CN1980904A - CETP inhibitors - Google Patents

Abstract

Compounds having structural formula I, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors and are useful for raising HDL-cholesterol, lowering LDL-cholesterol, and for treating or preventing atherosclerosis. In the compounds of formula , B or R²Is phenyl, which has ortho-aryl, heterocyclyl, benzoheterocyclyl or benzocycloalkyl substituents and, in one of the other positions on the 5-membered ring, is directly attached to the ring or via-CH₂-a ring-attached aryl, heterocyclyl, cycloalkyl, benzoheterocyclyl or benzocycloalkyl substituent.

Description

CETP inhibitor

field of invention

The present invention relates to a class of compounds that inhibit cholesteryl ester transfer protein (CETP) and are therefore useful in the treatment and prevention of atherosclerosis.

Background of the invention

Atherosclerosis and its clinical outcomes, coronary heart disease (CHD), stroke, and peripheral vascular disease impose a considerable burden on health management systems in developed countries. In the United States alone, approximately 13 million patients are diagnosed with CHD, and more than 500,000 patients die from CHD each year. Additionally, this cost is projected to increase over the next quarter century as the obesity and diabetes epidemics continue to grow.

It has long been recognized that, in mammals, changes in the distribution of circulating lipoproteins are associated with the risk of atherosclerosis and CHD. The clinical success of HMG-CoA reductase inhibitors, particularly statins, in reducing coronary events is based on reducing circulating low-density lipoprotein cholesterol (LDL-C), levels of which are directly related to increased atherosclerotic risk . Recently, epidemiological studies have shown an inverse relationship between high-density lipoprotein cholesterol (HDL-C) levels and atherosclerosis, concluding that low serum HDL-C levels are associated with increased risk of CHD.

Metabolic control of lipoprotein levels is a complex and dynamic process involving multiple factors. An important metabolic control in humans is cholesteryl ester transfer protein (CETP), a plasma glycoprotein that catalyzes the transfer of cholesteryl esters from HDL to apoB-containing lipoproteins, especially to VLDL (see Hesler, C.B. et al., (1987) Purification and characterization of human plasma cholesterol ester transfer protein., J.Biol.Chem.262(5), 2275-2282)). Under physiological conditions, the net reaction is a heteroexchange in which CETP carries triglycerides from apoB lipoproteins to HDL and cholesteryl esters from HDL to apoB lipoproteins.

In humans, CETP plays a role in reversing cholesterol transport, the process by which cholesterol returns from peripheral tissues to the liver. Interestingly, many animals lack CETP, including those with high HDL levels and known resistance to coronary heart disease, such as rodents (see Guyard-Dangremont, V. et al., (1998) Phospholipid and cholesterol ester transfer activities in plasma from 14 vertebral species. Relation to atherogenesis susceptibility, Comp. Biochem. Physiol. B Biochem. Mol. Biol. 120(3), 517-525). Numerous epidemiological studies involving the role of natural variation in CETP activity on coronary heart disease risk have been performed, including studies of the few known human null mutations (see Hirano, K.-I., Yamashita, S. and Matsuzawa, Y., (2000) Pros and cons of inhibiting cholesterol estertransfer protein, Curr. Opin. Lipidol. 11(6), 589-596). These studies clearly showed an inverse correlation between plasma HDL-C concentration and CETP activity (see Inazu, A. et al., (2000) Cholesteryl ester transfer protein and atherosclerosis, Curr. Opin. Lipidol. 11(4), 389- 396), leading to the hypothesis that pharmacological inhibition of CETP lipid transfer activity by increasing HDL-C levels while decreasing LDL levels is beneficial in humans.

Despite the major therapeutic advances represented by statins such as simvastatin (ZOCOR(R)), statins have only achieved about three-thirds of their usefulness in the treatment and prevention of atherosclerosis and subsequent atherosclerotic disease events. One-fold risk reduction. Currently, only few pharmacological treatments are available to beneficially raise circulating levels of HDL-C. Certain statins and some fibrates provide modest increases in HDL-C. Niacin, which has been clinically documented to provide the most effective treatment for raising HDL-C, suffers from patient compliance issues, in part due to side effects such as flushing. Drugs that safely and effectively raise HDL cholesterol levels would address a significant but as yet unmet medical need that would provide a means of pharmacological treatment that could significantly improve circulating lipid profiles through mechanisms that complement existing treatments.

Several pharmaceutical companies are researching or testing in clinical trials new classes of compounds that inhibit CETP. There are currently no CETP inhibitors on the market. New compounds are needed so that safe and effective pharmaceutical compound(s) can be discovered. The new compounds described herein are very potent CETP inhibitors. Compounds with similar structures can be found in WO2003/032981.

Summary of the invention

Compounds having the structure of formula I, including pharmaceutically acceptable salts thereof, are CETP inhibitors having uses as follows:

In compounds of formula I:

Y is selected from -C(=O)- and -(CRR ¹ )-;

X is selected from -O-, -NH-, -N(C ₁ -C ₅ alkyl)- and -(CRR ⁶ )-;

Z is selected from -C(=O)-, -S(O) ₂ - and -C(=NR ⁹ )-, wherein R ⁹ is selected from H, -CN and -C ₁ -C ₅ alkyl, said alkane The group is optionally substituted by 1-11 halogens;

Each R is independently selected from H, -C ₁ -C ₅ alkyl and halogen, wherein -C ₁ -C ₅ alkyl is optionally substituted by 1-11 halogens;

B is selected from ^A1 and ^A2 , wherein ^A1 has the following structure:

R ¹ and R ⁶ are independently selected from H, -C ₁ -C ₅ alkyl, halogen and -(C(R) ₂ ) _n A ² , wherein -C ₁ -C ₅ alkyl is optionally replaced by 1-11 a halogen substitution;

R ² is selected from H, -C ₁ -C ₅ alkyl, halogen, A ¹ and -(C(R) ₂ ) _n A ² , wherein -C ₁ -C ₅ alkyl is optionally substituted by 1-11 halogen ;

wherein one of B and R ² is A ¹ ; and one of B, R ¹ , R ² and R ⁶ is A ² or -(C(R) ₂ ) _n A ² ; such formula I compounds contain a group A ¹ and a group A ² ; A ³ is selected from:

(a) an aromatic ring selected from phenyl and naphthyl;

(b) a phenyl ring fused to a 5-7 membered non-aromatic cycloalkyl ring optionally containing 1-2 double bonds;

(c) 5-6 membered heterocycles having 1-4 heteroatoms independently selected from N, S, O and -N(O)-, and optionally containing 1-3 double bonds and carbonyl; wherein the point of attachment ^of A to the phenyl ring to which ^A is attached is a carbon atom; and

(d) a benzoheterocycle comprising a phenyl ring fused to a 5-6 membered heterocycle having 1-2 heteroatoms independently selected from O, N and S, and optionally having 1 - 2 double bonds (other than the double bond of the fused phenyl ring), wherein the point of attachment of ^A3 to the phenyl ring to which ^A3 is attached is a carbon atom;

A ² selected from:

(a) an aromatic ring selected from phenyl and naphthyl;

(b) a phenyl ring fused to a 5-7 membered non-aromatic cycloalkyl ring optionally containing 1-2 double bonds;

(c) 5-6 membered heterocycles having 1-4 heteroatoms independently selected from N, S, O and -N(O)-, and optionally containing 1-3 double bonds and carbonyl;

(d) a benzoheterocycle comprising a phenyl ring fused to a 5-6 membered heterocycle having 1-2 heteroatoms independently selected from O, N and S, and optionally having 1 - 2 double bonds (other than those of fused phenyl rings); and

(e) -C ₃ -C ₈ cycloalkyl ring optionally having 1-3 double bonds;

wherein ^A3 and ^A2 are each optionally substituted by 1-5 substituents independently selected from R ^a ;

Each R ^a is independently selected from -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₈ alkynyl, -C ₃ - optionally having 1-3 double bonds C ₈ cycloalkyl, -OC ₁ -C ₆ alkyl, -OC ₂ -C ₆ alkenyl, -OC ₂ -C ₆ alkynyl, -OC ₃ -C ₈ optionally having 1-3 double bonds Cycloalkyl, -C(=O)C ₁ -C ₆ Alkyl, -C(=O)C ₃ -C ₈ Cycloalkyl, -C(=O)H, -CO ₂ H, -CO ₂ C ₁ -C ₆ alkyl, -C(=O)SC ₁ -C ₆ alkyl, -OH, -NR ³ R ⁴ , -C(=O)NR ³ R ⁴ , -NR ³ C(=O)OC ₁ -C ₆ alkyl, -NR ³ C(=O)NR ³ R ⁴ , -S(O) _x C ₁ -C ₆ alkyl, -S(O) _y NR ³ R ⁴ , -NR ³ S( O) _y NR ³ R ⁴ , halogen, -CN, -NO ₂ and 5-6 membered heterocycles, the heterocycles have 1-4 heteroatoms independently selected from N, S and O, the heterocycles It also optionally contains a carbonyl group and also optionally contains 1-3 double bonds, wherein the point of attachment to the ring to which ^R is attached is a carbon atom, wherein the heterocyclic ring is optionally selected from 1-5 independently selected from Substituents of halogen, -C ₁ -C ₃ alkyl and -OC ₁ -C ₃ alkyl, wherein -C ₁ -C ₃ alkyl and -OC ₁ -C ₃ alkyl are optionally substituted by 1-7 halogen Substitution; wherein for wherein R ^a is selected from -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, optionally having 1-3 double bonds -C ₃ -C ₈ cycloalkyl, -OC ₁ -C ₆ alkyl, -OC ₂ -C ₆ alkenyl, -OC ₂ -C ₆ alkynyl, -OC ₃ -C optionally with 1-3 double bonds ₈ cycloalkyl, -C(=O)C ₁ -C ₆ alkyl, -C(=O)C ₃ -C ₈ cycloalkyl, -CO ₂ C ₁ -C ₆ alkyl, -C(=O ) SC ₁ -C ₆ alkyl, -NR ³ C(=O)OC ₁ -C ₆ alkyl and -S(O) _x C ₁ -C ₆ alkyl compounds, R ^a is optionally replaced by 1-15 Halogen substituted, and also optionally substituted by 1-3 substituents independently selected from the following substituents: (a)-OH, (b)-CN, (c)-NR ³ R ⁴ , (d) optionally having 1 -C ₃ -C ₈ cycloalkyl with 3 double bonds and optionally substituted by 1-15 halogens, (e) optionally substituted by 1-9 halogens and also optionally 1-2 independently selected -OC ₁ -C ₄ alkyl substituted by substituents from -OC ₁ -C ₂ alkyl and phenyl, (f) optionally having 1-3 double bonds and optionally substituted by 1-15 halogens- OC ₃ -C ₈ cycloalkyl, (g) -CO ₂ H, (h) -C(=O)CH ₃ , (i) -CO ₂ C ₁ -C ₄ optionally substituted by 1-9 halogens Alkyl, and (j) phenyl optionally substituted with 1-3 groups independently selected from halogen, _-CH3 , _-CF3 , _-OCH3 , and _-OCF3 ;

Provided that when B is A ¹ , X and Y are -CH ₂ -, Z is -C(=O)-, and R ² is phenyl with a substituent R ^a at the 4-position, wherein R ^a is any When selecting -OC ₁ -C ₆ alkyl substituted as described above, there is no other R ^a substituent on R ² , wherein R ^a is selected from -OH, -OC ₁ -C ₆ alkyl, -OC ₂ - C ₆ alkenyl, -OC ₂ -C ₆ alkynyl and -OC ₃ -C ₈ cycloalkyl optionally having 1 to 3 double bonds, all of which are optionally substituted as described above,

n is 0 or 1;

p is an integer of 0-4;

x is 0, 1 or 2;

y is 1 or 2;

R ³ and R ⁴ are independently selected from H, -C ₁ -C ₅ alkyl, -C(=O)C ₁ -C ₅ alkyl and -S(O) _y C ₁ -C ₅ alkyl, wherein In all cases, -C ₁ -C ₅ alkyl is optionally substituted with 1-11 halogens; and

R ⁵ is selected from H, -OH, -C ₁ -C ₅ alkyl and halogen, wherein -C ₁ -C ₅ alkyl is optionally substituted by 1-11 halogens.

In the compounds of formula I and subsequent compounds, unless otherwise stated, the alkyl, alkenyl and alkynyl groups may be straight or branched.

Detailed description of the invention

Many of the compounds of the present invention have the following Formula Ia, or a pharmaceutically acceptable salt thereof:

Many compounds of the present invention have the following formula Ib, or a pharmaceutically acceptable salt thereof:

Many other compounds of the present invention have the following formula Ic, or a pharmaceutically acceptable salt thereof:

Other compounds of the invention have the following formula Id, or a pharmaceutically acceptable salt thereof:

In a group of compounds of formula I,

Each R ^a is independently selected from -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ - optionally having 1-3 double bonds C ₈ cycloalkyl, -OC ₁ -C ₆ alkyl, -OC ₂ -C ₆ alkenyl, -OC ₂ -C ₆ alkynyl, -OC ₃ -C ₈ optionally having 1-3 double bonds Cycloalkyl, -C(=O)C ₁ -C ₆ Alkyl, -C(=O)C ₃ -C ₈ Cycloalkyl, -C(=O)H, -CO ₂ H, -CO ₂ C ₁ -C ₆ alkyl, -C(=O)SC ₁ -C ₆ alkyl, -NR ³ R ⁴ , -C(=O)NR ³ R ⁴ , -NR ³ C(=O)OC ₁ -C ₆ alkyl, -NR ³ C(=O)NR ³ R ⁴ , -S(O) _x C ₁ -C ₆ alkyl, -S(O) _y NR ³ R ⁴ , -NR ³ S(O) _y NR ³ R ⁴ , halogen, -CN, -NO ₂ and 5-6 membered heterocyclic rings, the heterocyclic rings have 1-4 heteroatoms independently selected from N, S and O, and the heterocyclic rings are also optionally Contains a carbonyl group and optionally also contains 1-3 double bonds, wherein the point of attachment of the heterocyclic ring to the attached ring is a carbon atom, wherein the heterocyclic ring is optionally composed of 1-5 independently selected from halogen, -C Substituents of ₁ -C ₃ alkyl and -OC ₁ -C ₃ alkyl, wherein -C ₁ -C ₃ alkyl and -OC ₁ -C ₃ alkyl are optionally substituted by 1-7 halogens; wherein for Wherein R ^a is selected from -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ ring optionally having 1-3 double bonds Alkyl, -OC ₁ -C ₆ alkyl, -OC ₂ -C ₆ alkenyl, -OC ₂ -C ₆ alkynyl, -OC ₃ -C ₈ cycloalkyl optionally with 1-3 double bonds , -C(=O)C ₁ -C ₆ alkyl, -C(=O)C ₃ -C ₈ cycloalkyl, -CO ₂ C ₁ -C ₆ alkyl, -C(=O)SC ₁ - Compounds of C ₆ alkyl, -NR ³ C(=O)OC ₁ -C ₆ alkyl and -S(O) _x C ₁ -C ₆ alkyl, R ^a is optionally substituted by 1 to 15 halogens, and Also optionally substituted with 1-3 substituents independently selected from the following: (a)-OH, (b)-CN, (c)-NR ³ R ⁴ , (d) optionally having 1-3 double bonded and optionally substituted by 1-15 halogens -C ₃ -C ₈ cycloalkyl, (e) optionally substituted by 1-9 halogens and also optionally 1-2 independently selected from -OC ₁ -OC ₁ -C ₄ alkyl substituted by a substituent of -C ₂ alkyl, (f) -OC ₃ -C ₈ cycloalkane optionally having 1 to 3 double bonds and optionally substituted by 1 to 15 halogens radical, (g) -CO ₂ H, (h) -C(=O)CH ₃ , and (i) -CO ₂ C ₁ -C ₄ alkyl optionally substituted by 1 to 9 halogens,

Provided that when B is A ¹ , X and Y are -CH ₂ -, Z is -C(=O)-, and R ² is phenyl with a substituent R ^a at the 4-position, wherein R ^a is any When selecting -OC ₁ -C ₆ alkyl substituted by 1-11 halogens, there is no other R ^a substituent on R ² , wherein R ^a is selected from -OH, -OC ₁ -C ₆ alkyl, -OC ₂ -C ₆ alkenyl, -OC ₂ -C ₆ alkynyl and -OC ₃ -C ₈ cycloalkyl optionally having 1 to 3 double bonds, all of which are optionally substituted as described above.

In compounds of formula I, Ia, Ib, Ic and Id and pharmaceutically acceptable salts thereof,

A ³ is phenyl, which is optionally substituted by 1-4 substituents R ^a , wherein R ^{a is} independently selected from -C ₁ -C ₅ alkyl, -OC ₁ -C ₃ alkyl, -CO ₂ C ₁ -C ₃ alkyl, -CO ₂ H, halogen, -NR ³ R ⁴ , -C(=O)C ₁ -C ₃ alkyl, -C(=O)H, -C(=O) NR ³ R ⁴ , -SC ₁ -C ₃ alkyl, -C ₂ -C ₃ alkenyl, -CN, -NO ₂ and 1,2,4-oxadiazolyl, all occurrences of -C ₁ - C ₃ alkyl and -C ₁ -C ₅ alkyl are optionally substituted by 1-6 substituents independently selected from 1-5 halogen and one -OH group; and -C ₂ -C ₃ alkenyl Optionally substituted with 1-3 halogens.

In compounds of formula I, Ia, Ib, Ic and Id and pharmaceutically acceptable salts thereof,

A ^is selected from phenyl, cyclohexyl, and 5-6 membered heterocycles having 1-2 heteroatoms independently selected from N, S, O, and -N(O)-, and optionally comprising 1-3 double bonds, wherein A ² is optionally substituted by 1-2 substituents independently selected from the following: -C ₁ -C ₄ alkyl, -OC ₁ -C ₃ alkyl, -NO ₂ , - CN, -S(O) _x C ₁ -C ₃ alkyl, -NHS(O) ₂ C ₁ -C ₃ alkyl, -NR ³ R ⁴ , -NR ³ C(=O)R ⁴ , -C ₂ -C ₃ alkenyl, -C(=O)NR ³ R ⁴ , halogen and pyridyl, wherein in each case C ₁ -C ₃ alkyl, C ₁ -C ₄ alkyl and C ₂ -C ₃ Alkenyl is optionally substituted with 1-3 halogens, provided that, for compounds of formula Ia, when B is A ¹ , X and Y are -CH ₂ -, Z is -C(=O)-, and R ² is When phenyl, then the number of R ^a groups selected from optionally substituted -OC ₁ -C ₃ alkyl on R ² is 0 or 1.

In compounds of formulas I, Ia, Ib, Ic and Id and pharmaceutically acceptable salts thereof, R ³ and R ⁴ are independently selected from H and -C ₁ -C ₃ alkyl.

In compounds of formulas I, Ia, Ib, Ic and Id and pharmaceutically acceptable salts thereof, p is 0-2.

In a subgroup of compounds of formula I, including their pharmaceutically acceptable salts,

A ¹ is

Wherein R ⁷ and R ⁸ are independently selected from H, halogen, -NR ³ R ⁴ , -C ₁ -C ₃ alkyl, -OC ₁ -C ₃ alkyl, -CN, -NO ₂ and pyridyl, wherein In all cases, C ₁ -C ₃ alkyl is optionally substituted with 1-3 halogen.

In a subgroup of formula I compounds, A ² is selected from phenyl, pyridyl and cyclohexyl, wherein A ² is optionally replaced by 1-2 independently selected from -C ₁ -C ₄ alkyl, -OC ₁ -C ₄ Alkyl, -NO ₂ , -CN and halogen substituents, wherein all uses of C ₁ -C ₄ alkyl are optionally substituted by 1 to 3 halogen, with the proviso that, for compounds of formula I, when B is A ¹ , X and Y are -CH ₂ -, Z is -C(=O)-, and R ² is phenyl, then on R ² is selected from - optionally substituted by 1-3 halogens The number of R ^a groups of OC ₁ -C ₄ alkyl is 0 or 1.

In other subgroups, A ² is optionally substituted with 1-2 substituents independently selected from halogen, -C ₁ -C ₄ alkyl and -CN, wherein -C ₁ -C ₄ alkyl is optionally substituted by 1 -3 halogen substitutions.

In many embodiments of the invention as described above, including pharmaceutically acceptable salts thereof, ^A is

wherein R ⁷ is selected from H, halogen, -NR ³ R ⁴ , -C ₁ -C ₃ alkyl, -OC ₁ -C ₃ alkyl, -CN, -NO ₂ and pyridyl, wherein in all cases, C ₁ - _C3 alkyl is optionally substituted by 1-3 halogens; and

R ⁸ is selected from H, halogen, -CH ₃ , -CF ₃ , -OCH ₃ and -OCF ₃ .

In many preferred embodiments of the present invention, A ³ is phenyl, which is substituted by 1-3 substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, O C ₁ -C ₄ alkyl , -CN, Cl, F, -C(=O)CH ₃ , -CH=CH ₂ , -CO ₂ H, -CO ₂ CH ₃ , -S-CH ₃ , -S(O)CH ₃ , -S (O) ₂ CH ₃ and -C(=O)NR ³ R ⁴ , wherein C ₁ -C ₄ alkyl and -OC ₁ -C ₄ alkyl are optionally substituted by 1-5 F substituents, and also optionally is optionally substituted by a group -OH.

In other embodiments, A ³ is phenyl optionally substituted with 1-3 substituents independently selected from the group consisting of Cl, F, -C ₁ -C ₄ alkyl, and -OC ₁ - C ₄ alkyl, wherein -C ₁ -C ₄ alkyl and -OC ₁ -C ₄ alkyl are optionally substituted by 1-5 F.

A preferred value for Y is -(CRR ¹ )-.

In certain embodiments, R and R ⁶ are each independently selected from H and -C ₁ -C ₅ alkyl, wherein -C ₁ -C ₅ alkyl is optionally substituted with 1-11 halogens. In groups of these embodiments, R ¹ is selected from H, -C ₁ -C ₅ alkyl and -(C(R) ₂ ) _n A ² , wherein -C ₁ -C ₅ alkyl is optionally replaced by 1-11 a halogen substitution. In these schemes, one of B and R ² is A ¹ ; and one of B, R ¹ and R ² is A ² or -(C(R) ₂ ) _n A ² ; such that the compound of formula I comprises a group group A ¹ and one group A ² .

In a subgroup of compounds, ^A3 is selected from:

(a) an aromatic ring selected from phenyl and naphthyl;

(b) 5-6 membered heterocycles having 1-4 heteroatoms independently selected from N, S, O and -N(O)-, and optionally containing 1-3 double bonds and Carbonyl, wherein the point of attachment ^of A to the phenyl ring to which ^A is attached is a carbon atom; and

(c) A benzoheterocycle comprising a phenyl ring fused to a 5-6 membered heterocycle having 1-2 heteroatoms independently selected from O, N and -S(O) _x - , and optionally have 1-2 double bonds, wherein the point of attachment of ^A3 to the phenyl ring to which ^A3 is attached is a carbon atom.

In a subgroup of compounds, ^A is selected from:

(a) an aromatic ring selected from phenyl and naphthyl;

(b) 5-6 membered heterocycles having 1-4 heteroatoms independently selected from N, S, O and -N(O)-, and optionally containing 1-3 double bonds and carbonyl;

(c) a benzoheterocycle comprising a phenyl ring fused to a 5-6 membered heterocycle having 1-2 heteroatoms independently selected from O, N and S, and optionally having 1 - 2 double bonds; and

(d) -C ₃ -C ₈ cycloalkyl ring optionally having 1-3 double bonds.

In the above subgroups of ^A3 and ^A2 , ^A3 and ^A2 are optionally substituted with 1-4 substituents independently selected from ^Ra .

Subgroups of ^R include substituents independently selected from the group consisting of -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₃ -C ₈ optionally having 1-3 double bonds Cycloalkyl, -OC ₁ -C ₆ alkyl, -C(=O)C ₁ -C ₆ alkyl, -C(=O)H, -CO ₂ H, -CO ₂ C ₁ -C ₆ alkyl , -OH, -NR ³ R ⁴ , -NR ³ C(=O)OC ₁ -C ₆ alkyl, -S(O) _x C ₁ -C ₆ alkyl, halogen, -CN, -NO ₂ and 5 - a 6-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from N, S and O, said heterocyclic ring optionally further comprising a carbonyl group and further optionally comprising 1 to 3 double bonds, wherein The point of attachment of the heterocycle to the ring to which R ^a is attached is a carbon atom, wherein the heterocycle is optionally represented by 1 to 5 members independently selected from halogen, -C ₁ -C ₃ alkyl and -OC ₁ - Substituents of C ₃ alkyl, wherein -C ₁ -C ₃ alkyl and -OC ₁ -C ₃ alkyl are optionally substituted by 1-7 halogens;

Wherein for wherein R ^a is independently selected from -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₃ -C ₈ cycloalkyl optionally having 1-3 double bonds, -O )C ₁ -C ₆ alkyl, -C(=O)C ₁ -C ₆ alkyl, -CO ₂ C ₁ -C ₆ alkyl, -NR ³ C(=O)OC ₁ -C ₆ alkyl and -S(O) _x C ₁ -C ₆ alkyl compounds, R ^a is optionally substituted by 1-15 halogens, and is also optionally substituted by 1 substituent selected from the group consisting of: (a) -OH, ( b) -NR ³ R ⁴ , (c) optionally substituted by 1-9 halogens and optionally substituted by 1-2 substituents independently selected from -OC ₁ -C ₂ alkyl and phenyl - OC ₁ -C ₄ alkyl, and (d) phenyl optionally replaced by 1-3 groups independently selected from halogen, -CH ₃ , -CF ₃ , -OCH ₃ and -OCF ₃ replace;

Provided that when B is A ¹ , X and Y are -CH ₂ -, Z is -C(=O)-, and R ² is phenyl with a substituent R ^a at the 4-position, wherein R ^a is any When -OC ₁ -C ₆ alkyl substituted as described above is selected, there are no other R ^a substituents on R ² , wherein R ^a is selected from -OH or -OC ₁ -C optionally substituted as described above ₆ alkyl.

