362] MS (ESI) m/z 677.2 (M.sup.++H).
EXAMPLE 71
Compound 654
methyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl-
)-3-fluorobenzoate
[0363] Starting material 31 (0.07 g, 0.11 mmol), boronic acid 26
(0.04 g, 0.12 mmol),
[0364] Pd(dbpf)Cl.sub.2 (4.0 mg, 0.006 mmol) and sodium carbonate
(24 mg, 0.23 mmol) were added to dimethoxyethane/water (v/v 4:1,
1.25 mL), and then stirred with microwave irradiation at
120.degree. C. for 15 minutes. After completion of the reaction,
the reaction mixture was cooled to room temperature, diluted with
ethyl acetate, and then washed with water and brine. The organic
layer was dried with anhydrous magnesium sulfate, filtered, and
then concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (SiO.sub.2, EtOAc/hexane=0%-20%) to
obtain compound 654 (61 mg, 78%) as colorless oil.
[0365] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.39 (d, 1H, J=10.5 Hz), 8.01-8.06 (m, 1H), 7.88-7.92 (m,
1H), 7.85 (s, 1H), 7.71-7.82 (m, 3H), 7.50-7.52 (m, 1H), 5.65 (d,
0.5H, J=8.0 Hz), 5.55 (d, 0.5H, J=8.0 Hz), 3.93-4.05 (m, 8H), 3.62
(d, 0.5H, J=15.0 Hz), 3.41 (d, 0.5H, J=15.0 Hz), 2.00-2.60 (m, 2H),
1.92-1.96 (m, 2H), 1.46-1.55 (m, 2H), 1.02-1.05 (m, 6H), 0.47 (d,
1.5H, J=6.5 Hz), 0.40 (d, 1.5H, J=6.5 Hz)
[0366] MS (ESI) m/z 695.2 (M.sup.++H).
EXAMPLE 72
Compound 646
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl)-3-flu-
orobenzoic acid
[0367] Starting material 654 (0.05 g, 0.07 mmol) and lithium
hydroxide monohydrate (8 mg, 0.35 mmol) were dissolved in
dioxane/water (v/v=4:1, 1.25 mL), and then stirred at 50.degree. C.
for 8 hours. After completion of the reaction, the reaction mixture
was cooled to room temperature, diluted with ethyl acetate, and
then washed with 1M hydrochloric acid solution and brine. The
organic layer was dried with anhydrous magnesium sulfate, filtered,
and then concentrated under reduced pressure to remove the solvent.
The residue was purified by MPLC (SiO.sub.2, EtOAc/hexane=0%-50%)
to obtain compound 646 (20 mg, 41.7%) as a white foam solid.
[0368] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.48 (d, 1H, J=6.4 Hz), 7.95-8.05 (m, 2H), 7.81-7.89 (m,
2H), 7.75 (d, 2H, J=5.9 Hz), 7.52-7.54 (m, 1H), 5.66 (d, 0.5H,
J=6.0 Hz), 5.57 (d, 0.5H, J=6.1 Hz), 3.96-4.07 (m, 5H), 3.64 (d,
0.5H, J=11.2 Hz), 3.43 (d, 0.5H, J=11.3 Hz), 2.00-2.60 (m, 2H),
1.93-1.98 (m, 2H), 1.50-1.60 (m, 2H), 1.03-1.07 (m, 6H), 0.42-0.50
(m, 3H)
[0369] MS (ESI) m/z 681.2 (M.sup.++H).
EXAMPLE 73
Compound 655
methyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl-
)-3-chlorobenzoate
[0370] Starting material 31 (0.07 g, 0.11 mmol), boronic acid 26
(0.03 g, 0.12 mmol), Pd(dbpf)Cl.sub.2 (4.0 mg, 0.006 mmol) and
sodium carbonate (24 mg, 0.23 mmol) were added to
dimethoxyethane/water (v/v 4:1, 1.25 mL), and then stirred with
microwave irradiation at 120.degree. C. for 15 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=0%.about.30%) to obtain compound 655 (40 mg, 49.9%) as
colorless oil.
[0371] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.34 (m, 1H), 8.10-8.14 (m, 1H), 7.96-8.02 (m, 1H), 7.87
(s, 1H), 7.63-7.73 (m, 3H), 7.37-7.39 (m, 1H), 5.59-5.63 (m, 1H),
3.91-4.02 (m, 8H), 3.47-3.67 (m, 1H), 2.00-2.60 (m, 2H), 1.97 (s,
2H), 1.50-1.53 (m, 2H), 1.00-1.07 (m, 6H), 0.42-0.48 (m, 3H)
[0372] MS (ESI) m/z 711.2 (M.sup.++H).
EXAMPLE 74
Compound 647
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl)-3-chl-
orobenzoic acid
[0373] Starting material 655 (0.03 g, 0.04 mmol) and lithium
hydroxide monohydrate (5 mg, 0.20 mmol) were dissolved in
dioxane/water (v/v=4:1, 1.25 mL), and then stirred at 50.degree. C.
for 8 hours. After completion of the reaction, the reaction mixture
was cooled to room temperature, diluted with ethyl acetate, and
then washed with 1M hydrochloric acid solution and brine. The
organic layer was dried with anhydrous magnesium sulfate, filtered,
and then concentrated under reduced pressure to remove the solvent.
The residue was purified by MPLC (Sift, EtOAc/hexane=0%.about.50%)
to obtain compound 647 (10 mg, 35.2%) as white foam solid.
[0374] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.40-8.48 (m, 1H), 8.14-8.17 (m, 1H), 8.01-8.06 (m, 1H),
7.86-7.87 (m, 1H), 7.62-7.74 (m, 3H), 7.34-7.40 (m, 1H), 5.58-5.62
(m, 1H), 3.90-4.05 (m, 5H), 3.49-3.69 (m, 1H), 2.00-2.60 (m, 2H),
1.97 (s, 2H), 1.20-1.30 (m, 2H), 1.01-1.06 (m, 6H), 0.43-0.48 (m,
3H)
[0375] MS (ESI) m/z 697.1 (M.sup.++H).
EXAMPLE 75
Compound 656
methyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl-
)-2,3-difluorobenzoate
[0376] Starting material 30 (0.070 g, 0.113 mmol),
2,3-difluoro-4-(methoxycarbonyl)phenyl boronic acid compound (0.027
g, 0.124 mmol), Pd(di-t-Bupf)Cl.sub.2 (0.004 g, 0.006 mmol) and
sodium carbonate (0.024 g, 0.225 mmol) were added to
dimethoxyethane (1 mL)/water (0.25 mL) and heated by microwave
irradiation at 120.degree. C. for 20 minutes. Then, the temperature
was lowered to room temperature, and water was poured into the
reaction mixture, which was then extracted with ethyl acetate. The
organic layer was washed with brine, dried with anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The
concentrate was purified by column chromatography (SiO.sub.2,
EtOAc/hexane=0%.about.20%) to obtain desired compound 656 (0.0410
g, 49.8%) as brown oil.
[0377] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1 atropisomeric
mixture; .delta. 8.39 (d, 1H, J=9.9 Hz), 7.73-7.86 (m, 5H), 7.52
(dd, 1H, J=6.8, 2.2 Hz), 5.66 (d, 0.54H, J=8.1 Hz), 5.57 (d, 0.46H,
J=8.1 Hz), 3.94-4.07 (m, 8H), 3.61 (d, 0.46H, J=14.1 Hz), 3.40 (d,
0.56H, J=15.0 Hz), 2.13-2.43 (m, 2H), 1.96 (s, 2H), 1.47-1.55 (m,
2H), 1.20-1.06 (m, 6H), 0.42-0.48 (m, 3H)
[0378] MS (ESI) m/z 713.2 (M.sup.++H).
Preparation of Novel Compounds According to Reaction Scheme 8
Intermediate compound 33a: methyl
4-(6-bromo-5-methoxypyridin-2-yl)-3-methylbenzoate
[0379] Starting material 32 (0.2 g, 0.64 mmol) and boronic acid
pinacol ester (0.18 g, 0.64 mmol) were added to
dimethoxyethane/water (v/v=3:1, 0.4 mL), and then degassed.
Pd(dbpf)Cl.sub.2 (26 mg, 0.03 mmol) and sodium carbonate (0.14 g,
1.27 mmol) were added thereto, and the mixture was stirred with
microwave irradiation at 120.degree. C. for 20 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=10%.about.15%) to obtain compound 33a (80 mg, 37%) as
a white solid.
[0380] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.94 (s, 1H),
7.91-7.89 (m, 1H), 7.46 (d, 1H, J=7.9 Hz), 7.36 (d, 1H, J=8.2 Hz),
7.23 (d, 1H, J=8.3 Hz), 3.97 (s, 3H), 3.93 (s, 3H), 2.42 (s,
3H)
[0381] MS (ESI) m/z 336.0, 338.0 (M, M.sup.++2H).
Intermediate compound 33b: methyl
4-(6-bromo-5-methoxypyridin-2-yl)-3-fluorobenzoate
[0382] Starting material 32 (0.1 g, 0.32 mmol) and
2-fluoro-4-(methoxycarbonyl)phenylboronic acid (70 mg, 0.35 mmol)
were added to dimethoxyethane/water (v/v=3:1, 0.4 mL), and then
degassed. Pd(dbpf)Cl.sub.2 (10 mg, 0.02 mmol) and sodium carbonate
(68 mg, 0.64 mmol) were added thereto, and the mixture was stirred
with microwave irradiation at 120.degree. C. for 20 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (Sift,
EtOAc/hexane=5%-20%) to obtain compound 33b (70 mg, 65%) as a white
solid.
[0383] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.15 (t, 1H,
J=8.0 Hz), 7.91-7.78 (m, 3H), 7.22 (d, 1H, J=8.5 Hz), 3.98-3.94 (m,
6H)
[0384] MS (ESI) m/z 340.0, 342.0 (M, M.sup.++2H).
Intermediate compound 33c: methyl
4-(6-bromo-5-methoxypyridin-2-yl)-3-chlorobenzoate
[0385] Starting material 32 (0.1 mg, 0.32 mmol) and
2-chloro-4-(methoxycarbonyl)phenylboronic acid (68 mg, 0.32 mmol)
were added to dimethoxyethane/water (v/v=3:1, 0.4 mL), and then
degassed. Pd(dbpf)Cl.sub.2 (10 mg, 0.02 mmol) and sodium carbonate
(68 mg, 0.64 mmol) were added thereto, and the mixture was stirred
with microwave irradiation at 120.degree. C. for 20 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (Sift,
EtOAc/hexane=5%-15%) to obtain compound 33c (33 mg, 29%) as a white
solid.
[0386] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.13 (d, 1H,
J=1.6 Hz), 7.99 (dd, 1H, J=8.0, 1.6 Hz), 7.74-7.68 (m, 2H), 7.24
(d, 1H, J=8.4 Hz), 3.98 (s, 3H), 3.94 (s, 3H)
[0387] MS (ESI) m/z 356.0, 358.0 (M, M.sup.++2H).
EXAMPLE 76
Compound 621
methyl
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-yl-
)-3-methylbenzoate
[0388] Starting material 17 (0.1 mg, 0.18 mmol) and methyl
4-(6-bromo-5-methoxypyridin-2-yl)-3-methylbenzoate (78 mg, 0.23
mmol) were added to dimethoxyethane/water (v/v=3:1, 0.4 mL), and
then degassed. Pd(dbpf)Cl.sub.2 (7 mg, 0.009 mmol) and sodium
carbonate (38 mg, 0.36 mmol) were added thereto, and the mixture
was stirred with microwave irradiation at 120.degree. C. for 20
minutes. After completion of the reaction, the reaction mixture was
cooled to room temperature, diluted with ethyl acetate, and then
washed with water and brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=20%) to obtain compound 621 (26 mg,
21%) as a white solid.
[0389] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.92 (s, 1H),
7.86-7.81 (m, 2H), 7.60 (s, 2H), 7.35 (d, 1H, J=7.9 Hz), 7.28 (d,
1H, J=8.5 Hz), 7.24 (d, 1H, J=7.0 Hz), 5.38 (br s, 1H), 4.08-3.95
(m, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 3.41-3.36 (m, 1H), 2.48-2.32
(m, 5H), 1.99-1.90 (br m, 2H), 1.53 (t, 2H, J=6.4 Hz), 1.04 (d, 6H,
J=7.0 Hz), 0.29 (br m, 3H)
[0390] MS (ESI) m/z 691.2 (M.sup.++H).
EXAMPLE 77
Compound 622
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-yl)-3-met-
hylbenzoic acid
[0391] Starting material 621 (24 mg, 0.04 mmol) was dissolved in
dioxane (1 mL), and a solution of lithium hydroxide monohydrate (7
mg, 0.17 mmol) in water (0.25 mL) was added dropwise thereto,
followed by stirring overnight at 50.degree. C. After completion of
the reaction, the reaction mixture was cooled to room temperature,
diluted with ethyl acetate, and then washed with water, saturated
ammonium chloride and brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
preparative TLC (EtOAc/hexane=33%) to obtain compound 622 (12 mg,
51%) as a white solid.
[0392] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.95 (s, 1H),
7.89 (d, 1H, J=7.0 Hz), 7.81 (s, 1H), 7.65 (s, 2H), 7.60-7.27 (m,
3H), 5.60-5.33 (br m, 1H), 4.17-4.01 (m, 2H), 3.92 (s, 3H),
3.44-3.38 (m, 1H), 2.51-2.23 (m, 5H), 1.95-1.91 (br m, 2H),
1.60-1.47 (br m, 2H), 4.01 (d, 6H, J=7.0 Hz), 0.31 (br s, 3H)
[0393] MS (ESI) m/z 677.2 (M.sup.++H).
EXAMPLE 78
Compound 696
methyl
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl-4-methyl-2-oxoo-
xazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-yl)-
-3-fluorobenzoate
[0394] Starting material 17 (56 mg, 0.09 mmol) and methyl
4-(6-bromo-5-methoxypyridin-2-yl)-3-fluorobenzoate (33 mg, 0.1
mmol) were added to dimethoxyethane/water (v/v=3:1, 0.4 mL), and
then degassed. Pd(dbpf)Cl.sub.2 (4 mg, 0.004 mmol) and sodium
carbonate (19 mg, 0.18 mmol) were added thereto, and the mixture
was stirred with microwave irradiation at 120.degree. C. for 20
minutes. After completion of the reaction, the reaction mixture was
cooled to room temperature, diluted with ethyl acetate, and then
washed with water and brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=10%.about.20%) to obtain compound 696
(9 mg, 15%) as yellow oil.
[0395] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.03-7.99 (m,
1H), 7.87-7.73 (m, 4H), 7.62 (br s, 2H), 7.24-7.22 (m, 1H), 5.39
(br s, 1H), 4.08-3.96 (br m, 2H), 3.94-3.82 (m, 6H), 3.42-3.38 (br
m, 1H), 2.45-2.32 (br m, 2H), 2.01-1.93 (br m, 2H), 1.56-1.53 (m,
2H), 1.04 (d, 6H, J=7.0 Hz), 0.30 (br s, 3H)
[0396] MS (ESI) m/z 695.2 (M.sup.++H).
EXAMPLE 79
Compound 637
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-yl)-3-flu-
orobenzoic acid
[0397] Starting material 696 (9 mg, 0.01 mmol) was dissolved in
dioxane (1 mL), and a solution of lithium hydroxide monohydrate (3
mg, 0.07 mmol) in water (0.25 mL) was added dropwise thereto,
followed by stirring at 50.degree. C. for 2 hours. After completion
of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with
water, saturated ammonium chloride and brine. The organic layer was
dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by preparative TLC
(EtOAc/hexane=35%.fwdarw.CH.sub.3OH/CH.sub.2Cl.sub.2=5%) to obtain
compound 637 (6 mg, 68%) as colorless oil.
[0398] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.05 (t, 1H,
J=7.8 Hz), 7.93 (dd, 1H, J=8.1, 1.4 Hz), 7.84-7.80 (m, 2H),
7.77-7.74 (m, 1H), 7.51 (s, 2H), 7.26-7.24 (m, 1H), 5.52-5.21 (br
m, 1H), 4.13-4.02 (m, 2H), 3.87 (s, 3H), 3.42-3.37 (m, 1H),
2.46-2.26 (br m, 2H), 2.01-1.88 (br m, 2H), 1.55 (t, 2H, J=6.5 Hz),
1.06 (d, 6H, J=7.0 Hz), 0.40-0.20 (br m, 3H)
[0399] MS (ESI) m/z 681.2 (M.sup.++H).
EXAMPLE 80
Compound 697
methyl
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl-4-methyl-2-oxoo-
xazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-yl)-
-3-chlorobenzoate
[0400] Starting material 17 (56 mg, 0.09 mmol) and methyl
4-(6-bromo-5-methoxypyridin-2-yl)-3-chlorobenzoate (35 mg, 0.1
mmol) were added to dimethoxyethane/water (v/v=3:1, 0.4 mL), and
then degassed. Pd(dbpf)Cl.sub.2 (4 mg, 0.004 mmol) and sodium
carbonate (19 mg, 0.18 mmol) were added thereto, and the mixture
was stirred with microwave irradiation at 120.degree. C. for 20
minutes. After completion of the reaction, the reaction mixture was
cooled to room temperature, diluted with ethyl acetate, and then
washed with water and brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (Sift, EtOAc/hexane=10%.about.20%) to obtain compound 697 (9
mg, 14%) as oil.
[0401] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.09 (m, 1H),
7.96-7.94 (m, 1H), 7.81 (s, 1H), 7.67-7.54 (m, 4H), 7.23 (s, 1H),
5.40 (br s, 1H), 4.11-3.84 (m, 8H), 3.43-3.39 (br m, 1H), 2.44-2.35
(m, 2H), 2.00-1.93 (m, 2H), 1.55-1.52 (m, 2H), 1.09-1.03 (m, 6H),
0.31-0.30 (br m, 3H)
[0402] MS (ESI) m/z 711.1 (M.sup.++H).
EXAMPLE 81
Compound 636
4-(2-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-yl)-3-chl-
orobenzoic acid
[0403] Starting material 697 (9 mg, 0.01 mmol) was dissolved in
dioxane (1 mL), and a solution of lithium hydroxide monohydrate (3
mg, 0.06 mmol) in water (0.25 mL) was added dropwise thereto,
followed by stirring at 50.degree. C. for 2 hours. After completion
of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with
water, saturated ammonium chloride and brine. The organic layer was
dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by preparative TLC
(EtOAc/hexane=35%.fwdarw.CH.sub.3OH/CH.sub.2Cl.sub.2=5%) to obtain
compound 636 (4 mg, 45%) as colorless oil.
[0404] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.13 (d, 1H,
J=7.0 Hz), 7.97 (dd, 1H, J=8.0, 1.6 Hz), 7.81 (s, 1H), 7.65 (s,
2H), 7.61-7.55 (m, 2H), 7.27 (d, 1H, J=7.0 Hz), 5.44-5.26 (br m,
1H), 4.14-3.98 (m, 2H), 3.88 (s, 3H), 3.43-3.40 (m, 1H), 2.52-2.35
(br m, 2H), 1.96-1.90 (br m, 2H), 1.56-1.52 (m, 2H), 1.04 (d, 6H,
J=7.0 Hz), 0.35-0.30 (m, 3H)
[0405] MS (ESI) m/z 697.2 (M.sup.++H).
Preparation of Novel Compounds According to Reaction Scheme 9
Intermediate compound 35: methyl
4-(5-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazol-
idin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-6-methoxypyridin-3-yl)-3-(p-
rope-1-en-2-yl)benzoate
[0406] Starting material compound 583 (0.1 g, 0.14 mmol) and
propan-2-ylboronic acid (47 mg, 0.28 mmol) were added to
dimethoxyethane/water (v/v=4:1, 0.5 mL), followed by degassing.
Pd(dbpf)Cl.sub.2 (9 mg, 0.01 mmol) and sodium carbonate (30 mg,
0.28 mmol) were added thereto, and the mixture was stirred with
microwave irradiation at 120.degree. C. for 30 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (Sift,
EtOAc/hexane=5%.about.15%) to obtain compound 35 (48 mg, 48%) as
brown oil.
[0407] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.9 atropisomeric
mixture; .delta. 8.15-8.11 (m, 1H), 7.99-7.94 (m, 2H), 7.86 (br s,
1H), 7.74-7.71 (br m, 2H), 7.38-7.28 (m, 2H), 5.64-5.56 (m, 1H),
5.16-5.13 (m, 1H), 4.99-4.96 (m, 1H), 4.04-3.96 (m, 2H), 3.95-3.91
(m, 6H), 3.58-3.55 (m, 1H), 2.60-2.17 (br m, 2H), 1.98-1.95 (br m,
2H), 1.71 (d, 3H, J=8.7 Hz), 1.53-1.45 (m, 2H), 1.06-0.99 (m, 6H),
0.51-0.31 (m, 3H)
[0408] MS (ESI) m/z 717.2 (M.sup.++H).
EXAMPLE 82
Compound 577
methyl
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl-
)-3-isopropylbenzoate
[0409] Starting material 35 (41 mg, 0.06 mmol) was dissolved in
ethanol (3 mL), and 5% palladium/carbon (4 mg) was added dropwise
thereto, followed by hydrogenation overnight. After completion of
the reaction, the reaction mixture was filtered through celite
under reduced pressure to remove palladium, and then concentrated
under reduced pressure to remove the solvent. The residue was
purified by MPLC (Sift, EtOAc/hexane=10%-20%) to obtain compound
577 (41 mg, 100%) as colorless oil.
[0410] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.5 atropisomeric
mixture; .delta. 8.06, 8.04 (2d, 1H, J=1.6 Hz), 8.01-8.00 (m, 1H),
7.88-7.82 (m, 2H), 7.74-7.71 (br m, 2H), 7.24-7.13 (m, 2H),
5.65-5.57 (m, 1H), 4.07-3.88 (m, 8H), 3.59-3.49 (m, 1H), 3.03-2.94
(m, 1H), 2.58-2.07 (br m, 2H), 1.94-1.66 (br m, 2H), 1.55-1.38 (m,
2H), 1.20-1.11 (m, 6H), 1.06-0.94 (m, 6H), 0.50, 0.36 (2d, 3H,
J=6.5 Hz)
[0411] MS (ESI) m/z 719.2 (M.sup.++H).
EXAMPLE 83
Compound 578
4-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-iso-
propylbenzoic acid
[0412] Starting material 577 (36 mg, 0.05 mmol) was dissolved in
dioxane (2 mL), and a solution of lithium hydroxide monohydrate (11
mg, 0.25 mmol) in water (0.5 mL) was added dropwise thereto,
followed by stirring overnight at 50.degree. C. After completion of
the reaction, the reaction mixture was cooled to room temperature,
diluted with ethyl acetate, and then washed with water, saturated
ammonium chloride and brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (Sift, EtOAc/hexane=10%-70%) to obtain compound 578 (26 mg,
74%) as a white solid.
[0413] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.5 atropisomeric
mixture; .delta. 8.14-8.12 (m, 1H), 8.04-8.03 (m, 1H), 7.96-7.90
(m, 2H), 7.87 (s, 1H), 7.74 (d, 2H, J=11.4 Hz), 7.24-7.17 (m, 1H),
5.66-5.58 (m, 1H), 4.06-3.90 (m, 5H), 3.60-3.42 (m, 1H), 3.05-2.97
(m, 1H), 2.60-2.07 (br m, 2H), 1.95-1.92 (br m, 2H), 1.55-1.47 (m,
2H), 1.23-1.13 (m, 6H), 1.06-1.00 (m, 6H), 0.52-0.37 (m, 3H)
[0414] MS (ESI) m/z 705.2 (M.sup.++H).
