# Patent

## Title
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.

## Background
RELATED APPLICATIONS
This application is the U.S. National Stage of International Application. No. PCT/KR2014/000889, filed 29 Jan. 2014, which claims benefit of priority to Korean Patent Application KR 10-2014-0011555, filed 29 Jan. 2014, and to Korean Patent Application KR 10-2013-0011206, filed 31 Jan. 2013, the specification of each of which is incorporated by reference herein.
TECHNICAL FIELD
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
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).
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).
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.
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).
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).
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).
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).
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
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.
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.
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
Novel CETP Inhibitor Compounds
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:




wherein
R1 is —H or —C1-C3 alkyl;
R2 is —H, halogen or —C1-C3 alkyl;
R3, R4, R5 and R6 are each independently —H, halogen, —NO2, —C1-C3 alkyl, or —OC1-C3 alkyl;
R7 is —H, —(C═O)OR8, or




R8 is —H or —C1-C3 alkyl;
R11 and R12 are each independently —H or —C1-C3 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;
A1, A2 and A3 are each independently N or CR9, wherein if A2 or A3 is N, A1 is CR9;
R9 is —H, halogen, —C1-C3 alkyl or —OC1-C3 alkyl;
B is N or CR10;
R10 is —H, halogen, —C1-C3 alkyl, —OC1-C3 alkyl, —(C═O)OR8, or




provided that one or more —H atoms in the —C1-C3 alkyl or the —OC1-C3 alkyl may be substituted with —F or —CH3, and if R7 is —H, B is CR10, and R10 is —(C═O)OR8 or




and if R7 is not —H, R10 cannot be —(C═O)OR8 or





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
R1 is —H or —CH3;
R2 is —F or —CF3;
R3, R4, R5 and R6 are each independently —H, —F, —NO2, —CH3, —CH(CH3)2, —CF3 or —OCH3;
R7 is —H, —(C═O)OR8, or




R8 is —H, —CH3 or —CH2CH3;
R11 and R12 are each independently —H, —CH3 or —CH2CH3 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;
A1, A2 and A3 are each independently N or CR9, wherein if A2 or A3 is N, A′ is CR9;
R9 is —H, —F, —Cl, —CH3, —CF3 or —OCH3;
B is N or CR10;
R10 is —H, —F, —Cl, —CH3, —OCH3, —CO2H, —CO2CH3, —CO2CH2CH3, or




provided that if R7 is —H, B is CR10, and R10 is —CO2H, —CO2CH3, —CO2CH2CH3, or




and if R7 is not —H, R10 is not —CO2H, —CO2CH3, —CO2CH2CH3, or





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
R1 is —CH3;
R2 is —CF3;
R3 is —H, —F, —Cl or —OCH3;
R4 is —H, —F, —Cl, —CH3, —CH(CH3)2, —CF3 or —OCH3;
R5 is —H, —F or —Cl;
R6 is —H;
R7 is —H, —(C═O)OH,




A1, A2 and A3 are each independently N or CR9, wherein if A2 or A3 is N, A1 is CR9;
R9 is —H, —F, —CH3, —CF3 or —OCH3;
B is CR10;
R10 is —H, —F or —CO2CH3;
provided that if R7 is —H, B is CR10, and R10 is —CO2CH3, and if R7 is not —H, R10 is not —CO2CH3.
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
R3 is —H, —F or —OCH3;
R4 is —H, —F, —Cl, —CH3 or —CF3;
R5 is —H or —F;
R7 is —(C═O)OH;
A1 is N or CR9;
A2 and A3 are each independently CR9;
R9 is —H or —F; and
B is CH.
Preferred Examples of the compounds of formula I are as follows:











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

The present invention provides pharmaceutical compositions comprising the compounds of formula I, isomers thereof, or pharmaceutically acceptable salts thereof, together with pharmaceutically acceptable carriers.
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.
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.
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.
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.
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.
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.
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.
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.
The dyslipidemia-related vascular diseases may include angina pectoris, myocardial infarction, and atherosclerosis.
Method for Prevention or Treatment of Dyslipidemia or Dyslipidemia-Related Vascular Diseases
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.
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.
In addition, the subject in the prevention or treatment method of the present invention includes mammals, particularly humans.
Methods for Preparing Novel CETP Inhibitor Compounds
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.
Hereinafter, methods for preparing the compounds of formula I will be described in detail with reference to the following reaction schemes 1 and 2.




wherein R1, R2, R3, R4, R5, R6, R7, A1, A2, A3 and B are each as defined in formula I. In addition, X, Y, Z and Q may each independently be halogen,




and the halogen is preferably chloride (—Cl) or bromide (—Br).

First, a compound of formula III as a starting material may be reacted with phosphorus tribromide (PBr3) or phosphorous oxychloride (POCl3) in dimethylformamide (DMF) [Vilsmeier reaction] to prepare a halogenated compound of formula IV.
In the Vilsmeier reaction, methylene chloride may be used as a solvent, and the reaction temperature is 0 ̃70° C., and preferably 0 ̃45° C.
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.
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 ̃150° C., and preferably 80 ̃100° C.
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).
The prepared compound of formula VIII may be subjected to cyclization with triphosgene to prepare a desired compound of formula II.
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.
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.




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.























Compounds
R1
R4
R5
R6
R7
B







553
CH3
CH3
H
H
CO2CH3
CH


554
CH3
CH3
H
H
CO2H
CH


559
CH3
H
H
H
CO2CH3
CH


565
CH3
H
H
H
CO2H
CH


560
CH3
F
H
H
CO2CH3
CH


561
CH3
F
H
H
CO2H
CH


564
CH3
H
H
H
CO2CH3
N


567
CH3
H
H
H
H
CCO2CH3


568
CH3
H
H
H
H
CCO2H


569
CH3
NO2
H
H
CO2CH3
CH


579
H
CH3
H
H
CO2CH3
CH


581
H
CH3
H
H
CO2H
CH


580
H
F
H
H
CO2CH3
CH


582
H
F
H
H
CO2H
CH


590
CH3
F
H
H
CO2CH3
CF


592
CH3
F
H
H
CO2H
CF


591
CH3
F
F
H
CO2CH3
CH


593
CH3
F
F
H
CO2H
CH


599
CH3
H
H
H
CO2CH3
COCH3


601
CH3
H
H
H
CO2H
COCH3


600
CH3
H
H
CH3
CO2CH3
N


602
CH3
H
H
CH3
CO2H
N


665
CH3
CH3
H
H
CO2CH3
N


666
CH3
CH3
H
H
CO2H
N









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, R1, R4, R5, R6, R7 and B are each as defined above, and Q may be




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.




















Compounds
R4
R7
B







555
CH3
CO2CH3
CH


557
CH3
CO2H
CH


556
H
CO2CH3
CH


558
H
CO2H
CH


583
Cl
CO2CH3
CH


584
Cl
CO2H
CH


585
F
CO2CH3
CH


586
F
CO2H
CH


587
H
H
CCO2CH3


588
H
H
CCO2H


595
F
CO2CH3
CF


596
F
CO2H
CF









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, R4, R7 and B are each as defined above, and Q may be




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.
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.























Compounds
R3
R4
R7
B
A2
A3







603
OCH3
CH3
CO2CH3
CH
N
N


604
OCH3
CH3
CO2H
CH
N
N


610
OCH3
F
CO2CH3
CH
N
N


617
OCH3
F
CO2H
CH
N
N


625
OCH3
H
CO2CH3
CH
N
N


628
OCH3
H
CO2H
CH
N
N


626
OCH3
H
CO2CH2CH3
CF
N
N


629
OCH3
H
CO2H
CF
N
N


673
H
H
CO2CH3
CH
CCH3
CH


676
H
H
CO2H
CH
CCH3
CH


674
H
CH3
CO2CH3
CH
CCH3
CH


677
H
CH3
CO2H
CH
CCH3
CH


675
H
F
CO2CH3
CH
CCH3
CH


678
H
F
CO2H
CH
CCH3
CH


763
OCH3
CF3
CO2CH3
CH
CH
N


764
OCH3
CF3
CO2H
CH
CH
N









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, R3, R4, R7, B, A2 and A3




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.




















Compounds
R4
R7
B







572
CH3
CO2CH3
CH


574
CH3
CO2H
CH


573
H
CO2CH3
CH


575
H
CO2H
CH


630
Cl
CO2CH3
CH


631
Cl
CO2H
CH


657
F
CO2CH3
CH


661
F
CO2H
CH


658
H
CO2CH2CH3
CF


662
H
CO2H
CF


659
H
CO2CH3
COCH3


663
H
CO2H
COCH3


660
F
CO2CH3
CF


664
F
CO2H
CF









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, R4, R7 and B are each as defined above, and Q may be




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.




















Compounds
R4
R7
B







652
H
CO2CH3
CH


644
H
CO2H
CH


653
CH3
CO2CH3
CH


645
CH3
CO2H
CH


654
F
CO2CH3
CH


646
F
CO2H
CH


655
Cl
CO2CH3
CH


647
Cl
CO2H
CH


656
F
CO2CH3
CF









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, R4, R7 and B are each as defined above, and Q may be




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.
















Compounds
R4
R7







621
CH3
CO2CH3


622
CH3
CO2H


696
F
CO2CH3


637
F
CO2H


697
Cl
CO2CH3


636
Cl
CO2H









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, R4 and R7 are each as defined above, and Q may be




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.







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.
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.