In a subgroup of compounds, n is an integer from 0-2. In other subgroups, n is 1 or 2.

In a separate subgroup, R ^and R are ^each independently selected from H and -C ₁ -C ₅ alkyl, wherein in each case -C ₁ -C ₅ alkyl is optionally replaced by 1-11 halogen replace. In other independent subgroups, R ³ and R ⁴ are each independently selected from H and -C ₁ -C ₃ alkyl, or from H and -C ₁ -C ₂ alkyl.

In a subgroup of formula I, Z is selected from -C(=O)-, -S(O) ₂ - and -C(=NR ⁹ )-, wherein R ⁹ is selected from H, -CN and CH ₃ . A preferred value for Z is -C(=O)-.

In a separate subgroup, R ⁵ is selected from H, -OH and -C ₁ -C ₅ alkyl, wherein -C ₁ -C ₅ alkyl is optionally substituted with 1-11 halogens. In other subgroups, R ⁵ is selected from H and -C ₁ -C ₃ alkyl, or from H and -C ₁ -C ₂ alkyl.

In certain subgroups, each R is independently selected from H and C ₁ -C ₃ alkyl. In other groups, R is selected from H and C ₁ -C ₂ alkyl. In other groups R is H or _CH3 .

In certain subgroups, ^R6 is selected from H and _-C1 - _C3 alkyl, wherein _C1 - _C3 alkyl is optionally substituted with 1-5 halogen. In other subgroups, ^R6 is selected from H and _C1 - _C2 alkyl. In other groups, ^R6 is H or _CH3 .

In certain subgroups, R ¹ is selected from H, -C ₁ -C ₃ alkyl, and -(C(R) ₂ ) _n A ² , wherein -C ₁ -C ₃ alkyl is optionally replaced by 1-5 Halogen substitution; and R ² is selected from H, -C ₁ -C ₃ alkyl, A ¹ and -(C(R) ₂ ) _n A ² , wherein -C ₁ -C ₃ alkyl is optionally replaced by 1-5 Halogen substituted, and R ⁶ is H or alkyl. In these schemes, one of B and R ² is A ¹ ; and one of B, R ¹ and R ² is A ² or -(C(R) ₂ ) _n A ² ; such that the compound of formula I comprises a group group A ¹ and one group A ² .

In a subgroup of compounds, ^A3 is selected from:

(a) phenyl;

(b) 5-6 membered heterocyclic ring, said heterocyclic ring has 1-2 heteroatoms independently selected from N, S, O and -N(O)-, wherein A ³ is connected to the phenyl group with A ³ the point of attachment of the ring is a carbon atom; and

(c) A benzoheterocycle comprising a phenyl ring fused to a 5-membered aromatic heterocycle having 1-2 heteroatoms independently selected from O, N, and -S(O) _x - , wherein the point of attachment of ^A3 to the phenyl ring to which ^A3 is attached is a carbon atom.

In the subgroup, ^A2 is selected from:

(a) phenyl;

(b) 5-6 membered heterocyclic rings having 1-4 heteroatoms independently selected from N, S, O and -N(O)-, and also optionally containing 1-3 double bonds ;

(c) a benzoheterocycle comprising a phenyl ring fused to a 5-membered heterocycle having 1-2 heteroatoms independently selected from O, N and S; and

(d) -C ₅ -C ₆ cycloalkyl ring.

In many compounds, ^A3 and ^A2 are each optionally substituted with 1-4 substituents independently selected from ^Ra . In each subgroup, A ³ is optionally substituted with 1-3 substituents R ^a , or substituted with 2-3 substituents R ^a . In each subgroup, A ² is optionally substituted with 1-3 substituents R ^a , or substituted with 1-2 substituents R ^a . ^R2 is often substituted with 2 substituents R ^a , or with 2-3 substituents R ^a .

In many compounds, A ^is selected from phenyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, pyridyl, N-oxy-pyridyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzene benzothienyl, benzothienyl-S-oxide and benzothienyl-S-dioxide.

In many compounds, A ^is selected from phenyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, pyrazolyl, 1,2,4-triazolyl, tetrazolyl, benzodioxole yl, pyridyl, N-oxy-pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, cyclopentyl, cyclohexyl and tetrahydropyranyl.

In certain subgroups, Ra ^is selected from -C ₁ -C ₄ alkyl, -C ₂ -C ₄ alkenyl, cyclopropyl, -OC ₁ -C ₂ alkyl, -C(=O)C ₁ -C ₂ alkyl, -C(=O)H, -CO ₂ C ₁ -C ₄ alkyl, -OH, -NR ³ R ⁴ , -NR ³ C(=O)OC ₁ -C ₄ alkyl , -S(O) _x C ₁ -C ₂ alkyl, halogen, -CN, -NO ₂ and 5-6 membered heterocycles, the heterocycles have 1-2 independently selected from N, S and O A heteroatom, wherein the point of attachment of the heterocycle to the ring to which ^R is attached is a carbon atom, wherein the heterocycle is optionally substituted by 1-5 substituents independently selected from halogen;

Wherein for wherein R ^a is selected from -C ₁ -C ₄ alkyl, -C ₂ -C ₄ alkenyl, -OC ₁ -C ₂ alkyl, -C(=O)C ₁ -C ₂ alkyl, - Compounds of CO ₂ C ₁ -C ₄ alkyl, -NR ³ C(=O)OC ₁ -C ₄ alkyl and -S(O) _x C ₁ -C ₂ alkyl, the alkyl of R ^a is optionally substituted by 1-5 halogens, and optionally substituted by one substituent selected from (a)-OH, (b)-NR ³ R ⁴ , (c) optionally substituted by 1-3 fluorine atoms, and -OCH ₃ optionally substituted by one phenyl, and (d) phenyl optionally substituted by 1-3 independently selected from halogen, -CH ₃ , -CF ₃ , -OCH ₃ and - Group substitution of OCF ₃ ;

Provided that when B is A ¹ , X and Y are -CH ₂ -, Z is -C(=O)-, and R ² is phenyl with a substituent R ^a at the 4-position, wherein R ^a is any When -OC ₁ -C ₂ alkyl substituted as described above is selected, there are no other R ^a substituents on R ² , wherein R ^a is selected from -OH or -OC ₁ -C optionally substituted as described above ₂ alkyl.

In a preferred group, X is selected from -O-, -NH- and -N(C ₁ -C ₃ alkyl)-. X may also be selected from -O-, -NH- and -N( _CH3 ). In a highly preferred group, X is O.

In many groups, Z is -C(=O)-.

A preferred subgroup of compounds has formula Ie, including pharmaceutically acceptable salts thereof

In the compound of formula Ie, X is selected from -O-, -NH-, -N(C ₁ -C ₅ alkyl)- and -(CH ₂ )-;

Z is selected from -C(=O)-, -S(O) ₂ - and -C(=NR ⁹ )-, wherein R ⁹ is selected from H, -CN and C ₁ optionally substituted with 1-11 halogens -C ₅ alkyl.

each R is independently selected from H and _-CH3 ;

B is selected from ^A1 and ^A2 , wherein ^A1 has the following structure:

R ¹ is selected from H, -C ₁ -C ₅ alkyl and -(C(R) ₂ ) _n A ² , wherein -C ₁ -C ₅ alkyl is optionally substituted by 1-11 halogens;

R ² is selected from H, -C ₁ -C ₅ alkyl, A ¹ and -(C(R) ₂ ) _n A ² , wherein -C ₁ -C ₅ alkyl is optionally substituted by 1-11 halogens;

wherein one of B and R ² is A ¹ ; and one of B, R ¹ and R ² is A ² or -(C(R) ₂ ) _n A ² ; such formula I compounds comprise a group A ¹ and a group A ² ;

A ² is selected from phenyl, cyclohexyl and pyridyl, wherein A ² is optionally substituted by 1-2 substituents independently selected from halogen, -C ₁ -C ₄ alkyl and -CN, wherein -C ₁ - C ₄ alkyl is optionally substituted by 1-3 halogens;

Each R ^a is independently selected from -C ₁ -C ₃ alkyl and halogen, wherein -C ₁ -C ₃ alkyl is optionally substituted by 1-3 halogen;

Each R ^b is independently selected from Cl, F, -C ₁ -C ₄ alkyl and -OC ₁ -C ₄ alkyl, wherein -C ₁ -C ₄ alkyl and -OC ₁ -C ₄ alkyl are optionally Replaced by 1-5 F's;

n is 0 or 1;

p is an integer from 0 to 2; and

q is an integer of 0-3.

The group of compounds having formula Ie includes compounds of formula If, Ig and Ih and pharmaceutically acceptable salts thereof:

和

and

In the compounds of formulas If, Ig and Ih, R ¹ and R ² are independently selected from H and -C ₁ -C ₅ alkyl, wherein -C ₁ -C ₅ alkyl is optionally substituted by 1-11 halogens. Other groups are as defined above.

In a subgroup of the above compounds, ^A2 may be selected from phenyl, cyclohexyl and pyridyl, wherein ^A2 is optionally substituted with 1-2 independently selected from halogen, _-CH3 , _-CF3 and -CN base substitution.

In a subset of the above compounds, each Ra ^is independently selected from _-CF3 and Cl.

In a subgroup of the above compounds, each R ^b is independently selected from -C ₁ -C ₃ alkyl, -OCH ₃ and F.

In a subgroup of the above compounds, R ¹ and R ² are each independently selected from H and -C ₁ -C ₂ alkyl.

In a subgroup of the above compounds, X is selected from -O-, NH-, -N( _CH3 )- and _-CH2- .

In a subgroup of the above compounds, Z is selected from -C(=O)-, -S(O) _2- and -C(=N-CN)-.

In a subset of the above compounds, p is 1.

In a subgroup of the above compounds, q is 2 or 3.

A subgroup of compounds defined above includes compounds of formula Ii and pharmaceutically acceptable salts thereof:

In formula Ii, R ⁷ is selected from Cl and -CF ₃ ;

R ^c is selected from halogen, -CH ₃ , -CF ₃ , and -CN; and t is an integer of 0-2. Other groups are as defined above.

A subgroup of compounds defined above includes compounds having the formula Ij and pharmaceutically acceptable salts thereof:

In formula Ij, R ⁷ is selected from Cl and -CF ₃ ;

^Rc is selected from halogen, _-CH3 , _-CF3 , and -CN; and

t is an integer of 0-2. Other groups are as defined above.

definition

"Ac" is acetyl, ie _CH3C (=O)-.

Unless otherwise defined, "alkyl" means a saturated carbon chain which may be straight or branched or combinations thereof. Other groups with the prefix "alk", such as alkoxy and alkanoyl, can also be straight or branched or combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

"Alkylene" refers to an alkyl group having difunctionality rather than monofunctionality. For example, methyl is an alkyl group and methylene ( _-CH2- ) is the corresponding alkylene group.

"Alkenyl" means a carbon chain comprising at least one carbon-carbon double bond, and which may be straight or branched or combinations thereof. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, etc. .

"Alkynyl" means a carbon chain comprising at least one carbon-carbon triple bond, and which may be straight or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl, and the like.

Unless otherwise specified, "cycloalkyl" means a saturated carbocyclic ring having 3 to 8 carbon atoms. The term also includes cycloalkyl rings fused to aryl groups. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. "Cycloalkenyl" means a non-aromatic carbocyclic ring having one or more double bonds.

"Aryl" (and "arylene") when used to describe a substituent or group in a structure refers to a monocyclic or bicyclic compound in which the ring is aromatic and contains only ring-forming carbon atoms. The term "aryl" may also refer to an aryl group fused to a cycloalkyl or heterocycle. Preferred "aryl" groups are phenyl and naphthyl. In general, phenyl is the most preferred aryl group.

"EDC" is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

Unless otherwise stated, "heterocyclyl", "heterocycle" and "heterocyclic" refer to fully saturated or partially saturated rings containing 1 to 4 heteroatoms independently selected from N, S and O Or aromatic 5-6 membered ring.

"Benzoheterocycle" means a phenyl ring fused to a 5-6 membered heterocycle having 1-2 heteroatoms each being O, N or S, wherein the heterocycle may be saturated or unsaturated. Examples thereof include indole, benzofuran, 2,3-dihydrobenzofuran and quinoline.

"DIPEA" is diisopropylethylamine.

"Halogen" includes fluorine, chlorine, bromine and iodine.

"HOBT" is 1-hydroxybenzotriazole.

"IPAC" is isopropyl acetate.

"Me" means methyl.

"Weinreb's amine" is N,O-dimethylhydroxylamine.

The term "composition" as it appears in pharmaceutical compositions is intended to include products comprising the active ingredient, the inert ingredient constituting the carrier, and any product resulting directly or indirectly from the combination, complexation, or association of any two or more ingredients , or any product resulting directly or indirectly from the dissociation of one or more components, or from other types of reactions or other types of interactions of one or more components. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

The substituent "tetrazole" refers to a 2H-tetrazol-5-yl substituent and tautomers thereof. Optical isomers - diastereomers - geometric isomers - tautomers

Compounds of formula I may contain one or more asymmetric centers and thus exist as racemates, racemic mixtures, individual enantiomers, mixtures of diastereomers and individual diastereomers. Where a structure having a stereochemical configuration is shown, other stereochemical structures are also included, such as enantiomers, diastereomers (where diastereomers exist), and enantiomers and/or diastereomers, individually and collectively mixtures, including racemic mixtures.

Some of the compounds described herein may contain olefinic double bonds and, unless otherwise stated, are intended to include both E and Z geometric isomers.

Some of the compounds described herein may exist as tautomers. Examples are ketones and their enol forms, known as keto-enol tautomers. Both individual tautomers and mixtures thereof are included within compounds of formula I.

Compounds of formula I having one or more asymmetric centers can be separated into diastereoisomers, enantiomers and the like by methods well known in the art.

Alternatively, enantiomers and other compounds having chiral centers may be synthesized by stereospecific synthesis using optically pure starting materials and/or reagents of known configuration.

Some of the biphenyl and biaryl compounds herein are observed as mixtures of atropisomers (rotamers) in NMR spectra. Both individual atropisomers and mixtures thereof are included within the scope of the compounds of the present invention.

Salt

The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including salts prepared from inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron(III), iron(II), lithium, magnesium, manganese(II), potassium, sodium, zinc, and the like. Particular preference is given to the ammonium, calcium, magnesium, potassium and sodium salts. Salts in solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable nontoxic organic bases include primary, secondary, tertiary, substituted amines (including naturally occurring substituted amines), cyclic amines and base ion exchange resins such as arginine, betaine, coffee Cause, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- Ethylpiperidine, glucosamine, glucosamine, histidine, halamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine , purine, theobromine, triethylamine, trimethylamine, tripropylamine and tromethamine, etc.

When the compound of the present invention is basic, its salt can be prepared from pharmaceutically acceptable non-toxic acids such as inorganic acids and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, Tonic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc. Particular preference is given to citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.

It should be understood that, as used herein, compounds of Formula I are also intended to include pharmaceutically acceptable salts. metabolite-prodrug

Therapeutically active metabolites, wherein the metabolites themselves fall within the scope of the invention, are also compounds of the invention. Compounds that convert to compounds of the invention, ie, prodrugs, upon or after administration to a patient are also compounds of the invention.

use

The compounds of the present invention are potent inhibitors of CETP. They are therefore useful in the treatment of diseases and conditions treated by CETP inhibitors.

One aspect of the present invention provides treatment of a disease or condition treatable or preventable by inhibition of CETP or reduction of progression to a disease or condition treatable or preventable by inhibition of CETP by administering a therapeutically effective amount of a compound of the present invention to a patient in need thereof. Dangerous approach to illness. The patient is a human or a mammal, most often a human. A "therapeutically effective amount" is an amount of a compound effective to achieve the desired clinical result in the treatment of a particular disease.

Diseases or disorders that can be treated with the compounds of the present invention and diseases for which the risk of developing the disease can be reduced by treatment with the compounds of the present invention include: atherosclerosis, peripheral vascular disease, dyslipidemia, hyperlipoproteinemia hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disease, angina, ischemia, myocardial ischemia, stroke, myocardial infarction, reperfusion Injury, restenosis after angioplasty, hypertension, diabetic vascular complications, obesity, endotoxemia, and metabolism.

The compounds of the invention are expected to be particularly effective at raising HDL-C and/or increasing the ratio of HDL-C to LDL-C. These changes in HDL-C and LDL-C may be beneficial for treating atherosclerosis, reducing or reversing the progression of atherosclerosis, reducing the risk of developing atherosclerosis, or preventing atherosclerosis.

Administration and Dose Range

Any suitable route of administration may be employed for providing an effective dose of a compound of the invention to a mammal, especially a human. For example, oral administration, rectal administration, topical administration, parenteral administration, ophthalmic administration, transpulmonary administration, nasal administration and the like can be employed. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably, the compound of formula I is administered orally.

The effective dose of active ingredient employed will vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosages can be readily determined by those skilled in the art.

When treating diseases for which compounds of formula I are useful, satisfactory results are generally obtained when the compounds of the present invention are administered at daily doses of from about 0.01 mg to about 100 mg per kilogram of animal or human, preferably as a single daily dose or It is administered in divided doses of about two to six times daily, or in a controlled release form. In the case of a 70 kg human adult, the total target dose will generally be from about 0.5 mg to about 500 mg. For particularly potent compounds, adult doses may be as low as 0.1 mg. Dosage regimens can be adjusted within this range, and even outside this range, to provide the optimum therapeutic response.

Oral administration is usually performed using tablets. Examples of dosages in tablets are 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 250 mg and 500 mg. Other oral dosage forms may also have the same dosage (eg capsules).

pharmaceutical composition

Another aspect of the invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention comprises a compound of formula I or a pharmaceutically acceptable salt as an active ingredient, together with a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including salts prepared from inorganic bases or acids and organic bases or acids. If a prodrug is administered, the pharmaceutical composition may also include the prodrug, or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions can also consist essentially of a compound of formula I and a pharmaceutically acceptable carrier.

Compositions include those suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ophthalmic (ophthalmic), pulmonary (nasal or buccal inhalation) or nasally administered compositions, but the most appropriate route in any given case will depend upon the nature and severity of the condition being treated and the nature of the active ingredient. They may conveniently be presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

In practical application, the compound of formula I as an active ingredient can be mixed homogeneously with a pharmaceutical carrier according to conventional pharmaceutical preparation techniques to combine. The carrier can take a variety of forms depending on the form of preparation desired for administration, eg, oral or parenteral (including intravenous). In preparing compositions for oral dosage form, any usual pharmaceutical medium may be employed, for example, water, glycols, oils, alcohols, flavoring agents, preservatives in the case of oral liquid preparations such as suspensions, elixirs and solutions. , coloring agents, etc.; or use carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, Disintegrants and the like, solid oral preparations are more preferable than liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. Tablets may, if desired, be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of active compound in these compositions may, of course, vary and may conveniently range from about 2% to about 60% by weight of the dosage unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered nasally, for example, as liquid drops or spray.

Tablets, pills, capsules, etc. may also contain binders such as tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid; lubricants such as magnesium stearate; and sweetening agents such as sucrose, lactose or saccharin. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent methyl and propyl parabens as preservatives, a dye and flavoring such as cherry flavor or orange flavor. .

Compounds of formula I may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions and dispersion. In all cases, the dosage form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

combination therapy

The compounds of the present invention (such as formulas I and Ia-Ij) may be used in combination with other drugs that are also useful in the treatment or amelioration of diseases or conditions for which compounds of formula I are indicated. These other drugs may be administered simultaneously or sequentially with the compound of formula I by their usual routes and amounts. When the compound of formula I is used simultaneously with one or more other drugs, a pharmaceutical composition in unit dosage form is preferred, which comprises said other drugs and the compound of structural formula I. However, combination therapy also includes treatments in which the compound of formula I and one or more other drugs are administered on different schedules.

When oral formulations are used, the drugs may be combined in a single combination tablet or other oral dosage form, or the drugs may be packaged together as separate tablets or other oral dosage forms. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the invention and other active ingredients may be used in lower dosages than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include compositions comprising, in addition to the compound of formula I, one or more other active ingredients.

Examples of other active ingredients that may be administered in combination with a compound of the present invention (such as formula I), and administered separately or in the form of the above-mentioned pharmaceutical compositions include, but are not limited to: Other compounds such as (i) HMG-CoA reductase inhibitors (which are usually statins including lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, vastatin, itavastatin, pitavastatin and other statins), (ii) bile acid sequestrants (cholestyramine, dialkylaminoalkyl derivatives of colestipol and cross-linked dextran, Colestid(R) , LoCholest(R), (iii) nicotinic acid and related compounds such as nicotinic alcohol, nicotinamide and nicotinic acid or salts thereof, (iv) PPARα agonists such as gemfibrozil and fenofibric acid derivatives (fibrates ), including clofibrate, fenofibrate, bezafibrate, ciprofibrate and etofibrate, (v) cholesterol absorption inhibitors such as stanol esters, β-sitosterol, sterol glycosides such as tequimide and azetidinones such as ezetimibe, (vi) acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors such as avasimibe and linoleylbenzylamine, and include selective ACAT-I and ACAT-2 inhibitors and dual inhibitors; (vii) phenolic antioxidants such as probucol, (viii) microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitors, (ix) antioxidant vitamins, eg vitamins C and E and beta-carotene, (x) thyromimetic drugs, (xi) LDL (low density lipoprotein) receptor inducers, (xii) platelet aggregation inhibitors eg glycoprotein IIb/IIIa fibrin Protoreceptor antagonists and aspirin, (xiii) vitamin B12 (also known as cyanocobalamin), (xiv) folic acid or its pharmaceutically acceptable salts or esters, such as sodium and methylglucamine salts, (xv) FXR and LXR ligands, including inhibitors and agonists, (xvi) agents that increase ABCAl gene expression, and (xvii) ileal bile acid carriers.

A preferred class of therapeutic compounds that can be used with the compounds of the invention to improve the lipid profile (i.e. raise HDL-C and lower LDL-C) in a patient includes either or both of statins and cholesterol absorption inhibitors . Particular preference is given to combinations of compounds of the invention with simvastatin, ezetimibe or with both simvastatin and ezetimibe. Also preferred are combinations of the compounds of the invention with statins other than simvastatin, such as lovastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itastatin and ZD A combination of -4522.

Finally, the compounds of the present invention may be used together with compounds useful in the treatment of other diseases such as diabetes, hypertension and obesity, as well as other anti-atherosclerotic compounds. Such combinations may be used to treat one or more diseases such as diabetes, obesity, atherosclerosis and dyslipidemia, or more than one disease associated with metabolic syndrome. Such combinations may exhibit a synergistic effect in the treatment of these diseases, enabling the administration of reduced doses of the active ingredients, eg doses which may be below therapeutic doses when used alone.

Examples of other active ingredients that may be used in combination with the compounds of this invention include, but are not limited to, principal antidiabetic compounds, including:

(a) PPARγ agonists and partial agonists, including glitazones and figlitazones (such as pioglitazone, emglitazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, T-131, LY- 300512 and LY-818);

(b) biguanides such as metformin and phenformin;

(c) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;

(d) inhibitors of dipeptidyl peptidase IV (DP-IV), including vildagliptin, sitagliptin, and saxagliptin;

(e) Insulin or insulin mimetics such as insulin lispro, insulin glargine, insulin zinc suspension and inhaled insulin preparations;

(f) Sulfonylureas, such as tolbutamide, glipizide, glimepiride, acetohexamide, chlorpropamide, glibenclamide or related substances;

(g) Alpha-glucosidase inhibitors (e.g. acarbose; adiposine; caglibose; emigretate; miglitol; voglibose; pramicin-Q; and salbostatin ); (h) PPARα/γ dual agonists such as muraglitazar, tesaglitazar, farglitazar and Raveglitazar;

(i) PPARδ agonists such as GW501516 and those disclosed in WO97/28149;

(j) glucagon receptor antagonists;

(k) GLP-1; GLP-1 derivatives; GLP-1 analogs, such as exendins such as exenatide (Byetta); and non-peptidyl GLP-1 receptor agonists;

(l) GIP-1; and

(m) Non-sulfonylurea insulin secretagogues such as meglitinides (eg nateglinide and rapeglinide).

Other active ingredients that may be used in combination with the present invention include anti-obesity compounds including 5-HT (serotonin) inhibitors, neuropeptide Y5 (NPY5) inhibitors, melanocortin 4 receptor (Mc4r) agonists, Cannabinoid receptor 1 (CB-I) antagonist/inverse agonist, and β3 adrenergic receptor agonist. They are described in more detail later in this section.

These other active ingredients also include active ingredients used in the treatment of inflammatory conditions, such as aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids, salicyl azosulfapyridine, and selective cyclooxygenase-2 (COX-2 ) inhibitors, including etoricoxib, celecoxib, rofecoxib, and Bextra.

Antihypertensive compounds may also be used advantageously in combination therapy with the compounds of the invention. Examples of antihypertensive compounds that may be used in combination with the compounds of the present invention include (1) angiotensin II agonists such as losartan; (2) angiotensin converting enzyme inhibitors (ACE inhibitors) such as enalapril (3) calcium channel blockers such as nifedipine and diltiazem; and (4) endothelin antagonists.