Preparation of Novel Compounds According to Reaction Scheme 10
Intermediate compound 38a:
2-(2-methoxy-4-methyl-5-nitrophenyl)-5,5-dimethylcyclohex-1-enecarbaldehy-
de
[0415] Starting material 37a (2.7 g, 9.2 mmol), compound 1 (2.0 g,
9.2 mmol), Pd2dba3 (0.42 g, 0.46 mmol) and copper (2.93 g, 46.1
mmol) were dissolved in dimethylsulfoxide (20 mL), and then stirred
at 80.degree. C. for 16 hours. After completion of the reaction,
the reaction mixture was cooled to room temperature, diluted with
ethyl acetate, and then washed with water and brine. The residue
was purified by MPLC (SiO.sub.2, EtOAc/hexane=0%-25%) to obtain
compound 38a (0.7 g, 25%) as yellow oil.
Intermediate compound 38b:
2-(2-methoxy-5-nitro-4-(trifluoromethyl)phenyl)-5,5-dimethylcyclohex-1-en-
ecarbaldehyde
[0416] Starting material 37b (2.65 g, 7.64 mmol), compound 1 (1.66
g, 7.64 mmol), Pd2dba3 (0.35 g, 0.38 mmol) and copper (2.43 g, 38.2
mmol) were dissolved in dimethylsulfoxide (10 mL), and then stirred
overnight at 80.degree. C. After completion of the reaction, the
reaction mixture was cooled to room temperature, diluted with ethyl
acetate, and then washed with water and brine. The residue was
purified by MPLC (SiO.sub.2, hexane/EtOAc=10%-60%) to obtain
compound 38b (1.6 g, 59.4%) as a gray solid.
Intermediate compound 39a:
(1R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((2-(2-methoxy-4-methyl-5-ni-
trophenyl)-5,5-dimethylcyclohex-1-enyl)methylamino)propan-1-ol
[0417] Starting material 38a (0.7 g, 2.31 mmol), aminoalcohol
compound 4 (0.66 g, 2.31 mmol) and acetic acid (0.16 mL, 2.54 mmol)
were dissolved in methylene chloride (10 mL), and then stirred at
room temperature for 30 minutes. Then, sodium cyanoborohydride
(0.16 g, 2.54 mmol) was added to the reaction mixture, and water
was added thereto, followed by extraction with methylene chloride.
The organic layer was washed with brine, dried with anhydrous
magnesium sulfate, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (Sift,
CH.sub.3OH/CH.sub.2Cl.sub.2=0%-10%) to obtain compound 39a (0.98 g,
74.0%) as yellow oil.
Intermediate compound 39b:
(1R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((2-(2-methoxy-5-nitro-4-(tr-
ifluoromethyl)phenyl)-5,5-dimethylcyclohex-1-enyl)methylamino)propan-1-ol
[0418] Starting material 38b (1.6 g, 5.3 mmol) and aminoalcohol
compound 4 (1.8 g) were dissolved in methylene chloride (10 mL),
and acetic acid (0.3 mL) and sodium cyanoborohydride (0.4 g) were
added thereto at the same temperature. The mixture was stirred at
the same temperature for 5 hours, and water was added thereto,
followed by extraction with ethyl acetate. The organic layer was
washed with brine, dried with anhydrous magnesium sulfate to remove
water, and then concentrated under reduced pressure to remove the
solvent. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=20%.about.70%) to obtain compound 39b (1.9 g, 57.9%)
as colorless oil.
Intermediate compound 40a:
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(2-methoxy-4-methyl-5-ni-
trophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
[0419] Starting material 39a (0.98 g, 1.71 mmol) was dissolved in
methylene chloride (10 mL), and diisopropylethylamine (1.32 g, 10.2
mmol) was added dropwise thereto at 0.degree. C., followed by
stiffing for 30 minutes. Then, triphosgene (0.76 g, 2.56 mmol) was
slowly added dropwise to the mixture, followed by stirring at the
same temperature for 2 hours. After completion of the reaction,
water was added to the reaction mixture, followed by extraction
with methylene chloride. The organic layer was washed with brine,
dried with anhydrous magnesium sulfate, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (Sift, EtOAc/hexane=0%.about.30%) to obtain compound 40a (0.6
g, 58.5%) as colorless oil.
Intermediate compound 40b:
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(2-methoxy-5-nitro-4-(tr-
ifluoromethyl)phenyl)-5,5-dimethylcyclohex-1-enyl)methyl)-4-methyloxazolid-
in-2-one
[0420] Starting material 39b (1.9 g, 3.3 mmol) was dissolved in
methylene chloride (5 mL), and diisopropylethylamine (3.5 mL) and
triphosgene (0.6 g) were slowly added dropwise thereto at 0.degree.
C., followed by stirring at room temperature for 3 hours. After
completion of the reaction, the reaction mixture was diluted with
ethyl acetate, and then washed with water and brine. The residue
was dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=15%.about.50%) to obtain compound 40b (0.9 g, 41.9%)
as colorless oil.
Intermediate compound 41a:
(4S,5R)-3-((2-(5-amino-2-methox-4-methylphenyl)-5,5-dimethylcyclohex-1-en-
yl)methyl)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one
[0421] Starting material 40a (0.6 g, 1.0 mmol) was dissolved in
methanol (10 mL), and Raney nickel (small amount) was added
dropwise thereto, followed by hydrogenation at room temperature for
2 hours. After completion of the reaction, the reaction mixture was
filtered through celite to remove a solid compound, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (SiO.sub.2, EtOAc/hexane=0%.about.30%)
to obtain compound 41a (0.41 g, 71.9%) as a yellow solid.
Intermediate compound 41b:
(4S,5R)-3-((2-(5-amino-2-methoxy-4-(trifluoromethyl)phenyl)-5,5-dimethylc-
yclohex-1-enyl)methyl)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazolid-
in-2-one
[0422] Starting material 40b (0.9 g, 1.38 mmol) was dissolved in
methanol (5 mL), and Raney nickel (3 mL) was added dropwise
thereto, followed by hydrogenation overnight at room temperature.
After completion of the reaction, the reaction mixture was filtered
through celite to remove a solid compound, and then concentrated
under reduced pressure to remove the solvent. The residue was
diluted with ethyl acetate, washed with water and brine, dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (Sift, hexane/EtOAc=20%-60%) to obtain compound 41b (0.7 g,
91.5%) as a white foam solid.
Intermediate compound 42a:
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(5-iodo-2-methoxy-4-meth-
ylphenyl)-5,5-dimethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
[0423] Starting material 41a (0.4 g, 0.70 mmol) was dissolved in
acetonitrile (20 mL), and then para-toluenesulfonic acid
monohydrate (0.4 g, 2.1 mmol) and a solution of sodium nitrite
(0.05 g, 0.74 mmol) in water (2 mL) were sequentially slowly added
dropwise thereto, followed by stirring at room temperature for 2
hours. Then, potassium iodide (0.13 g, 0.77 mmol) was added
dropwise thereto, followed by stirring at room temperature for 1
hour. After completion of the reaction, the reaction mixture was
diluted with ethyl acetate, and then washed with water and sodium
thiosulfate solution. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by MPLC
(SiO.sub.2, EtOAc/hexane=0%.about.20%) to obtain compound 42a (0.18
g, 37.7%) as colorless oil.
Intermediate compound 42b:
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(5-iodo-2-methoxy-4-(tri-
fluoromethyl)phenyl)-5,5-dicyclohex-1-enyl)methyl)-4-methyloxazolidin-2-on-
e
[0424] Starting material 41b (0.7 g, 1.12 mmol) was dissolved in
acetonitrile (15 mL), and then para-toluenesulfonic acid
monohydrate (0.64 g) and a solution of sodium nitrite (0.08 g) in
water (2 mL) were sequentially slowly added dropwise thereto,
followed by stirring at room temperature for 1 hour. Then,
potassium iodide (0.2 g) was added dropwise thereto, followed by
stirring overnight at room temperature. After completion of the
reaction, the reaction mixture was diluted with ethyl acetate, and
then washed with water and sodium thiosulfate solution. The organic
layer was dried with anhydrous magnesium sulfate, filtered, and
then concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (SiO.sub.2, hexane/EtOAc=10.about.50%)
to obtain compound 42b (0.48 g, 58.2%) as colorless oil.
EXAMPLE 84
Compound 605
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2'-(trifluor-
omethyl)biphenyl-4-carboxy late
[0425] Starting material 42b (0.06 g, 0.08 mmol), boronic acid 7
(0.02 g, 0.1 mmol), Pd(dppf)Cl.sub.2 (3.0 mg, 0.004 mmol) and
sodium carbonate (0.02 g, 0.18 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 4 mL), and then stirred with
microwave irradiation at 120.degree. C. for 30 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by preparative TLC
(Sift, hexane/EtOAc=4:1) to obtain compound 605 (24 mg, 40.9%) as
colorless oil.
[0426] MS (ESI) m/z 744.2 (M.sup.++H).
EXAMPLE 85
Compound 606
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-4'-methoxy-2'--
(trifluoromethyl)biphenyl-4-carboxylate
[0427] Starting material 42b (0.06 g, 0.08 mmol), boronic acid 7
(0.02 g, 0.1 mmol), Pd(dppf)Cl.sub.2 (3.0 mg, 0.004 mmol) and
sodium carbonate (0.02 g, 0.18 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 4 mL), and then stirred with
microwave irradiation at 120.degree. C. for 30 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by preparative TLC
(Sift, hexane/EtOAc=4:1) to obtain compound 606 (14 mg, 23.3%) as
colorless oil.
[0428] MS (ESI) m/z 762.2 (M.sup.++H).
EXAMPLE 86
Compound 607
ethyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxa-
zolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-fluoro-4'-methoxy-2'-(-
trifluoromethyl)biphenyl-4-carboxylate
[0429] Starting material 42b (0.06 g, 0.08 mmol), boronic acid 7
(0.02 g, 0.1 mmol), Pd(dppf)Cl.sub.2 (3.0 mg, 0.004 mmol) and
sodium carbonate (0.02 g, 0.18 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 4 mL), and then stirred with
microwave irradiation at 120.degree. C. for 30 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by preparative TLC
(SiO.sub.2, hexane/EtOAc=4:1) to obtain compound 607 (21 mg, 34.3%)
as colorless oil.
[0430] MS (ESI) m/z 776.2 (M.sup.++H).
EXAMPLE 87
Compound 608
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4'-methoxy-2'--
(trifluoromethyl)biphenyl-4-carboxylate
[0431] Starting material 42b (0.06 g, 0.08 mmol), boronic acid 7
(0.02 g, 0.1 mmol), Pd(dppf)Cl.sub.2 (3.0 mg, 0.004 mmol) and
sodium carbonate (0.02 g, 0.18 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 4 mL), and then stirred with
microwave irradiation at 120.degree. C. for 30 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by preparative TLC
(SiO.sub.2, hexane/EtOAc=4:1) to obtain compound 608 (14 mg, 22.9%)
as colorless oil.
[0432] MS (ESI) m/z 778.1 (M.sup.++H).
EXAMPLE 88
Compound 609
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methyl-2'--
(trifluoromethyl)biphenyl-4-carboxylate
[0433] Starting material 42b (0.06 g, 0.08 mmol), boronic acid 7
(0.03 g, 0.1 mmol), Pd(dppf)Cl.sub.2 (3.0 mg, 0.004 mmol) and
sodium carbonate (0.02 g, 0.18 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 4 mL), and then stirred with
microwave irradiation at 120.degree. C. for 30 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by preparative TLC
(SiO.sub.2, hexane/EtOAc=4:1) to obtain compound 609 (27 mg, 45.2%)
as colorless oil.
[0434] MS (ESI) m/z 758.2 (M.sup.++H).
EXAMPLE 89
Compound 611
5-(5-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxy-2-(trifluoromethyl-
)phenyl)-3-fluoro picolinic acid
[0435] Starting material 42b (0.06 g, 0.08 mmol), boronic acid 7
(0.03 g, 0.1 mmol),
[0436] Pd(dppf)Cl.sub.2 (3.0 mg, 0.004 mmol) and sodium carbonate
(0.02 g, 0.18 mmol) were dissolved in dimethoxyethane/water
(v/v=3:1, 4 mL), and then stirred with microwave irradiation at
120.degree. C. for 30 minutes. After completion of the reaction,
the reaction mixture was cooled to room temperature, diluted with
ethyl acetate, and then washed with water and brine. The organic
layer was dried with anhydrous magnesium sulfate, filtered, and
then concentrated under reduced pressure to remove the solvent. The
residue was purified by preparative TLC (SiO.sub.2,
CH.sub.2Cl.sub.2/CH.sub.3OH=15:1) to obtain compound 611 (2.1 mg,
3.4%) as colorless oil.
[0437] MS (ESI) m/z 749.1 (M.sup.++H).
EXAMPLE 90
Compound 612
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2'-(trifluoromethyl-
)biphenyl-4-carboxylic acid
[0438] Starting material 605 (0.02 g, 0.03 mmol) and lithium
hydroxide monohydrate (3.0 mg, 0.13 mmol) were dissolved in
dioxane/water (v/v=3:1, 4 mL), and then stirred overnight at
50.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, and 1M hydrochloric acid
solution was added dropwise thereto until a pH of 6.0 was reached.
The reaction mixture was diluted with ethyl acetate, and then
washed with brine. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by
preparative TLC (Sift, hexane/EtOAc=1:1) to obtain compound 612 (10
mg, 53.6%) as colorless oil.
[0439] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 7.90 (2d, 2H, J=8.4 Hz), 7.67 (s, 1H), 7.53 (2s, 2H), 7.16
(2d, 2H, J=8.1 Hz), 7.0 (2s, 1H), 6.75 (s, 1H), 5.41 (t, 1H, J=8.3
Hz), 3.85-3.65 (m, 5H), 3.30 (2d, 1H, J=14.4 Hz), 2.49-1.66 (m,
4H), 1.46 (m, 2H), 0.82 (3s, 6H), 0.25 (2d, 3H, J=6.5 Hz)
[0440] MS (ESI) m/z 730.3 (M.sup.++H).
EXAMPLE 91
Compound 613
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-4'-methoxy-2'-(triflu-
oromethyl)biphenyl-4-carboxylic acid
[0441] Starting material 606 (0.01 g, 0.02 mmol) and lithium
hydroxide monohydrate (2.0 mg, 0.09 mmol) were dissolved in
dioxane/water (v/v=3:1, 4 mL), and then stirred overnight at
50.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, and 1M hydrochloric acid
solution was added dropwise thereto until a pH of 6.0 was reached.
The reaction mixture was diluted with ethyl acetate, and then
washed with brine. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by
preparative TLC (Sift, hexane/EtOAc=1:1) to obtain compound 613 (9
mg, 62.7%) as colorless oil.
[0442] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 7.98-7.73 (m, 5H), 7.39-7.22 (m, 3H), 6.98 (2s, 1H), 5.59
(m, 1H), 4.04-3.87 (m, 5H), 3.42 (2s, 1H), 2.45-1.89 (m, 4H), 1.48
(m, 2H), 1.01 (t, 6H, J=14.1 Hz), 0.43 (d, 3H, J=6.4 Hz)
[0443] MS (ESI) m/z 749.2 (M.sup.++H).
EXAMPLE 92
Compound 614
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-fluoro-4'-methoxy-2'-(triflu-
oromethyl)biphenyl-4-carboxylic acid
[0444] Starting material 607 (0.02 g, 0.03 mmol) and lithium
hydroxide monohydrate (3.0 mg, 0.13 mmol) were dissolved in
dioxane/water (v/v=3:1, 4 mL), and then stirred overnight at
50.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, and 1M hydrochloric acid
solution was added dropwise thereto until a pH of 6.0 was reached.
The reaction mixture was diluted with ethyl acetate, and then
washed with brine. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by
preparative TLC (Sift, hexane/EtOAc=1:1) to obtain compound 614 (8
mg, 41.5%) as colorless oil.
[0445] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 7.96 (m, 1H), 7.89 (s, 1H), 7.72 (2s, 2H), 7.23-6.94 (m,
4H), 5.61 (t, 1H, J=8.4 Hz), 4.04-3.85 (m, 5H), 3.47 (2d, 1H,
J=15.1 Hz), 2.45-1.89 (m, 4H), 1.49 (m, 2H), 1.01 (2d, 6H, J=14.8
Hz), 0.49 (2d, 3H, J=6.6 Hz)
[0446] MS (ESI) m/z 748.2 (M.sup.++H).
EXAMPLE 93
Compound 615
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4'-methoxy-2'-(triflu-
oromethyl)biphenyl-4-carboxylic acid
[0447] Starting material 608 (0.01 g, 0.02 mmol) and lithium
hydroxide monohydrate (2.0 mg, 0.08 mmol) were dissolved in
dioxane/water (v/v=3:1, 4 mL), and then stirred overnight at
50.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, and 1M hydrochloric acid
solution was added dropwise thereto until a pH of 6.0 was reached.
The reaction mixture was diluted with ethyl acetate, and then
washed with brine. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by
preparative TLC (Sift, hexane/EtOAc=1:1) to obtain compound 615 (9
mg, 71.3%) as colorless oil.
[0448] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.16-7.66 (m, 5H), 7.38 (t, 1H, J=11.8 Hz), 7.26 (2s, 1H),
6.95 (2s, 1H), 5.63 (m, 1H), 4.05-3.85 (m, 5H), 3.71-3.39 (m, 1H),
2.54-1.89 (m, 4H), 1.49 (m, 2H), 0.96 (m, 6H), 0.43 (m, 3H)
[0449] MS (ESI) m/z 762.2 (M.sup.+-H).
EXAMPLE 94
Compound 616
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methyl-2'-(triflu-
oromethyl)biphenyl-4-carboxylic acid
[0450] Starting material 609 (0.03 g, 0.03 mmol) and lithium
hydroxide monohydrate (4.0 mg, 0.17 mmol) were dissolved in
dioxane/water (v/v=3:1, 4 mL), and then stirred overnight at
50.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, and 1M hydrochloric acid
solution was added dropwise thereto until a pH of 6.0 was reached.
The reaction mixture was diluted with ethyl acetate, and then
washed with brine. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by
preparative TLC (Sift, hexane/EtOAc=1:1) to obtain compound 616 (16
mg, 65.2%) as colorless oil.
[0451] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 7.99-7.84 (m, 3H), 7.74-7.71 (m, 2H), 7.22 (m, 2H),
7.06-6.84 (m, 1H), 5.62 (m, 1H), 4.13-3.92 (m, 2H), 3.87 (4s, 3H),
3.59-3.39 (m, 1H), 2.53-1.85 (m, 7H), 1.46 (m, 2H), 1.01 (m, 6H),
0.44 (m, 3H)
[0452] MS (ESI) m/z 744.3 (M.sup.++H).
EXAMPLE 95
Compound 619
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2'-methylbip-
henyl-4-carboxylate
[0453] Starting material 42a (0.05 g, 0.07 mmol), boronic acid 7
(14 mg, 0.08 mmol), Pd(dppf)Cl.sub.2 (2.0 mg, 0.003 mmol) and
sodium carbonate (15 mg, 0.14 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 1.3 mL), and then stirred with
microwave irradiation at 120.degree. C. for 15 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (Sift,
EtOAc/hexane=0%.about.30%) to obtain compound 619 (18 mg, 38.6%) as
colorless oil.
[0454] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.01-8.08 (m, 2H), 7.86 (s, 1H), 7.73 (d, 2H, J=10.1 Hz),
7.27-7.37 (m, 2H), 6.85 (d, 1H, J=4.2 Hz), 6.76 (d, 1H, J=19.4 Hz),
5.58-5.62 (m, 1H), 3.93-4.01 (m, 5H), 3.80 (d, 3H, J=13.7 Hz), 3.66
(d, 0.6H, J=13.7 Hz), 3.51 (d, 0.4H, J=14.6 Hz), 2.00-2.60 (m, 5H),
1.90-1.98 (m, 2H), 1.43-1.54 (m, 2H), 1.00-1.06 (m, 6H), 0.38-0.44
(m, 3H)
[0455] MS (ESI) m/z 690.2 (M.sup.++H).
EXAMPLE 96
Compound 620
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2'-methylbiphenyl-4-
-carboxylic acid
[0456] Starting material 619 (0.02 g, 0.02 mmol) and lithium
hydroxide monohydrate (3.0 mg, 0.11 mmol) were dissolved in
dioxane/water (v/v=5:1, 0.6 mL), and then stirred overnight at
50.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and then washed with 1M hydrochloric acid solution and brine. The
organic layer was dried with anhydrous magnesium sulfate, filtered,
and then concentrated under reduced pressure to remove the solvent.
The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=0%.about.50%) to obtain compound 620 (9 mg, 61.2%) as
colorless oil.
[0457] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.09 (m, 2H), 7.87 (s, 1H), 7.74 (d, 2H, J=9.7 Hz), 7.41
(d, 1H, J=8.3 Hz), 7.32 (d, 1H, J=8.3 Hz), 6.86 (d, 1H, J=5.0 Hz),
6.77 (d, 1H, J=19.3 Hz), 5.59-5.62 (m, 1H), 3.89-4.07 (m, 2H),
3.78-3.82 (m, 3H), 3.49-3.68 (m, 1H), 2.00-2.60 (m, 5H), 1.86-1.98
(m, 2H), 1.43-1.54 (m, 2H), 0.96-1.06 (m, 6H), 0.39-0.45 (m,
3H)
[0458] MS (ESI) m/z 676.2 (M.sup.++H).
EXAMPLE 97
Compound 638
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-chloro-4'-methoxy-2'--
(trifluoromethyl)biphenyl-4-carboxylate
[0459] Starting material 42b (0.06 g, 0.08 mmol), boronic acid 7
(0.04 g, 0.12 mmol),
[0460] Pd(dppf)Cl.sub.2 (3.0 mg, 0.004 mmol) and sodium carbonate
(0.03 g, 0.24 mmol) were dissolved in dimethoxyethane/water
(v/v=3:1, 4 mL), and then stirred with microwave irradiation at
120.degree. C. for 30 minutes. After completion of the reaction,
the reaction mixture was cooled to room temperature, diluted with
ethyl acetate, and then washed with water and brine. The organic
layer was dried with anhydrous magnesium sulfate, filtered, and
then concentrated under reduced pressure to remove the solvent. The
residue was purified by preparative TLC (Sift, hexane/EtOAc=4:1) to
obtain compound 638 (15 mg, 25.7%) as colorless oil.
[0461] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 7.86-7.80 (m, 2H), 7.72 (2s, 2H), 7.36 (2d, 1H, J=1.6 Hz),
7.24-7.16 (m, 2H), 6.92 (d, 1H, J=1.1 Hz), 5.61 (t, 1H, J=7.9 Hz),
4.04-3.84 (m, 8H), 3.47 (2d, 1H, J=14.5 Hz), 2.51-1.89 (m, 4H),
1.49 (m, 2H), 1.01 (2d, 6H, J=14.0 Hz), 0.46 (2d, 3H, J=6.6 Hz)
[0462] MS (ESI) m/z 778.1 (M.sup.++H).
EXAMPLE 98
Compound 639
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3,4'-dimethoxy-2'-(trif-
luoromethyl)biphenyl-4-carboxylate
[0463] Starting material 42b (0.06 g, 0.08 mmol), boronic acid 7
(0.03 g, 0.1 mmol), Pd(dppf)Cl.sub.2 (3.0 mg, 0.004 mmol) and
sodium carbonate (0.02 g, 0.19 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 4 mL), and then stirred with
microwave irradiation at 120.degree. C. for 30 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by preparative TLC
(Sift, hexane/EtOAc=4:1) to obtain compound 639 (11 mg, 20.3%) as
colorless oil.
[0464] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 7.87 (s, 1H), 7.79 (2d, 1H, J=7.8 Hz), 7.72 (2s, 2H), 7.18
(2s, 1H), 6.96-6.79 (m, 3H), 5.60 (2d, 1H, J=8.2 Hz), 4.05-3.83 (m,
11H), 3.48 (2d, 1H, J=14.7 Hz), 2.49-1.89 (m, 4H), 1.49 (m, 2H),
1.01 (2d, 6H, J=15.0 Hz), 0.46 (2d, 3H, J=6.6 Hz)
[0465] MS (ESI) m/z 774.2 (M.sup.++H).