Compounds
R4
R5
R6
R7
A2
B







605
H
H
H
CO2CH3
CCF3
CH


612
H
H
H
CO2H
CCF3
CH


606
F
H
H
CO2CH3
CCF3
CH


613
F
H
H
CO2H
CCF3
CH


607
H
H
H
CO2Et
CCF3
CF


614
H
H
H
CO2H
CCF3
CF


608
Cl
H
H
CO2CH3
CCF3
CH


615
Cl
H
H
CO2H
CCF3
CH


609
CH3
H
H
CO2CH3
CCF3
CH


616
CH3
H
H
CO2H
CCF3
CH


611
H
H
F
CO2H
CCF3
N


619
H
H
H
CO2CH3
CCH3
CH


620
H
H
H
CO2H
CCH3
CH


638
H
H
H
CO2CH3
CCF3
CCl


632
H
H
H
CO2H
CCF3
CCl


639
H
H
H
CO2CH3
CCF3
COCH3


633
H
H
H
CO2H
CCF3
COCH3


683
CH3
H
H
CO2CH3
CCH3
CH


684
CH3
H
H
CO2H
CCH3
CH









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, R4, R5, R6, R7, B and A2 are each as defined above, and Q may be




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.



















Compounds
R3
R4
R7
A1
A2







594
OCH3
OCH3
CO2CH3
CH
CH


597
OCH3
OCH3
CO2H
CH
CH


667
H
CF3
CO2CH3
CF
CH


668
H
CF3
CO2H
CF
CH


692
F
CH3
CO2CH3
CH
CH


694
F
CH3
CO2H
CH
CH


693
F
CF3
CO2CH3
CH
CH


695
F
CF3
CO2H
CH
CH


699
H
F
CO2CH3
CF
CH


702
H
F
CO2H
CF
CH


700
H
H
CO2CH3
CF
CH


703
H
H
CO2H
CF
CH


701
H
F
CO2CH3
CH
CH


704
H
F
CO2H
CH
CH


708
F
H
CO2CH3
CH
CH


709
F
H
CO2H
CH
CH


714
H
CH3
CO2CH3
CH
N


716
H
CH3
CO2H
CH
N


726
Cl
CH3
CO2CH3
CH
CH


727
Cl
CH3
CO2H
CH
CH









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, R3, R4, R7, A1 and A2 are each as defined above, and Y, Z and Q may each independently be halogen,




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.







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.
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.







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.
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.

















Compounds
R3
R4
R7







642
OCH3
Cl
CO2CH3


643
OCH3
Cl
CO2H


728
Cl
CF3
CO2CH3


729
Cl
CF3
CO2H


738
F
Cl
CO2CH3


739
F
Cl
CO2H









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, R3, R4 and R7 are each as defined above, and Q may be




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.



















Compounds
R3
R4
R7
A1
A2







670
H
H
CO2CH3
CH
CF


679
H
H
CO2H
CH
CF


671
H
F
CO2CH3
CH
CF


680
H
F
CO2H
CH
CF


672
H
CH3
CO2CH3
CH
CF


681
H
CH3
CO2H
CH
CF


686
H
H
CO2CH3
COCH3
CH


687
H
H
CO2H
COCH3
CH


688
H
CH3
CO2CH3
COCH3
CH


689
H
CH3
CO2H
COCH3
CH


690
H
F
CO2CH3
COCH3
CH


691
H
F
CO2H
COCH3
CH


724
F
F
CO2CH3
CH
CH


722
F
F
CO2H
CH
CH


725
H
CF3
CO2CH3
CH
CF


723
H
CF3
CO2H
CH
CF


743
H
CH3
CO2CH3
CCF3
CH


744
H
CH3
CO2H
CCF3
CH


745
H
H
CO2CH3
CCF3
CH


746
H
H
CO2H
CCF3
CH


747
H
F
CO2CH3
CCF3
CH


748
H
F
CO2H
CCF3
CH









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,




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.




















Compounds
Stating material
Condition
R3
R4
A2











682
554
1
OCH3
CH3
CH
NH2


740
643
1
OCH3
Cl
CH
NH2


741
681
1
H
CH3
CF
NH2


742
695
1
F
CF3
CH
NH2


 


754
695
2
F
CF3
CH






 


755
695
2
F
CF3
CH






 


756
695
2
F
CF3
CH






 


757
695
2
F
CF3
CH






 


758
695
2
F
CF3
CH













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, R3, R4, A2 and




are as defined above.

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.










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.
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.