Anti-obesity compounds that may be administered in combination with the compounds of the present invention include: (1) growth hormone secretagogues and growth hormone secretagogue receptor agonists/antagonists, such as NN703, hexarelin, and MK-0677; (2) protein casein (3) cannabinoid receptor ligands such as cannabinoid CB ₁ receptor antagonists or inverse agonists such as rimonabant (Sanofi Synthelabo), AMT -251 and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319 (Solvay), BAY 65-2520 (Bayer); (4) anti-obesity serotonergic agent (serotonergic agent), such as fenfluramine, dexamethasone Fenfluramine, phentermine, and sibutramine; (5) beta3-adrenoreceptor agonists such as AD9677/TAK677 (Dainippon/Takeda), CL-316, 243, SB 418790, BRL-37344, 1-796568 , BMS-196085, BRL-35135A, CGP12177A, BTA-243, trocadrine, ZenecaD7114, and SR59119A; (6) pancreatic lipase inhibitors, such as orlistat (Xenical®), Triton WR1339, RHC80267, lipstatin, tetrahydrolipstatin, teasaponin, and Diethylumbelliferyl phosphate; (7) Neuropeptide Y1 antagonists such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906 and GI-264879A; (8) Neuropeptide Y5 Antagonists such as GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SRA-12SR95 and JCF-104; (9) melanin-concentrating hormone (MCH) receptor antagonists; 10) melanin-concentrating hormone 1 receptor (MCH1R) antagonists such as T-226296 (Takeda); (11) melanin Concentrating hormone 2 receptor (MCH2R) agonists/antagonists; (12) orexin-1 receptor antagonists, such as SB-334867-A; (13) Melanocorticoid agonists, such as Melanotan II; (14) Other Mc4r (melanocortin 4 receptor) agonists such as CHIR86036 (Chiron), ME-10142 and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141 and PT-14 (Palatin); (15) 5HT-2 agonists; (16) 5HT2C (serotonin receptor 2C) agonists such as BVT933, DPCA37215, WAY161503 and R-1065; (17) galanin antagonists; (18) CCK agonists; (19) CCK- A (cholecystokinin-A) agonists such as AR-R 15849, GI181771, JMV-180, A-71378, A-71623, and SR146131; (20) GLP-I agonists; (21) corticotropin releasing Hormone agonists; (22) Histamine receptor-3 (H3) modulators; (23) Histamine receptor-3 (H ₃ ) antagonists/inverse agonists such as hioperamide, N-(4-pentyl ) 3-(1 H-imidazol-4-yl)propyl carbamate, clobenpropit, iodophenpropit, imoproxifan and GT2394 (Gliatech); (24) β-hydroxysteroid dehydrogenase-1 inhibitor (11β-HSD-1 inhibitors) such as BVT3498 and BVT 2733, (25) PDE (phosphodiesterase) inhibitors such as theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilomid, rolipram, and cilomilast; (26) phosphodiesterase-3B (PDE3B) inhibitors; (27) NE (norepinephrine) transport inhibitors such as GW 320659, despiramine, tasupram, and Nomifensine; (28) ghrelin receptor antagonists; (29) leptins, including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen; (30) leptin (31) BRS3 (bombesin receptor subtype 3) agonists such as [D-Phe6, β-Ala11, Phe13, Nle14]Bn (6-14) and [D-Phe6, Phe13]Bn (6-13) Propylamide; (32) CNTF (Ciliary Neurotrophic Factor), such as GI-181771 (Glaxo-SmithKline), SR146131 (SanofiSynthelabo), butabindide, PD170, 292 and PD 149164 (Pfizer); (33) CNTF derivatives such as axokine (Regeneron); (34) monoamine reuptake inhibitors such as sibutramine; (35) UCP-I (uncoupled protein-1, 2 or 3) activators such as phytane acid, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propenyl]benzoic acid (TTNPB ) and retinoic acid; (36) thyroid hormone beta agonists such as KB-2611 (KaroBioBMS); (37) FAS (fatty acid synthase) inhibitors such as Cerulenin and C75; (38) DGAT1 (diacylglycerol acyl transfer Enzyme 1) inhibitors; (39) DGAT2 (diacylglycerol acyltransferase 2) inhibitors; (40) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (41) glucocorticoid antagonists; (42) ) acyl estrogens, such as oleoyl estrone; (43) dicarboxylic acid transporter inhibitors; (44) peptide YY, PYY 3-36, peptide YY analogs, derivatives and fragments, such as BIM-43073D, BIM- 43004C, (45) Neuropeptide Y2 (NPY2) receptor agonists such as NPY3-36, N-acetyl[Leu(28,31)]NPY 24-36, TASP-V and Cyclo-(28/32)-Ac -[Lys28-Gru32]-(25-36)-pNPY; (46) Neuropeptide Y4 (NPY4) agonists such as pancreatic peptide (PP); (47) Neuropeptide Y1 (NPY1) antagonists such as BIBP3226, J-115814 , BIBO 3304, LY-357897, CP-671906 and GI-264879A; (48) Opioid antagonists such as Nalmefene (Revex(R), 3-Methoxynaltrexone, Naloxone and Naltrexone ; (49) glucose transport inhibitors; (50) phosphate transport inhibitors; (51) 5-HT (serotonin) inhibitors; (52) beta-blockers; (53) neurokinin-1 receptor Antagonist (NK-I antagonist); (54) clobenzylrex; (55) cloforex; (56) chloramine; (57) chlorteramine; (58) cyclexedrine; Amphetamine; (60) diphemethoxidine, (61) N-ethylamphetamine; (62) Fenbuxate; (63) Phenerex; (64) Feprex; (65) Fludorex; (66) (67) Furfuryl methamphetamine; (68) Levoamphetamine; (69) Levofaperate; (70) Mefenex; (71) Methamphetamine; (72) Methamphetamine (73) norpseudoephedrine; (74) pentorex; (75) phendimetrazine; (76) fenmetrazine; (77) picirex; (78) phytopharm 57; (79 ) zonisamide; (80) amirex; (81) amphetamine; (82) amphetamine; (83) benzphetamine; and (84) chlorphentermine.

The aforementioned combination therapy with the compounds of the invention may also be used in the treatment of metabolic syndrome. According to a widely used definition, patients with metabolic syndrome are characterized by at least three symptoms selected from the following five symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low (4) high blood pressure; and (5) elevated fasting glucose, which may fall within the range characteristic of type 2 diabetes if the patient also has diabetes. Each of these symptoms is described in the recently published Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (AdultTreatment Panel III, or ATP III), National Institutes of Health, 2001, Clinically defined in NIH Publication No. 01-3670. Patients with the metabolic syndrome have an increased risk of developing the aforementioned macrovascular and microvascular complications, including atherosclerosis and coronary heart disease. The above combination can simultaneously improve more than one symptom (eg, two symptoms, three symptoms, four symptoms, or all five symptoms) of metabolic syndrome.

CETP test

Serial in vitro assays for determining _IC50 values to identify CETP inhibitor compounds were performed according to a modification of the method described by Epps et al. using BODIPY(R)-CE as the cholesteryl ester lipid donor. See Epps et al., (1995) Method for measuring the activities of cholesterol ester transfer protein (lipid transfer protein), Chem. Phys. Lipids. 77, 51-63.

The particles used in the experiments were produced from the following sources: Synthetic donor HDL particles comprising DOPC (dioleoylphosphatidylcholine), BODIPY®-CE (Molecular Probes C-3927), triolein (triglyceride) and apoHDL Generated essentially by sonication of the probe as described by Epps et al., but with the addition of a non-scattering quencher molecule, dabcyldacetylamide, to reduce background fluorescence. Dabcyl dicetylamide is prepared by heating dabcyl n-succinimide with dihexadecylamine in DMF at 95 °C overnight in the presence of diisopropylamine catalyst. Native lipoproteins from human blood were used as acceptor particles. Particles with a density less than 1.063 g/ml were collected by ultracentrifugation. These particles include VLDL, IDL and LDL. Particle concentrations are expressed as protein concentrations determined according to the BCA assay (Pierce, USA). The particles were stored at 4°C until use.

Assays were performed in Dynex Microfluor 2 U-bottom black 96-well plates (Cat#-7205). Prepare an assay mix containing CETP, 1× CETP buffer (50 mM Tris, pH 7.4, 100 mM NaCl, 1 mM EDTA) and half of the final concentration of acceptor particles and add 100 μL of the assay mix to each well of the plate. Add 3 μL of test compound in DMSO. Plates were mixed on a plate shaker and then incubated at 25°C for 1 hour. A second assay mixture was prepared containing donor particles, remaining acceptor particles and 1X CETP buffer. Add 47 μL of the second assay mixture to the reaction wells to start the assay. Assays were performed at 25°C in a final volume of 150 μL. Final concentrations of materials were: 5 ng/μL of donor particles, 30 ng/μL of acceptor particles (each expressed by protein content), 1X CETP buffer, 0.8 nM recombinant human CETP (expressed in CHO cells and partially purified) and up to 2% DMSO when testing compounds. The experiment was carried out in a fluorescence plate reader (Molecular Devices Spectramax GeminiXS), which was set at 25°C as a kinetic run for 45 minutes, and samples were read every 45 seconds at Ex=480nm, Em=511nm, using a 495nm Cutoff filter, medium photomultiplier tube set, calibration turned on, and 6 readings per well.

Data were evaluated by obtaining initial velocities expressed as relative fluorescence units per second for the pseudo-linear portion of the curve (typically 0-500 or 1000 seconds). The percent inhibition was obtained by comparing the rates of positive control samples with inhibitor to non-inhibited (DMSO only). Plots of percent inhibition versus logarithm of inhibitor concentration fitted to a Sigmoidal 4 parameter equation were used to calculate _IC50 .

Example

The following examples are provided so that the present invention may be more fully understood and practiced. The starting materials were prepared by known methods or as shown below.

The examples should not be construed as limiting the invention in any way. The scope of the invention is defined by the claims. Compounds of the invention have _IC50 values measured by the assay described above of less than or equal to 50 [mu]M.

Reaction Scheme 1

Intermediates 1-2, 1-3, 1-4, 1-5 and 1-6 used in the present invention are commercially available or prepared as shown in Reaction Scheme 1 . Appropriately substituted 2-haloanilines 1-1, wherein Ra ^and p are as defined in the claims, and wherein halo is preferably iodo or bromo, are treated with CuCN in DMF at elevated temperature to give the corresponding 2-cyano Aniline. Alternatively, nitrile compounds can be prepared by treating 1-1 with KCN and CuI in the presence of palladium(II) salts or in the presence of certain copper or nickel complexes (see: Smith, MB and March, J."March's Advanced Organic Chemistry", 5th Edition, John Wiley and Sons, New York, pp. 867 (2001) and references cited therein). Iodides 1-3 were prepared by treating 1-2 with isoamyl nitrite, n-amyl nitrite or tert-butyl nitrite, etc. in the presence of diiodomethane (see for example: Smith et al., J. Org. Chem. 55, 2543, (1990) and references cited therein), the reaction was performed without solvent or in a solvent such as THF or acetonitrile. Alternatively, iodide can be formed by first forming a diazonium salt using isoamyl nitrite, n-amyl nitrite, tert-butyl nitrite, sodium nitrite, or nitrous acid, etc. Prepared by heating in the presence of sodium iodide, potassium iodide, tetrabutylammonium iodide, etc. Reduction of 1-3 with DIBAL in dichloromethane affords aldehyde 1-4. Reduction of aldehydes 1-4 using sodium borohydride, etc. in methanol or ethanol affords alcohols 1-5. Treatment of 1-5 with carbon tetrabromide and triphenylphosphine in solvents such as dichloromethane, dichloroethane, etc. yields benzyl bromide 1-6 (see: Smith, MB and March, J. "March' Advanced Organic Chemistry", ^5th Ed., John Wiley and Sons, New York, Pp.518-519 (2001) and references cited therein).

Reaction scheme 2

Intermediates 2-2 and 2-3 of the present invention, wherein R ^a , p and A ³ are as defined in the claims, can be prepared as shown in Reaction Scheme 2. 2-cyanoiodobenzene 2-1 can be purchased or prepared according to the method shown in Reaction Scheme 1. Compound 2-2 is prepared by palladium-catalyzed cross-linking of iodide 2-1 with an appropriately substituted aryl or heteroaryl boronic acid, boronate, or trialkyltin compound via the Suzuki or Stille reaction or variants thereof obtained, the reaction as described by Miyaua et al., Chem. Rev. 95, 2457 (1995) and references cited therein, and as described by Smith, MB and March, J. "March's Advanced Organic Chemistry", 5 ^th Ed., John Wiley and Sons, New York, pp. 868-869 (2001) and references cited therein. Reduction of nitrile 2-2 using lithium aluminum hydride in diethyl ether gave 2-aminomethylaniline 2-3. Alternatively, nitriles can be reduced using palladium on carbon or Raney nickel in methanol, ethanol, etc., under a hydrogen atmosphere. Other methods for reducing nitriles to aminomethyl groups can be found in Smith, MB and March, J. "March's Advanced Organic Chemistry", ^5th Ed., John Wiley and Sons, New York, pp.1204 (2001) and citations therein references.

Reaction scheme 3

Compound 3-4 of the present invention, wherein R, R ^a , p, A ² , A ³ and n are as defined in the claims, can be prepared as shown in Reaction Scheme 3. Benzylamine 3-1 can be purchased or prepared according to the method shown in Reaction Scheme 2. Reaction of 3-1 with an appropriately substituted alkyl acetate bearing a leaving group at the 2-position affords the secondary amine 3-2. Alkyl acetates are commercially available or can be prepared using known methods. Preferred leaving groups may be bromide or iodide, but also mesylate, tosylate, etc., and solvents may be difluoromethane, dichloroethane, tetrahydrofuran, dimethoxyethane wait. The reaction can be carried out with or without a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, and the like. Reduction of the ester function of 3-2 affords the aminoalcohol 3-3. A preferred reducing agent is _LiAlH4 in a solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, and the like. Additional methods for reducing esters are found in "March's Advanced Organic Chemistry" ^5th Ed., John Wiley and Sons, New York, pp 1551. In a solvent such as dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, etc. and a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, etc., using phosgene (Y= Cl) or phosgene equivalents such as triphosgene (Y=OCCl ₃ ) or carbonyl-diimidazole (Y=imidazole), etc. Cycling amino alcohol 3-3 to oxazolidinone 3-4. Enantiomerically pure products can be obtained by chiral chromatography.

Reaction Scheme 4

Compound 4-3 of the present invention, wherein R, R ^a , p, A ² , A ³ and n are as defined in the claims, can be prepared according to Reaction Scheme 4. Appropriately substituted benzylamines 4-1 can be reacted with appropriately substituted oxiranes to afford aminoalcohols 4-2. Ethylene oxide can be purchased or prepared from the corresponding aldehyde and thioylide as described in "March's Advanced Organic Chemistry" ^5th Ed., John Wiley and Sons, New York, pp 1247. Alternatively, the epoxide can be obtained by epoxidation of alkenes, cyclization of halohydrins or 1,2-diols or "March's Advanced Organic Chemistry" 5 ^th Ed., Jobn Wiley and Sons, New York, pp. 1051 described in other methods to prepare. For this reaction, the preferred solvent is isopropanol. In addition, the epoxide ring opening can be performed in a solvent such as acetonitrile or the like by means of a Lewis acid catalyst such as Yb(OTf) ₃ or the like. In a solvent such as dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, etc. and a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, etc., using phosgene (Y= Cl) or phosgene equivalents such as triphosgene (Y= _OCCl3 ) or carbonyl-diimidazole (Y=imidazole), etc. Cycling of aminoalcohol 4-2 to oxazolidinone 4-3. Alternatively, by using a reagent such as dibenzyl dicarbonate in the presence of a base such as triethylamine, diisopropylethylamine, etc., in a solvent such as dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, etc. Amino alcohols 4-2 can be converted to the appropriate carbamates by treatment with esters or benzyl chloroformate. The carbamate can then be converted to the oxazolidinedione 4-3 by treatment with a base such as lithium, sodium or potassium hexamethyldisilazane in a solvent such as tetrahydrofuran, dimethoxyethane, and the like. Enantiomerically pure products can be obtained by chiral chromatography.

Reaction scheme 5

Compound 5-5 of the present invention, wherein R, R ^a , p, A ² , A ³ and n are as defined in the claims, can be prepared as shown in Reaction Scheme 5. Appropriately substituted aminoalcohols 5-1 can be prepared as shown in Reaction Scheme 4 and are preferably protected as carbamates such as tert-butyl carbamate (BOC) or benzyl carbamate (Cbz). Other carbamates and additional nitrogen protecting groups can be found in "Protective Groups in Organic Synthesis", ^3rd Ed. John Wiley and Sons, New York, pp 494. The protection of nitrogen with BOC or Cbz group can be achieved by reacting 5-1 with di-tert-butyl dicarbonate or dibenzyl dicarbonate in a suitable solvent such as dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane Alkanes and other reactions to carry out. By reacting with methanesulfonate in dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, etc. in the presence of a suitable base such as triethylamine, diisopropylethylamine, N-methylmorpholine, etc. The acid chloride reaction can convert the alcohol 5-2 into the azide 5-3. Additionally, alcohols can be converted to additional leaving groups such as tosylate, iodide, bromide, and the like. The mesylate is then displaced with a suitable azide source such as NaN ₃ , LiN ₃ , Bu ₄ NN ₃ , etc. in a suitable solvent such as DMF, DMPU, etc. Azides 5-3 can also be prepared by treating alcohols 5-2 with diphenylphosphoryl azide, diethyl azodicarboxylate and triphenylphosphine in THF. Azide 5-3 can be reduced by hydrogenation using a metal catalyst such as _PtO2 or Pd/C, etc. in a suitable solvent such as EtOAc, THF, EtOH, etc. After reduction and removal of the protecting group, diamine 5-4 is obtained. For the BOC protecting group TFA/ _CH2Cl2 is the preferred deprotection method; for the CBZ protecting group hydrogenation with _a metal catalyst such as eg _PtO2 or Pd/C in a suitable solvent such as EtOAc, THF, EtOH etc. is preferred deprotection method. In a solvent such as dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, etc. and a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, etc., using phosgene (Y= Cl) or phosgene equivalents such as triphosgene (Y= _OCCl3 ) or carbonyl-diimidazole (Y=imidazole), etc. Cyclize diamine 5-4 to imidazolidinone 5-5. Enantiomerically pure products can be obtained by chiral chromatography.

Reaction Scheme 6

Compound 6-4 of the present invention, wherein R, R ^a , p, A ² , A ³ and n are as defined in the claims, can be prepared according to Reaction Scheme 6. In methanol, ethanol, dichloroethane, tetrahydrofuran, etc., in the presence of reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc., or according to Smith, MB and March, J."March's Advanced Organic Chemistry", 5 ^th Ed., John Wiley and Sons, New York, pp.1187-1189 (2001) and the methods described in the references cited therein, 6-1 was prepared by commercially available or by known methods. Treatment of the prepared appropriately substituted protected aminoaldehydes affords 6-2. The preferred conditions for this transformation are the use of sodium cyanoborohydride in methanol with catalytic acetic acid. Deprotection of 6-2 affords 6-3. For the BOC protecting group, TFA/ _CH2Cl2 is _the preferred deprotection method. Phosgene (Y =Cl) or phosgene equivalents such as triphosgene (Y= _OCCl3 ) or carbonyl-diimidazole (Y=imidazole), etc. Cycling of diamine 6-3 to imidazolidinone 6-4. Enantiomerically pure products can be obtained by chiral chromatography.

Reaction Scheme 7

Compound 7-5 of the present invention, wherein R, R ^a , p, A ² , A ³ and n are as defined in the claims, can be prepared as shown in Reaction Scheme 7. Treatment of amine 7-1 prepared as described in Reaction Scheme 4 with the appropriate dicarbonate or chloroformate affords 7-2. By reacting with methanesulfonic acid in dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, etc., in the presence of a suitable base such as triethylamine, diisopropylethylamine, N-methylmorpholine, etc. Acid chloride reaction can convert 7-2 into azide 7-3. Alternatively, the alcohol can be converted to another leaving group such as tosylate, iodide, bromide, and the like. The mesylate is then displaced with a suitable azide source such as NaN ₃ , LiN ₃ , Bu ₄ NN ₃ , etc. in a suitable solvent such as DMF, DMPU, etc. Azides 7-3 can also be prepared by treating alcohols 5-2 with diphenylphosphoryl azide, diethyl azodicarboxylate and triphenylphosphine in THF. When ^R4 is benzyl, azide 7-3 can be reduced to amine 7-4 by _H2 using _PtO2 using THF as solvent. by using a suitable base such as lithium diisopropylamide or lithium bis(trimethylsilyl)amide, sodium or potassium in a suitable solvent such as THF, dimethoxyethane, DMF, DMA, etc. 7-4 Ring Synthesis of Imidazolidinone 7-5. Enantiomerically pure products can be obtained by chiral chromatography.

Reaction Scheme 8

By in a suitable solvent such as THF, dimethoxyethane, DMF, DMA, etc., in the presence of a suitable base such as lithium diisopropylamide or lithium bis(trimethylsilyl)amide, sodium or potassium, etc. , treated with a suitable alkylating agent such as alkyl halide, alkyl toluenesulfonate, alkyl methanesulfonate, etc. (eg methyl iodide), wherein R, R ^a , A ² , A ³ , p and n Compound 8-1 (prepared as described in Reaction Schemes 5, 6 and 7) as defined in the claims is transformed into 8-2.

Reaction scheme 9

Intermediates 9-3 and 9-4, wherein ^Ra , p and ^A3 are as defined in the claims, can be prepared as described in Reaction Scheme 9. Appropriately substituted benzyl nitriles 9-1, prepared as shown in Reaction Scheme 2, can be heated with a base such as sodium hydroxide or potassium hydroxide, etc., in a suitable aqueous alcohol, such as ethanol, propanol, etc., to obtain the appropriately substituted benzene Formic acid 9-2 (See: Smith, MB and March, J. "March's Advanced Organic Chemistry", 5 ^th Ed., John Wiley and Sons, New York, pp.1179-1180 (2001) and references cited therein literature). Benzoic acid 9-2 can be reduced to benzyl alcohol 9-3 using a reducing agent such as borane in a solvent such as tetrahydrofuran or the like (see: Smith, MB and March, J. "March's Advanced Organic Chemistry", 5 ^th Ed., John Wiley and Sons, New York, pp. 1549 (2001) and references cited therein). Alternatively, 9-2 can be esterified by known methods including treatment with trimethylsilyldiazomethane and reduction of the resulting ester to alcohol 9-3 using LiAIH ₄ or the like. Intermediate 9-3 can be converted to benzyl bromide 9-4 using reagents such as triphenylphosphine and carbon tetrabromide in solvents such as diaminomethane, dichloroethane, etc. (See: Smith, MB and March, J. "March's Advanced Organic Chemistry", 5 ^th Ed., John Wiley and Sons, New York, pp. 518-519 (2001) and references cited therein).

Reaction Scheme 10

The intermediate 10-4 of the present invention, wherein R, R ¹ , A ² , p and n are as defined in the claims, can be prepared by combining appropriately substituted benzaldehyde 10-1 with nitric acid as shown in Reaction Scheme 10 Condensation of alkanes affords substituted nitroalcohols 10-2. This reaction can be catalyzed by an aqueous base solution such as an aqueous sodium hydroxide solution in a solvent such as ethanol, methanol, or the like. Nitroalcohol 10-2 can be reduced to aminoalcohol 10-3 using a reducing agent such as Raney nickel, palladium-coated activated carbon or platinum oxide in an alcoholic solvent such as methanol, ethanol, etc., in the presence of hydrogen and an aqueous acid solution (see : Langer, O., et al., Bioorg. Med. Chem., 2001, 9, 677-694). Using reagents such as phosgene (Y=Cl), triphosgene (Y=OCCl ₃ ) or carbonyldiimidazole (Y=imidazole) in solvents such as dichloromethane, diaminoethane, tetrahydrofuran, dimethoxyethane, etc. ) and bases such as triethylamine, diisopropylethylamine, etc., to synthesize oxazolidinone 10-4 from aminoalcohol 10-3.

Reaction Scheme 11

Intermediate 11-4 of the present invention, wherein R, R ¹ , A ² , p and n are as defined in the claims, can be prepared as shown in Reaction Scheme 11 . Treatment of the N-carbamoyl-(N-methoxy-N-methyl)amide of amino acid 11-1, either commercially available or prepared by known methods, with Grignard reagents or other organometallic reagents such as organolithium affords the corresponding Ketones 11-2. Reduction of the ketone with sodium borohydride or zinc borohydride in alcoholic solvents or THF, or other reducing agents such as phenyldimethylsilane in THF, affords alcohol 11-3, which can be Etc. and THF, dioxane, dimethoxyethane, etc., treated with a base such as KOH, the ring of 11-3 can be synthesized into oxazolidinone 11-4.

Reaction scheme 12

Compound 12-3 of the present invention, wherein R, R ¹ , R ^a , A ² , A ³ , p and n are as defined in the claims, can be prepared as shown in Reaction Scheme 1 2 . In a solvent such as tetrahydrofuran, dimethoxyethane, ether, dimethylformamide, dimethylacetamide, etc., using a base such as sodium hexamethyldisilazane or sodium hydride, as shown in Reaction Scheme 9 The resulting benzyl bromide 12-1 is alkylated with the oxazolidinone 12-2 prepared as shown in Reaction Schemes 10 and 11 to afford the product 12-3.

Reaction Scheme 13

Compound 13-4 of the present invention, wherein R, R ¹ , R ^a , A ² , A ³ , p and n are as defined in the claims, can be prepared as shown in Reaction Scheme 13. In a solvent such as tetrahydrofuran, dimethoxyethane, diethyl ether, etc., using a base such as sodium hexamethyldisilazane or sodium hydride, using benzyl bromide 13-1 prepared as shown in Reaction Scheme 1 will react as shown in Alkylation of oxazolidinone 13-2 prepared as shown in Schemes 10 and 11 affords product 13-3. Compound 13-4 was prepared by palladium-catalyzed crosslinking of iodide 13-3 with appropriately substituted aryl or heteroaryl boronic acids, borate esters or trialkyltin compounds by the Suzuki or Stille reaction or variants thereof obtained, the reaction as described by Miyaua et al., Chem. Rev. 95, 2457 (1995) and references cited therein, and as described by Smith, MB and March, J. "March's Advanced Organic Chemistry", 5 ^th Ed ., John Wiley and Sons, New York, pp.868-869 (2001) and references cited therein.