EXAMPLE 99
Compound 632
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-chloro-4'-methoxy-2'-(triflu-
oromethyl)biphenyl-4-carboxylic acid
[0466] Starting material 638 (0.02 g, 0.02 mmol) and lithium
hydroxide monohydrate (2.0 mg, 0.1 mmol) were dissolved in
dioxane/water (v/v=3:1, 4 mL), and then stirred overnight at
45.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, and 1M hydrochloric acid
solution was added dropwise thereto until a pH of 6.0 was reached.
The reaction mixture was diluted with ethyl acetate, and then
washed with brine. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by
preparative TLC (Sift, hexane/EtOAc=1:2) to obtain compound 632 (4
mg, 27.2%) as colorless oil.
[0467] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 7.99 (2d, 1H, J=8.0 Hz), 7.87 (s, 1H), 7.73 (2s, 2H), 7.39
(2d, 1H, J=1.5 Hz), 7.31-7.19 (m, 2H), 6.94 (2s, 1H), 5.62 (t, 1H,
J=8.1 Hz), 4.04-3.89 (m, 2H), 3.83 (2s, 3H), 3.48 (2d, 1H, J=14.6
Hz), 2.49-1.86 (m, 4H), 1.48 (m, 2H), 1.01 (2d, 6H, J=14.0 Hz),
0.46 (2d, 3H, J=6.6 Hz)
[0468] MS (ESI) m/z 764.1 (M.sup.++H).
EXAMPLE 100
Compound 633
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3,4'-dimethoxy-2'-(trifluorome-
thyl)biphenyl-4-carboxylic acid
[0469] Starting material 639 (9.0 mg, 0.01 mmol) and lithium
hydroxide monohydrate (1.0 mg, 0.06 mmol) were dissolved in
dioxane/water (v/v=3:1, 4 mL), and then stirred overnight at
45.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, and 1M hydrochloric acid
solution was added dropwise thereto until a pH of 6.0 was reached.
The reaction mixture was diluted with ethyl acetate, and then
washed with brine. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by
preparative TLC (Sift, hexane/EtOAc=1:2) to obtain compound 633 (7
mg, 73.6%) as colorless oil.
[0470] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.18 (2d, 1H, J=8.2 Hz), 7.85 (s, 1H), 7.71 (2s, 2H), 7.23
(2s, 1H), 7.09-6.97 (m, 3H), 5.60 (2d, 1H, J=8.1 Hz), 4.13 (2s,
3H), 4.01 (m, 2H), 3.81 (2s, 3H), 3.47 (2d, 1H, J=14.6 Hz),
2.55-1.93 (m, 4H), 1.52 (m, 2H), 1.04 (2d, 6H, J=12.2 Hz), 0.42
(2d, 3H, J=6.5 Hz)
[0471] MS (ESI) m/z 760.2 (M.sup.++H).
EXAMPLE 101
Compound 683
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2,2'-dimethy-
lbiphenyl-4-carboxylate
[0472] Starting material 42a (0.080 g, 0.117 mmol), methyl
3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
(0.036 g, 0.129 mmol), Pd(di-t-Bupf)Cl.sub.2 (0.004 g, 0.006 mmol)
and sodium carbonate (0.025 g, 0.235 mmol) were added to
dimethoxyethane (1 mL)/water (0.3 mL) and heated by microwave
irradiation at 120.degree. C. for 15 minutes. Then, the reaction
mixture was cooled to room temperature, and water was added
thereto, followed by extraction with ethyl acetate. The organic
layer was washed with brine, dried with anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The
concentrate was purified by column chromatography (Sift,
EtOAc/hexane=0%.about.15%) to obtain compound 683 (0.025 g, 30.3%)
as colorless oil.
[0473] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1 atropisomeric
mixture; .delta. 7.94 (s, 1H), 7.87-7.88 (m, 2H), 7.72-7.75 (m,
2H), 6.95-7.18 (m, 1H), 6.68-6.78 (m, 2H), 5.60-5.64 (m, 1H),
3.87-4.06 (m, 2H), 3.91-3.93 (m, 3H), 3.77-3.81 (m, 3H), 3.48-3.64
(m, 1H), 2.20-2.60 (m, 2H), 2.01-2.18 (m, 6H), 1.87-1.98 (m, 2H),
1.42-1.52 (m, 2H), 0.96-1.05 (m, 6H), 0.32-0.46 (m, 3H)
[0474] MS (ESI) m/z 704.2 (M.sup.++H).
EXAMPLE 102
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2,2'-dimethylbiphen-
yl-4-carboxylic acid
[0475] Starting material 683 (0.025 g, 0.036 mmol) and anhydrous
lithium hydroxide (0.004 g, 0.178 mmol) were dissolved in dioxane
(1 mL)/water (0.25 mL) at 50.degree. C., and the reaction mixture
was stirred at the same temperature for 8 hours. Then, an aqueous
solution of 1M hydrochloric acid was added to the reaction mixture,
followed by extraction with ethyl acetate. The organic layer was
washed with brine, dried with anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The concentrate was purified
by column chromatography (Sift, EtOAc/hexane=0%.about.50%) to
obtain desired compound 684 (0.011 g, 44.9%) as a white foam
solid.
[0476] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1 atropisomeric
mixture; .delta. 7.94-8.02 (m, 2H), 7.87 (s, 1H), 7.74 (d, 1H,
J=9.6 Hz), 7.00-7.23 (m, 1H), 6.69-6.79 (m, 2H), 5.61-5.63 (m, 1H),
3.88-4.02 (m, 2H), 3.78-3.82 (m, 3H), 3.50-3.36 (m, 1H), 2.20-2.60
(m, 2H), 2.03-2.18 (m, 6H), 1.87-1.94 (m, 2H), 1.40-1.60 (m, 2H),
0.96-1.06 (m, 6H), 0.33-0.47 (m, 3H)
[0477] MS (ESI) m/z 690.3 (M.sup.++H).
Preparation of Novel Compounds According to Reaction Scheme 11
EXAMPLE 103
Compound 594
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,4'-dimethoxybiphenyl--
4-carboxylate
[0478] Starting material 17 (50 mg, 0.09 mmol) and methyl
5'-chloro-2,4'-dimethoxybiphenyl-4-carboxylate 45 (36 mg, 0.12
mmol) were dissolved in dimethoxyethane/water (v/v=3:1, 0.4 mL),
followed by degassing. Then, Pd(dbpf)Cl.sub.2 (13 mg, 0.02 mmol)
and sodium carbonate (87 mg, 0.83 mmol) were added dropwise to the
reaction mixture, and the mixture was stirred with microwave
irradiation at 120.degree. C. for 20 minutes. After completion of
the reaction, the reaction mixture was cooled to room temperature,
diluted with ethyl acetate, and then washed with water and brine.
The organic layer was dried with anhydrous magnesium sulfate,
filtered, and then concentrated under reduced pressure to remove
the solvent. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=10%.about.30%) to obtain compound 594 (15 mg, 24%) as
colorless oil.
[0479] MS (ESI) m/z 706.2 (M.sup.++H).
EXAMPLE 104
Compound 597
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,4'-dimethoxybiphenyl-4-carbo-
xylic acid
[0480] Starting material 594 (13 mg, 0.02 mmol) was dissolved in
dioxane (1 mL), and a solution of lithium hydroxide monohydrate (4
mg, 0.09 mmol) in water (0.25 mL) was added dropwise thereto,
followed by stirring at 50.degree. C. for 3 hours. After completion
of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with
water, saturated ammonium chloride and brine. The organic layer was
dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by preparative TLC (hexane/EtOAc=50%) to
obtain compound 597 (5 mg, 39%) as a yellow solid.
[0481] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.6 atropisomeric
mixture; .delta. 7.85-7.83 (br m, 1H), 7.79-7.72 (m, 3H), 7.66-7.62
(m, 1H), 7.45-7.42 (m, 1H), 7.38-7.28 (m, 1H), 7.20-7.17 (m, 1H),
6.92-6.87 (m, 1H), 5.60-5.55 (m, 1H), 4.01-3.79 (m, 8H), 3.72-3.53
(m, 1H), 2.57-2.02 (br m, 2H), 1.99-1.94 (br m, 2H), 1.50-1.41 (m,
2H), 1.06-1.01 (m, 6H), 0.44-0.34 (m, 3H)
[0482] MS (ESI) m/z 692.2 (M.sup.++H).
EXAMPLE 105
Compound 667
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-fluoro-2-(trifluorom-
ethyl)biphenyl-4-carboxylate
[0483] Starting material 17 (0.26 g, 0.47 mmol), methyl
3'-chloro-5'-fluoro-2-(trifluoromethyl)biphenyl-4-carboxylate (0.13
g, 0.39 mmol), sodium carbonate (0.11 g, 1.02 mmol) and
Pd(dppf)Cl.sub.2 (12.7 mg, 0.02 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 12 mL), and then stirred with
microwave irradiation at 120.degree. C. for 30 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, and water was added thereto, followed by extraction
with ethyl acetate. The organic layer was washed with brine, dried
with anhydrous magnesium sulfate, filtered, and then concentrated
under reduced pressure to remove the solvent. The residue was
purified by MPLC (Sift, hexane/EtOAc=5%.about.20%) to obtain
compound 667 (0.31 g, 100%) as colorless oil.
[0484] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 8.41 (2d, 1H, J=1.5 Hz), 8.21 (dd, 1H, J=8.0, 1.3 Hz),
7.88-7.71 (m, 4H), 7.39 (d, 1H, J=8.0 Hz), 6.95-6.86 (m, 2H),
5.67-5.59 (m, 1H), 4.12-3.98 (m, 4H), 3.87 (m, 1H), 3.63 (2d, 1H,
J=14.7 Hz), 2.38-2.08 (m, 2H), 1.95, 1.76 (2s, 2H), 1.50, 1.35 (2t,
2H, J=6.4 Hz), 1.05-0.88 (m, 6H), 0.74, 0.41 (2d, 3H, J=6.6 Hz)
[0485] MS (ESI) m/z 732.2 (M.sup.++H).
EXAMPLE 106
Compound 668
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-fluoro-2-(trifluoromethyl)b-
iphenyl-4-carboxylic acid
[0486] Starting material 667 (0.05 g, 0.07 mmol) and anhydrous
lithium hydroxide (8.2 mg, 0.34 mmol) were dissolved in
dioxane/water (v/v=4:1, 4.0 mL), and then stirred at 50.degree. C.
for 12 hours. After completion of the reaction, the reaction
mixture was cooled to room temperature, and 1M hydrochloric acid
solution was added dropwise thereto until a pH of 2 was reached.
Then, the reaction mixture was extracted with ethyl acetate, and
then washed with brine. The organic layer was washed with brine,
dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by preparative TLC (Sift, hexane/EtOAc=1:2) to
obtain compound 668 (17 mg, 34%) as colorless oil.
[0487] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.47 (s, 1H),
8.27 (d, 1H, J=7.7 Hz), 7.86 (s, 1H), 7.74 (s, 2H), 7.42 (d, 1H,
J=7.9 Hz), 6.94-6.87 (m, 3H), 5.61 (d, 1H, J=8.1 Hz), 4.04 (d, 1H,
J=14.8 Hz), 3.88 (m, 1H), 3.77 (d, 1H, J=14.8 Hz), 2.34 (m, 2H),
1.95 (s, 2H), 1.50 (t, 2H, J=6.2 Hz), 1.01 (d, 6H, J=16.3 Hz), 0.41
(d, 3H, J=6.6 Hz)
[0488] MS (ESI) m/z 718.2 (M.sup.++H).
EXAMPLE 107
Compound 692
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-fluoro-2-methylbiphe-
nyl-4-carboxylate
[0489] Starting material 17 (0.050 g, 0.089 mmol), methyl
3'-chloro-4'-fluoro-2-methyl-[1,1'-biphenyl]-4-carboxylate (0.023
g, 0.081 mmol), Pd(dbpf)Cl.sub.2 (0.003 g, 0.004 mmol) and sodium
carbonate (0.019 g, 0.178 mmol) were added to dimethoxyethane/water
(v/v=3/1, 0.5 mL) and stirred with microwave irradiation at
120.degree. C. for 30 minutes. After completion of the reaction,
the reaction mixture was cooled to room temperature, diluted with
ethyl acetate, and then washed with water and brine. The organic
layer was dried with anhydrous magnesium sulfate, filtered, and
then concentrated under reduced pressure to remove the solvent. The
residue was purified by preparative TLC (Sift, EtOAc/hexane=14%) to
obtain compound 692 (0.053 g, 97%) as a white foam solid.
[0490] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.92-7.86 (m,
3H), 7.76-7.72 (m, 2H), 7.26-7.17 (m, 2H), 7.11-7.01 (m, 2H),
5.66-5.59 (m, 1H), 4.08-3.91 (m, 5H), 3.64-3.61 (m, 1H), 2.50-2.24
(m, 5H), 1.97 (s, 2H), 1.55-1.49 (m, 2H), 1.06-1.01 (m, 6H),
0.46-0.42 (m, 3H)
[0491] MS (ESI) m/z 678.1 (M.sup.++H).
EXAMPLE 108
Compound 694
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-fluoro-2-methylbiphenyl-4-c-
arboxylic acid
[0492] Starting material 692 (0.053 g, 0.078 mmol) and lithium
hydroxide monohydrate (0.016 g, 0.392 mmol) were dissolved in
dioxane/water (v/v=4:1, 1.0 mL), and then stirred at 50.degree. C.
for 4 hours. After completion of the reaction, the reaction mixture
was cooled to room temperature, concentrated under reduced pressure
to remove the solvent, and then diluted with ethyl acetate, and 1M
hydrochloric acid solution was added dropwise thereto until a pH of
2 was reached, followed by washing with water. The organic layer
was dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by preparative TLC (SiO.sub.2,
CH.sub.3OH/CH.sub.2Cl.sub.2=10%) to obtain compound 694 (0.031 g,
59%) as colorless oil.
[0493] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.02-7.96 (m,
2H), 7.86-7.77 (m, 3H), 7.31-7.20 (m, 2H), 7.19-7.03 (m, 2H),
5.67-5.60 (m, 1H), 4.13-4.01 (m, 2H), 3.65-3.62 (m, 1H), 2.53-2.22
(m, 5H), 1.98 (s, 2H), 1.56-1.49 (m, 2H), 1.07-1.00 (m, 6H),
0.48-0.44 (m, 3H)
[0494] MS (ESI) m/z 664.2 (M.sup.++H).
EXAMPLE 109
Compound 693
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-fluoro-2-(trifluorom-
ethyl)biphenyl-4-carboxylate
[0495] Starting material 17 (0.050 g, 0.089 mmol), methyl
3'-chloro-4'-fluoro-2-(trifluoromethyl)-[1,1'-biphenyl]-4-carboxylate
(0.027 g, 0.081 mmol), Pd(dbpf)Cl.sub.2 (0.003 g, 0.004 mmol) and
sodium carbonate (0.019 g, 0.178 mmol) were added to
dimethoxyethane/water (v/v=3/1, 0.5 mL) and stirred with microwave
irradiation at 120.degree. C. for 30 minutes. After completion of
the reaction, the reaction mixture was cooled to room temperature,
diluted with ethyl acetate, and then washed with water and brine.
The organic layer was dried with anhydrous magnesium sulfate,
filtered, and then concentrated under reduced pressure to remove
the solvent. The residue was purified by preparative TLC
(SiO.sub.2, EtOAc/hexane=14%) to obtain compound 693 (0.036 g, 61%)
as a pale yellow foam solid.
[0496] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.43 (d, 1H,
J=5.3 Hz), 8.23 (t, 1H, J=8.9 Hz), 7.88 (s, 1H), 7.78-7.74 (m, 2H),
7.42 (dd, 1H, J=19.7, 8.0 Hz), 7.23-7.21 (m, 1H), 7.17-7.06 (m,
2H), 5.67-5.61 (m, 1H), 4.15-3.91 (m, 5H), 3.68-3.60 (m, 1H),
2.50-2.19 (m, 2H), 2.06-1.94 (m, 2H), 1.59-1.49 (m, 2H), 1.08-1.02
(m, 6H), 0.48-0.41 (m, 3H)
[0497] MS (ESI) m/z 732.1 (M.sup.++H).
EXAMPLE 110
Compound 695
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-fluoro-2-(trifluoromethyl)b-
iphenyl-4-carboxylic acid
[0498] Starting material 693 (0.036 g, 0.050 mmol) and lithium
hydroxide monohydrate (0.010 g, 0.248 mmol) were dissolved in
dioxane/water (v/v=4:1, 1.0 mL), and then stirred at 50.degree. C.
for 4 hours. After completion of the reaction, the reaction mixture
was cooled to room temperature, concentrated under reduced pressure
to remove the solvent, and then diluted with ethyl acetate, and 1M
hydrochloric acid solution was added dropwise thereto until a pH of
2 was reached, followed by washing with water.
[0499] The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by preparative TLC
(SiO.sub.2, CH.sub.3OH/CH.sub.2Cl.sub.2=10%) to obtain compound 695
(0.018 g, 51%) as a white foam solid.
[0500] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.51 (d, 1H,
J=4.6 Hz), 8.31 (t, 1H, J=8.5 Hz), 7.89 (s, 1H), 7.78 (d, 2H,
J=15.4 Hz), 7.47 (dd, 1H, J=18.9, 8.0 Hz), 7.24 (s, 1H), 7.19-7.08
(m, 2H), 5.70-5.63 (m, 1H), 4.16-3.92 (m, 2H), 3.69-3.62 (m, 1H),
2.56-2.18 (m, 2H), 2.06-1.95 (m, 2H), 1.61-1.50 (m, 2H), 1.08-1.03
(m, 6H), 0.45-0.39 (m, 3H)
[0501] MS (ESI) m/z 718.1 (M.sup.++H).
EXAMPLE 111
Compound 699
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,5'-difluorobiphenyl-4-
-carboxylate
[0502] Starting material 17 (0.16 g, 0.28 mmol), methyl
3'-chloro-2,5'-difluorobiphenyl-4-carboxylate (0.06 g, 0.23 mmol),
sodium carbonate (0.06 g, 0.6 mmol) and Pd(dppf)Cl.sub.2 (7.5 mg,
0.01 mmol) were dissolved in dimethoxyethane/water (v/v=3:1, 4 mL),
and then stirred with microwave irradiation at 120.degree. C. for
30 minutes. After completion, the reaction mixture was cooled to
room temperature, and water was added thereto, followed by
extraction with ethyl acetate. The organic layer was washed with
brine, dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (SiO.sub.2, hexane/EtOAc=5%.about.30%)
to obtain compound 699 (67 mg, 56.7%) as colorless oil.
[0503] .sup.1H NMR (400 MHz, CDCl.sub.3); atropisomeric mixture;
.delta. 7.89-7.73 (m, 4H), 7.49-7.42 (m, 2H), 7.17-7.10 (m, 2H),
6.89-6.86 (m, 1H), 5.68-5.55 (m, 1H), 4.12-3.90 (m, 5H), 3.62 (2d,
1H, J=14.9 Hz), 2.37-2.07 (m, 2H), 1.97, 1.76 (2s, 2H), 1.51, 1.34
(2t, 2H, J=6.4 Hz), 1.06-0.94 (m, 6H), 0.37 (2d, 3H, J=6.5 Hz)
[0504] MS (ESI) m/z 682.2 (M.sup.++H).
EXAMPLE 112
Compound 702
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,5'-difluorobiphenyl-4-carbox-
ylic acid
[0505] Starting material 699 (0.02 g, 0.03 mmol) and anhydrous
lithium hydroxide (3.3 mg, 0.14 mmol) were dissolved in
dioxane/water (v/v=4:1, 1.25 mL), and then stirred at 45.degree. C.
for 12 hours. After completion of the reaction, the reaction
mixture was cooled to room temperature, and 1M hydrochloric acid
solution was added dropwise thereto until a pH of 2 was reached.
Next, the reaction mixture was extracted with ethyl acetate, and
then washed with brine. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by
preparative TLC (SiO.sub.2, hexane/EtOAc=1:2) to obtain compound
702 (11 mg, 59.1%) as colorless oil.
[0506] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.01-7.88 (m,
3H), 7.74 (s, 2H), 7.52 (m, 1H), 7.21-7.12 (m, 2H), 6.90 (m, 1H),
5.59 (d, 1H, J=6.8 Hz), 4.07 (d, 1H, J=15.0 Hz), 3.96 (m, 1H), 3.81
(d, 1H, J=14.9 Hz), 2.26 (m, 2H), 1.93 (s, 2H), 1.47 (m, 2H), 1.04
(d, 6H, J=12.9 Hz), 0.46 (d, 3H, J=6.7 Hz)
[0507] MS (ESI) m/z 669.1 (M.sup.++H).
EXAMPLE 113
Compound 700
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-fluorobiphenyl-4-car-
boxylate
[0508] Starting material 17 (0.14 g, 0.25 mmol), methyl
3'-chloro-5'-fluorobiphenyl-4-carboxylate (0.05 g, 0.2 mmol),
sodium carbonate (56.2 mg, 0.5 mmol) and Pd(dppf)Cl.sub.2 (6.6 mg,
0.01 mmol) were dissolved in dimethoxyethane/water (v/v=3:1, 4 mL),
and then stirred with microwave irradiation at 120.degree. C. for
30 minutes. After completion, the reaction mixture was cooled to
room temperature, poured into water, and extracted with ethyl
acetate. The organic layer was washed with brine, dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (SiO.sub.2, hexane/EtOAc=5%.about.30%) to obtain compound 700
(88 mg, 65%) as colorless oil.
[0509] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.09 (m, 2H),
7.85 (s, 1H), 7.71 (s, 2H), 7.59 (m, 2H), 7.21 (m, 1H), 7.13 (t,
1H, J=1.5 Hz), 6.84 (m, 1H), 5.60 (d, 1H, J=8.1 Hz), 4.07 (d, 1H,
J=12.9 Hz), 3.94 (m, 4H), 3.73 (d, 1H, J=14.9 Hz), 2.33 (m, 2H),
2.04 (m, 2H), 1.52 (t, 2H, J=6.4 Hz), 1.03 (d, 6H, J=15.4 Hz), 0.43
(d, 3H, J=6.6 Hz)
[0510] MS (ESI) m/z 664.2 (M.sup.++H).
EXAMPLE 114
Compound 703
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-fluorobiphenyl-4-carboxylic
acid
[0511] Starting material 700 (0.02 g, 0.04 mmol) and anhydrous
lithium hydroxide (4.3 mg, 0.18 mmol) were dissolved in
dioxane/water (v/v=4:1, 1.25 mL), and then stirred at 45.degree. C.
for 12 hours. After completion of the reaction, the reaction
mixture was cooled to room temperature, and 1M hydrochloric acid
solution was added dropwise thereto until a pH of 2 was reached.
Next, the reaction mixture was extracted with ethyl acetate, and
then washed with brine. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by
preparative TLC (SiO.sub.2, hexane/EtOAc=1:2) to obtain compound
703 (15 mg, 63.8%) as colorless oil.
[0512] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.16 (d, 2H,
J=4.1 Hz), 7.85 (s, 1H), 7.72 (s, 2H), 7.59 (d, 2H, J=11.5 Hz),
7.21-7.13 (m, 2H), 6.85 (m, 1H), 5.61 (d, 1H, J=8.2 Hz), 4.09 (d,
1H, J=14.9 Hz), 3.94 (m, 1H), 3.73 (d, 1H, J=14.9 Hz), 2.36 (m,
2H), 2.01 (m, 2H), 1.52 (t, 2H, J=6.2 Hz), 1.04 (d, 6H, J=15.6 Hz),
0.43 (d, 3H, J=6.5 Hz)
[0513] MS (ESI) m/z 650.1 (M.sup.++H).