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.
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.
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.
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.
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
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.
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
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
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)Cl2 (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° 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% ̃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-methoxyphenyl)-5,5-dimethylcyclohex-1-enyl)methylamino)propan-1-ol
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 (NaBH3CN) (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 (SiO2, EtOAc/hexane=0% ̃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-methoxyphenyl)cyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
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)Cl2 (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° 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 (SiO2 40 g, hexane/EtOAc=10% ̃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-methoxyphenyl)-5,5-dim ethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
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° 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% ̃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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxy-2-methylbiphenyl-4-carboxylate
Starting material 6b (0.53 g, 0.92 mmol), boronic acid 7 (0.38 g, 1.38 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=0% ̃10%) to obtain compound 553 (0.3 g, 47.3%) as a white foam solid.
1H NMR (400 MHz, CDCl3); 1:1.3 atropisomeric mixture; δ 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)
MS (ESI) m/z 690.2 (M++H).
Example 2
Compound 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
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° 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 (SiO2, EtOAc/hexane=0% ̃20%) to obtain compound 554 (1.8 g, 76.6%) as a white foam solid.
1H NMR (400 MHz, CDCl3); 1:1.30 atropisomeric mixture; δ 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)
MS (ESI) m/z 676.2 (M++H).
Example 3
Compound 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
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)Cl2 (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° 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 (SiO2, EtOAc/hexane=0% ̃10%→CH2Cl2 100%) to obtain compound 559 (89 mg, 51%) as a white solid.
1H NMR (400 MHz, CDCl3); 1:1.3 atropisomeric mixture; δ 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)
MS (ESI) m/z 676.2 (M++H).
Example 4
Compound 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
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)Cl2 (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° 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 (SiO2, EtOAc/hexane=10% ̃30%) to obtain compound 560 (63 mg, 52%) as colorless oil.
1H NMR (400 MHz, CDCl3); 1:1.3 atropisomeric mixture; δ 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)
MS (ESI) m/z 694.2 (M++H).
Example 5
Compound 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
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° 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, CH3OH/CH2Cl2=0% ̃10%) to obtain compound 561 (27 mg, 46%) as a yellow solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 680.2 (M++H).
Example 6
Compound 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
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)Cl2 (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° 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% ̃50%) to obtain compound 564 (14 mg, 12%) as yellow oil.
1H NMR (400 MHz, CDCl3); 1:1.3 atropisomeric mixture; δ 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)
MS (ESI) m/z 677.2 (M++H).
Example 7
Compound 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
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° 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 (SiO2, EtOAc/hexane=30%-50%) to obtain compound 565 (34 mg, 51%) as a white solid.
1H NMR (400 MHz, CDCl3); 1:1.4 atropisomeric mixture; δ 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)
MS (ESI) m/z 662.2 (M++H).
Example 8
Compound 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
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)Cl2 (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° 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.
1H NMR (400 MHz, CDCl3); 1:1.4 atropisomeric mixture; δ 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)
MS (ESI) m/z 676.2 (M++H).
Example 9
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); 1:1.4 atropisomeric mixture; δ 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)
MS (ESI) m/z 662.2 (M++H).
Example 10
Compound 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
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)Cl2 (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° 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 (SiO2, EtOAc/hexane=5% ̃50%) to obtain compound 569 (15 mg, 9%) as yellow oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 721.1 (M++H).
Example 11
Compound 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
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)Cl2 (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° 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 (SiO2, EtOAc/hexane=10% ̃20%) to obtain compound 579 (50 mg, 41%) as colorless oil.
1H NMR (400 MHz, CDCl3); 1:1.3 atropisomeric mixture; δ 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)
MS (ESI) m/z 662.2 (M++H).
Example 12
Compound 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
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)Cl2 (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° 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 (SiO2, EtOAc/hexane=10% ̃20%) to obtain compound 580 (50 mg, 41%) as brown oil.
1H NMR (400 MHz, CDCl3); 1:1.1 atropisomeric mixture; δ 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)
MS (ESI) m/z 666.2 (M++H).
Example 13
Compound 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
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° 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 (SiO2, EtOAc/hexane=20% ̃50%) to obtain compound 581 (21 mg, 47%) as a white solid.
1H NMR (400 MHz, CDCl3); 1:1.4 atropisomeric mixture; δ 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)
MS (ESI) m/z 648.2 (M++H).
Example 14
Compound 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
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° 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 (SiO2, EtOAc/hexane=20% ̃50%) to obtain compound 582 (10 mg, 23%) as a yellow solid.
1H NMR (400 MHz, CDCl3); 1:1.1 atropisomeric mixture; δ 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)
MS (ESI) m/z 650.2 (M+−H).
Example 15
Compound 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
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)Cl2 (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° 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 (SiO2, EtOAc/hexane=10% ̃15%) to obtain compound 590 (28 mg, 22%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 712.2 (M++H).
Example 16
Compound 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
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)Cl2 (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° 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 (SiO2, EtOAc/hexane=10% ̃15%) to obtain compound 591 (31 mg, 8%) as yellow oil.
1H NMR (400 MHz, CDCl3); 1:1.1 atropisomeric mixture; δ 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)
MS (ESI) m/z 712.3 (M++H).
Example 17
Compound 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
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° 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 (SiO2, EtOAc/hexane=10% ̃60%) to obtain compound 592 (15 mg, 61%) as a yellow solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 698.2 (M++H).
Example 18
Compound 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
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° 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 (SiO2, EtOAc/hexane=10% ̃70%) to obtain compound 593 (10 mg, 33%) as a white solid.
1H NMR (400 MHz, CDCl3); 1:1.2 atropisomeric mixture; δ 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)
MS (ESI) m/z 698.2 (M++H).
Example 19
Compound 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
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)Cl2 (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° 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 (SiO2, hexane/EtOAc=10% ̃50%) to obtain compound 599 (64 mg, 69.7%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 706.2 (M++H).
Example 20
Compound 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
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)Cl2 (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° 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 (SiO2, hexane/EtOAc=10% ̃50%) to obtain compound 600 (15 mg, 15.3%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 691.2 (M++H).
Example 21
Compound 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
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° 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 (SiO2, hexane/EtOAc=0% ̃30%) to obtain compound 601 (30 mg, 52.9%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 692.3 (M++H).
Example 22
Compound 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
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° 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 (SiO2, hexane/EtOAc=0% ̃30%) to obtain compound 602 (2.5 mg, 23.6%) as colorless oil.
MS (ESI) m/z 677.3 (M++H)
Example 23
Compound 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
Starting material 6b (0.190 g, 0.686 mmol), boronic acid 7 (0.474 g, 0.823 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=0% ̃100%) to obtain desired compound 665 (0.160 g, 33.8%) as clear oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 691.2 (M++H).
Example 24
Compound 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
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 (SiO2, EtOAc/hexane=0% ̃100%) to obtain desired compound 666 (0.020 g, 12.8%) as a white foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 677.2 (M++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
Starting material 8 (1.14 g, 3.70 mmol), 5-bromo-3-iodo-2-methoxypyridine (1.40 g, 4.44 mmol), Pd(PPh3)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° 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 (SiO2, EtOAc/hexane=1:9) to obtain compound 10 (0.37 g, 27%) as colorless oil.
MS (ESI) m/z 368.0 (M++H).
Intermediate Compound 11: 2-(5-bromo-2-methoxypyridin-2-yl)-5,5-dimethylcyclohex-1-enecarbaldehyde
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° C., followed by stirring at 0° 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° 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 (SiO2, EtOAc/hexane=10%) to aldehyde obtain 11 (0.12 g, 71%) as colorless oil.
MS (ESI) m/z 324.0 (M++H).
Intermediate Compound 12: (1R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((2-(5-bromo-2-methoxypyridin-3-yl)-5,5-dimethylcyclohex-1-enyl)methylamino)propan-1-ol
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.
MS (ESI) m/z 595.2 (M++H).
Intermediate Compound 13: (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(5-bromo-2-methoxypyridin-3-yl)-5,5-dimethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
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 (SiO2, EtOAc/hexane=10%) to obtain compound 13 (0.15 g, 73%) as colorless oil.
MS (ESI) m/z 621.1 (M++H).
Example 25
Compound 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
Starting material 13 (0.07 g, 0.11 mmol), 2-methyl-4-methoxycarbonylphenylboronic acid, pinacol ester (0.04 g, 0.13 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=1:4) to obtain compound 555 (42 mg, 56%) as a white solid.
1H NMR (400 MHz, CDCl3); 1:1.5 atropisomeric mixture; δ 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)
MS (ESI) m/z 691.2 (M++H).
Example 26
Compound 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
Starting material 13 (0.06 g, 0.1 mmol), 4-methoxycarbonylphenylboronic acid (0.02 g, 0.12 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=1:4) to obtain compound 556 (12 mg, 18%) as a white solid.
1H NMR (400 MHz, CDCl3); 1:1.6 atropisomeric mixture; δ 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)
MS (ESI) m/z 677.2 (M++H).
Example 27
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); 1:1.6 atropisomeric mixture; δ 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)
MS (ESI) m/z 677.2 (M++H).
Example 28
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); 1:1.6 atropisomeric mixture; δ 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)
MS (ESI) m/z 663.2 (M++H).
Example 29
Compound 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
Starting material 13 (0.15 g, 0.24 mmol), boronic acid 14 (0.06 g, 0.27 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=0%-20%) to obtain compound 583 (0.12 g, 68.7%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 710.2 (M++H).
Example 30
Compound 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
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° 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 (SiO2, EtOAc/hexane=0%-50%) to obtain compound 584 (2 mg, 2.5%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 697.1 (M++H).
Example 31
Compound 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
Starting material 13 (0.15 g, 0.24 mmol), boronic acid 14 (0.05 g, 0.27 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=0% ̃20%) to obtain compound 585 (0.14 g, 82.9%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 694.2 (M++H)
Example 32
Compound 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
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° 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 (SiO2, EtOAc/hexane=0% ̃50%) to obtain compound 586 (15 mg, 23.9%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 681.2 (M++H).
Example 33
Compound 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
Starting material 13 (0.14 g, 0.22 mmol), boronic acid 14 (0.04 g, 0.24 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=0% ̃20%) to obtain compound 587 (0.12 g, 79.7%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 677.2 (M++H).
Example 34
Compound 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
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° 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 (SiO2, EtOAc/hexane=0% ̃50%) to obtain compound 588 (10 mg, 13.3%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 663.2 (M++H).
Example 35
Compound 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
Starting material 13 (6 mg, 0.009 mmol), difluorophenyl pinacol ester (3 mg, 0.01 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=10% ̃20%) to obtain compound 595 (6 mg, 91.8%) as a solid.
1H NMR (400 MHz, CDCl3); 1:1.3 atropisomeric mixture; δ 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)
MS (ESI) m/z 713.2 (M++H).
Example 36
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); 1:1.4 atropisomeric mixture; δ 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)
MS (ESI) m/z 699.1 (M++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-methoxypyrimidin-4-yl)-5,5-dimethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
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)Cl2 (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° 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 (SiO2, hexane/EtOAc=3:1) to obtain compound 19 (43 mg, 20%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 578.1 (M++H).
Example 37
Compound 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
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)Cl2 (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° 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 (SiO2, hexane/EtOAc=10% ̃50%) to obtain compound 603 (27 mg, 52.5%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 692.2 (M++H).
Example 38
Compound 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
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° 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 (SiO2, CH2Cl2/CH3OH=20:1) to obtain compound 604 (17 mg, 64.3%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 678.2 (M++H).
Example 39
Compound 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
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)Cl2 (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° 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 (SiO2, hexane/EtOAc=1:1) to obtain compound 610 (3.3 mg, 5.5%) as colorless oil.
MS (ESI) m/z 696.2 (M++H).
Example 40
Compound 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
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° 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.
MS (ESI) m/z 682.3 (M++H).
Example 41
Compound 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
Starting material 19 (0.06 g, 0.1 mmol), phenylboronic acid (0.02 g, 0.12 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=30%) to obtain compound 625 (36 mg, 53.9%) as a solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 678.2 (M++H).
Example 42
Compound 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
Starting material 19 (0.06 g, 0.1 mmol), 3-fluorophenyl boronic acid (0.03 g, 0.12 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=30%) to obtain compound 626 (59 mg, 84.3%) as a solid.