Reaction Scheme 14

Compound 14-5 of the present invention, wherein R, R ^a , A ² , A ³ , p and n are as defined in the claims, is prepared as shown in Reaction Scheme 14. Benzyl alcohol 14-1 can be purchased or prepared as described in Reaction Scheme 9. Reaction of 14-1 with Dess-Martin periodinane affords the corresponding benzaldehyde 14-2. Other methods for oxidation of primary hydroxyls to aldehydes can also be used, such as Swern oxidation conditions, tetrapropylammonium perruthenate, pyridinium chlorochromate, sulfur trioxide-pyridine, and the like. 2-Amino-1-phenylethanol 14-3 can be converted via the corresponding cyanogen silylate by treatment with trimethylsilyl cyanide and catalytic zinc iodide followed by reduction with a reducing agent such as lithium aluminum hydride Base alcohols were prepared from 14-2. Alternatively, 2-amino-1-phenylethanol 14-3 can be prepared from 14-2 via the corresponding cyanoalcohol by treatment with potassium cyanide followed by reduction. Using reagents such as phosgene (Y=Cl), triphosgene (Y=OCCl ₃ ) or carbonyldiimidazole (Y=imidazole) in solvents such as dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, etc. ) and a base such as triethylamine, diisopropylethylamine, etc. can synthesize oxazolidinone 14-4 from 2-amino-1-phenylethanol 14-3. Oxygen can be replaced with an alkyl, heteroalkyl, aryl or heteroaryl bromide using a base such as sodium hexamethyldisilazane or sodium hydride in a solvent such as tetrahydrofuran, dimethoxyethane, diethyl ether, etc. Alkylation of oxazolidinone 14-4 affords product 14-5. Enantiomerically pure products can be obtained by chiral chromatography.

Reaction Scheme 15

Compound 15-6 of the present invention, wherein R, R ¹ , ^Ra , A ² , A ³ , p and n are as defined in the claims, can be prepared as shown in Reaction Scheme 15. Aldehyde 15-1 can be purchased or prepared as described in Reaction Scheme 1. Condensation of 15-1 with nitroalkanes affords substituted nitroalcohols 15-2. This reaction can be catalyzed by an aqueous base solution such as an aqueous sodium hydroxide solution in a solvent such as ethanol, methanol, or the like. Nitroalcohol 15-2 can be reduced to aminoalcohol 15-3 using a reducing agent such as Raney nickel, palladium-coated activated carbon or platinum oxide in an alcoholic solvent such as methanol, ethanol, etc., in the presence of hydrogen and an aqueous acid solution (see : Langer, O., et al., Bioorg. Med. Chem., 2001, 9, 677-694). Reagents such as phosgene (Y=Cl), triphosgene (Y=OCCl ₃ ) or carbonyldiimidazole (Y= imidazole) and bases such as triethylamine, diisopropylethylamine, etc., to synthesize oxazolidinone 15-4 from aminoalcohol 15-3. Oxazolidinone 15-5 is palladium-catalyzed crosslinking of iodide 15-4 with appropriately substituted aryl or heteroaryl boronic acids, boronate esters or trialkyltin compounds via the Suzuki or Stille reaction or variants thereof reaction as described by Miyaua et al., Chem.Rev.95, 2457 (1995) and references cited therein, and as described by Smith, MB and March, J. "March's Advanced Organic Chemistry", ^5th Ed., John Wiley and Sons, New York, pp. 868-869 (2001) and references cited therein. Oxygen can be replaced with an alkyl, heteroalkyl, aryl or heteroaryl bromide using a base such as sodium hexamethyldisilazane or sodium hydride in a solvent such as tetrahydrofuran, dimethoxyethane, diethyl ether, etc. Alkylation of oxazolidinone 15-5 affords product 15-6. Enantiomerically pure products can be obtained by chiral chromatography.

Reaction Scheme 16

Compound 16-5 of the present invention, wherein R, R ¹ , R ^a , A ² , A ³ , p and n are as defined in the claims, can be prepared as shown in Reaction Scheme 16. Aldehyde 16-1 can be purchased or prepared as described in Reaction Scheme 1. Condensation of 16-1 with chiral N-acyloxazolidinones affords the alcohol adduct 16-2 as described in Evans, DA et al., J.Am.Chem.Soc, 2002, 124, 392-3 . Chiral N-acyloxazolidinones are commercially available or prepared as described in Ager, DJ.; Allen, DA; Schaad, DRSynthesis 1996, 1283-5. Compound 16-2 can be hydrolyzed to the corresponding carboxylic acid, followed by treatment with diphenylphosphorazidate and a trialkylamine base to undergo a Curtius rearrangement to afford chiral oxazolidinone 16-3. Oxazolidinone 16-4 is palladium-catalyzed crosslinking of iodide 16-3 with appropriately substituted aryl or heteroaryl boronic acids, boronate esters or trialkyltin compounds via the Suzuki or Stille reaction or variants thereof reaction as described by Miyaua et al., Chem.Rev.95, 2457 (1995) and references cited therein, and as described by Smith, MB and March, J. "March's Advanced Organic Chemistry" , 5 ^th Ed., John Wiley and Sons, New York, pp.868-869 (2001) and references cited therein. Oxygen can be replaced with an alkyl, heteroalkyl, aryl or heteroaryl bromide using a base such as sodium hexamethyldisilazane or sodium hydride in a solvent such as tetrahydrofuran, dimethoxyethane, diethyl ether, etc. Alkylation of oxazolidinone 16-4 affords product 16-5. Alternatively, oxazolidinone 16-3 can be alkylated with an appropriate bromide to obtain compound 16-6, which can be subjected to aryl or heteroaryl boronic acid, boronate ester or trialkyltin compound. The product 16-5 is obtained by Suzuki or Stille reactions or modifications thereof. Enantiomerically pure products can be obtained by chiral chromatography.

Example 1

2-Amino-5-(trifluoromethyl)benzonitrile

To a 2 liter flask was added 100 g (0.348 mol) 4-amino-3-iodobenzotrifluoride, 40 g CuCN and 750 mL DMF. The mixture was heated to reflux and held at reflux for 1 hour. The reaction was cooled and poured into 3 L of water containing 300 mL of concentrated ammonium hydroxide. To this mixture _was added 1 L _CH2Cl2 . The mixture was then filtered through celite. The layers were separated and _the aqueous layer was back extracted with _CH2Cl2 . The organic extracts were combined, and the solvent was evaporated under reduced pressure. The residue was dissolved in 1.5 L of ether, and the resulting solution was washed with 1N ammonium hydroxide, aqueous sodium bisulfite, 1N hydrochloric acid and brine. The solution was dried over anhydrous magnesium sulfate and filtered through a plug of silica gel with a layer of magnesium sulfate on top. The silica gel plug was washed with 0.5 L of ether. The ether solutions were combined, concentrated to 750 mL, and allowed to stand at room temperature. After 2 days, the resulting solid was collected, washed with hexane, and dried under reduced pressure to obtain 2-amino-5-(trifluoromethyl)benzonitrile.

¹ H NMR (CDCl ₃ , 500MHz) δ7.68(s, 1H), 7.58(d, J=8.5Hz, 1H), 6.81(d, J=8.5Hz, 1H), 4.80(brs, 2H).

Example 2

2-iodo-5-(trifluoromethyl)benzonitrile

To a solution of 2-amino-5-(trifluoromethyl)benzonitrile (15.1 g) and diiodomethane (24 mL) in acetonitrile (150 mL) was added tert-butyl nitrite (21 mL) dropwise at 35°C. During the addition, the reaction was maintained at 330-35°C. The reaction was aged for 30 minutes, then heated at 60°C for 30 minutes. The reaction mixture was cooled, washed with ether, followed by 2x water, 2x aqueous sodium bisulfite, water and brine. The solution was dried over anhydrous magnesium sulfate, filtered through a plug of silica gel, and concentrated to obtain 100 g of a red oil. Purification of _the product by silica gel chromatography eluting with hexanes, 3:1 hexanes/ _CH2Cl2 and 1:1 hexanes/ _CH2Cl2 gave 2-iodo-5-(trifluoromethyl ₎ benzyl Nitrile.

¹ HNMR (CDCl ₃ , 500MHz) δ8.10(d, J=8.5Hz, 1H), 7.85(d, J=1.8Hz, 1H), 7.52(dd, J=8.5, 1.8Hz, 1H).

Example 3

5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile

To 2-iodo-5-(trifluoromethyl)benzonitrile (2.0g, 6.7mmol) and (5-isopropyl-2-methoxyphenyl)boronic acid (1.6g, 8.4mmol) in dimethyl To a solution in ethylene glycol (30.4 mL) was added 2M _Na2CO3 (6.8 _mL ), ethanol (9.6 mL) and water (10 mL). The solution was degassed with nitrogen for 2 minutes. Pd( _PPh3 ) ₄ (774mg, 0.67mmol) was added and the solution was again degassed with nitrogen for 2 minutes. This solution was equally divided into two 40 mL microwave tubes. Each tube was degassed with nitrogen for 1 min, sealed, and placed in a microwave reactor. Set the wattage to 200W until the temperature reaches 150°C, then hold the temperature at 150°C for 10 minutes. The microwave tubes were then cooled to room temperature, combined, poured into _H2O (50 mL), and extracted with EtOAc (100 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography using 15% _CH2Cl2 /hexanes afforded 5'-isopropyl-2'-methoxy _- 4-(trifluoromethyl)biphenyl-2-carbonitrile , as light yellow oil. _Rf = 0.65 (25% EtOAc/Hex).

¹ H NMR (CDCl ₃ , 500MHz) δ7.97(s, 1H), 7.85(d, J=8.0Hz, 1H), 7.63(d, J=8.0Hz, 1H), 7.31(dd, J=8.5, 2.0Hz, 1H), 7.12(d, J=2.0Hz, 1H), 6.97(d, J=8.5Hz, 1H), 3.82(s, 3H), 2.93(m, 1H), 1.27(d, J= 7.0Hz, 6H)

Example 4

1-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanamine

5 Dissolve '-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (996.2 mg, 3.12 mmol) in diethyl ether (33 mL), and cool to 0°C. LAH (12.49 mL of a 1M solution in ether, 12.49 mmol) was added dropwise via syringe. After stirring at 0 °C for 10 minutes, the reaction was warmed to room temperature and stirred at room temperature for 6 hours. The solution was then quenched slowly dropwise with 1.5 mL _H2O (vigorous gas evolution), followed by 1.5 mL 30% NaOH, followed by 3.0 mL _H2O . The resulting gummy precipitate was washed with 5 x 20 mL _CH2Cl2 ; the organic washes were dried over sodium sulfate, filtered and concentrated _. Purification of the residue by flash chromatography, eluting with 2% MeOH/ _CH2Cl2 containing 0.1% _{Et3N ,} afforded 1-[5'-isopropyl-2'-methoxy-4-(tri Fluoromethyl) biphenyl-2-yl] methylamine. Rf = 0.30 (10% _MeOH / _CH2Cl2 ).

LCMS = 324.3(M+1) ⁺ .

¹ H NMR (CDCl ₃ , 500MHz) δ7.77(s, 1H), 7.55(d, J=6.8Hz, 1H), 7.32(d, J=7.8Hz, 1H), 7.25(dd, J=83, 2.1Hz, 1H), 7.00(d, J=2.1Hz, 1H), 6.92(d, J=8.4 Hz, 1H), 3.66-3.74(m, 5H), 2.91(m, 1H), 1.26(d, J = 6.9Hz, 6H),

Example 5

4-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl ]Methyl}-1,3-oxazolidin-2-one

Step A: Methyl [3,5-bis(trifluoromethyl)phenyl](hydroxy)acetate

To a solution of [3,5-bis(trifluoromethyl)phenyl](hydroxy)acetic acid (510 mg, 1.77 mmol) in benzene (10 mL) was added MeOH (1.5 mL) followed by (trimethylsilane base) diazomethane (1.06 mL of a 2M solution in hexane, 2.12 mmol). After 10 minutes, the reaction was quenched by adding a few drops of HOAc (added until yellow color disappeared). The reaction was concentrated and purified by flash chromatography eluting with 10-80% EtOAc/hexanes to afford methyl [3,5-bis(trifluoromethyl)phenyl](hydroxy)acetate.

¹ HNMR (CDCl ₃ , 500MHz) δ7.94(s, 2H), 7.85(s, 1H), 5.32(s, 1H), 3.83(s, 3H), 3.68(bs, 1H).

Step B: Methyl [3,5-bis(trifluoromethyl)phenyl](bromo)acetate

Methyl [3,5-bis(trifluoromethyl)phenyl](hydroxy)acetate (300 mg, 0.993 mmol) was dissolved in _CH2Cl2 (10 _mL ). The solution was cooled to 0 °C and _CBr4 (659 mg, 1.986 mmol) was added followed by _PPh3 (521 mg, 1.986 mmol). After 1 hour, the reaction was warmed to room temperature and stirred at room temperature for 1 hour. The reaction was filtered through _a short plug of silica gel, washing with _CH2Cl2 . The filtrate was concentrated and the residue was purified by flash chromatography eluting with 5% EtOAc/hexanes to afford methyl [3,5-bis(trifluoromethyl)phenyl](bromo)acetate. _Rf = 0.24 (5% EtOAc/Hex).

¹ H NMR (CDCl ₃ , 500 MHz) δ8.02(s, 2H), 7.87(s, 1H), 5.41(s, 1H), 3.83(s, 3H).

Step C: [3,5-Bis(trifluoromethyl)phenyl]({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl] Methyl}amino)acetate

To a flask containing methyl [3,5 _- bis(trifluoromethyl)phenyl](bromo)acetate (237.7 mg, 0.651 _mmol ) was added 1-[5'- Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanamine (102.1 mg, 0.316 mmol). The reaction was stirred at room temperature for 5 hours, then diluted with EtOAc (50ml). The organic solution was washed with water and brine (15 mL each). The organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography (5-15% EtOAc/hexanes) afforded [3,5-bis(trifluoromethyl)phenyl]({[5'-isopropyl-2'-methoxy- Methyl 4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)acetate. _Rf = 0.33 (15% EtOAc/Hex).

LCMS=608.4(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.76-7.79(m, 3H), 7.62(s, 1H), 7.56(d, J=7.8Hz, 1H), 7.31 (d, J=7.8Hz, 1H), 7.23(dd, J=8.2, 1.9Hz, 1H), 6.96(m, 1H), 6.89(d, J=8.5Hz, 1H), 4.30(m, 1H) , 3.54-3.70(m, 8H), 2.87(m, 1H), 1.21-1.23(m, 6H).

Step D: 2-[3,5-Bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl -2-yl]methyl}amino)ethanol

[3,5-bis(trifluoromethyl)phenyl]({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl }amino)methyl acetate (13.2mg, 0.0217mmol) was dissolved in _Et2O (1.5mL) and cooled to 0°C. LAH (108.5 μL of a 1M solution in LAH, 0.1085 mmol) was added dropwise via syringe. The reaction was warmed to room temperature and stirred at room temperature for 1 hour. The reaction was then quenched by the addition of _H2O (100 μL), 1 N NaOH (100 μL), followed by _H2O (300 μL). The gummy precipitate _was washed several times with _CH2Cl2 . The organic washes _were filtered through a plug of silica gel with 2% MeOH/ _CH2Cl2 , and the filtrate was concentrated. Purification of the residue by PTLC using 25% EtOAc/hexanes afforded 2-[3,5-bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2' -methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol. _Rf = 0.27 (25% EtOAc/Hex).

LCMS=580.4(M+1) ⁺ . ¹ H NMR (CD ₂ Cl ₂ , 500MHz) δ7.79(s, 1H), 7.75(s, 2H), 7.63-7.68(m, 1H), 7.55(d, J=7.8Hz, 1H), 7.31(d, J=7.8Hz, 1H), 7.23(m, 1H), 6.94(m, 1H), 6.89(m, 1H), 3.43-3.76(m, 9H), 2.86(m, 1H), 1.90(bs, 1H), 1.20(d, J=6.8Hz, 6H).

Step E: 4-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl- 2-yl]methyl}-1,3-oxazolidin-2-one

To a solution of phosgene (21 μL of 20 _% in toluene, ~0.0535 mmol) in _CH2Cl2 (0.5 _mL ) was added 2-[3,5 _- di (Trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol (3.1 mg, 0.00535 mmol), then DIPEA (19 μL, 0.107 mmol) was added. After stirring for 5 minutes, the reaction was poured into water (1 mL), and the mixture was extracted with EtOAc (20 mL). The organic extract was washed with _H2O , saturated _NaHCO3 and brine (5 mL each). The organic layer was then dried over sodium sulfate, filtered, and concentrated. Purification of the residue by PTLC afforded 4-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl) base) biphenyl-2-yl] methyl}-1,3-oxazolidin-2-one. _Rf = 0.27 (25% EtOAc/Hex). LCMS = 606.3 (M+1) ⁺ . ¹ H NMR (CD ₂ Cl ₂ , 500 MHz) (some peak overlap observed; atropisomers present in 1:1 ratio)

δ7.84(s, 1H), 7.19-7.60(m, 6H), 6.80-6.87(m, 2H), 3.84-4.68(m, 5H), 3.68&3.64(2 unimodal, 3H), 2.82( m, 1H), 1.17-1.21 (m, 6H).

Example 6

5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl ]Methyl}-1,3-oxazolidin-2-one

Step A: 2-[3,5-Bis(trifluoromethyl)phenyl]oxirane

NaH (1.09 g 60% NaH, 27.27 mmol) was added to the dry flask. DMSO (90 mL) was added followed by trimethylsulfonium iodide (7.0 g, 31.82 mmol). The reaction was stirred for 5 minutes, then a solution of 3,5-bis(trifluoromethyl)benzaldehyde (1.5 mL, 9.09 mmol) in DMSO (15 mL) was added. The reaction was stirred at room temperature for 1 hour, then poured into ice/water (300 mL). The mixture was extracted with pentane (3 x 150 mL). The pentane extracts were combined and filtered through a short plug of silica gel, washing with 10% _Et2O /pentane. The filtrate was concentrated and the residue was purified by flash chromatography eluting with 10% _Et2O /pentane to afford 2-[3,5-bis(trifluoromethyl)phenyl]oxirane. _Rf = 0.42 (10% _Et2O /pentane).

¹ H NMR (CDCl ₃ , 500MHz) 7.82(s, 1H), 7.74(s, 2H), 3.99(dd, J=3.9, 2.5 Hz, 1H), 3.23(dd, J=5.2, 4.1 Hz, 1H) , 2.79 (dd, J=5.5, 2.5Hz, 1H).

Step B: 1-[3,5-Bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl -2-yl]methyl}amino)ethanol

1-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanamine (300mg, 0.929mmol) and 2-[3,5-bis A solution of (trifluoromethyl)phenyl]oxirane (297 mg, 1.161 mmol) in 2-propanol (9 mL) was heated at reflux for 15 hours and then cooled to room temperature. The solution was concentrated and the residue was purified by flash chromatography using 10-80% EtOAc/hexanes to afford 1-[3,5-bis(trifluoromethyl)phenyl]-2-({ [5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol. _Rf = 0.24 (25% EtOAc/Hex).

LCMS=580.3(M+1) ⁺ . ¹ H NMR(CDCl ₃ , 500MHz) δ7.75-7.76(m, 3H), 7.69(s, 1H), 7.58(d, J=7.8Hz, 1H), 7.34 (d, J=7.7Hz, 1H), 7.25(m, 1H), 6.98(bs, 1H), 6.92(d, J=8.5Hz, 1H), 4.62(m, 1H), 3.65-3.82(m, 5H), 2.89(m, 1H), 2.79(dd, J=12.4, 3.0 Hz, 1H), 248(m, 1H), 1.23(d, J=6.8Hz, 6H).

Step C: 5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl- 2-yl]methyl}-1,3-oxazolidin-2-one

At 0°C, to 1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl) To a solution of biphenyl-2-yl]methyl}amino)ethanol (31.9 mg, 0.0551 mmol) in _CH2Cl2 (5 mL) was added DIPEA (67 μL _, 0.386 mmol) followed by triphosgene (8.2 mg, 0.0276 mmol). The reaction was stirred at 0 °C for 30 minutes. The solution was then poured into saturated _NaHCO3 (15 mL), and the mixture was extracted with EtOAc (50 mL). The organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography (20% EtOAc/hexanes) afforded 5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy yl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one. _Rf = 0.32 (25% EtOAc/Hex). LCMS = 606.3 (M+1) ⁺ . ¹ H NMR (CD ₂ Cl ₂ , 500MHz) (atropisomers exist in a 1:1 ratio, some peaks overlap)

δ7.90(s, 1H), 7.77(s, 2H), 7.57-7.62(m, 2H), 7.37(d, J=8.0Hz, 1H), 7.27(m, 1H), 6.98(s, 1H) , 6.93(dd, J=8.4, 3.2Hz, 1H), 5.42-5.53(m, 1H), 4.15-4.59(m, 2H), 3.72&3.73(2 unimodal, 3H), 3.05-3.65(m , 2H), 2.88(m, 1H), 1.19-1.23(m, 6H).

The two enantiomers can be separated by chiral HPLC using 15% IP A/heptane and AD chiral columns.

Example 7

3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-pyridin-2-yl-1,3- oxazolidin-2-one

Step A: 2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)-1-pyridin-2-yl ethanol

1-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanamine (300mg, 0.929mmol) and 2-oxirane-2 A solution of -ylpyridine (640 mg) [prepared by reacting 2-pyridinecarbaldehyde with NaH and trimethylsulfonium iodide in DMSO] in 2-propanol (9 mL) was heated at reflux for 5 h, then cooled to room temperature . The solution was concentrated and the residue was purified by flash chromatography eluting with 50-100% EtOAc/hexanes containing 0.5% _Et3N to afford 2-({[5'-isopropyl-2' -methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)-1-pyridin-2-ylethanol. Analysis by LCMS indicated the desired product contained several minor impurities. The product was used directly in the next reaction without further purification or analysis.

Step B: (2-Hydroxy-2-pyridin-2-ylethyl){[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol benzyl carbamate

A solution of (PhCH ₂ OCO) ₂ O (103 mg, 0.360 mmol) in anhydrous CH ₂ Cl ₂ (2 mL) was added via cannula to 2-({[5′-isopropyl yl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)-1-pyridin-2-ylethanol (160mg, 0.360mmol) in anhydrous CH ₂ Cl ₂ (10 mL) in a stirred solution. The reaction was stirred at room temperature for 2 hours and concentrated in vacuo to afford crude product. This was purified by flash chromatography (Si, 25 x 160 mm, gradient 0-50% EtOAc in hexanes) to afford (2-hydroxy-2-pyridin-2-ylethyl){[5'- Benzyl isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. _Rf = 0.63 (50% EtOAc/Hex). LCMS calcd = 579.25; found = 579.2 (M+1) ⁺ .

Step C: 3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-pyridin-2-yl-1, 3-oxazolidin-2-one

Lithium bis(trimethylsilyl)amide (464 μL of a 0.5M solution in toluene, 0.232 mmol) was added dropwise to (2-hydroxy-2-pyridin-2-ylethyl){ Benzyl [5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (134.3mg, 0.232mmol) in anhydrous THF (10mL ) in a stirred solution. After stirring at room temperature for 1 h, the reaction was quenched with saturated _NH4Cl (10 mL), extracted with EtOAc (3 x 20 mL). The combined extracts were dried (sodium sulfate) and concentrated in vacuo to afford the crude product. Purification by flash chromatography (Si, 25 x 160 mm, gradient 0-70% EtOAc in hexanes) gave 3-{[5'-isopropyl-2'-methoxy-4- (trifluoromethyl)biphenyl-2-yl]methyl}-5-pyridin-2-yl-1,3-oxazolidin-2-one. _Rf = 0.58 (50% EtOAc/Hex). LCMS calcd = 471.19; found = 471.2 (M+1) ⁺ .

Example 8

5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carboxylic acid

5′-Isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (727 mg, 2.28 mmol) and KOH (767 mg, 13.7 mmol) were dissolved in H ₂ O (7.70 mL) and i-PrOH (11.55 mL) were subjected to microwave irradiation (300W 130°C, 4 hours) in a sealed tube. The reaction mixture was concentrated in vacuo to remove i-PrOH. The resulting aqueous slurry was diluted with water (50 mL), extracted with EtOAc (50 mL). The organic extracts were dried ( _Na2SO4 ) and concentrated _in vacuo to afford 5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carboxamide. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried ( _Na2SO4 ) and concentrated _in vacuo to afford 5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carboxylic acid as free color solid.

¹ H NMR (CDCl ₃ , 500MHz) δ8.01(s, 1H), 7.71(d, J=7.8Hz, 1H), 7.41(d, J=7.8Hz, 1H), 7.14(d, J=8.1Hz , 1H), 7.04(s, 1H), 6.77(d, J=8.1, 1H), 3.68(s, 3H), 2.84(septet, J=6.7Hz, 1H), 1.19(d, J=6.7Hz , 6H).

Example 9

[5'-Isopropyl-2-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol

A solution of borane in THF (1M, 859 μL, 0.859 mmol) was added dropwise to 5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl- 2-Formic acid and 5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carboxamide (3:1, 96.8mg, 0.286mmol) in anhydrous THF in the stirred solution. The reaction was stirred at room temperature for 3 hours, and was carefully quenched with water (10 mL). The mixture was extracted with EtOAc (3 x 20 _mL ), and the combined extracts were washed with brine, dried ( _Na2SO4 ) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Si, 125 x 160 mm, gradient 0-30% EtOAc in hexanes) to afford [5'-isopropyl-2-methoxy-4-(trifluoromethane base) biphenyl-2-yl]methanol as a colorless oil. _Rf = 0.27 (10% EtOAc/Hex).