EXAMPLE 115
Compound 701
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluorobiphenyl-4-carb-
oxylate
[0514] Starting material 17 (0.16 g, 0.28 mmol), methyl
3'-chloro-2-fluorobiphenyl-4-carboxylate (0.06 g, 0.2 mmol), sodium
carbonate (63.5 mg, 0.6 mmol) and Pd(dppf)Cl.sub.2 (7.5 mg, 0.01
mmol) were dissolved in dimethoxyethane/water (v/v=3:1, 4 mL), and
then stirred with microwave irradiation at 120.degree. C. for 30
minutes. After completion, the reaction mixture was cooled to room
temperature, poured into water, and extracted with ethyl acetate.
The organic layer was washed with brine, dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by MPLC
(SiO.sub.2, hexane/EtOAc=5%.about.30%) to obtain compound 701 (64
mg, 41.8%) as colorless oil.
[0515] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.88 (2d, 1H,
J=1.6 Hz), 7.84 (s, 1H), 7.79 (2d, 1H, J=1.5 Hz), 7.73 (s, 2H),
7.50-7.42 (m, 3H), 7.32 (s, 1H), 7.15 (m, 1H), 5.56 (d, 1H, J=8.1
Hz), 4.04 (d, 1H, J=14.8 Hz), 3.94-3.89 (m, 4H), 3.75 (d, 1H,
J=14.8 Hz), 2.38 (m, 2H), 1.97 (s, 2H), 1.51 (t, 2H, J=6.4 Hz),
1.03 (d, 6H, J=12.9 Hz), 0.33 (d, 3H, J=6.5 Hz)
[0516] MS (ESI) m/z 664.1 (M.sup.++H).
EXAMPLE 116
Compound 704
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluorobiphenyl-4-carboxylic
acid
[0517] Starting material 701 (0.02 g, 0.04 mmol) and anhydrous
lithium hydroxide (4.3 mg, 0.18 mmol) were dissolved in
dioxane/water (v/v=4:1, 1.25 mL), and then stirred at 45.degree. C.
for 12 hours. After completion of the reaction, the reaction
mixture was cooled to room temperature, and 1M hydrochloric acid
solution was added dropwise thereto until a pH of 2 was reached.
Next, the reaction mixture was extracted with ethyl acetate, and
then washed with brine. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by
preparative TLC (SiO.sub.2, hexane/EtOAc=1:2) to obtain compound
704 (7 mg, 29.8%) as colorless oil.
[0518] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.95 (dd, 1H,
J=8.0, 1.6 Hz), 7.88-7.86 (m, 3H), 7.73 (s, 2H), 7.53 (t, 1H, J=7.8
Hz), 7.44 (m, 2H), 7.34 (s, 1H), 7.18 (m, 1H), 5.57 (d, 1H, J=8.1
Hz), 4.06 (d, 1H, J=15.0 Hz), 3.93 (m, 1H), 3.76 (d, 1H, J=14.9
Hz), 2.42 (m, 2H), 2.00 (m, 2H), 1.52 (t, 2H, J=6.3 Hz), 1.04 (d,
6H, J=12.9 Hz), 0.29 (d, 3H, J=6.6 Hz)
[0519] MS (ESI) m/z 650.2 (M.sup.++H).
EXAMPLE 117
Compound 708
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-fluorobiphenyl-4-car-
boxylate
[0520] Starting material 17 (0.050 g, 0.089 mmol), methyl
3'-chloro-4'-fluoro-[1,1'-biphenyl]-4-carboxylate (0.021 g, 0.081
mmol), Pd(dbpf)Cl.sub.2 (0.003 g, 0.004 mmol) and sodium carbonate
(0.019 g, 0.178 mmol) were dissolved in dimethoxyethane/water
(v/v=3/1, 1.0 mL) and stirred with microwave irradiation at
120.degree. C. for 30 minutes. After completion of the reaction,
the reaction mixture was cooled to room temperature, diluted with
ethyl acetate, and then washed with water and brine. The organic
layer was dried with anhydrous magnesium sulfate, filtered, and
then concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (SiO.sub.2, EtOAc/hexane=0%.about.20%)
to obtain compound 708 (0.028 g, 51%) as colorless oil.
[0521] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.10-8.02 (m,
2H), 7.85 (s, 1H), 7.73 (d, 2H, J=12.2 Hz), 7.57 (dd, 2H, J=20.1,
8.2 Hz), 7.51-7.47 (m, 1H), 7.32-7.30 (m, 1H), 7.18-7.09 (m, 1H),
5.64-5.58 (m, 1H), 4.07-3.97 (m, 2H), 3.94-3.92 (m, 3H), 3.63-3.57
(m, 1H), 2.50-2.20 (m, 2H), 1.99-1.98 (m, 2H), 1.58-1.51 (m, 2H),
1.09-1.01 (m, 6H), 0.44 (t, 3H, J=7.2 Hz)
[0522] MS (ESI) m/z 664.3 (M.sup.++H).
EXAMPLE 118
Compound 709
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-fluorobiphenyl-4-carboxylic
acid
[0523] Starting material 708 (0.012 g, 0.019 mmol) and lithium
hydroxide monohydrate (0.004 g, 0.093 mmol) were dissolved in
dioxane/water (v/v=4:1, 1.0 mL), and then stirred at 50.degree. C.
for 4 hours. After completion of the reaction, the reaction mixture
was cooled to room temperature, concentrated under reduced pressure
to remove the solvent, and then diluted with ethyl acetate, and 1M
hydrochloric acid solution was added dropwise thereto until a pH of
2 was reached, followed by washing with water. The organic layer
was dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by preparative TLC (SiO.sub.2,
EtOAc/hexane=50%) to obtain compound 709 (0.008 g, 64%) as
colorless liquid.
[0524] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.21-8.15 (m,
2H), 7.86 (s, 1H), 7.73 (d, 2H, J=12.6 Hz), 7.61 (dd, 2H, J=20.0,
8.4 Hz), 7.53-7.49 (m, 1H), 7.35-7.31 (m, 1H), 7.20-7.11 (m, 1H),
5.65-5.58 (m, 1H), 4.10-3.93 (m, 2H), 3.63-3.59 (m, 1H), 2.52-2.21
(m, 2H), 1.94 (s, 2H), 1.59-1.53 (m, 2H), 1.08-1.03 (m, 6H),
0.48-0.43 (m, 3H)
[0525] MS (ESI) m/z 650.2 (M.sup.++H).
EXAMPLE 119
Compound 714
methyl
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-
oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)pyridin-2-yl)-3-methyl-
benzoate
[0526] Starting material 17 (0.056 g, 0.099 mmol), methyl
4-(4-chloropyridin-2-yl)-3-methylbenzoate (0.026 g, 0.099 mmol),
sodium carbonate (0.032 g, 0.298 mmol) and Pd(dbpf)Cl.sub.2 (0.003
g, 0.005 mmol) were added to dimethoxyethane (0.9 mL)/water (0.3
mL) and heated by microwave irradiation at 120.degree. C. for 30
minutes. Then, the reaction mixture was cooled to room temperature,
and water was added thereto, followed by extraction with ethyl
acetate. The organic layer was dried with anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The residue
was purified by MPLC (SiO.sub.2, EtOAc/hexane=0%.about.50%) to
obtain desired compound 714 (0.020 g, 30.5%) as clear oil.
[0527] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.66 (d, 1H,
J=4.8 Hz), 7.94-7.85 (m, 3H), 7.70 (s, 2H), 7.41 (d, 1H, J=8.0 Hz),
7.18 (s, 1H), 7.07 (m, 1H), 5.60 (d, 1H, J=7.6 Hz), 4.08-4.04 (m,
1H), 3.91 (s, 4H), 3.70 (m, 1H), 2.45-2.20 (m, 5H), 1.95 (m, 2H),
1.51 (m, 2H), 1.25 (m, 2H), 1.01 (d, 6H, J=14.8 Hz), 0.43 (d, 3H,
J=6.0 Hz)
[0528] MS (ESI) m/z 661.1 (M.sup.++H).
EXAMPLE 120
Compound 716
4-(4-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazoli-
din-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)pyridin-2-yl)-3-methylbenzoic
acid
[0529] Starting material 714 (0.020 g, 0.030 mmol) and lithium
hydroxide monohydrate (0.025 g, 0.605 mmol) were dissolved in
dioxane (8 mL)/water (2 mL) at room temperature, and the reaction
mixture was stirred at the same temperature for 16 hours. Then, 1M
hydrochloric acid was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was dried with
anhydrous magnesium sulfate, and then concentrated under reduced
pressure. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=0%.about.100%) to obtain desired compound 716 (0.012
g, 61.3%) as a white foam solid.
[0530] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.72 (m, 1H),
7.97-7.81 (m, 3H), 7.66 (s, 2H), 7.45-7.14 (m, 3H), 5.58 (m, 1H),
3.97-3.91 (m, 2H), 3.61-3.54 (m, 1H), 2.36 (s, 3H), 2.28-2.09 (m,
2H), 1.91 (m, 2H), 1.50 (m, 2H), 1.01 (m, 6H), 0.46 (m, 3H)
[0531] MS (ESI) m/z 647.2 (M.sup.++H).
EXAMPLE 121
Compound 726
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-chloro-2-methylbiphe-
nyl-4-carboxylate
[0532] Starting material 17 (0.150 g, 0.267 mmol), methyl
3'-bromo-4'-chloro-2-methylbiphenyl-4-carboxylate (WO 2007/79186
A2) (0.136 g, 0.401 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (0.009 g,
0.013 mmol) and sodium carbonate (0.085 g, 0.802 mmol) were added
to dimethylformamide (0.8 mL)/water (0.4 mL) and heated by
microwave irradiation at 90.degree. C. for 20 minutes. Then, the
reaction mixture was cooled to room temperature, and water was
added thereto, followed by extraction with ethyl acetate. The
organic layer was dried with anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=0%.about.20%) to obtain desired
compound 726 (0.030 g, 16.2%) in an impure form.
[0533] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.97-7.73 (m,
5H), 7.46 (m, 1H), 7.18 (m, 2H), 7.05 (m, 1H), 5.67 (m, 1H), 4.15
(m, 2H), 3.95 (m, 3H), 3.55 (m, 1H), 2.60-2.35 (m, 2H), 2.30-2.26
(m, 3H), 2.00-1.90 (m, 2H), 1.57-1.45 (m, 2H), 1.00-0.91 (m, 6H),
0.50-0.46 (m, 3H)
[0534] MS (ESI) m/z 694.1 (M.sup.++H).
EXAMPLE 122
Compound 727
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-chloro-2-methylbiphenyl-4-c-
arboxylic acid
[0535] Starting material 726 (0.020 g, 0.029 mmol) and lithium
hydroxide monohydrate (0.012 g, 0.288 mmol) were dissolved in
dioxane (4 mL)/water (1 mL) at room temperature, and the reaction
mixture was stirred at the same temperature for 16 hours. Then, 1M
hydrochloric acid was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was dried with
anhydrous magnesium sulfate, and then concentrated under reduced
pressure. The concentrate was purified by PTLC to obtain desired
compound 727 (0.010 g, 51.0%) as a white foam solid.
[0536] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.04-7.94 (m,
2H), 7.89 (m, 1H), 7.78-7.74 (m, 2H), 7.50-7.44 (m, 1H), 7.33-7.18
(m, 2H), 7.08 (m, 1H), 5.67 (2d, 1H, J=8.1 Hz), 4.17-3.95 (m, 2H),
3.53 (2d, 1H, J=14.8 Hz), 2.60-2.35 (m, 2H), 2.33-2.29 (m, 3H),
1.98 (m, 2H), 1.60-1.50 (m, 2H), 1.11-1.04 (m, 6H), 0.50 (2d, 3H,
J=5.0 Hz)
[0537] MS (ESI) m/z 680.1 (M.sup.++H).
Preparation of Novel Compounds According to Reaction Scheme 12
Intermediate compound 48: methyl
4'-methoxy-2-(trifluoromethyl)biphenyl-4-carboxylate
[0538] Starting material 4-methoxyboronic acid 46 (0.32 g, 2.12
mmol), methyl 4-bromo-3-(trifluoromethyl)benzoate 47 (0.6 g, 2.12
mmol), Pd(dppf)Cl.sub.2 (0.07 g, 0.11 mmol) and sodium carbonate
(0.45 g, 4.24 mmol) were dissolved in dimethoxyethane/water
(v/v=4:1, 5 mL), and then stirred with microwave irradiation at
120.degree. C. for 30 minutes. After completion of the reaction,
the reaction mixture was cooled to room temperature, diluted with
ethyl acetate, and then washed with water and brine. The organic
layer was dried with anhydrous magnesium sulfate, filtered, and
then concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (Sift 12 g, EtOAc/hexane=0%.about.15%)
to obtain compound 48 (0.46 g, 70%) as colorless oil.
Intermediate compound 49: methyl
3'-iodo-4'-methoxy-2-(trifluoromethyl)biphenyl-4-carboxylate
[0539] Starting material 48 (0.46 g, 1.48 mmol), iodine (0.41 g,
1.63 mmol) and silver sulfate (0.51 g, 1.63 mmol) were dissolved in
methanol (10 mL), and then stirred at room temperature for 2 hours.
After completion of the reaction, the reaction mixture was diluted
with ethyl acetate, and then washed with saturated sodium
thiosulfate solution and brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (SiO.sub.2EtOAc/hexane=0%.about.15%) to obtain compound 49
(0.25 g, 39.1%) as a white solid.
Intermediate compound 50: methyl
4'-methoxy-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluorom-
ethyl)biphenyl-4-carboxylate
[0540] Starting material 49 (0.253 g, 0.580 mmol),
bis(pinacolate)diboron (0.22 g, 0.87 mmol), Pd(dppf)Cl.sub.2 (0.02
g, 0.03 mmol) and sodium carbonate (0.18 g, 1.74 mmol) were
dissolved in dimethylsulfoxide (10 mL), and then stirred at
80.degree. C. for 8 hours. After completion of the reaction, the
reaction mixture was cooled to room temperature, diluted with ethyl
acetate, and then washed with water and brine. The organic layer
was dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (SiO.sub.2, EtOAc/hexane=0%.about.25%)
to obtain compound 50 (75 mg, 29.6%) as colorless oil.
Intermediate compound 51: methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-(trifluoromethyl-
)biphenyl-4-carboxylate
[0541] Starting material 50 (75 mg, 0.17 mmol), compound 16 (0.09
g, 0.17 mmol), Pd(dbpf)Cl.sub.2 (6.0 mg, 0.009 mmol) and sodium
carbonate (36 mg, 0.34 mmol) were dissolved in
dimethoxyethane/water (v/v=4:1, 1.25 mL), and then stirred at
80.degree. C. for 3 hours. After completion of the reaction, the
reaction mixture was cooled to room temperature, diluted with ethyl
acetate, and then washed with water and brine. The organic layer
was dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (Sift, EtOAc/hexane=0%.about.30%) to
obtain compound 51 (0.4 g, 31.3%) as colorless oil.
EXAMPLE 123
Compound 618
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-(trifluoromethyl)-
biphenyl-4-carboxylic acid
[0542] Starting material 51 (0.04 g, 0.06 mmol) and anhydrous
lithium hydroxide (7.0 mg, 0.29 mmol) were dissolved in
dioxane/water (v/v=4:1, 1.25 mL), and then stirred at 50.degree. C.
for 8 hours. After completion of the reaction, the reaction mixture
was cooled to room temperature, diluted with ethyl acetate, and
then washed with 1M hydrochloric acid solution and brine. The
organic layer was dried with anhydrous magnesium sulfate, filtered,
and then concentrated under reduced pressure to remove the solvent.
The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=0%.about.50%) to obtain compound 618 (20 mg, 47.4%) as
colorless oil.
[0543] .sup.1H NMR (400 MHz, CDCl.sub.3); 2:3 atropisomeric
mixture; .delta. 8.50 (d, 0.6H, J=1.1 Hz), 8.48 (d, 0.4H, J=1.1
Hz), 8.29 (dd, 0.6H, J=6.0, 1.2 Hz), 8.26 (dd, 0.4H, J=6.0, 1.2
Hz), 7.88 (s, 1H), 7.77-7.74 (m, 2H), 7.49 (d, 0.6H, J=6.0 Hz),
7.42 (d, 0.4H, J=6.0 Hz), 7.24 (d, 0.4H, J=1.6 Hz), 7.22 (d, 0.6H,
J=1.6 Hz), 7.03-6.99 (m, 1H), 6.96 (d, 0.4H, J=8.6 Hz), 6.92 (d,
0.6H, J=8.6 Hz), 5.66-5.62 (m, 1H), 4.07-3.90 (m, 2H), 3.86-3.84
(m, 3H), 3.69 (d, 0.6H, J=10.9 Hz), 3.54 (d, 0.4H, J=11.2 Hz),
2.60-2.02 (br m, 2H), 1.98-1.90 (br m, 2H), 1.58-1.45 (br m, 2H),
1.08-1.01 (m, 6H), 0.45 (d, 1.2H, J=4.9 Hz), 0.35 (d, 1.8H, J=4.9
Hz)
[0544] MS (ESI) m/z 730.1 (M.sup.++H).
Preparation of Novel Compounds According to Reaction Scheme 13
Intermediate compound 53a: ethyl
2-(3-chlorophenyl)-5,5-dimethylcyclohex-1-enecarboxylate
[0545] Starting material 52 (0.31 g, 1.01 mmol), compound 8 (0.12
mL, 1.0 mmol), Pd(dppf)Cl.sub.2 (0.04 g, 0.05 mmol) and sodium
carbonate (0.27 g, 2.5 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 12 mL), and then stirred with
microwave irradiation at 120.degree. C. for 30 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=5%) to obtain compound 53a (0.25 g, 84.9%) as
colorless oil.
[0546] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.22 (m, 2H),
7.12 (dd, 1H, J=2.6, 1.6 Hz), 7.00 (m, 1H), 3.89 (q, 2H, J=7.2 Hz),
2.37 (m, 2H), 2.21 (t, 2H, J=2.4 Hz), 1.49 (t, 2H, J=6.4 Hz), 1.01
(s, 6H), 0.89 (t, 3H, J=7.2 Hz).
Intermediate compound 53b: ethyl
2-(3-chloro-5-fluorophenyl)-5,5-dimethylcyclohex-1-enecarboxylate
[0547] Starting material 52 (0.51 g, 1.66 mmol), compound 8 (0.20
mL, 1.62 mmol), Pd(dppf)Cl.sub.2 (0.07 g, 0.08 mmol) and sodium
carbonate (0.44 g, 4.14 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 12 mL), and then stirred with
microwave irradiation at 120.degree. C. for 30 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=5%.about.35%) to obtain compound 53b (0.37 g, 71.9%)
as colorless oil.
[0548] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 6.97 (m, 1H),
6.91 (d, 1H, J=1.4 Hz), 6.75 (m, 1H), 3.93 (q, 2H, J=7.2 Hz), 2.34
(m, 2H), 2.20 (t, 2H, J=2.4 Hz), 1.48 (t, 2H, J=6.4 Hz), 0.99 (s,
6H), 0.93 (t, 3H, J=7.2 Hz).
Intermediate compound 54a:
2-(3-chlorophenyl)-5,5-dimethylcyclohex-1-enecarbaldehyde
[0549] Starting material 53a (0.25 g, 1.0 mmol) was dissolved in
tetrahydrofuran (10 mL), and lithium aluminum hydride (2.6 mL) was
added dropwise thereto at 0.degree. C., followed by stirring
overnight at room temperature. After completion of the reaction,
the reaction mixture was diluted with ethyl acetate, and then
washed with brine. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent, thereby obtaining an alcohol
compound (0.17 g, 79.4%) as colorless oil, which was then used in
the next reaction without any additional purification.
[0550] The alcohol compound (0.17 g, 0.68 mmol) prepared as
described above was dissolved in methylene chloride (10 mL), and
DMP (0.43 g, 1.02 mmol) was added dropwise thereto. The reaction
mixture was stirred at room temperature for 3 hours, diluted with
ethyl acetate, and then washed with brine. The organic layer was
dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (SiO.sub.2, EtOAc/hexane=5%.about.20%)
to obtain compound 54a (0.13 g, 74.7%) as colorless oil.
Intermediate compound 54b:
2-(3-chloro-5-fluorophenyl)-5,5-dimethylcyclohex-1-enecarbaldehyde
[0551] Starting material 53b (0.31 g, 1.0 mmol) was dissolved in
tetrahydrofuran (10 mL), and lithium aluminum hydride (1.5 mL) was
added dropwise thereto at 0.degree. C., followed by stirring at
room temperature for 5 hours. After completion of the reaction, the
reaction mixture was diluted with ethyl acetate, and then washed
with brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent, thereby obtaining an alcohol compound (0.29 g,
100%) as colorless oil, which was then used in the next reaction
without any additional purification.
[0552] The alcohol compound (0.29 g, 1.06 mmol) was dissolved in
methylene chloride (10 mL), and Dess-Martin periodinane (DMP) (0.68
g, 1.60 mmol) was added dropwise thereto. The reaction mixture was
stirred overnight at room temperature, diluted with ethyl acetate,
and then washed with brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=5%.about.25%) to obtain compound 54b
(0.15 g, 53%) as yellow oil.
[0553] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 9.52 (s, 1H),
7.11 (m, 1H), 7.03 (m, 1H), 6.88 (m, 1H), 2.51 (m, 2H), 2.15 (t,
2H, J=2.1 Hz), 1.54 (t, 2H, J=6.4 Hz), 0.99 (s, 6H).
Intermediate compound 55a:
(1R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((2-(3-chlorophenyl)-5,5-dim-
ethylcyclohex-1-enyl)methylamino)propan-1-ol
[0554] Starting material 54a (0.13 g, 0.51 mmol), aminoalcohol
compound 4 (0.17 g) and acetic acid (0.03 mL) were dissolved in
methylene chloride (10 mL), and sodium cyanoborohydride (33.5 mg)
was added dropwise thereto at room temperature, followed by
stirring overnight. After completion of the reaction, the reaction
mixture was diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent, thereby obtaining compound 55a (0.28 g, 100%)
as colorless oil without additional purification.
Intermediate compound 55b:
(1R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((2-(3-chloro-5-fluorophenyl-
)-5,5-dimethylcyclohex-1-enyl)methylamino)propan-1-ol
[0555] Starting material 54b (0.15 g, 0.55 mmol), aminoalcohol
compound 4 (0.19 g) and acetic acid (0.03 mL) were dissolved in
methylene chloride (10 mL), and sodium cyanoborohydride (36.2 mg)
was added dropwise thereto at room temperature, followed by
stirring for 3 hours. After completion of the reaction, the
reaction mixture was diluted with ethyl acetate, and then washed
with water and brine. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent, thereby obtaining compound 55b
(0.33 g, 100%) as yellow oil without additional purification.
Intermediate compound 56a:
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(3-chlorophenyl)-5,5-dim-
ethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
[0556] Starting material 55a (0.28 g, 0.54 mmol) was dissolved in
methylene chloride (5 mL), and diisopropylethylamine (0.56 mL) and
triphosgene (0.1 g) were added thereto, followed by stirring
overnight. After completion of the reaction, the reaction mixture
was diluted with ethyl acetate, and then washed with water and
brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=5%.about.20%) to obtain compound 56a (0.19 g, 63.3%)
as colorless oil.
[0557] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.85 (s, 1H),
7.73 (s, 2H), 7.25-7.20 (m, 2H), 7.09 (t, 1H, J=1.8 Hz), 6.98 (dt,
1H, J=7.0, 1.6 Hz), 5.59 (d, 1H, J=8.2 Hz), 4.01 (d, 1H, J=14.8
Hz), 3.89 (m, 1H), 3.64 (d, 1H, J=14.8 Hz), 2.37-2.25 (m, 2H), 1.93
(s, 2H), 1.49 (t, 2H, J=6.4 Hz), 1.00 (m, 6H), 0.39 (d, 3H, J=6.6
Hz)
[0558] MS (ESI) m/z 546.1 (M.sup.++H).