1H NMR (400 MHz, CDCl3); 1:1.2 atropisomeric mixture; δ 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)
MS (ESI) m/z 710.2 (M++H).
Example 43
Compound 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
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° 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, CH3OH/CH2Cl2=10%) to obtain compound 628 (15 mg, 49.7%) as a solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 664.2 (M++H).
Example 44
Compound 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
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° 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, CH3OH/CH2Cl2=10%) to obtain compound 629 (22 mg, 41.6%) as a solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 682.2 (M++H).
Example 45
Compound 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
Starting material 19 (0.090 g, 0.161 mmol), 4-(methoxycarbonyl)phenylboronic acid (0.038 g, 0.209 mmol), Pd(dbpf)Cl2 (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° 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% ̃10%) to obtain compound 673 (0.052 g, 49.0%) as a white solid.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 660.2 (M++H).
Example 46
Compound 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
Starting material 19 (0.090 g, 0.161 mmol), 4-(methoxycarbonyl)2-methylphenylboronic acid (0.058 g, 0.209 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=10%) to obtain compound 674 (0.053 g, 49.2%) as a white solid.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 674.2 (M++H).
Example 47
Compound 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
Starting material 19 (0.090 g, 0.161 mmol), 2-fluoro-4-(methoxycarbonyl)phenylboronic acid (0.059 g, 0.209 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=10%) to obtain compound 675 (0.034 g, 31.1%) as a white solid.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 678.2 (M++H).
Example 48
Compound 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
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° 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 (SiO2, CH3OH/CH2Cl2=2%) to obtain compound 676 (0.033 g, 69.2%) as a white solid.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 646.2 (M++H).
Example 49
Compound 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
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° 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 (SiO2, CH3OH/CH2Cl2=5%) to obtain compound 677 (0.037 g, 71.3%) as a white solid.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 660.2 (M++H).
Example 50
Compound 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
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° 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 (SiO2, CH3OH/CH2Cl2=5%) to obtain compound 678 (0.022 g, 74.9%) as a white solid.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 664.2 (M++H).
Example 51
Compound 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
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)Cl2 (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° 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 (SiO2, EtOAc/hexane=0% ̃20%) to obtain desired compound 763 (0.020 g, 15.5%) as a brown solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 745.1 (M++H).
Example 52
Compounds 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
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 (SiO2, EtOAc/hexane=20% ̃50%) to obtain compound 764 (0.005 g, 47.6%) as a white solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 731.1 (M++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-nitrophenyl)-5,5-dimethylcyclohex-1-enyl)methylamino)propan-1-ol
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.
MS (ESI) m/z 579.2 (M++H).
Intermediate Compound 24: (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(4-fluoro-2-methoxy-5-nitrophenyl-5,5-dimethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
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 (SiO2 12 g, EtOAc/hexane=10%) to obtain compound 24 (0.29 g, 75%) as a yellow solid.
MS (ESI) m/z 605.1 (M++H).
Intermediate Compound 25: (4S,5R)-3-((2-(5-amino-4-fluoro-2-methoxyphenyl)-5,5-dimethylcyclohex-1-enyl)methyl)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one
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.
MS (ESI) m/z 575.3 (M++H).
Intermediate Compound 26: (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(4-fluoro-5-iodo-2-methoxyphenyl)-5,5-dimethylcyclohex-1-enyl)methyl-4-methyloxazolidin-2-one
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%).
MS (ESI) m/z 686.1 (M++H).
Example 53
Compound 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
Starting material 26 (0.05 g, 0.07 mmol), 2-methyl-4-methoxycarbonylphenylboronic acid pinacol ester (0.02 g, 0.09 mmol), Pd(dbpf)Cl2 (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° 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.
1H NMR (400 MHz, CDCl3); 1:1.2 atropisomeric mixture; δ 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)
MS (ESI) m/z 708.2 (M++H).
Example 54
Compound 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
Starting material 26 (0.05 g, 0.07 mmol), 4-methoxycarbonylphenylboronic acid (0.02 g, 0.09 mmol), Pd(dbpf)Cl2 (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° 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.
1H NMR (400 MHz, CDCl3); 1:1.3 atropisomeric mixture; δ 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)
MS (ESI) m/z 694.2 (M++H).
Example 55
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); 1:1.2 atropisomeric mixture; δ 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)
MS (ESI) m/z 694.2 (M++H).
Example 56
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); 1:1.3 atropisomeric mixture; δ 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)
MS (ESI) m/z 680.2 (M++H).
Example 57
Compound 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
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)Cl2 (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° 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 (SiO2, hexane/EtOAc=4:1) to obtain compound 630 (39 mg, 39%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 728.2 (M++H).
Example 58
Compound 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
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° 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 (SiO2, hexane/EtOAc=1:2) to obtain compound 631 (13 mg, 53%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 714.2 (M++H).
Example 59
Compound 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
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)Cl2 (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° 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 (SiO2, EtOAc/hexane=20%) to obtain compound 657 (0.049 g, 47.2%) as a white solid.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 712.3 (M++H).
Example 60
Compound 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
Starting material 26 (0.050 g, 0.073 mmol), 4-(ethoxycarbonyl)-3-fluorophenyl boronic acid (0.019 g, 0.088 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=20%) to obtain compound 658 (0.021 g, 39.7%) as a white solid.
1H NMR (400 MHz, CDCl3); 1:1.31 atropisomeric mixture; δ 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)
MS (ESI) m/z 726.3 (M++H).
Example 61
Compound 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
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)Cl2 (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° 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 (SiO2, EtOAc/hexane=20%) to obtain compound 659 (0.047 g, 44.5%) as a white solid.
1H NMR (400 MHz, CDCl3); 1:1.36 atropisomeric mixture; δ 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).
MS (ESI) m/z 724.3 (M++H).
Example 62
Compound 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
Starting material 26 (0.100 g, 0.146 mmol), 2,3-difluoro-4-(methoxycarbonyl)phenylboronic acid (0.038 g, 0.175 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=20%) to obtain compound 660 (0.031 g, 29.1%) as a white solid.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 730.3 (M++H).
Example 63
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 698.2 (M++H).
Example 64
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); 1:1.38 atropisomeric mixture; δ 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)
MS (ESI) m/z 698.2 (M++H).
Example 65
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); 1:1.44 atropisomeric mixture; δ 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)
MS (ESI) m/z 710.2 (M++H).
Example 66
Compound 664
5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-22′,3-trifluoro-4′-methoxybiphenyl-4-carboxylic acid
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° 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.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 716.2 (M++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
Starting material 1 (0.05 g, 0.22 mmol), boronic acid 28 (0.07 g, 0.22 mmol), Pd(PPh3)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° 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 (SiO2, EtOAc/hexane=0% ̃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-methoxypyridin-4-yl)-5,5-dimethylcyclohex-1-enyl)methylamino)propan-1-ol
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, CH3OH/CH2Cl2=0% ̃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-methoxypyridin-4-yl)-5,5-dimethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
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° 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 (SiO2, EtOAc/hexane=0% ̃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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl)benzoate
Starting material 31 (0.07 g, 0.11 mmol), boronic acid 26 (0.02 g, 0.12 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=0% ̃20%) to obtain compound 652 (35 mg, 45.9%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 677.2 (M++H).
Example 68
Compound 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
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° 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 (SiO2, EtOAc/hexane=0% ̃50%) to obtain compound 644 (20 mg, 56.7%) as a white foam solid.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 663.2 (M++H).
Example 69
Compound 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
Starting material 31 (0.07 g, 0.11 mmol), boronic acid 26 (0.03 g, 0.12 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=0% ̃20%) to obtain compound 653 (51 mg, 65.6%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 691.2 (M++H).
Example 70
Compound 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
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° 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 (SiO2, EtOAc/hexane=0% ̃50%) to obtain compound 645 (20 mg, 43.4%) as a white foam solid.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 677.2 (M++H).
Example 71
Compound 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
Starting material 31 (0.07 g, 0.11 mmol), boronic acid 26 (0.04 g, 0.12 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=0%-20%) to obtain compound 654 (61 mg, 78%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 695.2 (M++H).
Example 72
Compound 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
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° 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 (SiO2, EtOAc/hexane=0%-50%) to obtain compound 646 (20 mg, 41.7%) as a white foam solid.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 681.2 (M++H).
Example 73
Compound 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
Starting material 31 (0.07 g, 0.11 mmol), boronic acid 26 (0.03 g, 0.12 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=0% ̃30%) to obtain compound 655 (40 mg, 49.9%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 711.2 (M++H).
Example 74
Compound 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
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° 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% ̃50%) to obtain compound 647 (10 mg, 35.2%) as white foam solid.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 697.1 (M++H).
Example 75
Compound 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
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)Cl2 (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° 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 (SiO2, EtOAc/hexane=0% ̃20%) to obtain desired compound 656 (0.0410 g, 49.8%) as brown oil.
1H NMR (400 MHz, CDCl3); 1:1 atropisomeric mixture; δ 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)
MS (ESI) m/z 713.2 (M++H).
Preparation of Novel Compounds According to Reaction Scheme 8
Intermediate Compound 33a: methyl 4-(6-bromo-5-methoxypyridin-2-yl)-3-methylbenzoate
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)Cl2 (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° 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 (SiO2, EtOAc/hexane=10% ̃15%) to obtain compound 33a (80 mg, 37%) as a white solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 336.0, 338.0 (M, M++2H).
Intermediate Compound 33b: methyl 4-(6-bromo-5-methoxypyridin-2-yl)-3-fluorobenzoate
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)Cl2 (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° 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.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 340.0, 342.0 (M, M++2H).
Intermediate Compound 33c: methyl 4-(6-bromo-5-methoxypyridin-2-yl)-3-chlorobenzoate
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)Cl2 (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° 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.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 356.0, 358.0 (M, M++2H).
Example 76
Compound 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
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)Cl2 (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° 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 (SiO2, EtOAc/hexane=20%) to obtain compound 621 (26 mg, 21%) as a white solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 691.2 (M++H).
Example 77
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 677.2 (M++H).
Example 78
Compound 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
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)Cl2 (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° 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 (SiO2, EtOAc/hexane=10% ̃20%) to obtain compound 696 (9 mg, 15%) as yellow oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 695.2 (M++H).
Example 79
Compound 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
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° 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%→CH3OH/CH2Cl2=5%) to obtain compound 637 (6 mg, 68%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 681.2 (M++H).
Example 80
Compound 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
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)Cl2 (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° 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% ̃20%) to obtain compound 697 (9 mg, 14%) as oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 711.1 (M++H).
Example 81
Compound 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
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° 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%→CH3OH/CH2Cl2=5%) to obtain compound 636 (4 mg, 45%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 697.2 (M++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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-6-methoxypyridin-3-yl)-3-(prope-1-en-2-yl)benzoate
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)Cl2 (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° 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% ̃15%) to obtain compound 35 (48 mg, 48%) as brown oil.
1H NMR (400 MHz, CDCl3); 1:1.9 atropisomeric mixture; δ 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)
MS (ESI) m/z 717.2 (M++H).
Example 82
Compound 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
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.
1H NMR (400 MHz, CDCl3); 1:1.5 atropisomeric mixture; δ 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)
MS (ESI) m/z 719.2 (M++H).
Example 83
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); 1:1.5 atropisomeric mixture; δ 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)
MS (ESI) m/z 705.2 (M++H).
Preparation of Novel Compounds According to Reaction Scheme 10
Intermediate Compound 38a: 2-(2-methoxy-4-methyl-5-nitrophenyl)-5,5-dimethylcyclohex-1-enecarbaldehyde
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° 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 (SiO2, 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-enecarbaldehyde
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° 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 (SiO2, 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-nitrophenyl)-5,5-dimethylcyclohex-1-enyl)methylamino)propan-1-ol
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, CH3OH/CH2Cl2=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-(trifluoromethyl)phenyl)-5,5-dimethylcyclohex-1-enyl)methylamino)propan-1-ol
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 (SiO2, EtOAc/hexane=20% ̃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-nitrophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
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° 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% ̃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-(trifluoromethyl)phenyl)-5,5-dimethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