₁ H NMR (CDCl ₃ , 500MHz) δ7.89 (brs, 1H), 7.62 (dd, J=8.0, 1.3Hz, 1H), 7.36 (d, J=8.0Hz, 1H), 7.29 (dd, J= 8.5, 2.3Hz, 1H), 7.03(d, J=2.3Hz, 1H), 6.96(d, J=8.5, 1H), 4.51(m, 2H), 3.74(s, 3H), 2.93(septet, J=7.0Hz, 1H), 2.51(s, 1H), 1.29(d, J=7.0Hz, 6H).

Example 10

2-(bromomethyl)-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl

CBr ₄ (112 mg, 0.211 mmol) and Ph ₃ P (55 mg, 0.211 mmol) were added sequentially to [5′-isopropyl-2′-methoxy-4-(trifluoromethyl yl ₎ biphenyl-2-yl]methanol (57.1 mg, 0.176 mmol) in a stirred solution of anhydrous _CH2Cl2 (1 mL). The solution was stirred at room temperature for 1 hour, and the reaction mixture was concentrated in vacuo to obtain the crude product. Purification by flash chromatography (Si, 12 x 160 mm, gradient 0-20% EtOAc in hexanes) afforded 2-(bromomethyl)-5'-isopropyl-2'-methoxy Base-4-(trifluoromethyl)biphenyl, a colorless oil. _Rf = 0.95 (20% EtOAc/Hex). LCMS calcd = 387.05; found = 387.0 (M+1) ⁺ .

¹ H NMR (CDCl ₃ , 500 MHz) δ7.83 (brs, 1H), 7.60 (dd, J=8.0, 1.3Hz, 1H), 7.37 (d, J=8.0Hz, 1H), 7.29 (dd, J =8.5, 2.3Hz, 1H), 7.14(d, J=2.3Hz, 1H), 6.95(d, J=8.5, 1H), 4.45(d, J=10.6Hz, 1H), 4.33(d, J= 10.6Hz, 1H), 3.76(s, 3H), 2.94(septet, J=6.9Hz, 1H), 1.29(d, J=6.9Hz, 6H).

Example 11

1-(4-Methylphenyl)-2-nitroethanol

At 0 °C, a stirred solution of 4-methylbenzaldehyde (325 mg, 319 μL, 2.71 mmol) and nitromethane (531 μL, 9.89 mmol) in anhydrous EtOH (20 mL) was washed with 10% aqueous NaOH (m/ v) (1.14 mL, 2.84 mmol), stirred for 1 hour and treated with 2% aqueous acetic acid (m/v) (8.54 mL, 2.84 mmol). The reaction was stirred at room temperature for 1 hour, then partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL), the combined organic extracts were washed with saturated NaHCO ₃ (50 mL) and brine (50 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford 1-(4- Methylphenyl)-2-nitroethanol, a colorless oil.

¹ H NMR (CDCl ₃ , 500MHz) δ7.28 (d, J=8.1Hz, 2H), 7.21 (d, J=8.1Hz, 2H), 5.42 (dt, J=9.6, 3.3Hz, 1H), 4.60 (dd, J=13.3, 9.7Hz, 1H), 4.49(dd, J=13.3, 3.1Hz, 1H), 2.79(d, J=3.7, 1H), 2.36(s, 3H).

Example 12

2-Amino-1-(4-methylphenyl)ethanol

A suspension of 10% Pd/C (24 mg) in a solution of 1-(4-methylphenyl)-2-nitroethanol (50 mg, 0.276 mmol) in anhydrous EtOH (1 mL) was incubated at room temperature at 15 psi Stir overnight under H ₂ . The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford 2-amino-1-(4-methylphenyl)ethanol as an oil. LCMS calcd = 152.10; found = 152 (M+1) ⁺ .

¹ H NMR (CDCl ₃ , 500MHz) δ7.20 (d, J=8.0Hz, 2H), 7.13 (d, J=8.0Hz, 2H), 4.57 (dd, J=7.9, 3.9Hz, 1H), 2.86 (dd, J=12.7, 3.9Hz, 1H), 2.76(dd, J=12.7, 7.9Hz, 1H), 2.33(s, 3H).

Example 13

5-(4-Methylphenyl)-1,3-oxazolidin-2-one

Diisopropylethylamine (181 mg, 244 μL, 1.40 mmol) and triphosgene (138 mg, 0.466 mmol) were added sequentially to 2-amino-1-(4-methylphenyl)ethanol ( 35.2 mg, 0.233 mmol) in a stirred solution in anhydrous _{CH2Cl2 (} 22 mL). The reaction was stirred at 0 °C for 1 hour, then concentrated in vacuo to a volume of about 5 mL. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts _were dried ( _Na2SO4 ) and concentrated in vacuo to afford the crude product. It was purified by flash chromatography (Si, 12 x 160 mm, gradient 0-80% EtOAc in hexanes) to afford 5-(4-methylphenyl)-1,3-oxazolidine-2 -ketone. _Rf = 0.41 (50% EtOAc/Hex). LCMS calcd = 178.08; found = 178.1 (M+1) ⁺ .

¹ H NMR (CDCl ₃ , 500MHz) δ7.25(d, J=7.4Hz, 2H), 7.19(d, J=7.4Hz, 2H), 6.69(brs, 1H), 5.55(t, J=7.8Hz , 1H), 3.93(t, J=8.6Hz, 1H), 3.52(t, J=8.1Hz, 1H), 2.35 (s, 3H).

Example 14

3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-(4-methylphenyl)-1, 3-oxazolidin-2-one

Sodium hydride (6.4 mg 60% dispersion in mineral oil, 0.161 mmol) was added to 5-(4-methylphenyl)-1,3-oxazolidin-2-one ( 37.7 mg, 0.0973 mmol) in a stirred solution in anhydrous THF (1 mL). The reaction was stirred for 30 minutes and 2-(bromomethyl)-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl (19.0 mg, 0.107 mmol) was added via cannula Solution in dry THF (2 mL). The reaction was stirred at room temperature for 3 days. The reaction was quenched with saturated _NH4Cl (10 mL), extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford the crude product. Purification by flash chromatography (Si, 12 x 160 mm, gradient 0-80% EtOAc in hexanes) afforded 3-{[5'-isopropyl-2'-methoxy-4- (Trifluoromethyl)biphenyl-2-yl]methyl}-5-(4-methylphenyl)-1,3-oxazolidin-2-one, a colorless oil. _Rf = 0.37 (20% EtOAc/Hex). LCMS calcd = 484.21; found = 484.2 (M+1) ⁺ . ¹ H NMR (Benzene-d ₆ , 500 MHz, 1:1 mixture of atropisomers)

δ7.76(s, 0.5H), 7.65(s, 0.5H), 7.31(d, J=7.7Hz, 1H), 7.08(dd, J=8.4, 2.4Hz, 1H), 7.05(br d, J =7.8Hz, 1H), 6.95-6.86(m, 5H), 6.58(t, J=7.7Hz, 1H), 4.74(t, J=8.0Hz, 0.5H), 4.70(t, J=8.0Hz, 0.5H), 4.50(d, J=15.7Hz, 0.5H), 4.42(d, J=15.7Hz, 0.5H), 4.25(d, J=15.7Hz, 0.5H), 4.11(d, J=15.7 Hz, 0.5H), 3.26(s, 1.5H), 3.21(s, 1.5H), 2.81(t, J=8.6Hz, 0.5H), 2.76(septet, J=7.0Hz, 1H), 2.68( t, J=8.6Hz, 0.5H), 2.55(t, J=8.6Hz, 0.5H), 2.53(t, J=8.6Hz, 0.5H), 2.04(s, 3H), 1.20(t, J= 7.0Hz, 3H), 1.19(t, J=7.0Hz, 3H).

Example 15

1-[3,5-bis(trifluoromethyl)phenyl]-2-nitropropan-1-ol

3,5-Bis(trifluoromethyl)benzaldehyde (1.00 g, 4.13 mmol) and nitroethane (1.13 g, 1.08 mL, 15.1 mmol) were stirred in anhydrous EtOH (20 mL) at 0 °C The resulting solution was treated with 10% aqueous NaOH (m/v) (1.73 mL, 4.34 mmol), stirred for 1 h, and treated with 2% aqueous acetic acid (m/v) (13.0 mL, 4.32 mmol). The reaction was stirred at room temperature for 1 hour, then partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL), the combined organic extracts were washed with saturated NaHCO ₃ (50 mL) and brine (50 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo to give threo- and erythro- 1.5:1 mixture of 1-[3,5-bis(trifluoromethyl)phenyl]-2-nitropropan-1-ol as colorless oil. ¹ H NMR (CDCl ₃ , 500 MHz) threo-diastereomers:

δ7.88(br s, 1H), 7.86(br s, 2H), 5.22(d, J=8.4 Hz, 1H), 4.77(dq, J=8.4, 6.9Hz, 1H), 3.03(br s 1H) , 1.42 (d, J=6.9Hz, 3H), erythro-diastereomer:

δ7.90(br s, 1H), 7.86(br s, 2H), 5.59(d, J=3.2Hz, 1H), 4.72(dq, J=3.2, 6.9Hz, 1H), 3.03(br s 1H) , 1.50 (d, J=6.9Hz, 3H).

Example 16

2-Amino-1-[3,5-bis(trifluoromethyl)phenyl]propan-1-ol

Raney nickel (50mg) in a 1.5:1 mixture of threo- and erythro-1-[3,5-bis(trifluoromethyl)phenyl]-2-nitropropan-1-ol (50mg, 0.158mmol ) in a solution of 30% (v/v) _HCO2H in water (0.75 mL) and MeOH (10 mL) was stirred at room temperature under 15 psi _H2 overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to remove MeOH. The aqueous slurry was adjusted to pH 9-10 with 28% aqueous _NH4OH , diluted with water (20 mL), and extracted with EtOAc (3 x 20 mL). The combined extracts were washed with brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford threo- and erythro-2-amino-1-[3,5-bis(trifluoromethyl)phenyl ] a mixture of propan-1-ols as a colorless solid. LCMS calcd = 288.08; found = 288.1 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) threo-diastereomer:

δ7.79(br s, 3H), 4.35(br s, 1H), 3.25(br s, 1H), 2.59(br s, 3H), 0.86(d, J=6.1Hz, 3H), erythrotype-non Enantiomer:

δ7.79(br s, 3H), 4.71(br s, 1H), 3.00(br s, 1H), 2.59(br s, 3H), 1.06(d, J=5.0Hz, 3H).

Example 17

5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

Diisopropylethylamine (106 mg, 142 μL, 0.817 mmol) and triphosgene (20.2 mg, 0.068 mmol) were added sequentially to 2-amino-1-[3,5-bis(trifluoro A stirred solution _of methyl)phenyl]propan-1-ol (39.1 mg, 0.136 mmol) in anhydrous _CH2Cl2 (10 mL). The reaction was stirred at 0 °C for 1 hour, then concentrated in vacuo to a volume of about 5 mL. The mixture was diluted with water (50 mL), extracted with EtOAc (3 x 50 mL). The combined organic extracts _were dried ( _Na2SO4 ) and concentrated in vacuo to afford the crude product. Purification by flash chromatography (Si, 12 x 160 mm, gradient 0-70% EtOAc in hexanes) gave threo-5-[3,5-bis(trifluoromethyl)phenyl]- 4-methyl-1,3-oxazolidin-2-one (17.5 mg) and erythro-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3- Oxazolidin-2-one (14.4 mg) as a colorless solid, threo-diastereomer: _Rf = 0.63 (50% EtOAc/Hexanes). LCMS calcd = 314.06; found = 314.1 (M+1) ⁺ .

¹ H NMR (CDCl ₃ .600MHz) δ7.90 (br s, 1H), 7 83 (br s, 2H), 6.71 (br s, 1H), 5.17 (d, J=7.0Hz, 1H), 3.86 ( br pentet, J=6.2Hz, 1H), 1.48 (d, J=6.2Hz, 1H). The compound was obtained using chiral HPLC (AS column, 20×250 mm, 20% i-PrOH in heptane). Separation into its enantiomers (4R,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one and (4S, 5S)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one, erythro-diastereomer: R _f =0.38 (50% EtOAc/Hexanes). LCMS calcd = 314.06; found = 314.1 (M+1) ⁺ .

¹ H NMR (CDCl ₃ , 600 MHz) δ7.90 (br s, 1H), 7.79 (br s, 2H), 5.83 (d, J=8.0Hz, 1H), 5.34 (br s, 1H), 4.31 ( br pentet, J=7.0Hz, 1H), 0.84 (d, J=6.6Hz, 1H).

This compound was separated into its two enantiomers (4S,5R)-5-[3,5-di( Trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one and (4R,5S)-5-[3,5-bis(trifluoromethyl)phenyl]- 4-Methyl-1,3-oxazolidin-2-one.

Chiral Synthesis of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

This intermediate can be directly prepared from the chiral raw material CBZ-1-alanine by the following three-step method. Compound (4R, 5S)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one can be prepared by CBZ-D- Alanine is produced.

step 1

Under nitrogen, CBZ-1-alanine (6.5 kg, 28.5 mol), HOBT-hydrate (4.8 kg, 34.8 mol), Weinreb amine-HCl salt (3.4 kg, 36.2 mol) and THF (32 L) were added to into a clean flask. The mixture was cooled to 0-10°C, then DFEA (12.4 L) was added slowly below 25°C. Then EDC-HCl (7Kg, 36.2mol) was added slowly under cooling at 15°C-25°C. The slurry was aged overnight at 20°C to 25°C. The mixture was then cooled to 0°C-10°C and 3 N HCl (12 L) was added slowly. IPAC (32L) was then added and the layers were separated. The organic layer was washed once with HCl (13 L) and twice with 8% _NaHCO3 (13 L) (Caution: foam formation). The organic layer was then concentrated in vacuo at 50 °C to about 15 L. The clear solution was cooled slowly to room temperature allowing the product to crystallize. Heptane (-70 L) was then added slowly. The slurry was filtered, washed with heptane (18 L), and dried in the filter vessel at room temperature. A product was obtained with >99.9% ee, determined by chiral HPLC.

step 2

The Weinreb amide from Step 1 (6 kg, 22.5 mol) and 3,5-bis(trifluoromethyl)bromobenzene (4.85 L, 28.1 mol) were dissolved in anhydrous THF (24 L). The solution was purged with nitrogen to remove oxygen. This is where the water content should be <500ppm. Atmospheric distillation was performed to remove water, if necessary. The solution was cooled to -10°C, and a solution of iso-PrMgCl in THF (56.4 mol) was slowly (2 hours) added to the reaction via addition funnel, keeping the reaction temperature ≤ -5°C. The solution was allowed to warm to 20°C and aged overnight at 20°C until the amide was <0.5 LCAP. The solution was then cooled to -10°C under nitrogen and added slowly to 5N HCl (14 L) maintained at 0-5°C over 2 hours. MTBE (12 L) was added and the biphasic mixture was stirred for 5 minutes. After warming to 20°C-25°C, it was left for 30 minutes before the layers were separated. The organic layer was washed twice with water (12 L). The organic layer was transferred to a distillation flask through a 1 micron in-line PTEE vessel, then concentrated in vacuo (internal temperature <40 °C) to ~12 L to maintain a stirred volume. The solution was azeotropically dried with stirring, concentrated again to the minimum stirring volume, and used directly in the next step.

If a solid product was desired, heptane was added to the organic layer, then concentrated to a minimum stirring volume. Vacuum distillation was continued at 40°C-55°C until the final volume was 40L. The solution was cooled to 35°C-37°C, seeded (-0.5%, 30 g) and aged for 30 minutes to grow a complete seed bed. The slurry was cooled to 10°C over 2-3 hours. The slurry was then filtered, washed with 5°C heptane (18 L) and allowed to dry completely in the filter vessel overnight using a vacuum/nitrogen purge. A dry solid was obtained with >99.9 ee%. If the optical purity is insufficient, the amide can be recrystallized from pure heptane.

step 3

Under an inert atmosphere, TFA (9 L) was charged to a 100 L Buchi reactor and cooled to -5 °C. The ketone product from step 2 (5.50 kg, 13.1 mol) was added as a solid, followed by a TFA wash (2 L). The solution was cooled to -5°C and stirred until all solids dissolved. Monosilane (2.18 kg, 15.7 mol) was added slowly (in two portions) over 1 hour while maintaining the temperature at <0°C. The reaction was aged at -2 to -6°C for 15-20 hours at which time LC showed <2% ketone remaining. A 50 w/w % KOH solution was prepared by slowly adding 13.6 kg KOH pellets (87 w%) to 10 L of water while maintaining the highly exothermic dissolution <30°C. Store this solution in the refrigerator.

The reaction was quenched with ~2L of 50w/w% KOH solution under vigorous stirring and cooling, maintaining the temperature at about 20°C. THF (16.5 L, stored in refrigerator above) was added, followed by the remaining KOH solution (ca. 13.7 L) slowly, and a 2 L water wash, while maintaining the temperature <20°C. After the KOH addition was complete, the reaction was aged at room temperature. After 3 hours, the reaction was treated with 27.5 L of PAC and 20 L of 20% w/v aqueous NaCl.

The aqueous and organic layers were separated. The organic layer was washed successively with 26L of 20% w/v aqueous NaCl, 36L of water, 31L of 0.5N HCl and 32L of water. The organic layer was concentrated to about 10 L. Heptane (20 L) was added and crystals formed. The organic layer was concentrated to about 10 L. Additional heptane (20 L) was added, and the organic layer was concentrated to about 10 L. Heptane (22 L) was added and the slurry was aged at room temperature. The solid was filtered off and washed with 24 L of heptane. The product was obtained as a solid (98.8% purity, >99.95% ee by LC). The solid was redissolved in 12.5 L MeOH (exotherm). 3 L of water was added at room temperature and the mixture was aged to initiate crystallization. Water (9.5 L) was added at room temperature over 60 minutes. After aging for 60 minutes, the slurry was filtered and the solids were washed with 5 L MeOH/water (1/1.5), 5 L MeOH/water (1/4), and 4 L water. The solid product was dried under vacuum at 50°C (99.9% purity by LC, >99.95% ee).

The reaction in step 3 was also performed using Al(Oi-Pr) ₃ as a reducing agent. For example, a ketone (6 kg) was heated with 0.3 equivalents of Al(Oi-Pr) ₃ (790 g) in 12 L of IPA and 18 L of toluene at 50 °C for 15.5 hours. The solution was cooled to room temperature and solid KOH pellets (1.35 kg) were added with vigorous stirring while maintaining the temperature at <25°C. After about 2 hours, when HPLC indicated >99.5% crystallization, the reaction was quenched by adding 33 L of 1N HCl solution, which was maintained at <25°C. If a fractal solid formed, it should be filtered to increase the enantiomeric excess. The organic layer was then washed first with 36L of 0.5N HCl. It was then washed with a mixture of 6L IPA and 45L of water, and finally with a mixture of 6L IPA and 36L of water. Transfer the organic layer to an in-line filter. The solvent was replaced with heptane (target volume ~42 L) at about 40 °C until <2 v% toluene remained. Aging at room temperature for 2 hours gave a solid product.

HPLC method for the analysis used in step 3:

Ace-C8 column 250×4.6mm A: MeCN; B: 0.1% H ₃ PO ₄ in H ₂ O;

Gradient: 5A:95B at 0 minutes to 95A:5B at 9 minutes; hold 95A:5B until 13 minutes; return to 5A:95B for 13-15 minutes Conditions: 35°C, 1.5mL/min, 210nm

Example 18

Erythro-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl- 2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Lithium bis(trimethylsilyl)amide (172 μL of a 1M solution in THF, 0.172 mmol) was added to erythro-5-[3,5-bis(trifluoromethyl)phenyl ]-4-Methyl-1,3-oxazolidin-2-one (50 mg, 0.129 mmol) in a stirred solution in anhydrous THF (1 mL). The reaction was stirred for 15 minutes and 2-(bromomethyl)-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl (27.0 mg, 0.0861 mmol) was added via cannula Solution in dry THF (2 mL). The reaction was stirred at room temperature for 3 days. The reaction was quenched with saturated _NH4Cl (10 mL), extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford the crude product. Purification by flash chromatography (Si, 12 x 160 mm, gradient 0-40% EtOAc in hexanes) gave erythro-5-[3,5-bis(trifluoromethyl)phenyl] -3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidine -2-one, as a colorless oily substance. _Rf = 0.64 (20% EtOAc/Hex). LCMS calcd = 620.18; found = 620.2 (M+1) ⁺ .

¹ H NMR (Benzene-d6, 600 MHz, 1:1 mixture of atropisomers)

δ7.94(s, 0.5H), 7.72(s, 0.5H), 7.64(s, 0.5H), 7.63(s, 0.5H), 7.39-7.34(m, 3H), 7.12-7.04(m, 2H ), 6.95(d, J=2.1Hz, 0.5H), 6.86(d, J=1.7Hz, 0.5H), 6.64(d, J=8.5Hz, 0.5H), 6.56(d, J=8.5Hz, 0.5H), 4.99(d, J=15.9Hz, 0.5H), 4.93(d, J=15.9Hz, 0.5H), 4.73(d, J=7.9Hz, 0.5H), 4.61(d, J=7.9 Hz, 0.5H), 3.88(d, J=15.9Hz, 0.5H), 3.82(d, J=15.9Hz, 0.5H), 3.35(s, 1.5H), 3.24(s, 1.5H), 3.05( Septet, J=6.9Hz, 0.5H), 3.01(Septet, J=6.9Hz, 0.5H), 2.75(m, 1H), 1.19(dd, J=6.9, 2.7Hz, 3H), 1.17(dd , J=10.9, 6.9Hz, 3H), -0.18(d, J=6.4Hz, 1.5H), -0.33(t, J=6.4Hz, 1.5H).

This compound was separated into its two enantiomers (4R,5S)-5-[3,5-di( Trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl -1,3-oxazolidin-2-one and (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2' -Methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.

Example 19

4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl ]methyl}imidazolidin-2-one

Step A: {2-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxyethyl}{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl Base) biphenyl-2-yl] methyl} carbamate tert-butyl ester

To 1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2 -yl]methyl}amino)ethanol (Example 6 Step B, 325.0 mg, 0.561 mmol) in CH ₂ Cl ₂ (15 mL) was added BOC ₂ O (122 mg, 0.561 mmol) and DIPEA (98 μL, 0.561 mmol). The reaction was stirred at room temperature. After 5 hours, additional _BOC2O (50 mg, 0.229 mmol) and DIPEA (50 μL, 0.287 mmol) were added. The reaction was stirred at room temperature for 48 hours. The solution was then concentrated to ~2 mL, diluted with hexanes (8 mL), and purified by flash chromatography eluting with 10-20% EtOAc/hexanes to afford {2-[3,5-bis(trifluoromethane Base) phenyl] -2-hydroxyethyl}{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate tert-butyl ester. _Rf = 0.38 (25% EtOAc/Hex).

LCMS=580.3(M+1-BOC) ⁺ . ¹ H NMR (CD ₂ Cl ₂ , 500MHz) δ7.78(s, 1H), 7.54-7.67(m, 4H), 7.23-7.33(m, 2H), 6.90-6.95(m, 2H), 3.15-4.82(m, 9H), 2.87(m, 1H), 1.19-1.43(m, 15H).

Step B: 1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[5′-isopropyl-2′-methoxy- 4-(Trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl ester

To {2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethyl}{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl) To a solution of tert-butyl biphenyl-2-yl]methyl}carbamate (350.1 mg, 0.516 mmol) in _CH2Cl2 ( ₁₅ mL) was added DIPEA (450 μL, 2.58 mmol). The solution was cooled to 0 °C and MsCl (100 μL, 1.29 mmol) was added. After stirring at 0 °C for 45 min, the reaction was diluted with EtOAc (100 mL), washed with saturated _NaHCO3 (25 mL), brine (25 mL), 1 N HCl (25 mL) and brine (2 x 25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was passed through a short plug of silica gel, washed with 25% EtOAc/hexanes and concentrated. Product methanesulfonic acid 1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[5′-isopropyl-2′-methoxy-4- (Trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl ester was used immediately in the next reaction without further characterization. _Rf = 0.33 (25% EtOAc/Hex).

Step C: {2-azido-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5'-isopropyl-2'-methoxy-4-(tri tert-butyl fluoromethyl)biphenyl-2-yl]methyl}carbamate

The 1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[5′-isopropyl-2′-methyl Oxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl ester was dissolved in DMPU (15 mL) and treated with _NaN3 (140 mg, 2.15 mmol). The reaction was stirred at room temperature for 15 hours, then diluted with EtOAc (75 mL). The solution was washed with _H2O (5 x 40 mL) and brine (40 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification of the residue with 20% EtOAc/hexanes afforded {2-azido-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5'-isopropyl-2 tert-butyl '-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. _Rf = 0.52 (15% EtOAc/Hex).

LCMS=605.3(M+1-BOC) ⁺ . ¹ H NMR (C ₆ D ₆ , 500MHz, 70°C) δ7.80(s, 1H), 7.67(s, 1H), 7.48(s, 2H), 7.36 (d, J=7.8Hz, 1H), 7.01-7.11(m, 2H), 6.89(m, 1H), 6.64(d, J=8.6Hz, 1H), 4.22-4 69(m, 3H), 3.2 g(s, 3H), 2.61-3.16(m, 3H), 1.34(s, 9H), 1.13-1.18(m, 6H).

Step D: {2-Amino-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl base)biphenyl-2-yl]methyl}carbamate tert-butyl ester and [1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2 Mixture of tert-butyl '-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl]carbamate

To {2-azido-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl) 10% Pd/C (100 mg) was added to a solution of tert-butyl)biphenyl-2-yl]methyl}carbamate (300 mg, 0.426 mmol) in EtOAc (15 mL). The reaction was placed under _H2 and stirred at room temperature for 5 hours. At this point the reaction was complete and a mixture of two products was obtained, {2-amino-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5'-isopropyl-2'- Methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate tert-butyl ester and [1-[3,5-bis(trifluoromethyl)phenyl]-2-( tert-butyl {[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl]carbamate. The catalyst was filtered off and the filtrate was concentrated to give a product mixture. LCMS = 679.3 (M+1) ⁺ . The product was used in the next reaction without further purification or characterization.