Intermediate compound 56b:
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(3-chloro-5-fluorophenyl-
)-5,5-dimeth
[0559] ylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
[0560] Starting material 55b (0.33 g, 0.61 mmol) was dissolved in
methylene chloride (5 mL), and diisopropylethylamine (0.64 mL) and
triphosgene (0.1 g) were added thereto, followed by stirring
overnight. After completion of the reaction, the reaction mixture
was diluted with ethyl acetate, and then washed with water and
brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=5%.about.20%) to obtain compound 56b (0.17 g, 48.9%)
as colorless oil.
[0561] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.86 (s, 1H),
7.74 (s, 2H), 6.99 (dt, 1H, J=8.4, 2.1 Hz), 6.89 (t, 1H, J=1.4 Hz),
6.73 (m, 1H), 5.61 (d, 1H, J=8.1 Hz), 4.03 (d, 1H, J=14.9 Hz), 3.91
(m, 1H), 3.63 (d, 1H, J=14.9 Hz), 2.32-2.24 (m, 2H), 1.93 (s, 2H),
1.49 (t, 2H, J=6.5 Hz), 1.01 (2s, 6H), 0.45 (d, 3H, J=6.6 Hz).
EXAMPLE 124
Compound 649
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methylbiphenyl-4-carb-
oxylate
[0562] Starting material 56a (0.13 g, 0.24 mmol), boronic acid
pinacol ester 57 (0.08 g, 0.29 mmol), Pd(dbpf)Cl.sub.2 (8.0 mg,
0.01 mmol) and sodium carbonate (0.06 g, 0.57 mmol) were dissolved
in dimethoxyethane/water (v/v=3:1, 4 mL), and then stirred with
microwave irradiation at 120.degree. C. for 30 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (Sift,
EtOAc/hexane=5%.about.30%) to obtain compound 649 (15 mg, 9.5%) as
colorless oil.
[0563] MS (ESI) m/z 660.3 (M.sup.++H).
EXAMPLE 125
Compound 648
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-fluoro-2-methylbiphe-
nyl-4-carboxylate
[0564] Starting material 56b (0.07 g, 0.13 mmol), boronic acid
pinacol ester 57 (0.04 g, 0.15 mmol), Pd(dbpf)Cl.sub.2 (4.0 mg,
0.006 mmol) and sodium carbonate (0.03 g, 0.3 mmol) were dissolved
in dimethoxyethane/water (v/v=3:1, 4 mL), and then stirred with
microwave irradiation at 120.degree. C. for 30 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by preparative TLC
(Sift, hexane/EtOAc=1:4) to obtain compound 648 (21 mg, 24.6%) as
colorless oil.
[0565] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.94 (s, 1H),
7.88-7.87 (m, 2H), 7.73 (s, 2H), 7.21 (d, 1H, J=8.0 Hz), 6.92 (dt,
1H, J=6.9, 2.2 Hz), 6.84-6.82 (m, 2H), 5.61 (d, 1H, J=8.1 Hz), 4.06
(d, 1H, J=14.6 Hz), 3.93-3.90 (m, 4H), 3.74 (d, 1H, J=14.8 Hz),
2.38-2.27 (m, 5H), 1.95 (s, 2H), 1.51 (t, 2H, J=6.5 Hz), 1.03, 1.00
(2s, 6H), 0.42 (d, 3H, J=6.6 Hz)
[0566] MS (ESI) m/z 678.2 (M.sup.++H).
EXAMPLE 126
Compound 651
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methylbiphenyl-4-carboxylic
acid
[0567] Starting material 649 (0.02 g, 0.02 mmol) and lithium
hydroxide monohydrate (3.0 mg, 0.11 mmol) were dissolved in
dioxane/water (v/v=3:1, 4 mL), and then stirred overnight at
45.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and then washed with water and brine. The organic layer was dried
with anhydrous magnesium sulfate, filtered, and then concentrated
under reduced pressure to remove the solvent. The residue was
purified by preparative TLC (SiO.sub.2, hexane/EtOAc=1:2) to obtain
compound 651 (6.4 mg, 40.9%) as colorless oil.
[0568] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.00 (s, 1H),
7.94 (d, 1H, J=8.0 Hz), 7.85 (s, 1H), 7.72 (s, 2H), 7.39 (t, 1H,
J=7.6 Hz), 7.22 (m, 2H), 7.11 (d, 1H, J=7.6 Hz), 7.00 (s, 1H), 5.59
(d, 1H, J=8.0 Hz), 4.06 (d, 1H, J=14.6 Hz), 3.78 (m, 1H), 3.77 (d,
1H, J=14.7 Hz), 2.46-2.27 (m, 5H), 1.95 (s, 2H), 1.51 (t, 2H, J=6.2
Hz), 1.04, 1.01 (2s, 6H), 0.37 (d, 3H, J=6.5 Hz)
[0569] MS (ESI) m/z 646.2 (M.sup.++H).
EXAMPLE 127
Compound 650
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-fluoro-2-methylbiphenyl-4-c-
arboxylic acid
[0570] Starting material 648 (0.02 g, 0.03 mmol) and lithium
hydroxide monohydrate (4.0 mg, 0.15 mmol) were dissolved in
dioxane/water (v/v=3:1, 4 mL), and then stirred overnight at
45.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and then washed with water and brine. The organic layer was dried
with anhydrous magnesium sulfate, filtered, and then concentrated
under reduced pressure to remove the solvent. The residue was
purified by preparative TLC (SiO.sub.2, hexane/EtOAc=1:2) to obtain
compound 650 (5.5 mg, 30.6%) as colorless oil.
[0571] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.00 (s, 1H),
7.94 (d, 1H, J=8.0 Hz), 7.86 (s, 1H), 7.73 (s, 2H), 7.23 (s, 1H),
6.92-6.83 (m, 3H), 5.61 (d, 1H, J=8.0 Hz), 4.07 (d, 1H, J=14.8 Hz),
3.92 (m, 1H), 3.75 (d, 1H, J=14.7 Hz), 2.43-2.28 (m, 5H), 1.90 (s,
2H), 1.51 (t, 2H, J=6.4 Hz), 1.04, 1.00 (2s, 6H), 0.43 (d, 3H,
J=6.6 Hz)
[0572] MS (ESI) m/z 664.2 (M.sup.++H).
Preparation of Novel Compounds According to Reaction Formula 14
EXAMPLE 128
Compound 642
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4'-methoxybiph-
enyl-4-carboxylate
[0573] Starting material 59 (0.26 g, 0.39 mmol), boronic acid 60
(0.09 g, 0.43 mmol), Pd(dbpf)Cl.sub.2 (13 mg, 0.02 mmol) and sodium
carbonate (0.12 g, 1.17 mmol) were dissolved in
dimethoxyethane/water (v/v=3:1, 4 mL), and then stirred with
microwave irradiation at 120.degree. C. for 30 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=20%) to obtain compound 642 (0.12 g, 41.6%) as a white
solid.
[0574] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.40 atropisomeric
mixture; .delta. 8.14 (d, 0.6H, J=1.6 Hz), 8.10 (d, 0.4H, J=1.6
Hz), 7.96 (dd, 0.6H, J=8.0, 1.7 Hz), 7.92 (dd, 0.4H, J=8.0, 1.7
Hz), 7.86-7.85 (m, 1H), 7.74-7.71 (m, 2H), 7.41-7.30 (m, 2H),
7.13-7.11 (m, 1H), 6.96 (d, 0.4H, J=8.5 Hz), 6.92 (d, 0.6H, J=8.5
Hz), 5.59 (d, 1H, J=8.1 Hz), 4.00-3.89 (m, 5H), 3.84-3.81 (m, 3H),
3.70 (d, 0.6H, J=14.7 Hz), 3.53 (d, 0.4H, J=14.7 Hz), 2.58-2.05 (m,
2H), 1.95-1.93 (m, 2H), 1.55-1.45 (m, 2H), 1.07-1.02 (m, 6H), 1.42
(d, 1.2H, J=6.5 Hz), 0.36 (d, 1.8H, J=6.5 Hz)
[0575] MS (ESI) m/z 710.1 (M.sup.++H).
EXAMPLE 129
Compound 643
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4'-methoxybiphenyl-4--
carboxylic acid
[0576] Starting material 642 (0.02 g, 0.03 mmol) and lithium
hydroxide monohydrate (6.0 mg, 0.14 mmol) were dissolved in
dioxane/water (v/v=4:1, 0.5 mL), and then stirred overnight at
45.degree. C. After completion of the reaction, the reaction
mixture was cooled to room temperature, concentrated under reduced
pressure to remove the solvent, and then diluted with ethyl
acetate, and 1M hydrochloric acid solution was added dropwise
thereto until a pH of 2 was reached, followed by washing with
water. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (Sift,
CH.sub.2Cl.sub.2/CH.sub.3OH=5%) to obtain compound 643 (19 mg,
95.9%) as a white solid.
[0577] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.4 atropisomeric
mixture; .delta. 8.19 (d, 0.6H, J=1.6 Hz), 8.16 (d, 0.4H, J=1.6
Hz), 8.01 (dd, 0.6H, J=8.0, 1.7 Hz), 7.98 (dd, 0.4H, J=8.0, 1.7
Hz), 7.85-7.84 (m, 1H), 7.73-7.71 (m, 2H), 7.43 (d, 0.6H, J=8.0
Hz), 7.37 (d, 0.4H, J=8.0 Hz), 7.34-7.31 (m, 1H), 7.13-7.11 (m,
1H), 6.96 (d, 0.4H, J=8.6 Hz), 6.92 (d, 0.6H, J=8.6 Hz), 5.59 (d,
1H, J=8.1 Hz), 4.04-3.89 (m, 2H), 3.83-3.81 (m, 3H), 3.67-3.50 (m,
1H), 2.52-2.03 (m, 2H), 1.99-1.92 (m, 2H), 1.54-1.45 (m, 2H),
1.06-1.01 (m, 6H), 0.42 (d, 1.2H, J=6.5 Hz), 0.36 (d, 1.8H, J=6.5
Hz)
[0578] MS (ESI) m/z 696.1 (M.sup.++H).
EXAMPLE 130
Compound 728
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-chloro-2-(trifluorom-
ethyl)biphenyl-4-carboxylate
[0579]
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(2-chloro-5-iodoph-
enyl)-5,5-dimeth ylcyclohex-1-enyl)methyl)-4-oxooxazolidin-2-one
(0.030 g, 0.045 mmol),
methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl-
)benzoate (0.015 g, 0.045 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (0.002
g, 0.002 mmol) and sodium carbonate (0.014 g, 0.134 mmol) were
added to dimethylformamide (0.8 mL)/water (0.4 mL) and heated by
microwave irradiation at 90.degree. C. for 20 minutes. Then, the
reaction mixture was cooled to room temperature, and water was
added thereto, followed by extraction with ethyl acetate. The
organic layer was dried with anhydrous magnesium sulfate to remove,
and then concentrated under reduced pressure. The residue was
purified by MPLC (SiO.sub.2, EtOAc/hexane=0%-20%) to obtain
observed compound 728 (0.025 g, 76.5%) in an impure form.
[0580] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.51 (m, 1H),
8.33 (m, 1H), 7.88 (s, 1H), 7.78-7.75 (m, 2H), 7.50-7.41 (m, 2H),
7.22-7.19 (m, 1H), 7.12-7.09 (m, 1H), 5.68 (m, 1H), 4.17-3.93 (m,
5H), 3.60-3.46 (m, 1H), 2.60-2.35 (m, 2H), 1.98 (m, 2H), 1.60-1.45
(m, 2H), 1.12-1.02 (m, 6H), 0.50 (m, 3H)
[0581] MS (ESI) m/z 748.1 (M.sup.++H).
EXAMPLE 131
Compound 729
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-chloro-2-(trifluoromethyl)b-
iphenyl-4-carboxylic acid
[0582] Starting material 728 (0.018 g, 0.024 mmol) and lithium
hydroxide monohydrate (0.010 g, 0.241 mmol) were dissolved in
dioxane (4 mL)/water (1 mL) at room temperature, and the reaction
mixture was stirred at the same temperature for 16 hours. Then, 1M
hydrochloric acid was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The concentrate was
purified and concentrated by PTLC to obtain desired compound 729
(0.010 g, 56.6%) as a white foam solid.
[0583] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.44 (m, 1H),
8.23 (m, 1H), 7.88 (m, 1H), 7.78-7.74 (m, 2H), 7.40 (m, 2H),
7.20-7.18 (m, 1H), 7.10-7.07 (m, 1H), 5.67 (2d, 1H, J=7.8 Hz),
4.15-3.93 (m, 2H), 3.54 (2d, 1H, J=14.9 Hz), 2.60-2.35 (m, 2H),
1.58 (m, 2H), 1.58-1.49 (m, 2H), 1.10-1.03 (m, 6H), 0.50 (m,
3H)
[0584] MS (ESI) m/z 734.1 (M.sup.++H).
EXAMPLE 132
Compound 738
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4'-fluorobiphe-
nyl-4-carboxylate
[0585]
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2'-fluoro-5'-iodo-4,-
4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-4-methyloxazoli-
din-2-one (0.067 g, 0.102 mmol),
(2-chloro-4-(methoxycarbonyl)phenyl)boronic acid (0.024 g, 0.112
mmol), Pd(dbpf)Cl.sub.2 (0.007 g, 0.010 mmol) and potassium acetate
(0.001 g, 0.307 mmol) were added to dimethylformamide/water
(v/v=2/1, 0.6 mL) and stirred with microwave irradiation at
120.degree. C. for 20 minutes. After completion of the reaction,
the reaction mixture was cooled to room temperature, diluted with
ethyl acetate, and then washed with water and brine. The organic
layer was dried with anhydrous magnesium sulfate, filtered, and
then concentrated under reduced pressure to remove the solvent. The
residue was purified by preparative TLC (SiO.sub.2,
EtOAc/hexane=20%) to obtain compound 738 (0.024 g, 34%) as
colorless oil.
[0586] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.15 (dd, 1H,
J=11.9, 1.2 Hz), 8.00-7.95 (m, 1H), 7.88 (s, 1H), 7.76 (d, 2H,
J=15.5 Hz), 7.43-7.31 (m, 2H), 7.23-7.11 (m, 2H), 5.67-5.60 (m,
1H), 4.07-3.92 (m, 5H), 3.71-3.61 (m, 1H), 2.55-2.19 (m, 2H),
2.04-1.96 (m, 2H), 1.59-1.50 (m, 2H), 1.09-1.04 (m, 6H), 0.47-0.43
(m, 3H)
[0587] MS (ESI) m/z 698.1 (M.sup.++H).
EXAMPLE 133
Compound 739
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4'-fluorobiphenyl-4-c-
arboxylic acid
[0588] Starting material 738 (0.024 g, 0.035 mmol) and lithium
hydroxide monohydrate (0.007 g, 0.174 mmol) were dissolved in
dioxane/water (v/v=4:1, 1.0 mL), and then stirred at room
temperature for 4 hours. After completion of the reaction, the
reaction mixture was cooled to room temperature and concentrated
under reduced pressure to remove the solvent, after which it was
diluted with ethyl acetate, and 1M hydrochloric acid solution was
added dropwise thereto until a pH of 2 was reached, followed by
washing with water. The organic layer was dried with anhydrous
magnesium sulfate, filtered, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by
preparative TLC (SiO.sub.2, CH.sub.3OH/CH.sub.2Cl.sub.2=5%) to
obtain compound 739 (0.016 g, 67%) as a white foam solid.
[0589] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.24-8.21 (m,
1H), 8.07-8.03 (m, 1H), 7.89 (s, 1H), 7.76 (d, 2H, J=15.5 Hz), 7.44
(dd, 1H, J=18.5, 8.0 Hz), 7.37-7.33 (m, 1H), 7.24-7.13 (m, 2H),
5.68-5.61 (m, 1H), 4.12-3.93 (m, 2H), 3.72-3.62 (m, 1H), 2.51-2.21
(m, 2H), 2.04-1.96 (m, 2H), 1.58-1.52 (m, 2H), 1.09-1.04 (m, 6H),
0.49-0.44 (m, 3H)
[0590] MS (ESI) m/z 684.1 (M.sup.++H).
Preparation of Novel Compounds According to Reaction Scheme 15
Intermediate compound 62a:
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((3'-chloro-4'-fluoro-4,4-di-
methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-4-methyloxazolidin--
2-one
[0591] Starting material 16 (0.500 g, 0.972 mmol),
(3-chloro-4-fluorophenyl)boronic acid (0.186 g, 1.069 mmol),
Pd(dbpf)Cl.sub.2 (0.032 g, 0.049 mmol) and sodium carbonate (0.227
g, 2.139 mmol) were added to dimethoxyethane/water (v/v=3/1, 1.0
mL) and stirred with microwave irradiation at 120.degree. C. for 30
minutes. After completion of the reaction, the reaction mixture was
cooled to room temperature, diluted with ethyl acetate, and then
washed with water and brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=0%.about.20%) to obtain compound 62a
(0.455 g, 83%) as a pale yellow foam solid.
Intermediate compound 62b:
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(3-chloro-5-methoxypheny-
l)-5,5-dimethylcyclohex-1-enyl)methyl)-4-methoxyoxazolidin-2-one
[0592] Starting material 16 (0.500 g, 2.682 mmol),
3-chloro-5-methoxyphenyl boronic acid (1.380 g, 2.682 mmol),
Pd(di-t-Bupf)Cl.sub.2 (0.087 g, 0.134 mmol) and sodium carbonate
(0.569 g, 5.365 mmol) were added to dimethoxyethane (6 mL)/water (2
mL) and heated by microwave irradiation at 120.degree. C. for 15
minutes. Then, the reaction mixture was cooled to room temperature,
and water was added thereto, followed by extraction with ethyl
acetate. The organic layer was washed with brine and dried with
anhydrous magnesium sulfate, followed by concentration under
reduced pressure. The residue was purified and concentrated by MPLC
(Sift, EtOAc/hexane=0%-15%) to obtain desired compound 62b (0.900
g, 58.3%) as a brown foam solid.
Intermediate compound 62c:
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(5-chloro-2-fluorophenyl-
)-5,5-dimeth ylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
[0593] Starting material 16 (0.300 g, 0.583 mmol),
5-chloro-2-fluorophenylboronic acid (0.153 g, 0.875 mmol),
Pd(dbpf)Cl.sub.2 (0.019 g, 0.029 mmol) and Na.sub.2CO.sub.3 (0.185
g, 1.750 mmol) were added to dimethoxyethane (0.9 mL)/water (0.3
mL) and stirred with microwave irradiation at 120.degree. C. for 20
minutes. Then, the reaction mixture was cooled to room temperature,
and water was added thereto, followed by extraction with ethyl
acetate. The organic layer was dried with anhydrous magnesium
sulfate, followed by concentration under reduced pressure. The
residue was purified and concentrated by MPLC (SiO.sub.2,
cartridge; EtOAc/hexane=0%-10%) to obtain compound 62c (0.250 g,
76.0%) as brown oil.
Intermediate compound 62d: methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methyl-5'-(trifluoromethyl)-
biphenyl-4-carboxylate
[0594] Starting material 16 (0.500 g, 0.972 mmol),
3-chloro-5-(trifluoromethyl)phenylboronic acid (0.327 g, 1.458
mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (0.034 g, 0.049 mmol) and sodium
carbonate (0.309 g, 2.917 mmol) were added to dimethylformamide (2
mL)/water (1 mL) and heated by microwave irradiation at 100.degree.
C. for 20 minutes. Then, the reaction mixture was cooled to room
temperature, and water was added thereto, followed by extraction
with ethyl acetate. The organic layer was dried with anhydrous
magnesium sulfate, followed by concentration under reduced
pressure. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=0%.about.20%) to obtain desired compound 62d (0.380 g,
63.7%) as colorless oil.
EXAMPLE 134
Compound 670
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluorobiphenyl-4-car-
boxylate
[0595] Compound 62a (0.100 g, 0.177 mmol),
(4-(methoxycarbonyl)phenyl)boronic acid (0.048 g, 0.266 mmol),
Pd(dbpf)Cl.sub.2 (0.006 g, 0.009 mmol) and sodium carbonate (0.056
g, 0.532 mmol) were added to dimethoxyethane/water (v/v=3/1, 1.0
mL) and stirred with microwave irradiation at 120.degree. C. for 30
minutes. After completion of the reaction, the reaction mixture was
cooled to room temperature, diluted with ethyl acetate, and then
washed with water and brine. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
MPLC(SiO.sub.2, EtOAc/hexane=0%.about.10%) to obtain compound 670
(0.087 g, 74%) as pale yellow oil.
[0596] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.09 (d, 2H,
J=6.7 Hz), 7.86 (s, 1H), 7.72 (s, 2H), 7.57 (dd, 2H, J=8.4, 1.4
Hz), 7.18-7.06 (m, 3H), 5.60 (d, 1H, J=8.0 Hz), 4.07 (d, 1H, J=15.5
Hz), 3.95-3.90 (m, 4H), 3.72 (d, 1H, J=15.0 Hz), 2.43-2.25 (m, 2H),
1.94 (s, 2H), 1.51 (t, 2H, J=6.4 Hz), 1.03 (d, 6H, J=15.7 Hz), 0.41
(d, 3H, J=6.6 Hz)
[0597] MS (ESI) m/z 664.1 (M.sup.++H).
EXAMPLE 135
Compound 679
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluorobiphenyl-4-carboxylic
acid
[0598] Starting material 670 (0.078 g, 0.117 mmol) and lithium
hydroxide monohydrate (0.025 g, 0.587 mmol) were dissolved in
dioxane/water (v/v=4:1, 1.0 mL), and then stirred at 50.degree. C.
for 4 hours. After completion of the reaction, the reaction mixture
was cooled to room temperature, concentrated under reduced pressure
to remove the solvent, and then diluted with ethyl acetate, and 1M
hydrochloric acid solution was added dropwise thereto until a pH of
2 was reached, followed by washing with water. The organic layer
was dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by preparative TLC (Sift,
CH.sub.3OH/CH.sub.2Cl.sub.2=5%) to obtain compound 679 (0.024 g,
31%) as white oil.
[0599] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.02-8.00 (m,
3H), 7.93 (s, 2H), 7.52 (d, 2H, J=7.5 Hz), 7.29 (d, 1H, J=6.9 Hz),
7.18 (d, 2H, J=8.2 Hz), 5.82 (d, 1H, J=8.3 Hz), 4.18-4.14 (m, 1H),
3.99 (d, 1H, J=14.6 Hz), 3.77 (d, 1H, J=14.7 Hz), 2.47-2.31 (m,
2H), 2.04-1.92 (m, 2H), 1.58-1.52 (m, 2H), 1.05 (d, 6H, J=22.6 Hz),
0.44 (d, 3H, J=6.5 Hz)
[0600] MS (ESI) m/z 650.1 (M.sup.++H).
EXAMPLE 136
Compound 671
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,2'-difluorobiphenyl-4-
-carboxylate
[0601] Compound 62a (0.100 g, 0.177 mmol), methyl
3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
(0.075 g, 0.266 mmol), Pd(dbpf)Cl.sub.2 (0.006 g, 0.009 mmol) and
sodium carbonate (0.056 g, 0.532 mmol) were added to
dimethoxyethane/water (v/v=3/1, 1.0 mL) and stirred with microwave
irradiation at 120.degree. C. for 30 minutes. After completion of
the reaction, the reaction mixture was cooled to room temperature,
diluted with ethyl acetate, and then washed with water and brine.
The organic layer was dried with anhydrous magnesium sulfate,
filtered, and then concentrated under reduced pressure to remove
the solvent. The residue was purified by MPLC (Sift,
EtOAc/hexane=0%-10%) to obtain compound 671 (0.039 g, 33%) as
colorless oil.
[0602] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.90-7.77 (m,
3H), 7.73 (s, 2H), 7.47-7.45 (m, 1H), 7.16-7.13 (m, 3H), 5.59 (d,
1H, J=8.1 Hz), 4.08 (d, 1H, J=11.1 Hz), 3.95 (s, 3H), 3.90-3.88 (m,
1H), 3.73 (d, 1H, J=14.8 Hz), 2.42-2.24 (m, 2H), 1.96 (s, 2H), 1.50
(t, 2H, J=6.5 Hz), 1.02 (d, 6H, J=13.9 Hz), 0.38 (d, 3H, J=5.4
Hz)
[0603] MS (ESI) m/z 682.1 (M.sup.++H).