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° 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 (SiO2, EtOAc/hexane=15% ̃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-enyl)methyl)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one
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 (SiO2, EtOAc/hexane=0% ̃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-dimethylcyclohex-1-enyl)methyl)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one
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-methylphenyl)-5,5-dimethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
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 (SiO2, EtOAc/hexane=0% ̃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-(trifluoromethyl)phenyl)-5,5-dicyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
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 (SiO2, hexane/EtOAc=10 ̃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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxy-2′-(trifluoromethyl)biphenyl-4-carboxy late
Starting material 42b (0.06 g, 0.08 mmol), boronic acid 7 (0.02 g, 0.1 mmol), Pd(dppf)Cl2 (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° 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.
MS (ESI) m/z 744.2 (M++H).
Example 85
Compound 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
Starting material 42b (0.06 g, 0.08 mmol), boronic acid 7 (0.02 g, 0.1 mmol), Pd(dppf)Cl2 (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° 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.
MS (ESI) m/z 762.2 (M++H).
Example 86
Compound 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
Starting material 42b (0.06 g, 0.08 mmol), boronic acid 7 (0.02 g, 0.1 mmol), Pd(dppf)Cl2 (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° 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 (SiO2, hexane/EtOAc=4:1) to obtain compound 607 (21 mg, 34.3%) as colorless oil.
MS (ESI) m/z 776.2 (M++H).
Example 87
Compound 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
Starting material 42b (0.06 g, 0.08 mmol), boronic acid 7 (0.02 g, 0.1 mmol), Pd(dppf)Cl2 (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° 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 (SiO2, hexane/EtOAc=4:1) to obtain compound 608 (14 mg, 22.9%) as colorless oil.
MS (ESI) m/z 778.1 (M++H).
Example 88
Compound 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
Starting material 42b (0.06 g, 0.08 mmol), boronic acid 7 (0.03 g, 0.1 mmol), Pd(dppf)Cl2 (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° 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 (SiO2, hexane/EtOAc=4:1) to obtain compound 609 (27 mg, 45.2%) as colorless oil.
MS (ESI) m/z 758.2 (M++H).
Example 89
Compound 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-fluoro picolinic acid
Starting material 42b (0.06 g, 0.08 mmol), boronic acid 7 (0.03 g, 0.1 mmol), Pd(dppf)Cl2 (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° 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 (SiO2, CH2Cl2/CH3OH=15:1) to obtain compound 611 (2.1 mg, 3.4%) as colorless oil.
MS (ESI) m/z 749.1 (M++H).
Example 90
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 730.3 (M++H).
Example 91
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 749.2 (M++H).
Example 92
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 748.2 (M++H).
Example 93
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 762.2 (M+−H).
Example 94
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 744.3 (M++H).
Example 95
Compound 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
Starting material 42a (0.05 g, 0.07 mmol), boronic acid 7 (14 mg, 0.08 mmol), Pd(dppf)Cl2 (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° 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% ̃30%) to obtain compound 619 (18 mg, 38.6%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 690.2 (M++H).
Example 96
Compound 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
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° 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 (SiO2, EtOAc/hexane=0% ̃50%) to obtain compound 620 (9 mg, 61.2%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 676.2 (M++H).
Example 97
Compound 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
Starting material 42b (0.06 g, 0.08 mmol), boronic acid 7 (0.04 g, 0.12 mmol), Pd(dppf)Cl2 (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° 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.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 778.1 (M++H).
Example 98
Compound 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
Starting material 42b (0.06 g, 0.08 mmol), boronic acid 7 (0.03 g, 0.1 mmol), Pd(dppf)Cl2 (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° 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.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 774.2 (M++H).
Example 99
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 764.1 (M++H).
Example 100
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 760.2 (M++H).
Example 101
Compound 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
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)Cl2 (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° 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% ̃15%) to obtain compound 683 (0.025 g, 30.3%) as colorless oil.
1H NMR (400 MHz, CDCl3); 1:1 atropisomeric mixture; δ 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)
MS (ESI) m/z 704.2 (M++H).
Example 102
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
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° 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% ̃50%) to obtain desired compound 684 (0.011 g, 44.9%) as a white foam solid.
1H NMR (400 MHz, CDCl3); 1:1 atropisomeric mixture; δ 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)
MS (ESI) m/z 690.3 (M++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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,4′-dimethoxybiphenyl-4-carboxylate
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)Cl2 (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° 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 (SiO2, EtOAc/hexane=10% ̃30%) to obtain compound 594 (15 mg, 24%) as colorless oil.
MS (ESI) m/z 706.2 (M++H).
Example 104
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); 1:1.6 atropisomeric mixture; δ 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)
MS (ESI) m/z 692.2 (M++H).
Example 105
Compound 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
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)Cl2 (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° 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% ̃20%) to obtain compound 667 (0.31 g, 100%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 732.2 (M++H).
Example 106
Compound 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
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° 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.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 718.2 (M++H).
Example 107
Compound 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
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)Cl2 (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° 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.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 678.1 (M++H).
Example 108
Compound 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
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° 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 (SiO2, CH3OH/CH2Cl2=10%) to obtain compound 694 (0.031 g, 59%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 664.2 (M++H).
Example 109
Compound 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
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)Cl2 (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° 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 (SiO2, EtOAc/hexane=14%) to obtain compound 693 (0.036 g, 61%) as a pale yellow foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 732.1 (M++H).
Example 110
Compound 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
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° 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 (SiO2, CH3OH/CH2Cl2=10%) to obtain compound 695 (0.018 g, 51%) as a white foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 718.1 (M++H).
Example 111
Compound 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
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)Cl2 (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° 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 (SiO2, hexane/EtOAc=5% ̃30%) to obtain compound 699 (67 mg, 56.7%) as colorless oil.
1H NMR (400 MHz, CDCl3); atropisomeric mixture; δ 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)
MS (ESI) m/z 682.2 (M++H).
Example 112
Compound 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
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° 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 (SiO2, hexane/EtOAc=1:2) to obtain compound 702 (11 mg, 59.1%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 669.1 (M++H).
Example 113
Compound 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
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)Cl2 (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° 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 (SiO2, hexane/EtOAc=5% ̃30%) to obtain compound 700 (88 mg, 65%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 664.2 (M++H).
Example 114
Compound 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
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° 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 (SiO2, hexane/EtOAc=1:2) to obtain compound 703 (15 mg, 63.8%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 650.1 (M++H).
Example 115
Compound 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
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)Cl2 (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° 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 (SiO2, hexane/EtOAc=5% ̃30%) to obtain compound 701 (64 mg, 41.8%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 664.1 (M++H).
Example 116
Compound 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
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° 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 (SiO2, hexane/EtOAc=1:2) to obtain compound 704 (7 mg, 29.8%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 650.2 (M++H).
Example 117
Compound 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
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)Cl2 (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° 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 (SiO2, EtOAc/hexane=0% ̃20%) to obtain compound 708 (0.028 g, 51%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 664.3 (M++H).
Example 118
Compound 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
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° 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 (SiO2, EtOAc/hexane=50%) to obtain compound 709 (0.008 g, 64%) as colorless liquid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 650.2 (M++H).
Example 119
Compound 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
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)Cl2 (0.003 g, 0.005 mmol) were added to dimethoxyethane (0.9 mL)/water (0.3 mL) and heated by microwave irradiation at 120° 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 (SiO2, EtOAc/hexane=0% ̃50%) to obtain desired compound 714 (0.020 g, 30.5%) as clear oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 661.1 (M++H).
Example 120
Compound 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
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 (SiO2, EtOAc/hexane=0% ̃100%) to obtain desired compound 716 (0.012 g, 61.3%) as a white foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 647.2 (M++H).
Example 121
Compound 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
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(PPh3)2Cl2 (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° 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 (SiO2, EtOAc/hexane=0% ̃20%) to obtain desired compound 726 (0.030 g, 16.2%) in an impure form.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 694.1 (M++H).
Example 122
Compound 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
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.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 680.1 (M++H).
Preparation of Novel Compounds According to Reaction Scheme 12
Intermediate Compound 48: methyl 4′-methoxy-2-(trifluoromethyl)biphenyl-4-carboxylate
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)Cl2 (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° 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% ̃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
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 (SiO2EtOAc/hexane=0% ̃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-(trifluoromethyl)biphenyl-4-carboxylate
Starting material 49 (0.253 g, 0.580 mmol), bis(pinacolate)diboron (0.22 g, 0.87 mmol), Pd(dppf)Cl2 (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° 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 (SiO2, EtOAc/hexane=0% ̃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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxy-2-(trifluoromethyl)biphenyl-4-carboxylate
Starting material 50 (75 mg, 0.17 mmol), compound 16 (0.09 g, 0.17 mmol), Pd(dbpf)Cl2 (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° 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% ̃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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxy-2-(trifluoromethyl)biphenyl-4-carboxylic acid
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° 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 (SiO2, EtOAc/hexane=0% ̃50%) to obtain compound 618 (20 mg, 47.4%) as colorless oil.
1H NMR (400 MHz, CDCl3); 2:3 atropisomeric mixture; δ 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)
MS (ESI) m/z 730.1 (M++H).
Preparation of Novel Compounds According to Reaction Scheme 13
Intermediate Compound 53a: ethyl 2-(3-chlorophenyl)-5,5-dimethylcyclohex-1-enecarboxylate
Starting material 52 (0.31 g, 1.01 mmol), compound 8 (0.12 mL, 1.0 mmol), Pd(dppf)Cl2 (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° 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 (SiO2, EtOAc/hexane=5%) to obtain compound 53a (0.25 g, 84.9%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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
Starting material 52 (0.51 g, 1.66 mmol), compound 8 (0.20 mL, 1.62 mmol), Pd(dppf)Cl2 (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° 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 (SiO2, EtOAc/hexane=5% ̃35%) to obtain compound 53b (0.37 g, 71.9%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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
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° 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.
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 (SiO2, EtOAc/hexane=5% ̃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
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° 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.
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 (SiO2, EtOAc/hexane=5% ̃25%) to obtain compound 54b (0.15 g, 53%) as yellow oil.
1H NMR (400 MHz, CDCl3); δ 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-dimethylcyclohex-1-enyl)methylamino)propan-1-ol
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
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-dimethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
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 (SiO2, EtOAc/hexane=5% ̃20%) to obtain compound 56a (0.19 g, 63.3%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 546.1 (M++H).
Intermediate Compound 56b: (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(3-chloro-5-fluorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one
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 (SiO2, EtOAc/hexane=5% ̃20%) to obtain compound 56b (0.17 g, 48.9%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methylbiphenyl-4-carboxylate
Starting material 56a (0.13 g, 0.24 mmol), boronic acid pinacol ester 57 (0.08 g, 0.29 mmol), Pd(dbpf)Cl2 (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° 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% ̃30%) to obtain compound 649 (15 mg, 9.5%) as colorless oil.
MS (ESI) m/z 660.3 (M++H).
Example 125
Compound 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
Starting material 56b (0.07 g, 0.13 mmol), boronic acid pinacol ester 57 (0.04 g, 0.15 mmol), Pd(dbpf)Cl2 (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° 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.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 678.2 (M++H).
Example 126
Compound 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
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° 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 (SiO2, hexane/EtOAc=1:2) to obtain compound 651 (6.4 mg, 40.9%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 646.2 (M++H).
Example 127
Compound 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
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° 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 (SiO2, hexane/EtOAc=1:2) to obtain compound 650 (5.5 mg, 30.6%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 664.2 (M++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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4′-methoxybiphenyl-4-carboxylate
Starting material 59 (0.26 g, 0.39 mmol), boronic acid 60 (0.09 g, 0.43 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=20%) to obtain compound 642 (0.12 g, 41.6%) as a white solid.