Step E: 1-[3,5-Bis(trifluoromethyl)phenyl]-N ² -{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl -2-yl]methyl}ethane-1,2-diamine

To 283.5mg (0.418mmol) {2-amino-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5'-isopropyl-2'-methoxy-4- (Trifluoromethyl)biphenyl-2-yl]methyl}carbamate tert-butyl ester and [1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-iso A mixture of tert-butyl propyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl]carbamate in _CH2Cl2 (15 _mL ) TFA (1.5 mL) was added to the solution. The reaction was stirred at room temperature for 5 hours, then poured into 1N NaOH (50 mL). The mixture was extracted with _CH2Cl2 (3 x 50 mL), and the organic extracts were _combined , dried over sodium sulfate, filtered, and concentrated. _Purification of the residue by flash chromatography eluting with 5-10% MeOH/ _CH2Cl2 afforded 1-[3,5-bis(trifluoromethyl)phenyl] ^-N2 -{[5'- isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}ethane-1,2-diamine. _Rf = 0.46 (10% MeOH/ _{CH2Cl2 )} .

LCMS=579.2(M+1) ⁺ . ¹ H NMR (CD ₂ Cl ₂ , 500MHz) δ7.83(s, 2H), 7.77(s, 2H), 7.55(d, J=7.8Hz, 1H), 7.31 (d, J=8.1Hz, 1H), 7.24 (dd, J=8.4, 2.3Hz, 1H), 6.99 (d, J=2.0Hz, 1H), 6.92 (d, J=8.5Hz, 1H), 4.06 (m, 1H), 3.59-3.76(m, 2H), 3.69(s, 3H), 2.88(m, 1H), 2.67(dd, J=11.9, 4.3Hz, 1H), 2.51(m, 1H), 1.22(d, J=6.9Hz, 6H).

Step F: 4-[3,5-Bis(trifluoromethyl)phenyl]-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl- 2-yl]methyl}imidazolidin-2-one

1-[3,5-bis(trifluoromethyl)phenyl]-N ² -{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2 A solution of -yl]methyl}ethane-1,2-diamine (125.2 mg, 0.217 mmol) in _CH2Cl2 (30 _mL ) was cooled to 0 °C and DIPEA (227 μL, 1.30 mmol) was added. Triphosgene (32.2 mg, 0.109 mmol) was then added. The reaction was stirred at 0 °C for 45 min, then poured into saturated _NaHCO3 (20 mL). The mixture was extracted with EtOAc (100 mL), the organic layer was washed with brine (25 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with 40% EtOAc/hexanes to afford 4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5'-isopropyl- 2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}imidazolidin-2-one. _Rf = 0.22 (40% EtOAc/Hex). LCMS = 605.2 (M+1) ⁺ .

¹ H NMR (CDCl ₃ , 500 MHz) (atropisomers present in 1:1 ratio; some peak overlap observed)

δ7.83(s, 1H), 7.78(s, 2H), 7.55-7.62(m, 2H), 7.32(d, J=7.8Hz, 1H), 7.22(m, 1H), 6.94(s, 1H) , 6.88(d, J=8.3 Hz, 1H), 5.33&5.24(2 unimodal, 1H), 4.80-4.88(m, 1H), 4.00-4.61(m, 2H), 3.72&3.70(2 unimodal peak, 3H), 3.55-3.59(m, 1H), 2.83-2.93(m, 2H), 1.17-1.23(m, 6H).

The two enantiomers of this compound can be separated using an AD chiral column eluting with 5% IPA/heptane.

Example 20

(4R)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-phenylimidazolidine-2- ketone

Step A: tert-butyl [(1R)-2-hydroxy-1-phenylethyl]carbamate

To a solution of (2R)-2-amino-2-phenylethanol (400 mg, 2.91 mmol) in _CH2Cl2 (15 mL) was added _BOC2O (636 mg _, 2.91 mmol) and DIPEA (507 μL, 2.91 mmol) . The reaction was stirred at room temperature for 18 h, diluted with EtOAc (75 mL), washed with _H2O , brine, 1N HCl, brine, saturated _NaHCO3 and brine (25 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with 50% EtOAc/hexanes to afford tert-butyl [(1R)-2-hydroxy-1-phenylethyl]carbamate. _Rf = 0.23 (40% EtOAc/Hex).

¹ HNMR (CDCl ₃ , 600MHz) δ7.27-7.37 (m, 5H), 5.27 (bs, 1H), 4.78 (bs, 1H), 3.83 (bs, 2H), 2.46 (bs, 1H), 1.44 (bs , 9H).

Step B: tert-butyl [(1R)-2-oxo-1-phenylethyl]carbamate

To a solution of tert-butyl [(1R)-2-hydroxy-1-phenylethyl]carbamate ( ₂₀₀ mg, 0.844 mmol) in _CH2Cl2 (20 mL) was added Dess-Martin periodinane ( 447 mg, 1.05 mmol). The reaction was stirred at 0 °C for 15 minutes, then at room temperature for 30 minutes. _The solution was then diluted with EtOAc (75 mL) and washed rapidly with 10% _K2CO3 (2 x 30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified on a short silica gel column eluting with 50% EtOAc/hexanes to afford tert-butyl [(1R)-2-oxo-1-phenylethyl]carbamate. ¹ H NMR (CDCl ₃ , 600 MHz) (major and minor conformers observed) gives data for major conformer)

δ9.53(s, 1H), 7.29-7.40(m, 5H), 5.80(bs, 1H), 5.31(m, 1H), 1.42(s, 9H).

This product was used immediately in the following reaction.

Step C: [(1R)-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)-1 -Phenylethyl]carbamate tert-butyl ester

To a solution of tert-butyl [(1R)-2-oxo-1-phenylethyl]carbamate (113.8 mg, 0.484 mmol) in MeOH (7 mL) was added 1-[5′-isopropyl- 2'-Methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanamine (98 mg, 0.303 mmol), then _NaCNBH3 (30 mg, 0.477 mmol) and HOAc (2 drops). The reaction was stirred at room temperature overnight, diluted with EtOAc (75 mL), washed with 1N NaOH (25 mL) and brine (25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography, eluting with 5-25% EtOAc/hexanes, afforded [(1R)-2-({[5'-isopropyl-2'-methoxy-4-(tri fluoromethyl)biphenyl-2-yl]methyl}amino)-1-phenylethyl]carbamate tert-butyl ester. _Rf = 0.30 (25% EtOAc/Hex). LCMS = 543.4 (M+1) ⁺ .

Step D: (1R)-N ² -{[5-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1-phenylethane -1,2-diamine

To [(1R)-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)- To _a solution of tert-butyl 1-phenylethyl]carbamate (150 mg, 0.277 mmol) in _CH2Cl2 (10 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 2 hours, then poured into 1N NaOH (25 mL). The mixture was extracted with _CH2Cl2 (3 _x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography eluting with 0-10% MeOH/ _CH2Cl2 to afford (1R) ^-N2 -{[5 _- isopropyl-2'-methoxy-4-( Trifluoromethyl)biphenyl-2-yl]methyl}-1-phenylethane-1,2-diamine. _Rf = 0.27 (10% _MeOH / _CH2Cl2 ). LCMS = 443.4 (M+1) ⁺ .

Step E: (4R)-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-phenylimidazolidine -2-one

(1R)-N ² -{[5-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1-phenylethane-1 , A solution of 2-diamine (96.0 mg, 0.22 mmol) in _CH2Cl2 (15 _mL ) was cooled to 0 °C and DIPEA (230 μL, 1.32 mmol) was added followed by triphosgene (32.6 mg, 0.11 mmol). After 45 minutes, the reaction was poured into saturated _NaHCO3 (25 mL). The mixture was extracted with EtOAc (75 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography, eluting with 10-60% EtOAc/hexanes, afforded (4R)-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethane base) biphenyl-2-yl] methyl}-4-phenylimidazolidin-2-one. Removal of the minor enantiomer by chiral HPLC using an AD chiral column and 15% IP A/heptane afforded enantiomerically pure product. _Rf = 0.16 (40% EtOAc/Hex). LCMS = 469.3 (M+1) ⁺ . 1H NMR (CDCl ₃ , 500MHz) (Atropisomers exist in a 1:1 ratio, some overlapping peaks were observed)

δ7.65(m, 1H), 7.54(d, J=7.7Hz, 1H), 7.21-7.36(m, 7H), 6.87-6.94(m, 2H), 4.65-4.77(m, 2H), 4.10- 4.49(m, 2H), 3.71 & 3.72(2 unimodal, 3H), 3.49-3.53(m, 1H), 2.94-2.97(m, 1H), 2.87(m, 1H), 1.19-1.24(m, 6H ),

Example 21

4-(4-Chlorophenyl)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}imidazolidine-2 -ketone

Step A: 1-(4-Chlorophenyl)-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl} Amino)ethanol

1-[5'-isopropyl-2'-methoxy-5-(trifluoromethyl)biphenyl-2-yl]methanamine (300mg, 1.1mmol) and 2-(4-chlorophenyl ) A solution of ethylene oxide (143 μL, 1.2 mmol) in isopropanol (10.5 mL) was heated at reflux for 24 hours. The reaction was concentrated and purified by flash chromatography eluting with 5%-80% EtOAc/hexanes to afford 1-(4-chlorophenyl)-2-({[5'-isopropyl-2 '-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol. _Rf = 0.37 (50% EtOAc/Hex).

LCMS=478.1(M+1) ⁺ .1H NMR (CDCl ₃ , 500MHz) δ7.70(s, 1H), 7.55(d, J=7.5Hz, 1H), 7.33-7.19(m, 6H), 6.97( s, 1H), 6.90(d, J=8.5Hz, 1H), 4.52(m, 1H), 3.77-3.62(m, 5H), 2.89(m, 1H), 2.71(m, 1H), 2.51(m , 1H), 1.24(d, J=7.0Hz, 6H).

Step B: [2-(4-Chlorophenyl)-2-hydroxyethyl]{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl ]Methyl}carbamate

To 1-(4-chlorophenyl)-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino) To a solution of ethanol (40 mg, 0.08 mmol) in _CH2Cl2 (2 mL) was added dibenzyl dicarbonate (24 mg, 0.08 _mmol ). The reaction was stirred at room temperature for 24 hours, then poured into _H2O (15 mL). The resulting mixture was extracted with EtOAc (50 mL), the organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography, eluting with 5%-60% EtOAc/hexanes, afforded [2-(4-chlorophenyl)-2-hydroxyethyl]{[5'-isopropyl-2 Benzyl '-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. _Rf = 0.20 (25% EtOAc/Hex). LCMS = 612.2 (M+1) ⁺ . ¹ H NMR (C ₆ D ₆ , 600 MHz, peak broadening and/or overlapping; rotamers and/or atropisomers present)

δ7.98-6.45(m, 15H), 5.00-3.46(m, 6H), 3.20-2.96(m, 5H), 2.72(m, 1H), 1.20-1.15(m, 6H).

Step C: [2-Azido-2-(4-chlorophenyl)ethyl]{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2 -yl]methyl}carbamate

[2-(4-Chlorophenyl)-2-hydroxyethyl]{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol A solution of benzyl}carbamate (44 mg, 0.07 mmol) in CH ₂ Cl ₂ (6 mL) was cooled to 0° C., N,N-diisopropylethylamine (63 μL, 0.36 mmol) was added followed by methanesulfonate Acid chloride (14 μL, 0.18 mmol). The reaction was stirred at 0 °C for 30 minutes, then poured into saturated sodium bicarbonate (15 mL). The resulting mixture was extracted with EtOAc (50 mL), and the organic layer was washed with brine (15 mL), dried over sodium sulfate, filtered through a short plug of silica gel, and concentrated. The residue was redissolved in DMPU (6 mL) and sodium azide (12 mg, 0.18 mmol) was added. The reaction was stirred at room temperature for 24 hours, then poured into _H2O (15 mL). The resulting mixture was extracted with EtOAc (50 mL), the organic layer was washed with _H2O (2 x 15 mL), brine (15 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography using 25% EtOAc/hexanes afforded [2-azido-2-(4-chlorophenyl)ethyl]{[5'-isopropyl-2' -Benzyl methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. _Rf = 0.66 (25% EtOAc/Hex). LCMS = 637.3 (M+1) ⁺ . ¹ HNMR (C ₆ D ₆ , 600 MHz, overlapping peaks; rotamers and/or atropisomers present)

δ8.03-6.52(m, 15H), 5.00-5.08(m, 2H), 4.76-4.12(m, 3H), 3.28-2.86(m, 5H), 2.77(m, 1H), 1.23-1.18(m , 6H).

Step D: [2-Amino-2-(4-aminophenyl)ethyl]{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl ]Methyl}carbamate

To [2-azido-2-(4-chlorophenyl) ethyl] {[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl To a solution of benzyl ]methyl}carbamate (30 mg, 0.05 mmol) in THF (1 mL) was added _PtO2 (8 mg) and the reaction was stirred at room temperature under hydrogen for 1 h. The catalyst was removed by filtration through a plug of Celite, washed with 100% EtOAc, and the filtrate was concentrated to give [2-amino-2-(4-chlorophenyl)ethyl]{[5'-isopropyl - Crude benzyl 2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. _Rf = 0.66 (25% EtOAc/Hex). LCMS = 611.3 (M+1) ⁺ .

Step E: 4-(4-Fluorophenyl)-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}imidazole alkan-2-one

To [2-amino-2-(4-chlorophenyl)ethyl]{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol To a solution of benzyl}carbamate (30 mg, 0.05 mmol) in THF (2 mL) was added lithium bis(trimethylsilyl)amide (295 μL of a 0.5 M solution in toluene, 0.147 mmol), and the reaction Stir at room temperature for 30 minutes, then quench with saturated _NH4Cl (15 mL). The resulting mixture was extracted with EtOAc (25 mL), the organic layer was washed with _H2O (15 mL) and brine (15 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography using 5%-60% EtOAc/hexanes afforded 4-(4-chlorophenyl)-1-{[5'-isopropyl-2'-methoxy -4-(trifluoromethyl)biphenyl-2-yl]methyl}imidazolidin-2-one. _Rf = 0.46 (5% _MeOH / _CH2Cl2 ). LCMS = 503.1 (M+1) ⁺ . ¹ H NMR (C ₆ D6, 600 MHz, atropisomers observed; overlapping peaks)

δ7.90-7.03 (m, 6H), 6.89-6.20 (m, 4H), 4.69-3.88 (m, 3H), 3.16 (s, 3H), 2.88-2.30 (m, 3H), 1.18-1.13 (m , 6H).

Example 22

(4R)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-3-methyl-4-phenyl imidazolidin-2-one

To (4R)-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-phenylimidazolidine-2 - To a solution of the ketone (12.6 mg, 0.0269 mmol) in THF (1.5 mL) was added MeI (10 μL, 0.162 mmol) followed by KHMDS (162 μL of a 0.5M solution in toluene, 0.081 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into water (10 mL). The mixture was extracted with EtOAc (30 mL), the organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography using 50% EtOAc/hexanes afforded (4R)-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl) Biphenyl-2-yl]methyl}-3-methyl-4-phenylimidazolidin-2-one. _Rf = 0.26 (40% EtOAc/Hex). LCMS = 483.2 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz, atropisomers observed; peaks overlap)

δ7.68-7.53(m, 2H), 7.21-7.36(m, 7H), 6.87-6.94(m, 2H), 4.08-4.56(m, 3H), 3.72&3.71(2 unimodal, 3H), 3.34-3.38(m, 1H), 2.77-2.89(m, 2H), 2.67&2.63(2 unimodal, 3H), 1.18-1.26(m, 6H).

The compounds listed in Table 1 were prepared following the procedures outlined in Examples 1-22:

Table 1

Example 50

4-[3,5-bis(trifluoromethyl)phenyl]-2-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl ]Methyl}-1,2,5-thiadiazolidine 1,1-dioxide

1-[3,5-bis(trifluoromethyl)phenyl]-N ² -{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2 A solution of -yl]methyl}ethane-1,2-diamine (8.0 mg, 0.014 mmol) and sulfonamide (2.0 mg, 0.021 mmol) in pyridine (300 μL) was heated to 120° C. in a sealed tube. After 3 hours, the reaction was cooled to room temperature and diluted with 25 mL of EtOAc. The organic solution was washed with 1N HCl (2 x 5 mL) and brine (1 x 5 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the residue by PTLC using 25% EtOAc/hexanes afforded 4-[3,5-bis(trifluoromethyl)phenyl]-2-{[5'-isopropyl-2'- Methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,2,5-thiadiazolidine 1,1-dioxide. _Rf = 0.29 (25% EtOAc/Hex). LCMS = 641.1 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz; atropisomers present)

δ7.58-7.85(m, 5H), 7.35-6.86(m, 4H), 4.82-4.94(m, 2H), 3.54-4.42(m, 6H), 2.71-2.91(m, 2H), 1.11-1.26 (m, 6H).

Example 51

5-[5′-Isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one

Step A: [5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol

To a solution of 1.08 g 5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (Example 3) in 25 mL n-PrOH was added 0.97 g KOH . The mixture was heated to reflux and stirred at this temperature for 36 hours, then cooled and concentrated to a clear oil. The oil was partitioned between 15 mL water and 10 mL _Et2O . The aqueous phase was extracted with 10 mL _Et2O . The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on a Biotage Horizon 4OS column, eluting with 1 CV of 95% hexane-5% 5% formic acid in acetone, followed by 10 CV of 5-100% acetone in hexane Linear gradient elution. The _resulting white solid was dissolved in 10 mL 9:1 benzene-MeOH and excess _TMSCH2N2 was added. The mixture was stirred at room temperature for 10 minutes, then quenched with trifluoroacetic acid and concentrated. The residue was dissolved in 15 mL of ether and cooled to 0°C. A solution of 1-M _LiAlH4 in ether (5.4 mL) was added dropwise via addition funnel. Once the addition was complete, the cooling bath was removed and the mixture was stirred at room temperature for 2 hours, then recooled to 0 °C and quenched by the dropwise addition of 0.2 mL of water, 0.2 mL of 15% aqueous NaOH and 0.5 mL of water. Once the addition was complete, the cooling bath was removed and the mixture was stirred at room temperature for 30 minutes, filtered (washing the solid with _Et2O ) and concentrated. Purification by flash chromatography on a Biotage Horizon, 4OS column eluting with 1 CV of 4% EtOAc in hexanes followed by a linear gradient of 4-100% EtOAc in hexanes over 10 CVs gave The title compound. Mass spectrum (ESI) 307.2 (M-17).

¹ HNMR (500MHz, CDCl ₃ ): δ7.85(s, 1H), 7.60(d, J=8Hz, 1H), 7.33(d, J=8Hz, 1H), 7.25(dd, J=2Hz, 9Hz, 1H), 6.99(d, J=2.5Hz, 1H), 6.93(d, J=8.5Hz, 1H), 4.49(m, 2H), 3.74(s, 3H), 2.90(septet, J=7Hz, 1H), 1.25(d, J=7Hz, 6H).

Step B: 5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde

To a solution of 0.725 g of [5'-isopropyl-2'-methoxy _- 4-(trifluoromethyl)biphenyl-2-yl]methanol in 10 mL of _CH2Cl2 was added 1.14 g of Dess-Martin periodinane. The mixture was stirred at room temperature for 30 minutes, then filtered and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 4OS column, eluting with 1 CV of 1% EtOAc in hexanes, followed by a linear gradient of 1-100% EtOAc in hexanes over 10 CV, The title compound was obtained. Mass spectrum (ESI) 323.2 (M+1).

¹ H NMR (500MHz, CDCl ₃ ): δ9.81(s, 1H), 8.28(s, 1H), 7.88(dd, J=1.5Hz, 8Hz, 1H), 7.54(d, J=8Hz, 1H) , 7.33(dd, J=2Hz, 8Hz, 1H), 7.16(d, J=2.5Hz, 1H), 6.95(d, J=8.5Hz, 1H), 3.74(s, 3H), 2.95(septet, J=7Hz, 1H), 1.29(d, J=7Hz, 6H).

Step C: 2-Amino-1-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]ethanol

To a solution of 0.679 g 5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde in 1.5 mL CH ₂ Cl ₂ was added about 5 mg ZnI ₂ , followed by 0.23 g trimethylsilyl cyanide. The mixture was stirred at room temperature for 3 hours, then partitioned between 15 mL of water and 10 mL of _Et2O . The aqueous phase was extracted with 2 x 10 mL _Et2O . The combined organic phases were dried over sodium sulfate and concentrated. The residue was dissolved in 15 mL of ether and cooled to 0°C. A solution of 1-M L1AIH ₄ in ether (4.2 mL) was added dropwise via addition funnel. Once the addition was complete, the cooling bath was removed and the mixture was stirred at room temperature overnight, then quenched by the dropwise addition of 0.15 mL of water, 0.15 mL of 15% aqueous NaOH and 0.4 mL of water upon cooling to 0 °C. Once the addition was complete, the cooling bath was removed and the mixture was stirred at room temperature for 30 minutes, filtered (washing the solid with _Et2O ) and concentrated to afford the title compound which was used without further purification. Mass spectrum (ESI) 354.2 (M+1). ^Some1H NMR signals overlap due to rotamerism.

¹ H NMR (500MHz, CDCl ₃ ): δ7.88(s, 1H), 7.55(app t, J=7.5Hz, 1H), 7.22-7.28(m, 2H), 6.99, 6.95(d, J=2.5 Hz, 1H), 6.92, 6.90 (sm 1H), 4.52 (m, 1H), 3.70 (s, 3H), 2.90 (septet, J=7Hz, 1H), 2.81 (m, 1H), 2.60-2.70 ( m, 2H), 1.23-1.28 (m, 6H).

Step D: 5-[5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one

To 0.44 g 2-amino-1-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]ethanol in 15 mL CH ₂ Cl ₂ at 0°C 0.241 g of diisopropylethylamine was added to the solution, followed by 0.185 g of triphosgene. The mixture was stirred at 0 °C for 30 min, then diluted with 30 mL of EtOAc and 20 mL of saturated NaHCO ₃ . The phases were separated and the organic phase was washed with 20 mL of brine, _dried ( _Na2SO4 ) and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 4OS column, eluting with 1 CV of 5% EtOAc in hexanes, followed by a linear gradient of 5-100% EtOAc in hexanes over 10 CV , the title compound was obtained. Mass spectrum (ESI) 380.2 (M+1). ¹ H NMR signals overlap due to rotational enantiomerism

¹ H NMR (500 MHz, CDCl ₃ ): δ7.90, 7.86 (s, 1H), 7.66 (d, J=8 Hz, 1H), 7.35 (d, J=8 Hz, 1H), 7.27 (dd, J= 2.5Hz, 8.5Hz 1H), 7.03(d, J=2.5Hz, 0.5H), 6.87-6.93(m, 1.5H), 5.65, 5.50(t, J=8Hz, 1H), 5.23, 5.09(s, 1H), 3.75(s, 1.5H), 3.69(s, 1.5H), 3.68, 3.51(t, J=9Hz, 1H), 3.31, 3.19(t, J=8.5Hz, 0.5H), 2.90(sevenfold Peak, J=7 Hz, 1H), 1.25, 1.24 (d, J=7Hz, 6H).

Further purification by HPLC on a Chiralpak AD 2 x 25 cm, eluting with 10% isopropanol in heptane at 9 mL/min, afforded two enantiomers: Enantiomer A, _tR = 15.1 min; Enantiomer B, _tR = 17.4 min.

Example 52

3-Benzyl-5-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one

To 44mg 5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one in 1mL DMF Add 10 mg of sodium hydride to the 0°C solution. The mixture was stirred at room temperature for 10 minutes, then 24 mg of benzyl bromide was added. The mixture was stirred overnight at room temperature, then diluted with 15 mL EtOAc and 5 mL water. The phases were separated and the organic phase was washed with 5 mL each of water and brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column eluting with 1 CV of hexanes, followed by a linear gradient of 0-50% EtOAc in hexanes over 10 CVs to provide the title compound. Mass spectrum (ESI) 470.1 (M+1).

¹ H NMR (500MHz, CDCl ₃ ): δ7.86, 7.76(s, 1H), 7.62(d, J=8Hz, 1H), 7.14-7.40(m, 7H), 7.01, 6.77(d, J=2.5 Hz, 1H), 6.87, 6.83(d, J=8.5 Hz, 1H), 5.45, 5.53(m, 1H), 4.30-4.53(m, 2H), 3.73, 3.55(s, 3H), 3.48, 3.30( m, 1H), 3.10, 2.96 (t, J～8.5 Hz, 1H), 2.89, 2.82 (septet, J=7Hz, 1H), 1.24, 1.16 (m, 6H).

Example 53

3-[3,5-bis(trifluoromethyl)benzyl]-5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl] -1,3-oxazolidin-2-one (racemic)

Following the procedure described in Example 50, 43 mg of 5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazole was used Alkan-2-ones and 43 mg of 3,5-bis(trifluoromethyl)benzyl bromide afforded the title compound. Mass Spectrum (ESI) 606.1 (M+1). The ¹ H NMR signals overlap due to rotational enantiomerism.

¹ H NMR (500MHz, CDCl ₃ ): δ7.58-7.88(m, 5H), 7.34(d, J=8Hz, 1H), 7.23(m, 1H), 7.02, 6.79(d, J=2Hz, 1H ), 6.88, 6.85(d, J=8.5Hz, 1H), 5.45, 5.42(m, 1H), 4.52-4.64(m, 1.5H), 4.36(d, J=15.5Hz, 0.5H), 3.74, 3.57(s, 3H), 3.49, 3.34(m, 1H), 3.09, 2.99(t, J～8.5Hz, 1H), 2.89, 2.81(septet, J=7Hz, 1H), 1.24, 1.12(m, 6H).