EXAMPLE 137
Compound 680
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,2'-difluorobiphenyl-4-carbox-
ylic acid
[0604] Compound 671 (0.029 g, 0.042 mmol) and lithium hydroxide
monohydrate (0.009 g, 0.211 mmol) were dissolved in dioxane/water
(v/v=4:1, 1.0 mL), and then stirred at 50.degree. C. for 4 hours.
After completion of the reaction, the reaction mixture was cooled
to room temperature, concentrated under reduced pressure to remove
the solvent, and then diluted with ethyl acetate, and 1M
hydrochloric acid solution was added dropwise thereto until a pH of
2 was reached, followed by washing with water. The organic layer
was dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by preparative TLC (Sift,
CH.sub.3OH/CH.sub.2Cl.sub.2=5%) to obtain compound 680 (0.011 g,
38%) as colorless oil.
[0605] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.97-7.87 (m,
3H), 7.74 (s, 2H), 7.50 (t, 1H, J=7.3 Hz), 7.16 (d, 3H, J=7.5 Hz),
5.59 (d, 1H, J=8.1 Hz), 4.06 (d, 1H, J=14.9 Hz), 3.93-3.89 (m, 1H),
3.74 (d, 1H, J=14.7 Hz), 2.43-2.26 (m, 2H), 1.96 (s, 2H), 1.51 (t,
2H, J=6.4 Hz), 1.02 (d, 6H, J=13.7 Hz), 0.40 (d, 3H, J=6.6 Hz)
[0606] MS (ESI) m/z 668.1 (M.sup.++H).
EXAMPLE 138
Compound 672
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-2-methylbiphe-
nyl-4-carboxylate
[0607] Compound 62a (0.100 g, 0.177 mmol), methyl
3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
(0.073 g, 0.266 mmol), Pd(dbpf)Cl.sub.2 (0.006 g, 0.009 mmol) and
sodium carbonate (0.056 g, 0.532 mmol) were added to
dimethoxyethane/water (v/v=3/1, 1.0 mL) and stirred with microwave
irradiation at 120.degree. C. for 30 minutes. After completion of
the reaction, the reaction mixture was cooled to room temperature,
diluted with ethyl acetate, and then washed with water and brine.
The organic layer was dried with anhydrous magnesium sulfate,
filtered, and then concentrated under reduced pressure to remove
the solvent. The residue was purified by MPLC (Sift,
EtOAc/hexane=0%.about.10%) to obtain compound as 672 (0.073 g, 61%)
as colorless oil.
[0608] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.95-7.87 (m,
3H), 7.73 (s, 2H), 7.23 (d, 1H, J=7.9 Hz), 7.11 (d, 2H, J=8.2 Hz),
6.98 (d, 1H, J=7.2 Hz), 5.62 (d, 1H, J=8.2 Hz), 4.06 (d, 1H, J=14.8
Hz), 3.93 (s, 3H), 3.92-3.88 (m, 1H), 3.74 (d, 1H, J=14.7 Hz),
2.43-2.28 (m, 2H), 2.20 (s, 3H), 1.94 (s, 2H), 1.50 (t, 2H, J=6.5
Hz), 1.02 (d, 6H, J=14.6 Hz), 0.41 (d, 3H, J=6.6 Hz)
[0609] MS (ESI) m/z 678.1 (M.sup.++H).
EXAMPLE 139
Compound 681
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-2-methylbiphenyl-4-c-
arboxylic acid
[0610] Compound 672 (0.100 g, 0.148 mmol) and lithium hydroxide
monohydrate (0.031 g, 0.738 mmol) were dissolved in dioxane/water
(v/v=4:1, 1.0 mL), and then stirred at 50.degree. C. for 4 hours.
After completion of the reaction, the reaction mixture was cooled
to room temperature, concentrated under reduced pressure to remove
the solvent, and then diluted with ethyl acetate, and 1M
hydrochloric acid solution was added dropwise thereto until a pH of
2 was reached, followed by washing with water. The organic layer
was dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by preparative TLC (Sift,
CH.sub.3OH/CH.sub.2Cl.sub.2=5%) to obtain compound 681 (0.024 g,
25%) as colorless oil.
[0611] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.03-7.96 (m,
2H), 7.87 (s, 1H), 7.73 (s, 2H), 7.27 (d, 1H, J=1.3 Hz), 7.12 (dd,
2H, J=7.3, 1.0 Hz), 6.99 (d, 1H, J=7.2 Hz), 5.62 (d, 1H, J=8.1 Hz),
4.07 (d, 1H, J=15.2 Hz), 3.95-3.90 (m, 1H), 3.75 (d, 1H, J=14.7
Hz), 2.42-2.28 (m, 2H), 2.23 (s, 3H), 1.95 (s, 2H), 1.51 (t, 2H,
J=6.5 Hz), 1.02 (d, 6H, J=14.7 Hz), 0.42 (d, 3H, J=6.5 Hz)
[0612] MS (ESI) m/z 664.2 (M.sup.++H).
EXAMPLE 140
Compound 686
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-methoxybiphenyl-4-ca-
rboxylate
[0613] Starting material 62b (0.100 g, 0.174 mmol),
4-(methoxycarbonyl)phenylboronic acid (0.034 g, 0.191 mmol),
Pd(di-t-Bupf)Cl.sub.2 (0.006 g, 0.009 mmol) and sodium carbonate
(0.037 g, 0.347 mmol) were added to dimethoxyethane (1 mL)/water
(0.3 mL) and heated by microwave irradiation at 120.degree. C. for
15 minutes. Then, the reaction mixture was cooled to room
temperature, and water was added thereto, followed by extraction
with ethyl acetate. The organic layer was washed with brine, dried
with anhydrous magnesium sulfate, and then concentrated under
reduced pressure. The residue was purified and concentrated by MPLC
(Sift, EtOAc/hexane=0%-20%) to obtain compound 686 (0.100 g, 85.2%)
as colorless oil.
[0614] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.10 (d, 2H,
J=1.5 Hz), 7.85 (s, 1H), 7.72 (s, 2H), 7.61 (d, 2H, J=7.7 Hz), 7.02
(s, 1H), 6.92 (s, 1H), 6.67 (s, 1H), 5.60 (d, 1H, J=6.1 Hz),
3.90-4.06 (m, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 3.77 (d, 1H, J=11.1
Hz), 2.05-2.45 (m, 2H), 1.95-2.00 (m, 2H), 1.52 (t, 2H, J=4.8 Hz),
1.01-1.06 (m, 6H), 0.43 (d, 3H, J=4.9 Hz)
[0615] MS (ESI) m/z 676.2 (M.sup.++H).
EXAMPLE 141
Compound 687
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-methoxybiphenyl-4-carboxyli-
c acid
[0616] Starting material 686 (0.100 g, 0.148 mmol) and anhydrous
lithium hydroxide (0.018 g, 0.740 mmol) were dissolved in dioxane
(1 mL)/water (0.25 mL) at 50.degree. C., and the reaction mixture
was stirred at the same temperature for 8 hours. Then, an aqueous
solution of 1M hydrochloric acid was added to the reaction mixture,
followed by extraction with ethyl acetate. The organic layer was
washed with brine, dried with anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The residue was purified and
concentrated by MPLC (Sift, EtOAc/hexane=0%.about.35%) to obtain
desired compound 687 (0.045 g, 46.0%) as colorless oil.
[0617] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.98-8.00 (m,
3H), 7.92 (s, 2H), 7.58 (d, 2H, J=6.2 Hz), 7.09 (s, 1H), 7.00 (s,
1H), 6.71 (s, 1H), 5.80 (d, 1H, J=6.2 Hz), 4.15-4.20 (m, 1H), 3.99
(d, 1H, J=11.1 Hz), 3.79-3.84 (m, 4H), 2.33-2.49 (m, 2H), 1.98 (dd,
2H, J=28.5, 12.5 Hz), 1.50-1.60 (m, 2H), 1.00 (d, 6H, J=11.2 Hz),
0.44 (d, 3H, J=4.9 Hz)
[0618] MS (ESI) m/z 662.2 (M.sup.++H).
EXAMPLE 142
Compound 688
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-methoxy-2-methylbiph-
enyl-4-carboxylate
[0619] Starting material 62b (0.100 g, 0.174 mmol), methyl
3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
(0.072 g, 0.260 mmol), Pd(di-t-Bupf)Cl.sub.2 (0.006 g, 0.009 mmol)
and sodium carbonate (0.037 g, 0.347 mmol) were added to
dimethoxyethane (1 mL)/water (0.3 mL) and heated by microwave
irradiation at 120.degree. C. for 15 minutes. Then, the reaction
mixture was cooled to room temperature, and water was added
thereto, followed by extraction with ethyl acetate. The organic
layer was washed with brine, dried with anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The residue
was purified by MPLC (Sift, ethyl acetate/hexane=0%.about.20%) to
obtain desired compound 688 (0.070 g, 58.5%) as colorless oil.
[0620] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.93 (s, 1H),
7.86-7.88 (m, 2H), 7.74 (s, 2H), 7.23 (d, 1H, J=6.0 Hz), 6.72 (s,
1H), 6.62-6.64 (m, 2H), 5.61 (d, 1H, J=6.1 Hz), 4.05-4.10 (m, 1H),
3.78-3.93 (m, 8H), 2.20-2.50 (m, 5H), 1.94 (s, 2H), 1.51 (t, 2H,
J=4.9 Hz), 1.02 (d, 6H, J=10.6 Hz), 0.43 (d, 3H, J=4.9 Hz)
[0621] MS (ESI) m/z 690.2 (M.sup.++H).
EXAMPLE 143
Compound 689
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-methoxy-2-methylbiphenyl-4--
carboxylic acid
[0622] Compound 688 (0.072 g, 0.104 mmol) and anhydrous lithium
hydroxide (0.013 g, 0.522 mmol) were dissolved in dioxane (1
mL)/water (0.25 mL) at 50.degree. C., and the reaction mixture was
stirred at the same temperature for 8 hours. Then, an aqueous
solution of 1M hydrochloric acid was added to the reaction mixture,
followed by extraction with ethyl acetate. The organic layer was
washed with brine, dried with anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The residue was purified and
concentrated by MPLC (Sift, EtOAc/hexane=0%.about.35%) to obtain
compound 689 (0.035 g, 49.6%) as colorless oil.
[0623] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.01 (s, 1H),
7.95 (d, 1H, J=6.0 Hz), 7.87 (s, 1H), 7.73 (s, 2H), 7.26-7.28 (m,
1H), 6.73 (s, 1H), 6.65 (d, 2H, J=5.1 Hz), 5.61 (d, 1H, J=8.1 Hz),
4.08 (d, 1H, J=10.7 Hz), 3.90-3.96 (m, 1H), 3.82 (s, 3H), 3.50-3.77
(m, 1H), 2.20-2.50 (m, 5H), 1.95 (s, 2H), 1.52 (t, 2H, J=4.7 Hz),
1.03 (d, 6H, J=13.8 Hz), 0.38 (d, 3H, J=6.4 Hz)
[0624] MS (ESI) m/z 676.2 (M.sup.++H).
EXAMPLE 144
Compound 690
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-5'-methoxybiph-
enyl-4-carboxylate
[0625] Starting material 62b (0.100 g, 0.174 mmol), methyl
3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
(0.073 g, 0.260 mmol), Pd(di-t-Bupf)Cl.sub.2 (0.006 g, 0.009 mmol)
and sodium carbonate (0.037 g, 0.347 mmol) were added to
dimethoxyethane (1 mL)/water (0.3 mL) and heated by microwave
irradiation at 120.degree. C. for 15 minutes. Then, the reaction
mixture was cooled to room temperature, and water was added
thereto, followed by extraction with ethyl acetate. The organic
layer was washed with brine, dried with anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The residue
was purified and concentrated by MPLC (Sift,
EtOAc/hexane=0%.about.20%) to obtain desired compound 690 (0.060 g,
49.8%) as colorless oil.
[0626] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.85-7.88 (m,
2H), 7.76 (d, 1H, J=13.4 Hz), 7.73 (s, 2H), 7.40-7.47 (m, 1H), 6.95
(s, 1H), 6.89 (s, 1H), 6.66 (s, 1H), 5.55-5.60 (m, 1H), 3.95-4.10
(m, 2H), 3.96 (s, 3H), 3.83 (s, 3H), 3.75-3.79 (m, 1H), 2.20-2.50
(m, 2H), 1.96 (s, 2H), 1.40-1.60 (m, 2H), 1.03 (d, 6H, J=12.8 Hz),
0.40 (d, 3H, J=6.8 Hz)
[0627] MS (ESI) m/z 694.2 (M.sup.++H).
EXAMPLE 145
Compound 691
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-5'-methoxybiphenyl-4--
carboxylic acid
[0628] Starting material 690 (0.062 g, 0.089 mmol) and anhydrous
lithium hydroxide (0.011 g, 0.447 mmol) were dissolved in dioxane
(1 mL)/water (0.25 mL) at 50.degree. C., and the reaction mixture
was stirred at the same temperature for 8 hours. Then, an aqueous
solution of 1M hydrochloric acid was added to the reaction mixture,
followed by extraction with ethyl acetate. The organic layer was
washed with brine, dried with anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The residue was purified and
concentrated by MPLC (Sift, EtOAc/hexane=0%.about.35%) to obtain
desired compound 691 (0.010 g, 16.5%) as a brown foam solid.
[0629] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.98 (s, 1H),
7.92 (s, 2H), 7.80 (d, 1H, J=9.1 Hz), 7.70 (d, 1H, J=11.9 Hz), 7.44
(t, 1H, J=7.9 Hz), 7.00 (s, 1H), 6.93 (s, 1H), 6.74 (s, 1H), 5.80
(d, 1H, J=8.2 Hz), 4.11-4.18 (m, 1H), 3.98 (d, 1H, J=14.8 Hz),
3.78-3.83 (m, 4H), 2.16-2.47 (m, 2H), 1.90-2.04 (m, 2H), 1.50-1.60
(m, 2H), 1.08, 1.03 (2s, 6H), 0.43 (d, 3H, J=6.5 Hz)
[0630] MS (ESI) m/z 680.2 (M.sup.++H).
EXAMPLE 146
Compound 724
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,4'-difluorobiphenyl-4-
-carboxylate
[0631] Starting material 62c (0.240 g, 0.426 mmol),
(2-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (0.093 g, 0.468
mmol), Pd(dbpf)Cl.sub.2 (0.014 g, 0.021 mmol) and sodium carbonate
(0.099 g, 0.936 mmol) were added to dimethoxyethane/water (v/v=3/1,
2.0 mL) and stirred with microwave irradiation at 120.degree. C.
for 30 minutes. After completion of the reaction, the reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and then washed with water and brine. The organic layer was dried
with anhydrous magnesium sulfate, filtered, and then concentrated
under reduced pressure to remove the solvent. The residue was
purified by MPLC (Sift, EtOAc/hexane=0%.about.20%) to obtain
compound 724 (0.149 g, 51%) as a white foam solid.
[0632] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.92-7.88 (m,
2H), 7.85-7.77 (m, 3H), 7.54-7.44 (m, 2H), 7.33 (dd, 1H, J=16.2,
7.0 Hz), 7.22-7.13 (m, 1H), 5.65-5.62 (m, 1H), 4.12-4.01 (m, 2H),
3.97 (s, 3H), 3.68-3.57 (m, 1H), 2.53-2.20 (m, 2H), 2.01 (s, 2H),
1.60-1.54 (m, 2H), 1.09-1.05 (m, 6H), 0.47-0.40 (m, 3H)
[0633] MS (ESI) m/z 682 (M.sup.++H).
EXAMPLE 147
Compound 722
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,4'-difluorobiphenyl-4-carbox-
ylic acid
[0634] Starting material 724 (0.126 g, 0.185 mmol) and lithium
hydroxide monohydrate (0.039 g, 0.926 mmol) were dissolved in
dioxane/water (v/v=4:1, 2.0 mL), and then stirred at 50.degree. C.
for 2 hours. After completion of the reaction, the reaction mixture
was cooled to room temperature, concentrated under reduced pressure
to remove the solvent, and then diluted with ethyl acetate, and 1M
HCl solution was added dropwise thereto until a pH of 2 was
reached, followed by washing with water. The organic layer was
dried with anhydrous magnesium sulfate, filtered, and then
concentrated under reduced pressure to remove the solvent. The
residue was purified by MPLC (Sift, EtOAc/hexane=0%.about.30%) to
obtain compound 722 (0.093 g, 75%) as a white foam solid.
[0635] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.00-7.96 (m,
1H), 7.92-7.86 (m, 2H), 7.78 (s, 2H), 7.59-7.46 (m, 2H), 7.38-7.32
(m, 1H), 7.24-7.15 (m, 1H), 5.67-5.63 (m, 1H), 4.12-3.96 (m, 2H),
3.69-3.58 (m, 1H), 2.53-2.22 (m, 2H), 2.01 (s, 2H), 1.60-1.52 (m,
2H), 1.10-1.05 (m, 6H), 0.49-0.42 (m, 3H)
[0636] MS (ESI) m/z 668.2 (M.sup.++H).
EXAMPLE 148
Compound 725
methyl
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-2-(trifluorom-
ethyl)biphenyl-4-carboxylate
[0637] Compound 62a (0.140 g, 0.248 mmol), methyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzoa-
te (0.090 g, 0.273 mmol), Pd(dbpf)Cl.sub.2 (0.008 g, 0.012 mmol)
and sodium carbonate (0.058 g, 0.546 mmol) were added to
dimethylformamide/water (v/v=2/1, 1.0 mL) and stirred with
microwave irradiation at 120.degree. C. for 5 minutes. After
completion of the reaction, the reaction mixture was cooled to room
temperature, diluted with ethyl acetate, and then washed with water
and brine. The organic layer was dried with anhydrous magnesium
sulfate, filtered, and then concentrated under reduced pressure to
remove the solvent. The residue was purified by MPLC (Sift,
EtOAc/hexane=0%.about.10%) to obtain compound 725 (0.086 g, 47%) as
yellow oil.
[0638] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.47 (d, 1H,
J=7.1 Hz), 8.27 (t, 1H, J=8.6 Hz), 7.89 (d, 1H, J=4.7 Hz), 7.74 (d,
2H, J=9.4 Hz), 7.53 (t, 1H, J=7.9 Hz), 7.16-7.12 (m, 2H), 7.09-7.03
(m, 1H), 5.64-5.59 (m, 1H), 4.09-4.00 (m, 4H), 3.96-3.85 (m, 1H),
3.81-3.70 (m, 1H), 2.44-2.31 (m, 2H), 1.97 (s, 2H), 1.52-1.50 (m,
2H), 1.06-1.00 (m, 6H), 0.45-0.37 (m, 3H)
[0639] MS (ESI) m/z 732.1 (M.sup.++H).
EXAMPLE 149
Compound 723
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-2-(trifluoromethyl)b-
iphenyl-4-carboxylic acid
[0640] Compound 725 (0.086 g, 0.118 mmol) and lithium hydroxide
monohydrate (0.025 g, 0.588 mmol) were dissolved in dioxane/water
(v/v=4:1, 1.0 mL), and then stirred at 50.degree. C. for 4 hours.
After completion of the reaction, the reaction mixture was cooled
to room temperature, concentrated under reduced pressure to remove
the solvent, and then diluted with ethyl acetate, and 1M HCl
solution was added dropwise thereto until a pH of 2 was reached,
followed by washing with water. The organic layer was dried with
anhydrous magnesium sulfate, filtered, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
preparative TLC (SiO.sub.2, CH.sub.3OH/CH.sub.2Cl.sub.2=5%) to
obtain compound 723 (0.027 g, 32%) as a white foam solid.
[0641] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.55 (d, 1H,
J=7.2 Hz), 8.35 (t, 1H, J=8.5 Hz), 7.89 (d, 1H, J=4.4 Hz), 7.75 (d,
2H, J=10.0 Hz), 7.58 (t, 1H, J=7.8 Hz), 7.26-7.12 (m, 2H),
7.10-7.04 (m, 1H), 5.66-5.62 (m, 1H), 4.11-4.07 (m, 1H), 3.98-3.87
(m, 1H), 3.82-3.71 (m, 1H), 2.44-2.28 (m, 2H), 1.98 (s, 2H),
1.53-1.52 (m, 2H), 1.06-1.01 (m, 6H), 0.46-0.41 (m, 3H)
[0642] MS (ESI) m/z 718.1 (M.sup.++H).
EXAMPLE 150
Compound 743
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methyl-5'-(trifluorom-
ethyl)biphenyl-4-carboxylate
[0643] Compound 63d (0.100 g, 0.163 mmol), methyl
6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
(0.090 g, 0.326 mmol), sodium carbonate (0.052 g, 0.489 mmol) and
Pd(dbpf)Cl.sub.2 (0.005 g, 0.008 mmol) were added to
dimethylformamide (0.8 mL)/water (0.4 mL) and heated by microwave
irradiation at 100.degree. C. for 20 minutes. Then, the reaction
mixture was cooled to room temperature, and water was added
thereto, followed by extraction with ethyl acetate. The organic
layer was dried with anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=0%.about.20%) to obtain desired
compound 743 (0.075 g, 63.3%) as a white foam solid.
[0644] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.98 (s, 1H),
7.93 (dd, 1H, J=7.7, 1.5 Hz), 7.89 (s, 1H), 7.74 (s, 2H), 7.50 (s,
1H), 7.38 (s, 1H), 7.27-7.25 (m, 2H), 5.63 (d, 1H, J=8.1 Hz),
4.11-3.92 (m, 5H), 3.67 (d, 1H, J=14.9 Hz), 2.53-2.29 (m, 5H), 1.99
(m, 2H), 1.29 (m, 2H), 1.05 (m, 6H), 0.42 (d, 3H, J=6.6 Hz)
[0645] MS (ESI) m/z 728.2 (M.sup.++H).
EXAMPLE 151
Compound 744
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methyl-5'-(trifluoromethyl)b-
iphenyl-4-carboxylic acid
[0646] Starting material 743 (0.070 g, 0.096 mmol) and lithium
hydroxide monohydrate (0.040 g, 0.962 mmol) were dissolved in
1,4-dioxane (8 mL)/water (2 mL) at room temperature, and the
reaction mixture was stirred at the same temperature for 16 hours.
Water was added to the reaction mixture, followed by extraction
with ethyl acetate. The organic layer was dried with anhydrous
magnesium sulfate to remove water, after which it was filtered and
concentrated under reduced pressure. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=10%.about.50%) to obtain desired
compound 744 (0.046 g, 67.0%) as colorless oil.
[0647] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.06 (s, 1H),
8.01 (dd, 1H, J=7.9, 1.5 Hz), 7.89 (s, 1H), 7.75 (s, 2H), 7.51 (s,
1H), 7.40 (s, 1H), 7.32-7.29 (m, 2H), 5.64 (d, 1H, J=7.9 Hz), 4.11
(d, 1H, J=14.9 Hz), 3.96 (t, 1H, J=7.2 Hz), 3.68 (d, 1H, J=14.9
Hz), 2.50-2.31 (m, 5H), 1.99 (s, 2H), 1.56 (t, 2H, J=6.4 Hz), 1.06
(d, 6H, J=15.5 Hz), 0.44 (d, 3H, J=6.5 Hz)
[0648] MS (ESI) m/z 714.1 (M.sup.++H).