1H NMR (400 MHz, CDCl3); 1:1.40 atropisomeric mixture; δ 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)
MS (ESI) m/z 710.1 (M++H).
Example 129
Compound 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
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° 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, CH2Cl2/CH3OH=5%) to obtain compound 643 (19 mg, 95.9%) as a white solid.
1H NMR (400 MHz, CDCl3); 1:1.4 atropisomeric mixture; δ 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)
MS (ESI) m/z 696.1 (M++H).
Example 130
Compound 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
(4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(2-chloro-5-iodophenyl)-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(PPh3)2Cl2 (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° 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 (SiO2, EtOAc/hexane=0%-20%) to obtain observed compound 728 (0.025 g, 76.5%) in an impure form.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 748.1 (M++H).
Example 131
Compound 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
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.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 734.1 (M++H).
Example 132
Compound 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
(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-methyloxazolidin-2-one (0.067 g, 0.102 mmol), (2-chloro-4-(methoxycarbonyl)phenyl)boronic acid (0.024 g, 0.112 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=20%) to obtain compound 738 (0.024 g, 34%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 698.1 (M++H).
Example 133
Compound 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
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 (SiO2, CH3OH/CH2Cl2=5%) to obtain compound 739 (0.016 g, 67%) as a white foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 684.1 (M++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-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)-4-methyloxazolidin-2-one
Starting material 16 (0.500 g, 0.972 mmol), (3-chloro-4-fluorophenyl)boronic acid (0.186 g, 1.069 mmol), Pd(dbpf)Cl2 (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° 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 (SiO2, EtOAc/hexane=0% ̃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-methoxyphenyl)-5,5-dimethylcyclohex-1-enyl)methyl)-4-methoxyoxazolidin-2-one
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)Cl2 (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° 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
Starting material 16 (0.300 g, 0.583 mmol), 5-chloro-2-fluorophenylboronic acid (0.153 g, 0.875 mmol), Pd(dbpf)Cl2 (0.019 g, 0.029 mmol) and Na2CO3 (0.185 g, 1.750 mmol) were added to dimethoxyethane (0.9 mL)/water (0.3 mL) and stirred with microwave irradiation at 120° 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 (SiO2, 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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methyl-5′-(trifluoromethyl)biphenyl-4-carboxylate
Starting material 16 (0.500 g, 0.972 mmol), 3-chloro-5-(trifluoromethyl)phenylboronic acid (0.327 g, 1.458 mmol), Pd(PPh3)2Cl2 (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° 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 (SiO2, EtOAc/hexane=0% ̃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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2′-fluorobiphenyl-4-carboxylate
Compound 62a (0.100 g, 0.177 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (0.048 g, 0.266 mmol), Pd(dbpf)Cl2 (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° 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(SiO2, EtOAc/hexane=0% ̃10%) to obtain compound 670 (0.087 g, 74%) as pale yellow oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 664.1 (M++H).
Example 135
Compound 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
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° 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, CH3OH/CH2Cl2=5%) to obtain compound 679 (0.024 g, 31%) as white oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 650.1 (M++H).
Example 136
Compound 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
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)Cl2 (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° 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.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 682.1 (M++H).
Example 137
Compound 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
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° 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, CH3OH/CH2Cl2=5%) to obtain compound 680 (0.011 g, 38%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 668.1 (M++H).
Example 138
Compound 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
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)Cl2 (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° 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 as 672 (0.073 g, 61%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 678.1 (M++H).
Example 139
Compound 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
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° 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, CH3OH/CH2Cl2=5%) to obtain compound 681 (0.024 g, 25%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 664.2 (M++H).
Example 140
Compound 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
Starting material 62b (0.100 g, 0.174 mmol), 4-(methoxycarbonyl)phenylboronic acid (0.034 g, 0.191 mmol), Pd(di-t-Bupf)Cl2 (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° 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.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 676.2 (M++H).
Example 141
Compound 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
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° 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% ̃35%) to obtain desired compound 687 (0.045 g, 46.0%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 662.2 (M++H).
Example 142
Compound 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
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)Cl2 (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° 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% ̃20%) to obtain desired compound 688 (0.070 g, 58.5%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 690.2 (M++H).
Example 143
Compound 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
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° 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% ̃35%) to obtain compound 689 (0.035 g, 49.6%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 676.2 (M++H).
Example 144
Compound 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
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)Cl2 (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° 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 desired compound 690 (0.060 g, 49.8%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 694.2 (M++H).
Example 145
Compound 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
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° 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% ̃35%) to obtain desired compound 691 (0.010 g, 16.5%) as a brown foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 680.2 (M++H).
Example 146
Compound 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
Starting material 62c (0.240 g, 0.426 mmol), (2-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (0.093 g, 0.468 mmol), Pd(dbpf)Cl2 (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° 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% ̃20%) to obtain compound 724 (0.149 g, 51%) as a white foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 682 (M++H).
Example 147
Compound 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
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° 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% ̃30%) to obtain compound 722 (0.093 g, 75%) as a white foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 668.2 (M++H).
Example 148
Compound 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
Compound 62a (0.140 g, 0.248 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzoate (0.090 g, 0.273 mmol), Pd(dbpf)Cl2 (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° 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% ̃10%) to obtain compound 725 (0.086 g, 47%) as yellow oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 732.1 (M++H).
Example 149
Compound 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
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° 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 (SiO2, CH3OH/CH2Cl2=5%) to obtain compound 723 (0.027 g, 32%) as a white foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 718.1 (M++H).
Example 150
Compound 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
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)Cl2 (0.005 g, 0.008 mmol) were added to dimethylformamide (0.8 mL)/water (0.4 mL) and heated by microwave irradiation at 100° 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 (SiO2, EtOAc/hexane=0% ̃20%) to obtain desired compound 743 (0.075 g, 63.3%) as a white foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 728.2 (M++H).
Example 151
Compound 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
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 (SiO2, EtOAc/hexane=10% ̃50%) to obtain desired compound 744 (0.046 g, 67.0%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 714.1 (M++H).
Example 152
Compound 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
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)Cl2 (0.003 g, 0.004 mmol) were added to dimethylformamide (0.8 mL)/water (0.4 mL) and stirred with microwave irradiation at 100° 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 (SiO2, EtOAc/hexane=0% ̃20%) to obtain desired compound 745 (0.050 g, 86.0%) as a white foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 714.2 (M++H).
Example 153
Compound 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
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 (SiO2, EtOAc/hexane=10% ̃50%) to obtain desired compound 746 (0.021 g, 47.6%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 700.1 (M++H).
Example 154
Compound 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
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)Cl2 (0.003 g, 0.004 mmol) were added to dimethylformamide (0.8 mL)/water (0.4 mL) and heated by microwave irradiation at 100° 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 (SiO2, EtOAc/hexane=0% ̃20%) to obtain desired compound 747 (0.058 g, 97.3%) as a white foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 732.1 (M++H).
Example 155
Compound 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
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 (SiO2, EtOAc/hexane=10% ̃50%) to obtain desired compound 748 (0.030 g, 69.5%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 718.1 (M++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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxy-2-methylbiphenyl-4-carboxamide
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 (SiO2, CH3OH/CH2Cl2=0% ̃5%) to obtain compound 682 (1.180 g, 86.3%) as a white solid.
1H NMR (400 MHz, CDCl3); 1:1.40 atropisomeric mixture; δ 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)
MS (ESI) m/z 675.2 (M++H).
Example 157
Compound 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
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 (SiO2, EtOAc/hexane=0% ̃50%) to obtain desired compound 740 (0.006 g, 60.1%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 695.1 (M++H).
Example 158
Compound 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
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 (SiO2, EtOAc/hexane=0% ̃50%) to obtain desired compound 741 (0.007 g, 70.1%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 663.2 (M++H).
Example 159
Compound 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
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 (SiO2, EtOAc/hexane=0% ̃50%) to obtain desired compound 742 (0.008 g, 80.1%) as colorless oil.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 717.1 (M++H).
Example 160
Compound 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
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 (SiO2, EtOAc/hexane=33%) to obtain compound 754 (0.062 g, 78%) as a white foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 793.1 (M++H).
Example 161
Compound 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
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 (SiO2, EtOAc/hexane=33%) to obtain compound 755 (0.012 g, 16%) as a white foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z Not detected (M++H).
Example 162
Compound 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
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 (SiO2, EtOAc/hexane=33%) to obtain compound 756 (0.055 g, 74%) as a white foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 745.1 (M++H).
Example 163
Compound 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
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 (SiO2, EtOAc/hexane=33%) to obtain compound 757 (0.048 g, 64%) as a white foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 759.2 (M++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
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 (SiO2, EtOAc/hexane=33%) to obtain compound 758 (0.066 g, 83%) as a white foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 787.2 (M++H).
Preparation of Novel Compounds According to Reaction Scheme 17
Intermediate Compound 66: (2-(5-chloro-2-methoxyphenyl)-5,5-dimethylcyclohex-1-enyl)methanol
Starting material 65 (0.560 g, 2.009 mmol) was dissolved in THF (20 mL) at 0° 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 (SiO2, EtOAc/hexane=0% ̃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-methylbiphenyl-4-carboxylate
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)Cl2 (0.058 g, 0.089 mmol) were added to dimethoxymethane (1.2 mL)/water (0.4 mL) and heated by microwave irradiation at 120° 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 (SiO2, EtOAc/hexane=0% ̃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-methylbiphenyl-4-carboxylate
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° 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 (SiO2, EtOAc/hexane=0% ̃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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxyphenyl-2-methylbiphenyl-4-carboxylate
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° 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% ̃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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxyphenyl-2-methylbiphenyl-4-carboxylate
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° 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 (SiO2, EtOAc/hexane=0% ̃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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxyphenyl-2-methylbiphenyl-4-carboxylate
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° 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 (SiO2, 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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxy-2-methylbiphenyl-4-carboxylic acid
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.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 676.2 (M++H).
Example 166
Compound 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
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 (SiO2, EtOAc/hexane=0%-100%) to obtain desired compound 719 (0.025 g, 85.1%) as a white foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 676.2 (M++H).
Example 167
Compound 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
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 (SiO2, EtOAc/hexane=0% ̃100%) to obtain desired compound 720 (0.028 g, 95.3%) as a white foam solid.
1H NMR (400 MHz, CDCl3); δ 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)
MS (ESI) m/z 676.2 (M++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)methylamino)-1-(3,5-difluorophenyl)propan-1-ol
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 (SiO2, EtOAc/hexane=5% ̃10%) to obtain compound 76 (0.182 g, 22.6%) as colorless oil.
MS (ESI) m/z 450.2 (M++H).
Intermediate Compound 77: (4S,5R)-3-((2-(5-chloro-2-methoxyphenyl)-5,5-dimethylcyclohex-1-enyl)methyl)-5-(3,5-difluorophenyl)-4-methyloxazolidin-2-one
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 (SiO2, EtOAc/hexane=5% ̃10%) to obtain compound 77 (0.142 g, 90.2%) as a white solid.
MS (ESI) m/z 476.1 (M++H).
Example 168
Compound 705
methyl 3′-(2-(((4S,5R)-5-(3,5-difluorophenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-di methylcyclohex-1-enyl)-4′-methoxy-2-methylbiphenyl-4-carboxylate
Starting material 77 (0.138 g, 0.290 mmol), compound 57 (0.073 g, 0.377 mmol), Pd(dbpf)Cl2 (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° 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% ̃20%) to obtain compound 705 (0.110 g, 64.6%) as a white solid.
1H NMR (400 MHz, CDCl3); 1:1.31 atropisomeric mixture; δ 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)
MS (ESI) m/z 590.2 (M++H).
Example 169
Compound 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
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° 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, CH3OH/CH2Cl2=5%) to obtain compound 706 (0.051 g, 50.7%) as a white solid.
1H NMR (400 MHz, CDCl3); 1:1.35 atropisomeric mixture; δ 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)
MS (ESI) m/z 576.3 (M++H).
The structural formulas of compounds 553 to 764 prepared as described above are shown in Tables 1 to 29 below.