Example 54

3-[3,5-bis(trifluoromethyl)benzyl]-5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl] -1,3-oxazolidin-2-one (enantiomer A)

Following the procedure described in Example 50, 43 mg of 5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazole was used Alkan-2-one, enantiomer A and 43 mg of 3,5-bis(trifluoromethyl)benzyl bromide afforded the title compound. Analytical HPLC on Chiralpak AS 4.6 x 250 mm eluting with 5% isopropanol in heptane at 0.5 mL/min: _tR = 9.9 min

Example 55

3-[3,5-bis(trifluoromethyl)benzyl]-5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl] -1,3-oxazolidin-2-one (enantiomer B)

Following the method described in Example 50, 44 mg of 5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazole was used Alkan-2-one, enantiomer B and 43 mg of 3,5-bis(trifluoromethyl)benzyl bromide afforded the title compound. Analytical HPLC was performed on a Chiralpak AS 4.6 x 250 mm, eluting with 5% isopropanol in heptane at 0.5 mL/min: _tR = 11.0 min

Example 56

1-(4-fluorophenyl)-1-hydroxyacetone

Under nitrogen atmosphere, a suspension of _LaCl3 (26 mg, 0.104 mmol) in anhydrous THF (7.8 mL) was cooled to -78 °C and stirred for 1 min. A solution of n-BuLi (1.6M in hexane, 195 μL, 0.312 mmol) was added and stirring was continued for 15 minutes. The reaction was warmed to 0 °C and stirred for 30 minutes. Trimethylsilyl cyanide (31 mg, 42 μL, 0.312 mmol) was added and the reaction was stirred at 0 °C for 30 minutes and allowed to warm to room temperature over 30 minutes. Acetyltrimethylsilane (Cunico, RF, Kuan, C.-P., J. Org. Chem., 1985, 50, 5410-5413) (121 mg, 1.04 mmol) and 4-fluorobenzene were added via cannula Formaldehyde (1.42 mg, 1.14 mmol) was dissolved in anhydrous THF (19 mL), and the reaction was stirred at room temperature for 2 hours. 1N HCl (24 mL) was then added and the reaction was stirred for 1 hour. _Et2O (25 mL) was added, the organic layer was separated and washed with water (2 x 25 mL). The combined aqueous layers were extracted with ether (3 x 50 mL). The combined organic extracts were dried ( _MgSO4 ) and concentrated in vacuo to afford crude product. This was purified by flash chromatography (Si, 25 x 160 mm, gradient 0-50% EtOAc in hexanes) to afford 1-(4-fluorophenyl)-1-hydroxyacetone as a colorless solid. _Rf = 0.31 (20% EtOAc/Hex).

¹ H NMR (CDCl ₃ , 500MHz) δ7.29(m, 2H), 7.08-7.04(m, 2H), 5.06(d, J=3.6 Hz, 1H), 4.35(d, J=6.5 Hz, 1H) , 2.05(s, 3H).

Example 57

Erythro- and threo-1-(4-fluorophenyl)-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl ]methyl}amino)propan-1-ol

NaCNBH ₃ (19 mg, 0.306 mmol) was added to {[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amine ( 67 mg, 0.204 mmol) and 1-(3,5-diaminophenyl)-1-hydroxyacetone (45 mg, 0.204 mmol) in MeOH, then acetic acid (2 drops). The reaction was stirred at room temperature for 5 hours. The reaction mixture was diluted with EtOAc (20 mL), _H2O (20 mL) and brine (5 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic extracts _were dried ( _Na2SO4 ) and concentrated in vacuo to afford the crude product. It was purified by flash chromatography (Si, 12 x 160 mm, gradient 0-50% EtOAc in hexanes) to afford two possible diastereomers, erythro-1-(4-fluorophenyl )-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propan-1-ol (68.4mg) and threo-1-(4-fluorophenyl)-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl }amino)propan-1-ol (48.9 mg) as a colorless oil. Erythro-diastereomer: _Rf = 0.40 (20% EtOAc/Hex). LCMS calcd = 476.22; found = 476.2 (M+1) ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ7.72(s, 1H), 7.60(d, J=7.8Hz, 1H), 7.36(m, 1H), 7.27(dd, J=8.5, 23Hz, 1H), 7.19(m, 2H), 7.04-6.92(m, 4H), 4.63-4.56(m, 1H), 3.85-3.65(m, 7H), 2.92(m, 1H), 2.72(m, 1H), 1.26( t, J=8.0Hz, 6H), 0.64(t, J=5.4Hz, 3H).

Threo-diastereomer: _Rf = 0.20 (20% EtOAc/Hex). LCMS calcd = 476.22; found = 476.2 (M+1) ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ7.73(d, J=9.0Hz, 1H), 7.58(d, J=7.9Hz, 1H), 7.32(m, 1H), 7.24(m, 3H), 7.07 -6.97(m, 3H), 6.92(d, J=8.5Hz, 1H), 4.05(d, J=7.9Hz, 1H), 3.82-3.70(m, 5H), 3.59 (d, J=13Hz, 1H ), 3.51(d, J=13 Hz, 1H), 2.90(m, 1H), 2.51(m, 1H), 1.25(m, 6H), 0.73(d, J=6.4Hz, 3H)

Example 58

Erythro-5-(4-fluorophenyl)-3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}- 4-Methyl-1,3-oxazolidin-2-one

Prepare according to the method in Step 3 of Example 7. _Rf = 0.38 (20% EtOAc/Hex). LCMS calcd = 502.20; found = 502.2 (M+1) ⁺ . ¹ H NMR (500 MHz, benzene-d ₆ , 1:1 mixture of atropisomers)

δ7.96(s, 0.5H), 7.75(s, 0.5H), 7.35(d, J=7.7Hz, 1H), 7.10-7.06(m, 2H), 6.94(d, J=2.1Hz, 0.5H ), 6.88(d, J=2.1Hz, 0.5H), 6.69-6.62(m, 4.5H), 6.55(d, J=8.4Hz, 0.5H), 4 95(d, J=15.9Hz, 0.5H ), 4.86(d, J=15.8Hz, 0.5H), 4.80(d, J=7.9Hz, 0.5H), 4.70(d, J=7.8Hz, 0.5H), 4.04(d, J=15.8Hz, 0.5H), 3.93(d, J=15.9Hz, 0.5H), 3.36(s, 1.5H), 3.22(s, 1.5H), 3.14(m, 0.5H), 3.05(m, 0.5H), 2.79 -2.71(m, 1H), 1.18(m, 6H), 0.02(d, J=6.5Hz, 1.5H), -0.04(d, J=6.5Hz, 1.5H)

This compound was separated into its two enantiomers (4R,5S)-5-(4-fluorophenyl)-3 using chiral HPLC (AD column, 20×250 mm, 3% EtOH in heptane) -{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidine-2 -ketone and (4S, 5R)-5-(4-fluorophenyl)-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2- Base] methyl}-4-methyl-1,3-oxazolidin-2-one.

The compounds listed in Table 2 were prepared following the procedure described in Example 58:

Table 2

Example 64

1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-phenylpyrrolidin-2-one

Sodium bis(trimethylsilyl)amide (114 μL of a 1M solution in THF, 0.114 mmol) was added to 4-phenylpyrrolidin-2-one (Winans, CF, Adkins, H. , J. Am. Chem. Soc, 1933, 55, 4167-4176) (17 mg, 0.103 mmol) in a stirred solution in anhydrous THF (1 mL). The reaction was stirred for 5 minutes and 2-(bromomethyl)-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl (20 mg, 0.0516 mmol) was added via cannula at Solution in anhydrous THF (2 mL). The reaction was stirred at room temperature for 3 days. The reaction was treated with saturated _NH4Cl (10 mL), extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford the crude product. Purification by flash chromatography (Si, 12 x 160 mm, gradient 0-90% EtOAc in hexanes) afforded 1-{[5'-isopropyl-2'-methoxy-4- (Trifluoromethyl)biphenyl-2-yl]methyl}-4-phenylpyrrolidin-2-one, a colorless oil. _Rf = 0.11 (20% EtOAc/Hex). LCMS calcd = 468.22; found = 468.2 (M+1) ⁺ . ¹ H NMR (600 MHz, benzene-d ₆ , 1:1 mixture of atropisomers)

δ7.79(s, 0.5H), 7.73(s, 0.5H), 7.33(d, J=7.7Hz, 1H), 7.08-7.04(m, 4H), 6.99(m, 1H), 6.92(s, 0.5H), 6.88(s, 0.5H), 6.76(dd, J=16.0, 7.4Hz, 2H), 6.60(dd, J=8.5, 3.1Hz, 1H), 4.58(d, J=15.4Hz, 1H ), 4.38(t, J=13.9Hz, 1H), 3.29(s, 1.5H), 3.26(s, 1.5H), 2.85-2.73(m, 3H), 2.63-2.57(m, 1H), 2.38- 2.28(m, 1H), 2.21-2.11(m, 1H), 1.20-1.16(m, 6H).

Example 65

4-(3,4-Difluorophenyl)-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}pyrrole alkan-2-one

Following a method analogous to that described in Example 64, using 4-(3,4-difluorophenyl)pyrrolidin-2-one (by analogy to Marivet, MC, Bourguignon, J.-J.; Lugnier, C, Mann, A., Stoclet, J.-C, Wermuth, C.-GJ Med.Chem., 1989, 32, 1450-1457 described in the method) prepared). LCMS calcd = 504.20; found = 504.2 (M+1) ⁺ .

Example 66

5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one

A stirred suspension of sodium hydride (60% dispersion in oil, 167 mg, 4.18 mmol) in THF (5 mL) was washed with 5-[ 3,5-Bis(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one (500 mg, 1.67 mmol) was treated. The reaction was stirred for 20 minutes and a solution of 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (610 mg, 1.67 mmol) in THF (1 mL) was added dropwise. The reaction was stirred at room temperature for 18 hours. The reaction was treated with _H2O (1 mL), partitioned between EtOAc (80 mL) and _H2O (25 mL). The aqueous phase was further extracted with EtOAc (2 x 20 mL), the combined organic extracts were washed with brine (30 mL), dried ( _MgSO4 ) and concentrated in vacuo to afford the crude product. Purification by flash silica gel chromatography (gradient 0-30% EtOAc in hexanes) afforded 5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-( Trifluoromethyl)benzyl]-1,3-oxazolidin-2-one. _Rf = 0.55 (515% EtOAc/Hex).

LCMS 584 (M+1) ^{+ .1} H NMR (CDCl ₃ , 500MHz) δ8.05 (d, J=8.2Hz, 1H), 7.95 (br s, 1H), 7.85 (br s, 2H), 7.51 ( brs, 1H), 7.32(m, 1H), 5.72(t, J=8.0Hz, 1H), 4.74(d, J=15.5Hz, 1H), 4.64(d, J=15.3Hz), 4.14(t, J=7.1Hz, 1H), 3.47(dd, J=7.1, 1.6Hz).

Example 67

(4S)-4-Benzyl-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3- oxazolidin-2-one

Step A: (4S)-4-Benzyl-3-[2-iodo-5-(trifluoromethyl)benzyl]1,3-oxazolidin-2-one

A stirred suspension of sodium hydride (60% dispersion in oil, 27 mg, 0.68 mmol) in THF (3 mL) was dissolved with (S) dissolved in THF (1 mL) at 0 °C under nitrogen atmosphere. - Treatment with 4-benzyl-2-oxazolidinone (49 mg, 0.27 mmol). The reaction was stirred for 20 minutes and a solution of 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (100 mg, 0.27 mmol) in THF (1 mL) was added dropwise. The reaction was stirred at room temperature for 18 hours. The reaction was treated with _H2O (1 mL), partitioned between EtOAc (80 mL) and _H2O (25 mL). The aqueous phase was further extracted with EtOAc (2 x 20 mL), the combined organic extracts were washed with brine (30 mL), dried ( _MgSO4 ) and concentrated in vacuo to afford the crude product. Purification by flash silica gel chromatography (0-30% EtOAc in hexanes gradient) afforded (4S)-4-benzyl-3-[2-iodo-5-(trifluoromethyl)benzyl]1 , 3-oxazolidin-2-one. _Rf = 0.45 (15% EtOAc/Hex).

LCMS 462 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ8.04 (d, J=8.2Hz, 1H), 7.54 (br s, 1H), 7.33-7.27 (m, 5H), 7.11 -7.10(m, 2H), 7.32(m, 1H), 4.80(d, J=16.0Hz, 1H), 4.49(d, J=16.1Hz), 4.28(t, J=8.7Hz, 1H), 4.25 (t, J=9.1, 4.8Hz, 1H), 3.94(m, 1H), 3.16(dd, J=13.5, 4.8Hz, 1H), 2.73(dd, J=9.1, 4.4Hz, 1H).

Step B: (4S)-4-Benzyl-3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1 , 3-oxazolidin-2-one

(45)-4-Benzyl-3-[2-iodo-5-(trifluoromethyl)benzyl]1,3-oxazolidin-2-one (63mg, 0.137mmol), 2-methoxy Base-5-isopropylphenylboronic acid (52mg, 0.274mmol), K ₂ CO ₃ (47mg, 0.34mmol) and Pd(OAc) ₂ (9.2mg, 0.0137mmol) in acetone:H ₂ O (5:1 ) (6 mL) was heated to reflux for 1 h. The reaction mixture was concentrated in vacuo, diluted with _H2O (15 mL), extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried ( _MgSO4 ), filtered and concentrated. The crude product was purified by flash silica gel chromatography (0-20% EtOAc in hexanes gradient) to afford (4S)-4-benzyl-3-{[5'-isopropyl-2'-methoxy -4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one. _Rf = 0.35 (15% EtOAc/Hex). LCMS 484(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) (atropisomers present; some peak overlap observed in ¹ H NMR)

δ7.72(br s1H), 7.65(br s, 1H), 7.42(m, 1H), 7.32-7.22(m, 3H), 7.08(d, J=2.3Hz, 1H), 6.90-6.84(m, 3H), 4.80(d, J=15.8Hz, 1H), 4.35(d, J=15.8Hz), 4.28(t, J=8.7Hz, 1H), 3.96-3.92(m, 3H), 3.78(s, 3H), 3.62-3.52(m, 1H), 2.94-2.86(m, 1H), 2.82(dd, J=9.4, 3.9Hz, 1H), 2.42(dd, J=9.6, 3.9Hz), 1.26(s , 3H), 1.10(s, 3H).

Example 68

2-iodo-5-(trifluoromethyl)benzoic acid

Potassium hydroxide (3.78 g; 0.0673 mol) was added to 2-iodo-5-(trifluoromethyl)benzonitrile (Example 2; 4 g; 0.0135 mol) in a 1:1 isopropanol: _H2O solution ( 60mL) in a stirred solution. The reaction was heated to reflux for 14 hours, then partitioned between _H2O (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (50 mL) and acidified to pH 5 with 6N HCl. The aqueous layer was further extracted with EtOAc (4 x 50 mL), the combined extracts were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2-iodo-5-(trifluoromethyl) Benzoic acid as a yellow solid.

LCMS=317.0(M+1) ^{+ .1} H NMR (CDCl ₃ , 500MHz) δ8.27(d, J=1.6Hz, 1H), 8.25(d, J=8.2Hz, 1H), 7.47(dd, J =8.2, 1.8Hz, 1H).

Example 69

[2-iodo-5-(trifluoromethyl)phenyl]methanol

Borane-THF (1.0 M solution in THF; 94 mL; 94 mmol) was added to 2-iodo-5-(trifluoromethyl)benzoic acid (2.97 g; 9.4 mmol) at 0 °C under nitrogen atmosphere. a stirred solution in THF (300 mL). The reaction was heated to reflux for 90 minutes, then carefully treated with 6N HCl until no gas was evolved. The reaction was diluted with water (250 mL), extracted with EtOAc (3 x 250 mL). The combined extracts were washed with brine (300 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (0-25% EtOAc/hexanes gradient) to afford [2-iodo-5-(trifluoromethyl)phenyl]methanol as a white solid.

LCMS=285.0(M-17) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz): δ7.97(d, J=8.3Hz, 1H), 7.79(s, 1H), 7.28(d, J=8.4Hz, 1H), 4.75(s, 2H).

Another method was described as follows: To a solution of 2-iodo-5-(trifluoromethyl)benzaldehyde (Example 80, Step A, 9 g) in THF (100 mL) and water (10 mL) at 0° C. _NaBH4 (0.5 g) was added. The reaction was stirred for 30 minutes. To the reaction mixture was added dilute hydrochloric acid (cautiously). The mixture was extracted with ether, and the ether layer was washed successively with water and brine. The ether layer was then dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by silica chromatography using a gradient of 1 _: 3 _CH2Cl2 /hexane, 1 _: 1 _CH2Cl2 /hexane and 100 _{% CH2Cl2} to give [2-iodo -5-(Trifluoromethyl)phenyl]methanol as a white solid.

Example 70

2-(bromoethyl)-1-iodo-4-(trifluoromethyl)benzene

Carbon tetrabromide (1.86g; 5.6mmol) and triphenylphosphine (1.47g; 5.6mmol) were sequentially added to [2-iodo-5-(trifluoromethyl)phenyl ] in a stirred solution of methanol (1.13 g; 3.74 mmol) in _{CH2Cl2 (} 25 mL). The reaction was stirred at room temperature for 48 hours. A further portion of carbon tetrabromide (1.2 g; 3.74 mmol) and triphenylphosphine (0.98 g; 3.74 mmol) were added and the reaction was stirred for a further 14 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography (0-25% EtOAc/hexanes gradient) to afford 2-(bromoethyl)-1-iodo-4-(trifluoromethyl)benzene as a clear Oil.

¹ HNMR (CDCl ₃ , 500MHz): δ8.02 (d, J=8.2Hz, 1H), 7.73 (d, J=1.8Hz, 1H), 7.26 (dd, J=8.3, 1.8Hz, 1H), 4.64 (s, 2H).

Example 71

5-[3,5-bis(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one

According to the method described in Example 13, using 5.46 g of 2-amino-1-[3,5-bis(trifluoromethyl)phenyl]ethanol, 5-[3,5-bis(trifluoromethyl) was obtained )Phenyl]-1,3-oxazolidin-2-one as off-white solid.

LCMS=300.1(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz): δ7.94(s, 1H), 7.89(s, 2H), 5.81-5.77(m, 1H), 5.29(s, 1H ), 4.17-4.12(m, 1H), 3.59-3.55(m, 1H)

Example 72

5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)bis Benzene-2-yl]methyl}-1,3-oxazolidin-2-one

5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one ( 60 mg; 0.103 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (27 mg; 0.129 mmol), palladium acetate (7 mg; 0.0103 mmol) and potassium carbonate (36 mg; 0.257 mmol) The mixture in 5:1 acetone/water (6 mL) was heated at reflux for 1 hour. Acetone was _removed in vacuo, the residue was diluted with water (10 mL), extracted with _CH2Cl2 (3 x 10 mL). The combined extracts were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (0-25% EtOAc/hexanes gradient) to afford 5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5 '-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one, a clear glass. LCMS = 624.2 (M+1) ⁺ . ¹ H NMR (Benzene-d ₆ , 500 MHz, 1:1 mixture of atropisomers):

δ7.60(s, 1.5H), 7.45(s, 0.5H), 7.31-7.25(m, 3H), 6.98-6.94(m, 1H), 6.87-6.82(m, 1H), 6.43-6.37(m , 1H), 4.54(d, J=15.6Hz, 0.5H), 4.40-4.36(m, 1H), 4.47(d, J=15.6Hz, 0.5H), 3.96(d, J=15.5Hz, 0.5H ), 3.80(d, J=15.8Hz, 0.5H), 3.24-3.15(m, 1H), 3.02(s, 3H), 2.62-2.58(m, 0.5H), 2.53-2.48(m, 0.5H) , 2.12-2.07(m, 0.5H), 2.04-2.00(m, 0.5H), 1.22-1.11(m, 6H).

The racemic product was separated into its two enantiomers by chiral HPLC using a 15% IP A/heptane and OD column.

(5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′isopropyl-2′-methoxy-4-(trifluoromethyl yl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one: LCMS=624.2 (M+1) ⁺ . ¹ H NMR (Benzene-d ₆ , 500 MHz, 1:1 mixture of atropisomers):

δ7.62(s, 1.5H), 7.47(s, 0.5H), 7.34-7.27(m, 3H), 6.99-6.95(m, 1H), 6.88-6.83(m, 1H), 6.44-6.39(m , 1H), 4.54(d, J=15.5Hz, 0.5H), 4.47-4.41(m, 1H), 4.33(d, J=15.6 Hz, 0.5H), 3.98(d, J=15.7Hz, 0.5H ), 3.82(d, J=15.8Hz, 0.5H), 3.24-3.15(m, 1H), 3.05(s, 3H), 2.67-2.62(m, 0.5H), 2.57-2.52(m, 0.5H) , 2.16-2.11(m, 0.5H), 2.09-2.04(m, 0.5H), 1.22-1.11(m, 6H).

(5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′isopropyl-2′-methoxy-4-(trifluoromethyl yl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one: LCMS=624.2 (M+1) ⁺ . ¹ H NMR (Benzene-d ₆ , 500 MHz, 1:1 mixture of atropisomers):

δ7.63(s, 1.5H), 7.48(s, 0.5H), 7.35-7.27(m, 3H), 7.00-6.95(m, 1H), 6.88-6.83(m, 1H), 6.44-6.38(m , 1H), 4.54(d, J=15.8Hz, 0.5H), 4.48-4.42(m, 1H), 4.34(d, J=15.8Hz, 0.5H), 3.99(d, J=158Hz, 0.5H) , 3.83(d, J=15.8Hz, 0.5H), 3 25-3.15(m, 1H), 3.05(s, 3H), 2.68-2.63(m, 0.5H), 2.58-2.53(m, 0.5H) , 2.18-2.12(m, 0.5H), 2.10-2.05(m, 0.5H), 1.23-1.11(m, 6H).

Example 73

Step 1: (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl -1,3-oxazolidin-2-one

To a stirred suspension of sodium hydride (60% dispersion in mineral oil; 1.3 g; 0.0325 mol) in THF (60 mL) was added dropwise (4S,5R)-5 at 0°C under nitrogen atmosphere. -[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (Example 17) (4.077 g; 0.013 mol) in THF (50 mL) solution in. Gas evolution was observed. The resulting mixture was stirred at 0° C. for 30 minutes, then a solution of 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (4.754 g; 0.013 mol) in THF (20 mL) was added. The reaction was warmed to room temperature and stirred for 14 hours. The reaction was carefully treated with water (15 mL), partitioned between EtOAc (250 mL) and _H2O (75 mL). The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried ( _MgSO4 ), filtered and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc/hexanes gradient) to afford 6.4 g (82.5%) of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl ]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one as a white solid.

LCMS=598.1(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz): δ 8.03(d, J=8.2Hz, 1H), 7.90(s, 1H), 7.79(s, 2H), 7.58(s , 1H), 7.30(dd, J=8.2Hz, J=2.0Hz, 1H), 5.76(d, J=8Hz, 1H), 4.88(d, J=15.8Hz, 1H), 4.37(d, J= 15.8Hz, 1H), 4.09-4.02(m, 1H), 0.8(d, J=6.6Hz, 3H)

Step 2: (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropyl-2'-methoxy- 4-(Trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

(4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1 , 3-oxazolidin-2-one (4.29g; 7.19mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (Example 78) (4.57g; 21.57mmol) , a stirred mixture of tetrakis(triphenylphosphine)palladium(0) (1.0 g; 0.86 mmol) and sodium carbonate (6.35 g) in C ₆ H ₆ /EtOH/H ₂ O (120 mL/17 mL/51 mL) Heat to reflux (100° C.) for 14 hours under nitrogen atmosphere. The reaction was partitioned between EtOAc (200 mL) and _H2O (100 mL). The aqueous phase was extracted with EtOAc (3 x 200 mL). The combined organic phases were washed with brine (100 mL), dried ( _MgSO4 ), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[ 4'-fluoro-5'isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidine- 2-Kone, as a yellow solid. To remove yellow impurities, 2.7 g was dissolved in 165 mL EtOH, and 275 mg decolorizing charcoal (activated carbon, Darco, G-60, 100 mesh powder, Aldrich) was added. The mixture was stirred at room temperature for 40 minutes, filtered, and concentrated in vacuo. Trituration with about 25 mL of hexanes afforded 2.46 g of the title compound as a white solid. ¹ H NMR indicated trace impurities removed by flash silica gel chromatography (0-15% EtOAc/hexanes gradient). Residual solvent was removed by lyophilization from acetonitrile. LCMS = 638.3 (M+1) ⁺ . ¹ H NMR (Benzene-d ₆ , 500 MHz, 1:1 mixture of atropisomers):

δ7.82(s, 0.5H), 7.60(s, 0.5H), 7.57(s, 1H), 7.33(d, J=8Hz, 1H), 7.27(d, J=9.9Hz, 2H), 7.02- 6.98(m, 1H), 6.89(d, J=8.5Hz, 0.5H), 6.82(d, J=85Hz, 0.5H), 6.45(d, J=12.1Hz, 0.5H), 6.35(d, J =11.9Hz, 0.5H), 4.94(d, J=16.0Hz, 0.5H), 4.87(d, J=15.8Hz, 0.5H), 4.54(d, J=8.0Hz, 0.5H), 4.50(d , J=7.8Hz, 0.5H), 3.74-3.66(m, 1H), 3.23-3.15(m, 1H), 3.12(s, 1.5H), 2.99(s, 1.5H), 2.97-2.92(m, 0.5H), 2.89-2.84(m, 0.5H), 1.21-1.09(m, 6H), -0.27(d, J=6.7Hz, 1.5H), -0.40(d, J=6.7Hz, 1.5H) .

Preparation of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl 1-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4- Another method for (trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one:

(4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1 , 3-oxazolidin-2-one (50 mg; 0.084 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (Example 78, 22 mg; 0.105 mmol), palladium acetate (6 mg; 0.0103 mmol) and potassium carbonate (29 mg; 0.257 mmol) in 5:1 acetone/water (6 mL) was heated at reflux for 1 hour. Acetone was _removed in vacuo, the residue was diluted with water (10 mL), extracted with _CH2Cl2 (3 x 10 mL). The combined extracts were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[ 4'-fluoro-5'isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidine- 2-ketone is a clear glass. This product was also prepared by the method described in Example 372.