EXAMPLE 152
Compound 745
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-(trifluoromethyl)bip-
henyl-4-carboxylate
[0649] Starting material 6d (0.050 g, 0.081 mmol),
methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
(0.043 g, 0.163 mmol), sodium carbonate (0.026 g, 0.244 mmol) and
Pd(dbpf)Cl.sub.2 (0.003 g, 0.004 mmol) were added to
dimethylformamide (0.8 mL)/water (0.4 mL) and stirred with
microwave irradiation at 100.degree. C. for 20 minutes. Then, the
reaction mixture was cooled to room temperature, and water was
added thereto, followed by extraction with ethyl acetate. The
organic layer was dried with anhydrous magnesium sulfate to remove
water, and then concentrated under reduced pressure. The residue
was purified by MPLC (SiO.sub.2, EtOAc/hexane=0%.about.20%) to
obtain desired compound 745 (0.050 g, 86.0%) as a white foam
solid.
[0650] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.13 (m, 2H),
7.88 (m, 1H), 7.77-7.74 (m, 3H), 7.67-7.63 (m, 2H), 7.56 (s, 1H),
7.28 (m, 1H), 5.63 (d, 1H, J=7.7 Hz), 4.13 (m, 1H), 3.97 (m, 4H),
3.66 (d, 1H, J=14.9 Hz), 2.47-2.33 (m, 2H), 2.00 (s, 2H), 1.57 (t,
2H, J=6.2 Hz), 1.07 (d, 6H, J=14.6 Hz), 0.44 (d, 3H, J=6.3 Hz)
[0651] MS (ESI) m/z 714.2 (M.sup.++H).
EXAMPLE 153
Compound 746
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-(trifluoromethyl)biphenyl-4-
-carboxylic acid
[0652] Starting material 745 (0.045 g, 0.063 mmol) and lithium
hydroxide monohydrate (0.026 g, 0.631 mmol) were dissolved in
1,4-dioxane (8 mL)/water (2 mL) at room temperature, and the
reaction mixture was stirred at the same temperature for 16 hours.
Water was added to the reaction mixture, followed by extraction
with ethyl acetate. The organic layer was dried with anhydrous
magnesium sulfate to remove water, after which it was filtered and
concentrated under reduced pressure. The residue was purified and
concentrated by MPLC (SiO.sub.2, EtOAc/hexane=10%.about.50%) to
obtain desired compound 746 (0.021 g, 47.6%) as colorless oil.
[0653] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.23 (dd, 2H,
J=6.7, 1.8 Hz), 7.88 (s, 1H), 7.79 (s, 1H), 7.74 (s, 2H), 7.71 (dd,
2H, J=6.7, 1.8 Hz), 7.57 (s, 1H), 7.41 (s, 1H), 5.62 (d, 1H, J=8.1
Hz), 4.14-3.93 (m, 2H), 3.67-3.63 (m, 1H), 2.48-2.34 (m, 2H), 2.00
(s, 2H), 1.57 (t, 2H, J=6.4 Hz), 1.08 (d, 6H, J=14.1 Hz), 0.44 (m,
3H)
[0654] MS (ESI) m/z 700.1 (M.sup.++H).
EXAMPLE 154
Compound 747
methyl
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxoox-
azolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-5'-(trifluorom-
ethyl)biphenyl-4-carboxylate
[0655] Starting material 63d (0.050 g, 0.081 mmol), methyl
6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
(0.046 g, 0.163 mmol), sodium carbonate (0.026 g, 0.244 mmol) and
Pd(dbpf)Cl.sub.2 (0.003 g, 0.004 mmol) were added to
dimethylformamide (0.8 mL)/water (0.4 mL) and heated by microwave
irradiation at 100.degree. C. for 20 minutes. Then, the reaction
mixture was cooled to room temperature, and water was added
thereto, followed by extraction with ethyl acetate. The organic
layer was dried with anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=0%.about.20%) to obtain desired
compound 747 (0.058 g, 97.3%) as a white foam solid.
[0656] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.95-7.82 (m,
3H), 7.75-7.71 (m, 3H), 7.55-7.51 (m, 2H), 7.42 (s, 1H), 5.59 (d,
1H, J=20.0 Hz), 4.09 (d, 1H, J=14.9 Hz), 3.97 (s, 4H), 3.68 (d, 1H,
J=14.9 Hz), 2.42-2.36 (m, 2H), 2.00 (s, 2H), 1.55 (t, 2H, J=6.4
Hz), 1.08-1.04 (m, 6H), 0.41 (d, 3H, J=6.4 Hz)
[0657] MS (ESI) m/z 732.1 (M.sup.++H).
EXAMPLE 155
Compound 748
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-5'-(trifluoromethyl)b-
iphenyl-4-carboxylic acid
[0658] Starting material 747 (0.044 g, 0.060 mmol) and lithium
hydroxide monohydrate (0.025 g, 0.601 mmol) were dissolved in
1,4-dioxane (8 mL)/water (2 mL) at room temperature, and the
reaction mixture was stirred at the same temperature for 16 hours.
Water was added to the reaction mixture, followed by extraction
with ethyl acetate. The organic layer was dried with anhydrous
magnesium sulfate, after which it was filtered and concentrated
under reduced pressure. The residue was purified and concentrated
by MPLC (SiO.sub.2, EtOAc/hexane=10%.about.50%) to obtain desired
compound 748 (0.030 g, 69.5%) as colorless oil.
[0659] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.02 (dd, 1H,
J=8.0, 1.5 Hz), 7.92 (dd, 1H, J=10.8, 1.4 Hz), 7.88 (s, 1H),
7.76-7.73 (m, 3H), 7.60-7.54 (m, 2H), 7.44 (s, 1H), 5.63 (d, 1H,
J=7.8 Hz), 4.12-3.93 (m, 2H), 3.70 (m, 1H), 2.47-2.33 (m, 2H), 2.01
(s, 2H), 1.56 (t, 2H, J=6.3 Hz), 1.07 (d, 6H, J=14.0 Hz), 0.41 (m,
3H)
[0660] MS (ESI) m/z 718.1 (M.sup.++H).
Preparation of Novel Compounds According to Reaction Scheme 16
EXAMPLE 156
Compound 682
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methylbiphenyl-4--
carboxamide
[0661] Starting material 554 (1.370 g, 2.028 mmol), thionyl
chloride (0.221 mL, 3.041 mmol) and dimethylformamide (0.156 mL,
2.028 mmol) were added to dichloromethane (30 ml), and the reaction
mixture was heated under reflux for 4 hours, after which it was
cooled to room temperature, and then concentrated under reduced
pressure. The reaction mixture was dissolved in tetrahydrofuran (30
ml), and 2-3 drops of ammonia water was added thereto, followed by
stirring for 5 minutes. Water was added to the reaction mixture,
followed by extraction with ethyl acetate. The organic layer was
washed with saturated brine and dried with anhydrous magnesium
sulfate, followed by concentration under reduced pressure. The
residue was purified by MPLC (SiO.sub.2,
CH.sub.3OH/CH.sub.2Cl.sub.2=0%.about.5%) to obtain compound 682
(1.180 g, 86.3%) as a white solid.
[0662] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.40 atropisomeric
mixture; .delta. 7.85 (s, 1H), 7.73-7.70 (m, 3H), 7.64-7.61 (m,
1H), 7.27-7.15 (m, 2H), 6.94-6.87 (m, 2H), 6.10 (brs, 1H), 5.62
(brs, 1H), 5.61-5.57 (m, 1H), 4.01-3.92 (m, 2H), 3.82 (s, 1.3H),
3.79 (s, 1.7H), 3.64 (d, 0.6H, J=14.5 Hz), 3.51 (d, 0.4H, J=14.8
Hz), 2.56-2.06 (m, 5H), 1.98-1.86 (m, 2H), 1.56-1.46 (m, 2H),
1.05-1.00 (m, 6H), 0.42 (d, 1.3H, J=6.6 Hz), 0.35 (d, 1.7H, J=6.5
Hz)
[0663] MS (ESI) m/z 675.2 (M.sup.++H).
EXAMPLE 157
Compound 740
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4'-methoxybiphenyl-4--
carboxamide
[0664] Starting material 643 (0.01 g, 0.014 mmol), thionyl chloride
(0.002 mL, 0.022 mmol) and dimethylformamide (0.001 g, 0.007 mmol)
were dissolved in methylene chloride (3 mL) at room temperature,
and the reaction mixture was heated under reflux for 5 hours. Then,
ammonia water was added to the reaction mixture at room
temperature, followed by stirring at the same temperature for 16
hours. Water was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was washed with
brine and dried with anhydrous magnesium sulfate, after which it
was filtered and concentrated under reduced pressure. The residue
was purified and concentrated by MPLC (SiO.sub.2,
EtOAc/hexane=0%.about.50%) to obtain desired compound 740 (0.006 g,
60.1%) as colorless oil.
[0665] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.95-7.91 (m,
1H), 7.87 (s, 1H), 7.80 (m, 3H), 7.44-7.31 (m, 2H), 7.13 (m, 1H),
6.95 (2d, 1H, J=8.6 Hz), 6.20-5.80 (m, 2H), 5.61 (2d, 1H, J=5.5
Hz), 4.10-3.90 (m, 2H), 3.84 (2s, 3H), 3.72-3.50 (m, 1H), 2.60-2.20
(m, 2H), 1.96 (m, 2H), 1.60-1.40 (m, 2H), 1.10-1.02 (m, 6H), 0.40
(2d, 3H, J=6.6 Hz)
[0666] MS (ESI) m/z 695.1 (M.sup.++H).
EXAMPLE 158
Compound 741
5'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2'-fluoro-2-methylbiphenyl-4-c-
arboxamide
[0667] Starting material 681 (0.010 g, 0.014 mmol), thionyl
chloride (0.002 mL, 0.022 mmol) and dimethylformamide (0.001 g,
0.007 mmol) were dissolved in methylene chloride (3 mL) at room
temperature, and the reaction mixture was heated under reflux for 5
hours. Then, ammonia water was added to the reaction mixture at
room temperature, followed by stiffing at the same temperature for
16 hours. Water was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was washed with
brine and dried with anhydrous magnesium sulfate, after which it
was filtered and concentrated under reduced pressure. The residue
was purified and concentrated by MPLC (SiO.sub.2,
EtOAc/hexane=0%.about.50%) to obtain desired compound 741 (0.007 g,
70.1%) as colorless oil.
[0668] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.88 (s, 1H),
7.76 (m, 3H), 7.67 (m, 1H), 7.27 (m, 1H), 7.12 (m, 2H), 6.98 (m,
1H), 6.26-5.80 (m, 2H), 5.64 (d, 1H, J=8.1 Hz), 4.10-3.87 (m, 2H),
3.75 (d, 1H, J=14.7 Hz), 2.23-2.20 (m, 5H), 1.91 (m, 2H), 1.53 (t,
2H, J=6.5 Hz), 1.00 (m, 6H), 0.43 (d, 3H, J=6.5 Hz)
[0669] MS (ESI) m/z 663.2 (M.sup.++H).
EXAMPLE 159
Compound 742
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-fluoro-2-(trifluoromethyl)b-
iphenyl-4-carboxamide
[0670] Starting material 695 (0.010 g, 0.014 mmol), thionyl
chloride (0.002 mL, 0.021 mmol) and dimethylformamide (0.001 g,
0.007 mmol) were dissolved in methylene chloride (3 mL) at room
temperature, and the reaction mixture was heated under reflux for 5
hours. Then, ammonia water was added to the reaction mixture at
room temperature, followed by stiffing at the same temperature for
16 hours. Water was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was washed with
brine and dried with anhydrous magnesium sulfate, after which it
was filtered and concentrated under reduced pressure. The residue
was purified and concentrated by MPLC (SiO.sub.2,
EtOAc/hexane=0%.about.50%) to obtain desired compound 742 (0.008 g,
80.1%) as colorless oil.
[0671] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.21 (s, 1H),
8.03 (m, 1H), 7.88 (s, 1H), 7.78-7.74 (m, 1H), 7.47-7.40 (m, 2H),
7.21-7.05 (m, 3H), 6.98 (m, 1H), 6.30-5.75 (m, 2H), 5.64 (2d, 1H,
J=7.9 Hz), 4.10-3.82 (m, 2H), 3.80 (m, 1H), 2.53-2.26 (m, 2H), 2.00
(m, 2H), 1.53 (m, 2H), 1.05 (m, 6H), 0.44 (2d, 1H, J=6.3 Hz)
[0672] MS (ESI) m/z 717.1 (M.sup.++H).
EXAMPLE 160
Compound 754
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(4'-(3,3-difluoroazetidin-
e-1-carbonyl)-4-fluoro-2'-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcycl-
ohex-1-enyl)methyl)-4-methyloxazolidin-2-one
[0673] Compound 695 (0.072 g, 0.100 mmol), 3,3-difluoroazetidine
hydrochloride (0.014 g, 0.110 mmol), EDC (0.038 g, 0.201 mmol) and
HOBt (0.027 g, 0.201 mmol) were dissolved in methylene chloride (1
mL) at room temperature, and diisopropylethylamine (0.088 mL, 0.502
mmol) was added to the reaction mixture, followed by stiffing
overnight at the same temperature. Water was added to the reaction
mixture, which was then extracted with methylene chloride. The
extract was filtered through a plastic filter to remove the solid
residue and the aqueous layer, followed by concentration under
reduced pressure. The residue was purified by preparative TLC
(SiO.sub.2, EtOAc/hexane=33%) to obtain compound 754 (0.062 g, 78%)
as a white foam solid.
[0674] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.04 (s, 1H),
7.89-7.82 (m, 2H), 7.78-7.74 (m, 2H), 7.47-7.41 (m, 1H), 7.23-7.20
(m, 1H), 7.18-7.05 (m, 2H), 5.68-5.60 (m, 1H), 4.65-4.59 (m, 4H),
4.13-3.90 (m, 2H), 3.66-3.60 (m, 1H), 2.55-2.19 (m, 2H), 2.04-1.94
(m, 2H), 1.56-1.51 (m, 2H), 1.08-1.03 (m, 6H), 0.49-0.41 (m,
3H)
[0675] MS (ESI) m/z 793.1 (M.sup.++H).
EXAMPLE 161
Compound 755
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(4-fluoro-4'-(3-hydroxyaz-
etidine-1-carbonyl)-2'-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohe-
x-1-enyl)methyl)-4-methyloxazolidin-2-one
[0676] Compound 695 (0.072 g, 0.100 mmol), azetion-3-ol
hydrochloride (0.012 g, 0.110 mmol), EDC (0.038 g, 0.201 mmol) and
HOBt (0.027 g, 0.201 mmol) were dissolved in methylene chloride (1
mL) at room temperature, and diisopropylethylamine (0.088 mL, 0.502
mmol) was added to the reaction mixture, followed by stirring
overnight at the same temperature. Water was added to the reaction
mixture, which was then extracted with methylene chloride. The
extract was filtered through a plastic filter to remove the solid
residue and the aqueous layer, followed by concentration under
reduced pressure. The residue was purified by preparative TLC
(SiO.sub.2, EtOAc/hexane=33%) to obtain compound 755 (0.012 g, 16%)
as a white foam solid.
[0677] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.44-8.24 (m,
1H), 8.06-7.89 (m, 2H), 7.84-7.74 (m, 2H), 7.50-7.39 (m, 1H),
7.22-7.21 (m, 1H), 7.10-7.05 (m, 2H), 5.68-5.60 (m, 1H), 4.83-4.75
(m, 1H), 4.51-4.43 (m, 1H), 4.12-3.90 (m, 2H), 3.67-3.60 (m, 1H),
2.55-2.19 (m, 2H), 2.04-1.94 (m, 2H), 1.72-1.51 (m, 5H), 1.08-1.03
(m, 6H), 0.49-0.41 (m, 3H)
[0678] MS (ESI) m/z Not detected (M.sup.++H).
EXAMPLE 162
Compound 756
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-N-ethyl-4'-fluoro-2-(trifluoro-
methyl)biphenyl-4-carboxamide
[0679] Compound 695 (0.072 g, 0.100 mmol), ethylamine (0.005 g,
0.110 mmol), EDC (0.038 g, 0.201 mmol) and HOBt (0.027 g, 0.201
mmol) were dissolved in methylene chloride (1 mL) at room
temperature, and diisopropylethylamine (0.088 mL, 0.502 mmol) was
added to the reaction mixture, followed by stirring overnight at
the same temperature. Water was added to the reaction mixture,
which was then extracted with methylene chloride. The extract was
filtered through a plastic filter to remove the solid residue and
the aqueous layer, followed by concentration under reduced
pressure. The residue was purified by preparative TLC (SiO.sub.2,
EtOAc/hexane=33%) to obtain compound 756 (0.055 g, 74%) as a white
foam solid.
[0680] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.14 (s, 1H),
7.98 (dd, 1H, J=14.9, 7.9 Hz), 7.88 (s, 1H), 7.76 (d, 2H, J=14.2
Hz), 7.40 (dd, 1H, J=20.0, 8.0 Hz), 7.22-7.19 (m, 1H), 7.16-7.02
(m, 2H), 6.39-6.28 (m, 1H), 5.67-5.61 (m, 1H), 4.11-3.89 (m, 2H),
3.67-3.53 (m, 3H), 2.55-2.19 (m, 2H), 2.04-1.94 (m, 2H), 1.60-1.47
(m, 2H), 1.33-1.28 (m, 3H), 1.08-1.02 (m, 6H), 0.47-0.40 (m,
3H)
[0681] MS (ESI) m/z 745.1 (M.sup.++H).
EXAMPLE 163
Compound 757
3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-N-ethyl-4'-fluoro-N-methyl-2-(-
trifluoromethyl)biphenyl-4-carboxamide
[0682] Compound 695 (0.072 g, 0.100 mmol), N-methylethylamine
(0.009 mL, 0.110 mmol), EDC (0.038 g, 0.201 mmol) and HOBt (0.027
g, 0.201 mmol) were dissolved in methylene chloride (1 mL) at room
temperature, and diisopropylethylamine (0.088 mL, 0.502 mmol) was
added to the reaction mixture, followed by stirring overnight at
the same temperature. Water was added to the reaction mixture,
which was then extracted with methylene chloride. The extract was
filtered through a plastic filter to remove the solid residue and
the aqueous layer, followed by concentration under reduced
pressure. The residue was purified by preparative TLC (SiO.sub.2,
EtOAc/hexane=33%) to obtain compound 757 (0.048 g, 64%) as a white
foam solid.
[0683] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.89 (s, 1H),
7.80-7.75 (m, 3H), 7.63-7.59 (m, 1H), 7.37 (dd, 1H, J=20.0, 7.7
Hz), 7.21-7.20 (m, 1H), 7.16-7.04 (m, 2H), 5.67-5.61 (m, 1H),
4.13-3.89 (m, 2H), 3.68-3.61 (m, 2H), 3.35-3.34 (m, 1H), 3.13-3.01
(m, 3H), 2.55-2.16 (m, 2H), 2.04-1.94 (m, 2H), 1.59-1.48 (m, 2H),
1.30-1.21 (m, 3H), 1.08-1.03 (m, 6H), 0.48-0.41 (m, 3H)
[0684] MS (ESI) m/z 759.2 (M.sup.++H).
EXAMPLE 164
Compound 758
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(4-fluoro-4'-(morpholine--
4-carbonyl)-2'-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohex-1-enyl-
)methyl)-4-methyloxazolidin-2-one
[0685] Compound 695 (0.072 g, 0.100 mmol), morpholine (0.010 mL,
0.110 mmol), EDC (0.038 g, 0.201 mmol) and HOBt (0.027 g, 0.201
mmol) were dissolved in methylene chloride (1 mL) at room
temperature, and diisopropylethylamine (0.088 mL, 0.502 mmol) was
added to the reaction mixture, followed by stirring overnight at
the same temperature. Water was added to the reaction mixture,
which was then extracted with methylene chloride. The extract was
filtered through a plastic filter to remove the solid residue and
the aqueous layer, followed by concentration under reduced
pressure. The residue was purified by preparative TLC (SiO.sub.2,
EtOAc/hexane=33%) to obtain compound 758 (0.066 g, 83%) as a white
foam solid.
[0686] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.59 (s, 1H),
7.78 (t, 3H, J=14.9 Hz), 7.62 (t, 1H, J=9.0 Hz), 7.39 (dd, 1H,
J=17.9, 7.8 Hz), 7.23-7.19 (m, 1H), 7.17-7.03 (m, 2H), 5.67-5.60
(m, 1H), 4.13-3.89 (m, 2H), 3.83-3.51 (m, 9H), 2.55-2.18 (m, 2H),
2.04-1.94 (m, 2H), 1.59-1.49 (m, 2H), 1.08-1.05 (m, 6H), 0.48-0.41
(m, 3H)
[0687] MS (ESI) m/z 787.2 (M.sup.++H).
Preparation of Novel Compounds According to Reaction Scheme 17
Intermediate compound 66:
(2-(5-chloro-2-methoxyphenyl)-5,5-dimethylcyclohex-1-enyl)methanol
[0688] Starting material 65 (0.560 g, 2.009 mmol) was dissolved in
THF (20 mL) at 0.degree. C., and LAH (1.00M solution in THF, 4.018
mL, 4.018 mmol) was added to the reaction mixture at the same
temperature, followed by stirring for 1 hour. Then, 1M hydrochloric
acid was added to the reaction mixture, followed by extraction with
ethyl acetate. The organic layer was dried with anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The residue
was purified by MPLC (SiO.sub.2, EtOAc/hexane=0%.about.20%) to
obtain desired compound 66 (0.350 g, 62.1%) as colorless oil.
Intermediate compound 67: methyl
3'-(2-(hydroxymethyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methylbip-
henyl-4-carboxylate
[0689] Starting material 66 (0.500 g, 1.781 mmol), compound 57
(0.983 g, 3.561 mmol), sodium carbonate (0.566 g, 5.342 mmol) and
Pd(dbpf)Cl.sub.2 (0.058 g, 0.089 mmol) were added to
dimethoxymethane (1.2 mL)/water (0.4 mL) and heated by microwave
irradiation at 120.degree. C. for 20 minutes. Then, the reaction
mixture was cooled to room temperature, and water was added
thereto, followed by extraction with ethyl acetate. The organic
layer was dried with anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=0%.about.20%) to obtain compound 67
(0.250 g, 35.6%) as colorless oil.
Intermediate compound 68: methyl
3'-(2-(chloromethyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methylbiph-
enyl-4-carboxylate
[0690] Starting material 67 (0.250 g, 0.634 mmol) and thionyl
chloride (0.069 mL, 0.951 mmol) were dissolved in dimethylformamide
(10 mL) at 0.degree. C., and the reaction mixture was stirred at
the same temperature for 3 hours. Then, water was added to the
reaction mixture, followed by extraction with ethyl acetate. The
organic layer was dried with anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=0%.about.100%) to obtain compound 68
(0.190 g, 72.6%) as colorless oil.
Intermediate compound 70: methyl
3'-(2-(((4S,5S)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxyphenyl-2-methylbiph-
enyl-4-carboxylate
[0691] Starting material 68 (0.044 g, 0.107 mmol) and compound 69
(0.033 g, 0.107 mmol) were dissolved in dimethylformamide (10 ml),
and sodium hydride (0.003 g, 0.107 mmol) was added to the reaction
mixture at 0.degree. C., followed by stirring at the same
temperature for 3 hours. Then, water was added to the reaction
mixture, followed by extraction with ethyl acetate. The organic
layer was dried with anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The residue was purified by
MPLC (Sift, EtOAc/hexane=0%.about.100%) to obtain compound 70
(0.030 g, 40.8%) as a white foam solid.
Intermediate compound 72: methyl
3'-(2-(((4R,5S)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxyphenyl-2-methylbiph-
enyl-4-carboxylate
[0692] Starting material 68 (0.080 g, 0.194 mmol) and compound 71
(0.061 g, 0.194 mmol) were dissolved in dimethylformamide (10 mL),
and sodium hydride (0.005 g, 0.194 mmol) was added to the reaction
mixture at 0.degree. C., followed by stirring at the same
temperature for 3 hours. Then, water was added to the reaction
mixture, followed by extraction with ethyl acetate. The organic
layer was dried with anhydrous magnesium sulfate, and then
concentrated under reduced pressure. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=0%.about.20%) to obtain compound 72
(0.030 g, 22.5%) as a white foam solid.