TABLE 1





Compound
Structure







553






 


554






 


555






 


556






 


557






 


558





















TABLE 2





Compound
Structure







559






 


560






 


561






 


564






 


565






 


567





















TABLE 3





Compound
Structure







568






 


569






 


572






 


573






 


574






 


575





















TABLE 4





Compound
Structure







577






 


578






 


579






 


580






 


581






 


582





















TABLE 5





Compound
Structure







583






 


584






 


585






 


586






 


587






 


588





















TABLE 6





Compound
Structure







590






 


591






 


592






 


593






 


594






 


595





















TABLE 7





Compound
Structure







596






 


597






 


599






 


600






 


601






 


602





















TABLE 8





Compound
Structure







603






 


604






 


605






 


606






 


607






 


608





















TABLE 9





Compound
Structure







609






 


610






 


611






 


612






 


613






 


614





















TABLE 10





Compound
Structure







615






 


616






 


617






 


618






 


619






 


620





















TABLE 11





Compound
Structure







621






 


622






 


625






 


626






 


628






 


629





















TABLE 12





Compound
Structure







630






 


631






 


632






 


633






 


636






 


637





















TABLE 13





Compound
Structure







638






 


639






 


642






 


643






 


644






 


645





















TABLE 14





Compound
Structure







646






 


647






 


648






 


649






 


650






 


651





















TABLE 15





Compound
Structure







652






 


653






 


654






 


655






 


656






 


657





















TABLE 16





Com-



pound
Structure







658






 


659






 


660






 


661






 


662






 


663





















TABLE 17





Compound
Structure







664






 


665






 


666






 


667






 


668






 


670





















TABLE 18





Compound
Structure







671






 


672






 


673






 


674






 


675






 


676





















TABLE 19





Compound
Structure







677






 


678






 


679






 


680






 


681






 


682





















TABLE 20





Compound
Structure







683






 


684






 


686






 


687






 


688






 


689





















TABLE 21





Compound
Structure







690






 


691






 


692






 


693






 


694






 


695





















TABLE 22





Compound
Structure







696






 


697






 


699






 


700






 


701






 


702





















TABLE 23





Compound
Structure







703






 


704






 


705






 


706






 


708






 


709





















TABLE 24





Compound
Structure







714






 


716






 


718






 


719






 


720






 


722





















TABLE 25





Compound
Structure







723






 


724






 


725






 


726






 


727






 


728





















TABLE 26





Compound
Structure







729






 


738






 


739






 


740






 


741






 


742





















TABLE 27





Compound
Structure







743






 


744






 


745






 


746






 


747






 


748





















TABLE 28





Com-



pound
Structure







754






 


755






 


756






 


757






 


758






 


763





















TABLE 29





Compound
Structure







764













Measurement of Activities of Compounds According to the Present Invention—Test Protocols
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)
1. Construction of Cholesteryl Ester Donor
To construct a cholesteryl ester donor to be used in the test, radiolabeled recombinant HDL containing [41]-cholesteryl oleate (GE healthcare, TRK886, 3.5 μCi/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.
2. Cholesteryl Ester Transfer Test
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 μl of plasma, 50 μl of LDL (0.25 mg/ml) and 50 μl of rHDL-agarose (0.25 mg/ml) were added, and a solution containing a test compound was added, followed by reaction at 37° C. Then, centrifugation was performed at 4° C. for 3 minutes to stop the reaction, and 150 μl 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.
3. Statistical Processing
The ratio of [3H]-cholesteryl oleate from HDL to LDL was calculated and used as a result value, and from the result value, IC50 value was calculated using GraphPad Prism 5.0.







TABLE 30







Cholesteryl ester transfer test










Compound
IC50 (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










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)
1. Test Animals
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.
2. Anti-Hyperlipidemic Test in Hamsters
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).
3. Statistical Processing
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 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









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
1. Test Method
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 1×105/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 μM 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° C. The supernatant stored at −20° 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).
2. Statistical Processing
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 32







Evaluation of secretion of blood pressure-related


hormones (treated with 1 μM 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









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.

## Claims

1. A compound of Formula I:




or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
R1 is —H or —C1-C3 alkyl;
R2 is —H, halogen or —C1-C3 alkyl;
R3, R4, R5 and R6 are each independently —H, halogen, —NO2, —C1-C3 alkyl, or —OC1-C3 alkyl;
R7 is —H, —(C═O)OR8, or




R8 is —H or —C1-C3 alkyl;
R11 and R12 are each independently —H or —C1-C3 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;
A1, A2 and A3 are each independently N or CR9, wherein if A2 or A3 is N, A1 is CR9;
R9 is —H, halogen, —C1-C3 alkyl or —OC1-C3 alkyl;
B is N or CR10;
R10 is H, halogen, —C1-C3 alkyl, —OC1-C3 alkyl, —(C═O)OR8, or





provided that one or more —H atoms in the —C1-C3 alkyl or the —OC1-C3 alkyl may be substituted with —F or —CH3, and if R7 is —H, B is CR10, and R10 is —(C═O)OR8 or




and if R7 is not —H, R10 cannot be —(C═O)OR8 or

2. The compound of claim 1, wherein:
R1 is —H or —CH3;
R2 is —F or —CF3;
R3, R4, R5 and R6 are each independently —H, —F, —NO2, —CH3, —CH(CH3)2, —CF3 or —OCH3;
R7 is —H, —(C═O)OR8, or




R8 is —H, —CH3 or —CH2CH3;
R11 and R12 are each independently —H, —CH3 or —CH2CH3 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;
A1, A2 and A3 are each independently N or CR9, wherein if A2 or A3 is N, A1 is CR9;
R9 is —H, —F, —CH3, —CF3 or —OCH3;
B is N or CR10;
R10 is —H, —F, —CH3, —OCH3, —CO2H, —CO2CH3, —CO2CH2CH3, or





provided that if R7 is —H, B is CR10, and R10 is —CO2H, —CO2CH3, —CO2CH2CH3, or




and if R7 is not —H, R10 is not —CO2H, —CO2CH3, —CO2CH2CH3, or

3. The compound of claim 2, wherein:
R1 is —CH3;
R2 is —CF3;
R3 is —H, —F, —Cl or —OCH3;
R4 is —H, —F, —Cl, —CH3, —CH(CH3)2, —CF3 or —OCH3;
R5 is —H, —F or —Cl;
R6 is —H;
R7 is —H, —(C═O)OH,




A1, A2 and A3 are each independently N or CR9, wherein if A2 or A3 is N, A1 is CR9;
R9 is —H, —F, —CH3, —CF3 or —OCH3;
B is CR10;
R10 is —H, —F or —CO2CH3;

provided that if R7 is —H, B is CR10, and R10 is —CO2CH3, and if R7 is not —H, R10 is not —CO2CH3.

4. The compound of claim 3, wherein:
R3 is —H, —F or —OCH3;
R4 is —H, —F, —Cl, —CH3 or —CF3;
R5 is —H or —F;
R7 is —(C═O)OH;
A1 is N or CR9;
A2 and A3 are each independently CR9;
R9 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(trifluoromethyephenyl)-4-methyl-2-oxo-oxazolidin-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-oxazolidin-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-oxo-oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-methylbenzoate;
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;
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-methyl-benzoic acid;
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;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxybiphenyl-4-carboxylate;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-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-oxooxazolidin-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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxyphenyl)-picolinate;
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;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxybiphenyl-3-carboxylate;
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;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-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-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2′-fluoro-4′-methoxy-2-methylbiphenyl-4-carboxylate;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2′-fluoro-4′-methoxy-2-methylbiphenyl-4-carboxylic acid;
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;
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;
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-isopropyl-benzoic acid;
methyl 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-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-carboxylate;
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;
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;
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;
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;
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;
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;
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;
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;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,3-difluoro-4′-methoxy-biphenyl-4-carboxylate;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,6-difluoro-4′-methoxy-biphenyl-4-carboxylate;
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;
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;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,4′-dimethoxybiphenyl-4-carboxylate;
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;
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-difluoro-benzoic acid;
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;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyephenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-3,4′-dimethoxybiphenyl-4-carboxylate;
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;
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;
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;
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-methyl-benzoic acid;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxy-2′-(trifluoro-methyl)biphenyl-4-carboxylate;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-4′-methoxy-2′-(trifluoromethyl)biphenyl-4-carboxylate;
ethyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-3-fluoro-4′-methoxy-2′-(trifluoromethyl)biphenyl-4-carboxylate;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-4′-methoxy-2′-(trifluoromethyl)biphenyl-4-carboxylate;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxy-2-methyl-2′-(trifluoromethyl)biphenyl-4-carboxylate;
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;
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;
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;
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;
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-T-(trifluoromethyl)-biphenyl-4-carboxylic acid;
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;
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;
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-fluoro-benzoic acid;
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;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxy-T-methylbiphenyl-4-carboxylic acid;
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;
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;
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;
ethyl 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)-2-fluorobenzoate;
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;
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-fluoro-benzoic acid;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2-chloro-2′-fluoro-4′-methoxybiphenyl-4-carboxylate;
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;
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-T-(trifluoromethyl)-biphenyl-4-carboxylic acid;
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;
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;
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;
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;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-3,4′-dimethoxy-2′-(trifluoro-methyl)-biphenyl-4-carboxylate;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-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-oxooxazolidin-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-oxooxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-5-methoxypyridin-2-yl)benzoic 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-methoxypyridin-2-yl)-3-methylbenzoic 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-methoxypyridin-2-yl)-3-fluorobenzoic 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-methoxypyridin-2-yl)-3-chlorobenzoic acid;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-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-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2-methylbiphenyl-4-carboxylate;
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;
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;
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;
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;
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;
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;
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;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2,2′-difluoro-4′-methoxy-biphenyl-4-carboxylate;
ethyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2′,3-difluoro-4′-methoxy-biphenyl-4-carboxylate;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2′-fluoro-3,4′-dimethoxy-biphenyl-4-carboxylate;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2,2′,3-trifluoro-4′-methoxy-biphenyl-4-carboxylate;
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;
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;
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;
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;
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-methyl-picolinate;
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-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-5′-fluoro-2-(trifluoro-methyl)biphenyl-4-carboxylate;
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;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2′-fluorobiphenyl-4-carboxylate;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2,2′-difluorobiphenyl-4-carboxylate;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-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-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-T-methylbiphenyl-4-carboxylate;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2,2′-dimethylbiphenyl-4-carboxylate;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-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-oxooxazolidin-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-oxooxazolidin-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-oxooxazolidin-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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2′-fluorobiphenyl-4-carboxylic acid;
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;
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;
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;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxy-2,2′-dimethyl-biphenyl-4-carboxylate;
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;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-5′-methoxybiphenyl-4-carboxylate;
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;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-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-oxooxazolidin-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-oxo-oxazolidin-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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-fluoro-5′-methoxybiphenyl-4-carboxylic acid;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-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-oxo-oxazolidin-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-oxooxazolidin-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-oxooxazolidin-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-oxo-oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-3-methoxypyridin-6-yl)-3-fluorobenzoate;
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-chlorobenzoate;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2,5′-difluorobiphenyl-4-carboxylate;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-5′-fluorobiphenyl-4-carboxylate;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-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-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,5′-difluorobiphenyl-4-carboxylic acid;
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;
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;
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;
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;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-4′-fluorobiphenyl-4-carboxylate;
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;
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-methylbenzoate;
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;
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;
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;
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;
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;
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;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2,4′-difluorobiphenyl-4-carboxylate;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2′-fluoro-2-(trifluoromethyl)-biphenyl-4-carboxylate;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-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-oxooxazolidin-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-oxo-oxazolidin-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-oxooxazolidin-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-oxo-oxazolidin-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-oxooxazolidin-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-oxooxazolidin-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-oxooxazolidin-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-oxooxazolidin-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-oxo-oxazolidin-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-oxooxazolidin-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-oxo-oxazolidin-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-oxooxazolidin-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-oxo-oxazolidin-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-oxooxazolidin-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-difluoroazetidine-1-carbonyl)-4-fluoro-2′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohex-1-enyl)methyl)-4-methyl-oxazolidin-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-dimethylcyclohex-1-enyl)methyl)-4-methyloxazolidin-2-one;
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;
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-(trifluoro-methyl)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-enyl)methyl)-4-methyloxazolidin-2-one;
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; and
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.

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-oxazolidin-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-oxo-oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2-methoxypyridin-5-yl)-3-methylbenzoate;
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-methylbenzoic acid;
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;
methyl 3′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4′-methoxybiphenyl-3-carboxylate;
methyl 5′-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxo-oxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-2′-fluoro-4′-methoxy-2-methylbiphenyl-4-carboxylate;
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;
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;
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-isopropylbenzoic acid;
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;
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;
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;
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;
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;
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;
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;
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;
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;
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;
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;
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;
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;
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;
3′-(2-(((4 S,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;
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;
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;
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;
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;
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;
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;
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;
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;
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;
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;
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;
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;
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;
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;
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;
(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; and
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.

7. The compound of claim 6, wherein compound is selected from among the following compounds:
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;
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-methylbenzoic acid;
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-methyl-biphenyl-4-carboxylic acid;
4-(3-(2-(((4 S,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-chlorobenzoic acid;
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-fluorobenzoic acid;
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;
3′-(2-(((4 S,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;
5′-(2-(((4 S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-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-oxooxazolidin-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-oxooxazolidin-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-oxooxazolidin-3-yl)-methyl)-4,4-dimethylcyclohex-1-enyl)-2,2′-difluoro-4′-methoxybiphenyl-4-carboxylic acid;
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;
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; and
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.

8. A pharmaceutical composition, comprising:
a compound of formula I of claim 1; and
a pharmaceutically acceptable carrier.

9. A method for 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, wherein the dyslipidemia-related disease is angina pectoris, myocardial infarction or arteriosclerosis.

10. The method of claim 9, wherein the mammal is a human.