Intermediate compound 74: methyl
3'-(2-(((4R,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolid-
in-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxyphenyl-2-methylbiph-
enyl-4-carboxylate
[0693] Starting material 68 (0.090 g, 0.218 mmol) and compound 73
(0.048 g, 0.153 mmol) were dissolved in dimethylformamide (10 mL),
and the reaction mixture was cooled to 0.degree. C. Sodium hydride
(0.005 g, 0.218 mmol) was added to the reaction mixture, followed
by stirring room temperature for 2 hours. Then, water was added to
the reaction mixture, followed by extraction with ethyl acetate.
The organic layer was dried with anhydrous magnesium sulfate, and
then concentrated under reduced pressure. The residue was purified
by MPLC (SiO.sub.2, EtOAc/hexane=0%-20%) to obtain compound 74
(0.035 g, 23.3%) as a white foam solid.
EXAMPLE 165
Compound 718
3'-(2-(((4S,5S)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methylbiphenyl-4--
carboxylic acid
[0694] Starting material 70 (0.030 g, 0.043 mmol) and lithium
hydroxide monohydrate (0.037 g, 0.870 mmol) were dissolved in
dioxane (8 mL)/water (2 mL) at room temperature, and the reaction
mixture was stirred at the same temperature for 16 hours. Then, 1M
hydrochloric acid was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was dried with
anhydrous magnesium sulfate, and then concentrated under reduced
pressure. The residue was purified by MPLC (Sift,
EtOAc/hexane=0%-100%) to obtain desired compound 718 (0.025 g,
85.1%) as a white foam solid.
[0695] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.03-7.75 (m,
4H), 7.30-7.18 (m, 2H), 6.92 (m, 2H), 4.98 (2d, 1H, J=5.6 Hz),
4.00-3.88 (m, 1H), 3.80-3.74 (m, 3H), 3.70-3.31 (m, 2H), 2.45-2.12
(m, 4H), 2.32-2.29 (m, 3H), 2.22-2.12 (m, 1H), 2.00-1.83 (m, 2H),
1.57-1.23 (m, 4H), 1.09-1.00 (m, 3H), 0.98-0.60 (m, 6H)
[0696] MS (ESI) m/z 676.2 (M.sup.++H).
EXAMPLE 166
Compound 719
3'-(2-(((4R,5S)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methylbiphenyl-4--
carboxylic acid
[0697] Starting material 72 (0.030 g, 0.043 mmol) and lithium
hydroxide monohydrate (0.037 g, 0.870 mmol) were dissolved in
dioxane (8 mL)/water (2 mL) at room temperature, and the reaction
mixture was stirred at the same temperature for 16 hours. Then, 1M
hydrochloric acid was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was dried with
anhydrous magnesium sulfate, and then concentrated under reduced
pressure. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=0%-100%) to obtain desired compound 719 (0.025 g,
85.1%) as a white foam solid.
[0698] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.99-7.69 (m,
5H), 7.29-7.16 (m, 2H), 6.92 (m, 2H), 5.59 (m, 1H), 4.06-3.87 (m,
2H), 3.81-3.78 (m, 3H), 3.65-3.48 (m, 1H), 2.55-2.06 (m, 5H), 1.93
(m, 2H), 1.55-1.42 (m, 2H), 1.04-1.99 (m, 6H), 0.38 (2d, 3H, J=6.6
Hz)
[0699] MS (ESI) m/z 676.2 (M.sup.++H).
EXAMPLE 167
Compound 720
3'-(2-(((4R,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidi-
n-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methylbiphenyl-4--
carboxylic acid
[0700] Starting material 74 (0.030 g, 0.043 mmol) and lithium
hydroxide monohydrate (0.037 g, 0.870 mmol) were dissolved in
dioxane (8 mL)/water (2 mL) at room temperature, and the reaction
mixture was stirred at the same temperature for 16 hours. Then, 1M
hydrochloric acid was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was dried with
anhydrous magnesium sulfate, and then concentrated under reduced
pressure. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=0%.about.100%) to obtain desired compound 720 (0.028
g, 95.3%) as a white foam solid.
[0701] .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.03-7.75 (m,
5H), 7.30-7.18 (m, 2H), 6.92 (m, 2H), 4.98 (2d, 1H, J=5.6 Hz),
4.00-3.88 (m, 1H), 3.80-3.74 (m, 3H), 3.70-3.31 (m, 2H), 2.45-2.12
(m, 4H), 2.00-1.83 (m, 2H), 1.57-1.23 (m, 4H), 1.09-1.00 (m, 3H),
0.98-0.60 (m, 6H)
[0702] MS (ESI) m/z 676.2 (M.sup.++H).
Preparation of Novel Compounds According to Reaction Scheme 18
Intermediate compound 76:
(1R,2S)-2-((2-(5-chloro-2-methoxyphenyl)-5,5-dimethylcyclohex-1-enyl)meth-
ylamino)-1-(3,5-difluorophenyl)propan-1-ol
[0703] Starting material 3b (0.500 g, 1.794 mmol), compound 75
(0.353 g, 1.883 mmol), sodium cyanoborohydride (0.135 g, 2.152
mmol) and acetic acid (0.123 mL, 2.152 mmol) were dissolved in
dichloromethane (10 ml) at room temperature, and the reaction
mixture was stirred for 2 hours at room temperature. Then, an
aqueous solution of saturated sodium bicarbonate was added to the
reaction mixture, followed by extraction with ethyl acetate. The
organic layer was washed with aqueous solution of saturated sodium
bicarbonate and dried with anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was purified by
MPLC (SiO.sub.2, EtOAc/hexane=5%.about.10%) to obtain compound 76
(0.182 g, 22.6%) as colorless oil.
[0704] MS (ESI) m/z 450.2 (M.sup.++H).
Intermediate compound 77:
(4S,5R)-3-((2-(5-chloro-2-methoxyphenyl)-5,5-dimethylcyclohex-1-enyl)meth-
yl)-5-(3,5-difluorophenyl)-4-methyloxazolidin-2-one
[0705] Starting material 76 (0.182 g, 0.331 mmol) and
diisopropylethylamine (0.347 mL, 1.986 mmol) were dissolved in
dichloromethane (5 ml), and triphosgene (0.118 g, 0.397 mmol) was
added thereto at room temperature, followed by stirring at the same
temperature for 30 minutes. Then, an aqueous solution of saturated
sodium bicarbonate was added to the reaction mixture, followed by
extraction with ethyl acetate. The organic layer was washed with
aqueous solution of saturated sodium bicarbonate and dried with
anhydrous magnesium sulfate, followed by concentration under
reduced pressure. The residue was purified by MPLC (SiO.sub.2,
EtOAc/hexane=5%.about.10%) to obtain compound 77 (0.142 g, 90.2%)
as a white solid.
[0706] MS (ESI) m/z 476.1 (M.sup.++H).
EXAMPLE 168
Compound 705
methyl
3'-(2-(((4S,5R)-5-(3,5-difluorophenyl)-4-methyl-2-oxooxazolidin-3-y-
l)methyl)-4,4-di
methylcyclohex-1-enyl)-4'-methoxy-2-methylbiphenyl-4-carboxylate
[0707] Starting material 77 (0.138 g, 0.290 mmol), compound 57
(0.073 g, 0.377 mmol), Pd(dbpf)Cl.sub.2 (0.009 g, 0.014 mmol) and
sodium carbonate (0.092 g, 0.870 mmol) were added to
dimethoxyethane/water (v/v=3:1, 2 ml) and heated by microwave
irradiation at 120.degree. C. for 30 minutes. Then, the reaction
mixture was cooled to room temperature, and water was added
thereto, followed by extraction with ethyl acetate. The organic
layer was washed with aqueous solution of saturated sodium
bicarbonate and dried with anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was purified by
MPLC (Sift, EtOAc/hexane=10%.about.20%) to obtain compound 705
(0.110 g, 64.6%) as a white solid.
[0708] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.31 atropisomeric
mixture; .delta. 7.93-7.82 (m, 2H), 7.26-7.15 (m, 2H), 6.93-6.87
(m, 2H), 6.82-6.74 (m, 3H), 5.46-5.41 (m, 1H), 3.98-3.84 (m, 5H),
3.81-3.79 (m, 3H), 3.61 (d, 0.6H, J=14.5 Hz), 3.47 (d, 0.4H, J=15.1
Hz), 2.56-2.04 (m, 5H), 1.97-1.84 (m, 2H), 1.52-1.42 (m, 2H),
1.06-0.99 (m, 6H), 0.45 (d, 1.3H, J=6.5 Hz), 0.39 (d, 1.7H, J=6.5
Hz)
[0709] MS (ESI) m/z 590.2 (M.sup.++H).
EXAMPLE 169
Compound 706
3'-(2-(((4S,5R)-5-(3,5-difluorophenyl)-4-methyl-2-oxooxazolidin-3-yl)methy-
l)-4,4-dimethylcyclohex-1-enyl)-4'-methoxy-2-methylbiphenyl-4-carboxylic
acid
[0710] Starting material 705 (0.103 g, 0.175 mmol) and lithium
hydroxide monohydrate (0.037 g, 0.874 mmol) were dissolved in
dioxane/water (v/v=4:1, 2 ml) at 45.degree. C., and the reaction
mixture was stirred overnight at the same temperature. Then, the
reaction mixture was concentrated, and water was added thereto,
followed by extraction with ethyl acetate. The organic layer was
washed with aqueous solution of 1M hydrochloric acid and dried with
anhydrous magnesium sulfate, followed by concentration under
reduced pressure. The residue was purified by MPLC (Sift,
CH.sub.3OH/CH.sub.2Cl.sub.2=5%) to obtain compound 706 (0.051 g,
50.7%) as a white solid.
[0711] .sup.1H NMR (400 MHz, CDCl.sub.3); 1:1.35 atropisomeric
mixture; .delta. 8.05-7.91 (m, 2H), 7.31-7.17 (m, 2H), 6.94-6.89
(m, 2H), 6.81-6.74 (m, 3H), 5.47-5.42 (m, 1H), 4.03-3.80 (m, 5H),
3.62 (d, 0.6H, J=14.6 Hz), 3.47 (d, 0.4H, J=15.0 Hz), 2.56-2.09 (m,
5H), 1.99-1.84 (m, 2H), 1.53-1.44 (m, 2H), 1.04-0.87 (m, 6H), 0.46
(d, 1.3H, J=6.6 Hz), 0.40 (d, 1.7H, J=6.5 Hz)
[0712] MS (ESI) m/z 576.3 (M.sup.++H).
[0713] The structural formulas of compounds 553 to 764 prepared as
described above are shown in Tables 1 to 29 below.
TABLE-US-00013 TABLE 1 Compound Structure 553 ##STR00059## 554
##STR00060## 555 ##STR00061## 556 ##STR00062## 557 ##STR00063## 558
##STR00064##
TABLE-US-00014 TABLE 2 Compound Structure 559 ##STR00065## 560
##STR00066## 561 ##STR00067## 564 ##STR00068## 565 ##STR00069## 567
##STR00070##
TABLE-US-00015 TABLE 3 Compound Structure 568 ##STR00071## 569
##STR00072## 572 ##STR00073## 573 ##STR00074## 574 ##STR00075## 575
##STR00076##
TABLE-US-00016 TABLE 4 Compound Structure 577 ##STR00077## 578
##STR00078## 579 ##STR00079## 580 ##STR00080## 581 ##STR00081## 582
##STR00082##
TABLE-US-00017 TABLE 5 Compound Structure 583 ##STR00083## 584
##STR00084## 585 ##STR00085## 586 ##STR00086## 587 ##STR00087## 588
##STR00088##
TABLE-US-00018 TABLE 6 Compound Structure 590 ##STR00089## 591
##STR00090## 592 ##STR00091## 593 ##STR00092## 594 ##STR00093## 595
##STR00094##
TABLE-US-00019 TABLE 7 Compound Structure 596 ##STR00095## 597
##STR00096## 599 ##STR00097## 600 ##STR00098## 601 ##STR00099## 602
##STR00100##
TABLE-US-00020 TABLE 8 Compound Structure 603 ##STR00101## 604
##STR00102## 605 ##STR00103## 606 ##STR00104## 607 ##STR00105## 608
##STR00106##
TABLE-US-00021 TABLE 9 Compound Structure 609 ##STR00107## 610
##STR00108## 611 ##STR00109## 612 ##STR00110## 613 ##STR00111## 614
##STR00112##
TABLE-US-00022 TABLE 10 Compound Structure 615 ##STR00113## 616
##STR00114## 617 ##STR00115## 618 ##STR00116## 619 ##STR00117## 620
##STR00118##
TABLE-US-00023 TABLE 11 Compound Structure 621 ##STR00119## 622
##STR00120## 625 ##STR00121## 626 ##STR00122## 628 ##STR00123## 629
##STR00124##
TABLE-US-00024 TABLE 12 Compound Structure 630 ##STR00125## 631
##STR00126## 632 ##STR00127## 633 ##STR00128## 636 ##STR00129## 637
##STR00130##
TABLE-US-00025 TABLE 13 Compound Structure 638 ##STR00131## 639
##STR00132## 642 ##STR00133## 643 ##STR00134## 644 ##STR00135## 645
##STR00136##
TABLE-US-00026 TABLE 14 Compound Structure 646 ##STR00137## 647
##STR00138## 648 ##STR00139## 649 ##STR00140## 650 ##STR00141## 651
##STR00142##
TABLE-US-00027 TABLE 15 Compound Structure 652 ##STR00143## 653
##STR00144## 654 ##STR00145## 655 ##STR00146## 656 ##STR00147## 657
##STR00148##
TABLE-US-00028 TABLE 16 Com- pound Structure 658 ##STR00149## 659
##STR00150## 660 ##STR00151## 661 ##STR00152## 662 ##STR00153## 663
##STR00154##
TABLE-US-00029 TABLE 17 Compound Structure 664 ##STR00155## 665
##STR00156## 666 ##STR00157## 667 ##STR00158## 668 ##STR00159## 670
##STR00160##
TABLE-US-00030 TABLE 18 Compound Structure 671 ##STR00161## 672
##STR00162## 673 ##STR00163## 674 ##STR00164## 675 ##STR00165## 676
##STR00166##
TABLE-US-00031 TABLE 19 Compound Structure 677 ##STR00167## 678
##STR00168## 679 ##STR00169## 680 ##STR00170## 681 ##STR00171## 682
##STR00172##
TABLE-US-00032 TABLE 20 Compound Structure 683 ##STR00173## 684
##STR00174## 686 ##STR00175## 687 ##STR00176## 688 ##STR00177## 689
##STR00178##
TABLE-US-00033 TABLE 21 Compound Structure 690 ##STR00179## 691
##STR00180## 692 ##STR00181## 693 ##STR00182## 694 ##STR00183## 695
##STR00184##
TABLE-US-00034 TABLE 22 Compound Structure 696 ##STR00185## 697
##STR00186## 699 ##STR00187## 700 ##STR00188## 701 ##STR00189## 702
##STR00190##
TABLE-US-00035 TABLE 23 Compound Structure 703 ##STR00191## 704
##STR00192## 705 ##STR00193## 706 ##STR00194## 708 ##STR00195## 709
##STR00196##
TABLE-US-00036 TABLE 24 Compound Structure 714 ##STR00197## 716
##STR00198## 718 ##STR00199## 719 ##STR00200## 720 ##STR00201## 722
##STR00202##
TABLE-US-00037 TABLE 25 Compound Structure 723 ##STR00203## 724
##STR00204## 725 ##STR00205## 726 ##STR00206## 727 ##STR00207## 728
##STR00208##
TABLE-US-00038 TABLE 26 Compound Structure 729 ##STR00209## 738
##STR00210## 739 ##STR00211## 740 ##STR00212## 741 ##STR00213## 742
##STR00214##
TABLE-US-00039 TABLE 27 Compound Structure 743 ##STR00215## 744
##STR00216## 745 ##STR00217## 746 ##STR00218## 747 ##STR00219## 748
##STR00220##
TABLE-US-00040 TABLE 28 Com- pound Structure 754 ##STR00221## 755
##STR00222## 756 ##STR00223## 757 ##STR00224## 758 ##STR00225## 763
##STR00226##
TABLE-US-00041 TABLE 29 Compound Structure 764 ##STR00227##
[0714] Measurement of Activities of Compounds According to the
Present Invention--Test Protocols
[0715] In the present invention, in order to test the preventive or
therapeutic effects of the compounds of formula I against
arteriosclerosis and hyperlipidemia and the safety of the
compounds, comparative tests were performed using previously
developed compounds as a control group.
EXPERIMENTAL EXAMPLE 1
Test for Inhibition of Cholesteryl Ester Transfer (In Vitro)
[0716] 1. Construction of Cholesteryl Ester Donor
[0717] To construct a cholesteryl ester donor to be used in the
test, radiolabeled recombinant HDL containing [41]-cholesteryl
oleate (GE healthcare, TRK886, 3.5 .mu.Ci/mg of apoA-1) and apoA-1
was synthesized. Then, rHDL-agarose having the recombinant HDL
immobilized thereon by CNBr-activated Sepharose 4B (Amersham
Biosciences, Sweden) resin was used in the test.
[0718] 2. Cholesteryl Ester Transfer Test
[0719] As a protein source for cholesteryl ester transfer, plasma
from healthy persons was used, and as a cholesteryl ester receptor,
LDL from healthy persons was used. Samples were treated with each
test compound to final concentrations of 16, 80, 400, 2000 and
10000 nM and analyzed in duplicate. For the cholesteryl ester
transfer test, 20 .mu.l of plasma, 50 .mu.l of LDL (0.25 mg/ml) and
50 .mu.l of rHDL-agarose (0.25 mg/ml) were added, and a solution
containing a test compound was added, followed by reaction at
37.degree. C. Then, centrifugation was performed at 4.degree. C.
for 3 minutes to stop the reaction, and 150 .mu.l of the
supernatant was taken and transferred to a 96-well plate for
radioactivity measurement, and the radioactivity of the plate was
measured with a beta-ray detector.
[0720] 3. Statistical Processing
[0721] The ratio of [.sup.3H]-cholesteryl oleate from HDL to LDL
was calculated and used as a result value, and from the result
value, IC.sub.50 value was calculated using GraphPad Prism 5.0.
TABLE-US-00042 TABLE 30 Cholesteryl ester transfer test Compound
IC.sub.50 (nM) 554 5.8 555 28.4 557 5.4 561 23.2 567 56.6 572 15.0
574 3.9 575 14.6 578 12.6 584 5.3 586 13.0 592 8.4 593 1.5 596 17.9
597 50.2 612 6.9 613 9.1 614 27.0 615 12.3 616 7.6 618 1.6 620 11.6
631 1.9 643 7.3 650 11.9 651 10.7 661 2.5 668 5.0 677 15.9 681 6.6
684 1.9 689 24.3 695 6.4 723 9.6 727 11.4 729 7.5 739 20.3 748 15.9
756 5.9 758 7.1 764 8.9
[0722] As can be seen from the cholesteryl ester transfer test
results in Table 30 above, the biaryl- or heterocyclic
biaryl-substituted cyclohexene compounds show excellent abilities
to inhibit cholesterol transfer.
TEST EXAMPLE 2
Test for Anti-Hyperlipidemic Effect in Hamsters (In Vivo)
[0723] 1. Test Animals
[0724] In this test, 8-week-old male golden Syrian hamsters were
used. The breeding room was maintained at constant temperature and
constant humidity and a 12-hr light/12-hr dark cycle. The animals
were allowed access to feed and water ad libitum.
[0725] 2. Anti-Hyperlipidemic Test in Hamsters
[0726] The test animals were acclimated for 1 week before use in
the test. The test animals were divided according to body weight
into several groups, each consisting of 5-8 animals, and were then
administered orally with a dose of 3 mg/kg. A solvent control and a
CETP inhibitor were dissolved in imwitor 742: tween 80 (1:1) and
administered orally for 5 days, and at 4 hours after the final
administration, blood was collected from the heart. The collected
blood was centrifuged at 3000 rpm for 15 minutes, and the separated
serum was measured for HDL-Cholesterol (Biosystem) and
LDL-Cholesterol (Biosystem) using a biochemical analysis instrument
(ILab 300 plus, Instrumentation Laboratory).
[0727] 3. Statistical Processing
[0728] All test results were expressed as Mean.+-.SEM, and to
evaluate the effect of each test group, each test group was
compared with the control group using one-way ANOVA test (Dunnett's
test, p<0.001).
TABLE-US-00043 TABLE 31 Measurement of increase in HDL-c and
decrease in LDL-c in blood of hamsters Increase in Decrease in
Compound HDL-c (%) LDL-c (%) 554 72 42 557 77 39 574 41 36 584 46
40 586 37 34 593 61 29 618 65 26 631 56 30 643 68 17 650 50 24 661
53 20 668 44 16 681 25 29 695 71 35
[0729] As can be seen from the measurement of the increase in the
HDL-c in the blood of hamsters in Table 31 above, the biaryl- or
heterocyclic biaryl-substituted cyclohexene compounds show
excellent effects of increasing HDL-c and reducing LDL-c.
TEST EXAMPLE 3
Evaluation of the Ability of CETP Inhibitor to Secrete Blood
Pressure-Hormone
[0730] 1. Test Method
[0731] The results of ILLUMINATE regarding the results of phase III
clinical trials for the first CETP inhibitor torcetrapib (Pfizer)
indicated that morbidity rate and mortality rate in patients
administered with a combination of torcetrapib and atorvastatin
increase compared to those in patients administered with
atorvastatin alone. Indeed, the secretion of hormones from human
adrenal cortical tumor cells was evaluated using torcetrapib, and
as a result, it was found that torcetrapib increased the secretion
of aldosterone and cortisol that are blood pressure-increasing
hormones (Endocrinology, 2009, 150(5), 2211-2219). Based on this,
the secretion of blood pressure-increasing hormones from human
adrenal cortical tumor cells was evaluated. The cell line H295R was
purchased from ATCC (CRL-2128) and cultured in DMEM/F-12 medium (1%
ITS, 2.5% Nu-serum). The H295R cell line was dispensed into a
24-well plate at a cell density of 1.times.10.sup.5/well, and
stabilized for 24 hours, after which the cells were starved for 24
hours using serum-free DMEM/F-12. Then, the cells were treated with
each of 100 nM of torcetrapib and 1 .mu.M of test compounds 554,
557, 574, 584, 586, 593, 618, 643, 650, 661, 681 and 695. At 24
hours after treatment with the drug or the compound, the
supernatant was taken and stored at -20.degree. C. The supernatant
stored at -20.degree. C. was thawed, and the amounts of aldosterone
and cortisol secreted from the cells were measured using an
aldosterone EIA kit (Cayman-10004377) and cortisol EIA kit
(Cayman-500360).
[0732] 2. Statistical Processing
[0733] All test results were expressed as Mean.+-.SEM, and to
evaluate the effect of each test group, each test group was
compared with the control group using one-way ANOVA test (Dunnett's
test, p<0.001).
TABLE-US-00044 TABLE 32 Evaluation of secretion of blood
pressure-related hormones (treated with 1 .mu.M of compound)
Aldosterone Cortisol Compound (fold, vs con.) (fold, vs con.) 554
0.90 0.93 557 0.96 1.01 574 1.13 1.32 584 0.95 0.92 586 0.99 1.10
593 1.14 0.75 618 0.73 1.09 643 0.72 0.81 650 0.80 0.82 661 0.80
0.68 681 0.83 0.76 695 0.67 0.89 Torcetrapib 1.21~2.25
2.08~3.77
[0734] From the test results for the secretion of blood
pressure-related hormones aldosterone and cortisol in Table 32
above, it can be seen that the control compound torcetrapib
increased the secretion of the two hormones, but the biaryl- or
heterocyclic biaryl-substituted cyclohexene compounds of the
present invention did not influence the secretion of aldosterone
and cortisol, which have a connection with blood pressure-related
side effects. Thus, it can be seen that the compounds of the
present invention does not cause increased blood pressure and side
effects related to increased blood pressure.
* * * * *