Example 74

(4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl) Biphenyl-2-yl]methyl}-5-methylimidazolidin-2-one

Step A: (4S,5S)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl) Methyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

((4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one) (46.2mg, 0.148mmol) Place in a dry flask and add DMA (3 mL). NaHMDS (296 [mu]L of 1M in THF, 0.296 mmol) was added and the reaction was stirred for min. 2'-(bromomethyl)-5-isopropyl-4'-(trifluoromethyl)biphenyl-2-ylmethyl ether (80.0 mg, 0.207 mmol) in DMA (2 mL) was added via cannula ). After 30 minutes, the reaction was treated with saturated _NH4Cl (2 mL). The mixture was diluted with EtOAc (40 mL). The organic layer was washed with water (15 mL) and brine (15 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography eluting with 25% EtOAc/hexanes afforded (4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. _Rf = 0.27 (25% EtOAc/Hex). LCMS = 620.2 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz; atropisomers present)

δ6.90-7.88(m, 9H), 4.04-5.05(m, 3H), 3.25-3.74(m, 4H), 2.88(m, 1H), 1.19-1.24(m, 6H), 0.99-1.07(m , 3H). Step B: (1S,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy- 4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propan-1-ol

To (4S, 5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl )biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (147.7 mg, 0.239 mmol) in EtOH (7.5 mL) was added H ₂ O ( 1.5 mL) and KOH (150 mg, 2.67 mmol). The solution was heated at 75°C for 30 hours and then cooled to room temperature. A solution in EtOAc (75 mL) was added and the organic layer was washed with _H2O (15 mL) and brine (2 x 15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography afforded (1S,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'- Methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propan-1-ol. _Rf = 0.44 (40% EtOAc/Hex).

LCMS=594.2(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ6.93-7.78(m, 9H), 3.51-4.20(m, 6H), 2.91(m, 1H), 2.49(m, 1H), 1.22-1.26(m, 6H), 0.79-0.81(m, 3H).

Step C: {(1S,2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1-methylethyl}{[5'-isopropyl-2' -Methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate tert-butyl ester

To (1S, 2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl yl)biphenyl-2-yl]methyl}amino)propan-1-ol (135.5 mg, 0.228 mmol) in _CH2Cl2 (5 mL) was added _{BOC2O (} 49.7 mg, 0.228 mmol). The reaction was stirred at room temperature for 2 days; during which time two more batches of _BOC2O (25 mg each) were added. After 2 days, the reaction was concentrated and the residue was purified by flash chromatography eluting with 20% EtOAc/hexanes to afford {(1S,2S)-2-[3,5-bis(trifluoromethyl )phenyl]-2-hydroxy-1-methylethyl} {[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-ylJ methyl} tert-butyl carbamate. _Rf = 0.41 (40% EtOAc/Hex). LCMS = 594.2 (M+1-BOC) ⁺ .

Step D: {(1S,2R)-2-Azido-2-[3,5-bis(trifluoromethyl)phenyl]-1-methylethyl}{[5'-isopropyl- tert-butyl 2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate

To a dry flask was added THF (1 mL), diethyl azodicarboxylate (DEAD) (11 μL, 0.0698 mmol) and diphenylphosphoryl azide (DPPA) (15 μL, 0.0698 mmol). {(1S,2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1-methylethyl}{[5 tert-butyl '-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (20.7 mg, 0.0698 mmol). Then _Ph3P (18.3 mg, 0.0698 mmol) was added. The reaction was stirred at room temperature for 30 minutes before additional DEAD (11 μL, 0.0698 mmol), DPPA (15 μL, 0.0698 mmol) and _Ph3P (18.3 mg, 0.0698 mmol) were added. After 30 minutes, the reaction was diluted with EtOAc (40 mL), washed with water and brine (15 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography eluting with 15% EtOAc/hexanes afforded {(1S,2R)-2-azido-2-[3,5-bis(trifluoromethyl)phenyl] - tert-butyl 1-methylethyl}{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. _Rf = 0.60 (25% EtOAc/Hex). LCMS = 619.3 (M+1-BOC) ⁺ .

Step E: (1R,2S)-1-Azido-1-[3,5-bis(trifluoromethyl)phenyl]-N-{[5'-isopropyl-2'-methoxy -4-(trifluoromethyl)biphenyl-2-yl]methyl}propan-2-amine

To {(1S, 2R)-2-azido-2-[3,5-bis(trifluoromethyl)phenyl]-1-methylethyl}{[5'-isopropyl-2' To a solution of tert-butyl-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (21.7 mg, 0.030 mmol) in _CH2Cl2 (2 _mL ) was added TFA ( 200 μL). The reaction was stirred at room temperature for ₁ h, then diluted with _CH2Cl2 (25 mL). The _{CH2Cl2 solution} was washed with 1N NaOH (15 mL), and the aqueous phase was extracted with _CH2Cl2 ( ₂₅ mL). The organic extracts were combined, washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography using 15% EtOAc/hexanes afforded (1R,2S)-1-azido-1-[3,5-bis(trifluoromethyl)phenyl]- N-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propan-2-amine. _Rf = 0.45 (15% EtOAc/Hex). LCMS = 619.2 (M+1) ⁺ .

Step F: (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N ² -{[5′-isopropyl-2′-methoxy-4-(tri Fluoromethyl)biphenyl-2-yl]methyl}propane-1,2-diamine

To (1R, 2S)-1-azido-1-[3,5-bis(trifluoromethyl)phenyl]-N-{[5'-isopropyl-2'-methoxy-4 To a solution of -(trifluoromethyl)biphenyl-2-yl]methyl}propan-2-amine (17.8 mg, 0.0288 mmol) in THF (3 mL) was added PtO ₂ (12 mg, 0.053 mmol). The reaction was placed under a balloon of hydrogen and stirred at room temperature for 3 hours. The catalyst was removed by filtration and the filtrate was concentrated. Passing the residue through a short plug of silica gel, washing with 0-10% MeOH/ _CH2Cl2 afforded (1R,2S)-1-[3,5- _bis (trifluoromethyl)phenyl] ^-N2 -{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propan-1,2-diamine. LCMS = 619.2 (M+1) ⁺ .

Step G: (4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5'-isopropyl-2'-methoxy-4-(trifluoro Methyl)biphenyl-2-yl]methyl}-5-methylimidazolidin-2-one

(1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N ² -{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl yl)biphenyl-2-yl]methyl}propane-1,2-diamine (8.0 mg, 0.0135 mmol) in CH ₂ Cl ₂ (2 mL) was cooled to 0° C., DIPEA (14 μL, 0.081 mmol) was added ), followed by the addition of triphosgene (2mg, 0.00657mmol). The reaction was stirred at 0 °C for 30 minutes, then diluted with EtOAc (30 mL). The reaction was washed with saturated sodium bicarbonate (10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography using 40% EtOAc/hexanes afforded (4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methylimidazolidin-2-one. _Rf = 0.24 (40% EtOAc/Hex). LCMS = 619.2 (M+1) ⁺ . ¹ H NMR (CD ₂ Cl ₂ , 600 MHz; atropisomers present)

δ6.91-7.84(m, 9H), 3.84-4.94(m, 4H), 3.64-3.80(m, 4H), 2.88(m, 1H), 1.18-1.26(m, 6H), 0.27-0.42(m , 3H).

Example 75

(3S, 4R)-4-[3,5-bis(trifluoromethyl)phenyl]-2-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl) Biphenyl-2-yl]methyl}-3-methyl-1,2,5-thiadiazolidine 1,1-dioxide

Add (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N ² -{[5′-isopropyl-2′-methoxy-4 -(trifluoromethyl)biphenyl-2-yl]methyl}propan-1,2-diamine (15.9 mg, 0.0269 mmol), sulfonamide (4 mg, 0.0403 mmol) and pyridine (600 μL). The reaction tube was purged with nitrogen, sealed, and heated at 120°C for 2 hours. The solution was then cooled to room temperature, diluted with EtOAc (40 mL), washed with _H2O , 1 N HCl and brine (10 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography using 25% EtOAc/hexanes afforded (3S,4R)-4-[3,5-bis(trifluoromethyl)phenyl]-2-{[5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-3-methyl-1,2,5-thiadiazolidine 1,1- dioxide. _Rf = 0.27 (25% EtOAc/Hex). LCMS = 655.2 (M+1) ⁺ . ¹ H NMR (C ₆ D ₆ , 500 MHz; atropisomers present)

δ6.51-8.19(m, 9H), 3.64-4.53(m, 4H), 3.00-3.18(m, 4H), 2.73(m, 1H), 1.13-1.20(m, 6H), -0.03-0.09( m, 3H).

Example 76

2-fluoro-1-isopropenyl-4-methoxybenzene

Step A: 2-(2-Fluoro-4-methoxyphenyl)propan-2-ol

To a solution of 2'-fluoro-4'-methoxyacetophenone (4.45 g, 26.5 mmol) in THF (50 ml) was added 2.4M MeMgBr solution (11.6 mmol, 27.8 mmol) at 0°C. The mixture was stirred at 0°C and then at room temperature for 4 hours. The reaction was treated with saturated ammonium chloride solution. The organic phase was extracted with ethyl acetate (3 x 50ml). The combined ethyl acetate layers were washed with brine and dried over sodium sulfate. Purification by flash column using EtOAc:hexane = 2:8 as eluent gave the resulting alcohol as an oil.

Step B: 2-Fluoro-1-isopropenyl-4-methoxybenzene

To a solution of 2-(2-fluoro-4-methoxyphenyl)propan-2-ol (3.89 g, 21.14 mmol) from step A in dichloromethane (50 ml) was added MsCl ( 1.95ml, 25.4mmol) and triethylamine (6.52ml, 46.5mmol). The solution was stirred at 0°C, then at room temperature for 2 hours. The solution was diluted with dichloromethane (100ml), washed with water and dried over sodium sulfate. Purification by flash column using EtOAc:Hexane = 1:9 as eluent afforded the title compound as an oil.

¹ H NMR (CDCl ₃ , 500MHz) δ7.25 (t, J=9.0Hz, 1H), 6.68 (dd, J=8.5, 2.5Hz, 1H), 6.63 (dd, J=13, 2.5Hz, 1H) , 5.20(d, J=17.0Hz, 2H), 3.82(s, 3H), 2.18(s, 3H).

Another method for preparing 2-fluoro-1-isopropenyl-4-methoxybenzene:

Sodium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (714ml, 0.714m) was added to a solution of methyltriphenylphosphonium bromide (255g, 0.714m) in THF (2.50L). The suspension was cooled in an ice bath. The resulting yellow suspension was stirred at ice bath temperature for 30 minutes, then cooled to -78°C. All 2-fluoro-4-methoxyacetophenone (100 g, 0.595 m) in THF (200 mL) was added dropwise and stirred at -78°C for 1.5 hours. The reaction mixture was warmed to room temperature for hr, treated with acetic acid (~80ml), observed color change from yellow to off-white, and stirred for 30 minutes (pH~7) (slight exotherm noted). The mixture was concentrated to a slurry, diluted with 7:2 hexanes:ethyl acetate and allowed to stand overnight. The solids were removed by filtration and the filtrate was concentrated to a yellow oil. Purification by flash column using 9:1 hexane:ethyl acetate as eluent afforded the title compound.

Example 77

1-fluoro-4-iodo-2-isopropyl-5-methoxybenzene

A solution of 2-fluoro-1-isopropenyl-4-methoxybenzene (Example 76, 1.96 g, 11.81 mmol) in MeOH (30 ml) was subjected to 1 atm of hydrogen and a catalytic amount of Pd/C. The mixture was stirred at room temperature for 1 hour. The mixture was filtered through celite. The filtrate was then added to a mixture of silver sulfate (3.68 g, 11.81 mmol) and iodine (3.00 g, 11.81 mmol) in MeOH (10 mL). The mixture was stirred at room temperature for 3 hours until the solution color changed to pale yellow. The mixture was filtered and the filtrate was concentrated. Purification by flash column using EtOAe hexanes 5:95 as eluent afforded the title compound.

¹ H NMR (CDCl ₃ , 500MHz) δ 7.61(d, J=8.0Hz, 1H), 6.56(d, J=12.5Hz, 1H), 3.90(s, 3H), 3.18(m, 1H), 1.28( m, 6H).

Example 78

(4-Fluoro-5-isopropyl-2-methoxyphenyl)boronic acid

To a solution of 1-fluoro-4-iodo-2-isopropyl-5-methoxybenzene (Example 77, 2.61 g, 8.88 mmol) in THF was added dropwise n-BuLi (4.26 ml, 10.65 mmol, 2.5M). The solution was stirred at -78°C for 30 minutes. Trimethyl borate (2.98ml, 26.6mmol) was added. The solution was then stirred at -78°C for 3 hours. The reaction was treated with saturated ammonium chloride at -78°C and the mixture was allowed to warm to room temperature. The organic phase was extracted with ethyl acetate (3 x 50ml). The combined ethyl acetate layers were washed with brine and dried over sodium sulfate. The title compound was obtained as a solid pure enough to be used in the next step. Further purification by silica gel was performed as the product decomposed.

¹ H NMR (CDCl ₃ , 500MHz) δ 7.74(d, J=10.0Hz, 1H), 6.62 (d, J=12.5Hz, 1H), 5.65(br s, 2H), 3.92(s, 3H), 3.20 (m, 1H), 1.22(m, 6H).

This boronic acid intermediate can also be prepared by following four-step method:

Convert 1 to 2:

THF (24 L) was added to a 100 L cylindrical reactor at room temperature. 2.75 kg CeCl ₃ was added thereto. The resulting slurry was aged at room temperature for 1.5 hours. The samples are then monitored under a microscope to confirm that the desired form has occurred. The slurry was cooled to 9°C and MeMgCl was added. The rate of addition was adjusted to keep the internal temperature below 19°C. The mixture was cooled to -11°C, and acetophenone 1 (4.0 kg diluted to 10 L with THF) was added dropwise. Keep the internal temperature below 0°C. The reaction mixture was then aged at a temperature below 0°C for 1 hour. 5.7 L of 3N HCl was added dropwise to the reaction, keeping the internal temperature below 15°C. The treated reaction mixture was then aged at 5-10°C for 1.5 hours and filtered through a Solka Floe plug.

Hydrogenation of 2 to 3:

The solvent in the THF solution of 2 was replaced by ethanol (~18 L volume), 1.9 L HCl was added, followed by 190 g 10% Pd/C (50% water). The mixture was placed at 40°C under 15 psi of hydrogen until HPLC analysis indicated the reaction was complete. The mixture was cooled to room temperature. The catalyst was removed by filtration using Solka-Flok as a filter aid. The anisole product in ethanol was then solvent switched to acetonitrile for the next step.

Bromide 3 to 4.

Dilute anisole 3 in acetonitrile (1.72 L, 4 mL MeCN/mMol 3). The mixture was warmed to 35 °C and solid NBS (1.1 eq, 84 g) was added in one portion. The reaction is complete within 2-4 hours. The solution was concentrated to a total volume of 400 mL and diluted with 1 L of toluene. The solution was then washed with sodium thiosulfate and water to remove the succinimide by-product. The organic layer was then concentrated and the solvent was changed to toluene.

Conversion of aryl bromide 4 to boronic acid 5:

To a 75 L glass reaction vessel was added 1.87 kg of aryl bromide 4 (7.6 MoI), which was added as 6.4 kg of a 29.1 wt% solution of 4 in toluene. The solution was diluted with 5.6 L THF. The vessel was purged with nitrogen and triisopropyl borate (1.35eq, 2.35L, 10.3Mol) was added. The mixture was cooled to <-70°C. Then 5.9 L of a solution of 1.6M n-BuLi in hexane (9.5 Mol) was added slowly over 4 hours, keeping the temperature <-55°C. Thirty minutes after the addition of n-BuLi was complete, the reaction was complete by LC analysis. _The reaction was warmed to -35°C and treated with 3.0M _H2SO4 solution (5.6L). The treated aqueous phase should be acidic (pH~2). MTBE (7.5 L) was added to the mixture to dilute the organic layer. The mixture was stirred (15 min) and the aqueous layer was removed. The organic layer was washed with 5.6L of 3.0M _{H2SO4 solution} (15min). After separating the layers again, the MTBE/toluene layer was extracted twice with 1M KOH (15.1 L first, then 7.6 L). The two KOH extracts were combined, diluted with 2-propanol (6.4 L), and cooled to 15°C. The solution was then acidified slowly to pH ~2 using 3.0 M sulfuric acid (-7.6 L) while maintaining the temperature at 15-20 °C. The resulting slurry was stirred for 1 hour, then filtered. The filter cake was washed with water (2 x 6 L) and dried under air stream for 1 day. The filtered solid was placed in a vacuum oven at 50 °C for 2-3 days to decompose the diaryl impurities and dry the solid. A crystalline off-white solid was isolated and 1.59 kg of boric acid 5 was obtained.

Example 79

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-chloro-4'-fluoro-5'-isopropyl-2'-methoxy Biphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

Step A: 1-Bromo-2-(bromomethyl)-4-chlorobenzene

A mixture of 2-bromo-5-chloro-toluene (2.00 g, 9.75 mmol), NBS (2.08 g, 11.7 mmol) and a catalytic amount of AIBN in carbon tetrachloride (50 ml) was stirred at reflux for 4 hours. TLC (EtOAc:Hexane=5:95) showed no starting material. The mixture was filtered and the filtrate was concentrated. Purification by flash column using EtOAc:hexane = 5:95 as eluent afforded the title compound as a white solid.

¹ H NMR (CDCl ₃ , 500MHz) δ7.53 (d, J=9.0Hz, 1H), 7.47 (d, J=2.5Hz, 1H), 7.18 (dd, J=8.5, 2.5Hz, 1H), 4.60 (s, 2H).

Step B. (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-chlorobenzyl)-4-methyl-1,3- oxazolidin-2-one

At 0°C, to (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (0.050g, 0.16 To a solution of mmol) in THF (1 ml) was added NaH (7.6 mg, 0.19 mmol, 60%). The mixture was stirred at 0°C for 30 minutes. Add the title compound from Step A (0.059 g, 0.21 mmol). The whole mixture was stirred at 0°C for 1 hour and allowed to warm to room temperature for 4 hours. The reaction was treated with saturated ammonium chloride. The organic phase was extracted with ethyl acetate (3 x 15ml). The combined ethyl acetate layers were washed with brine and dried over sodium sulfate. Preparative TLC purification using EtOAc:hexane = 2:8 as eluent afforded the title compound.

¹ H NMR (CDCl ₃ , 500MHz) δ7.92(s, 1H), 7.82(s, 2H), 7.55(d, J=8.5Hz, 1H), 7.43(d, J=2.5Hz, 1H), 7.23 (dd, J=8.5, 2.5Hz, 1H), 5.77(d, J=8.0Hz, 1H), 4.86(d, J=16.0Hz, 1H), 4.36(d, J=16.0Hz, 1H), 4.11 (m, 1H), 0.82 (d, J=6.5Hz, 3H).

Step C. (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-[(4-chloro-4'-fluoro-5'-isopropyl-2'- Methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

(4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-chlorobenzyl)-4-methyl-1,3-oxazole Alkan-2-ones (44 mg, 0.085 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (Example 78, 23 mg, 0.11 mmol), potassium carbonate (25 mg, 0.18 mmol) ) and a catalytic amount of PdOA in an acetone/water 4:1 mixture was heated at reflux for 1 hour. Acetone was removed, and water was added. The organic layer was extracted with dichloromethane (3 x 15ml). The combined dichloromethane layers were washed with brine and dried over sodium sulfate. Purification by preparative reverse phase HPLC afforded the title compound as a solid. ¹ H NMR (CDCl ₃ , 500 MHz) 1:1 mixture of rotamers

δ7.90(s, 1H), 7.73(s, 2H), 7.49(m, 1H), 7.40(m, 1H), 7.20(m, 1H), 7.00(m, 1H), 6.68(dd, J= 12.0, 3.0Hz, 1H), 5.63(d, J=8.0Hz, 1/2H), 5.44(d, J=8.0Hz, 1/2H), 4.85(d, J=10.0Hz, 1/2H), 4.82(d, J=10.0Hz, 1/2H), 4.03(d, J=16.0Hz, 1/2H), 3.84(m, 11/2H), 3.80(s, 3H), 3.20(m, 1H ), 1.20(m, 6H), 0.56(d, J=6.5Hz, 3/2H), 0.38(d, J=6.5H, 3/2H).LC-MS(M+1): 604.3, 4.61 min.

Example 80

5-[2-iodo-5-(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one

Step A: 2-iodo-5-(trifluoromethyl)benzaldehyde

To a solution of 2-iodo-5-(trifluoromethyl)benzonitrile (Example ₂ , 42 g) in _CH2Cl2 (300 mL) at -78°C was added DIBAL in _CH2Cl2 over ₃₀ minutes solution in (175 mL, 1M). A precipitate formed. The reaction was warmed to 0 °C. 25 mL of DIBAL solution was added dropwise over 30 minutes. The reaction was poured into 200 mL of 2N hydrochloric acid, diluted with ether, and stirred for 1 hour. TLC analysis indicated that the imine was still present, 100 mL of 2N aqueous solution was added and the reaction was stirred overnight. TLC analysis indicated that the imine was still present, 200 mL of 2N hydrochloric acid was added, and the mixture was stirred for 2 hours. The layers were separated and the aqueous layer was back extracted with ether. The ether extracts were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The product was purified by silica gel chromatography, eluting with 95:5 hexanes/EtOAc, to afford 2-iodo-5-(trifluoromethyl)benzaldehyde as a white solid.

¹ HNMR (500MHz, CDCl ₃ ): δ10.00(s, 1H), 8.12(s, 1H), 8.11(d, J=8Hz, 1H), 7.53(dd, J=2Hz, 8Hz, 1H).

Step B: 5-[2-iodo-5-(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one

To a solution of 0.2 g of 2-iodo-5-(trifluoromethyl)benzaldehyde in 3 mL of EtOH at 0° C. was added 0.13 mL of nitromethane followed by 0.28 mL of 2.5N NaOH solution. The mixture was stirred at 0 °C for 3 hours, then neutralized by adding 2.1 mL of 0.33 N aqueous AcOH. The mixture was partitioned between 10 mL of water and 10 mL of EtOAc. The aqueous phase was extracted with 2 x 5 mL EtOAc. The combined organic layers were washed with 10 mL of brine, dried over sodium sulfate, and concentrated. The residue was dissolved in 4 mL of MeOH and 0.5 mL of 88% aqueous formic acid was added. About 200 mg of Raney nickel slurry was added and the mixture was purged with hydrogen and stirred under a balloon of hydrogen for 4 hours. The mixture was filtered through celite, washed with MeOH, and the filtrate was concentrated. The residue was partitioned between 10 mL of 10% aqueous _NH4OH and 20 mL of EtOAc. The aqueous phase was extracted with 2 x 10 mL EtOAc. The combined organic layers were washed with 10 mL of brine, dried over sodium sulfate, and concentrated. The residue was dissolved in ₂ mL _CH2Cl2 . To this solution was added 0.114 mL of diisopropylethylamine followed by 0.065 g of triphosgene. The mixture was stirred at 0° C. for 30 min, then diluted with 10 mL EtOAc and 10 mL sat. NaHCO ₃ . The aqueous phase was extracted with 2 x 10 mL EtOAc. The combined organic layers were washed with 10 mL of brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 4% EtOAc in hexanes, followed by a linear gradient of 4-100% EtOAc in hexanes over 10 CV , the title compound was obtained. Mass spectrum (ESI) 350.0 (M+1).

¹ H NMR (500MHz, CDCl ₃ ): δ8.00(d, J=8Hz, 1H), 7.74(br s, 1H), 7.33(br d, J=8Hz, 1H), 5.80(dd, J=7Hz , 9Hz1H), 5.05-5.50(br, 1H), 4.28(t, J=9Hz, 1.5H), 3.36(dd, J=7Hz, 9Hz, 1H).

Example 81

5-[5′-Isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one

To 65mg 5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one, 45mg (5 - To a solution of isopropyl-2-methoxyphenyl)boronic acid and 66 mg of potassium carbonate in 6 mL of acetone and 1.5 mL of water was added approximately 5 mg of palladium acetate. The mixture was heated to reflux and stirred at this temperature for 1.5 hours. Acetone was removed by rotary evaporation and the residue was diluted with 10 mL EtOAc and 10 mL water. The aqueous phase was extracted with 10 mL EtOAc. The combined organic layers were washed with 10 mL of brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 10% EtOAc in hexanes, followed by a linear gradient of 10-100% EtOAc in hexanes with 10 CV Elution afforded the title compound. Spectral data are provided in Example 49.

The compounds listed in Table 3 were prepared following the procedure described in Example 52.

table 3

Example 90

5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

Following the procedure described in Example 80 using nitroethane, 0.2 g of 2-iodo-5-(trifluoromethyl)benzaldehyde, 0.102 g of the desired product was obtained, which was separated into cis and Trans diastereomer: flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 10% EtOAc in hexanes, followed by 10 CV of 10-100% EtOAc in hexanes Perform a linear gradient elution.

trans-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one: mass spectrum (ESI) 372.1 (M+1).

¹ H NMR (500MHz, CDCl ₃ ): δ8.02 (d, J=8Hz, 1H), 7.61 (d, J=1.5Hz, 1H), 7.32 (dd, J=2Hz, 8Hz, 1H), 6.16( s, 1H), 5.39(d, J=4Hz, 1H), 3.76(dq, J=6Hz, 4.5 Hz, 1H), 1.62(d, J=6 Hz, 3H).cis-5-[2- Iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one: mass spectrum (ESI) 372.1 (M+1).

¹ H NMR (500MHz, CDCl ₃ ): δ7.98(d, J=8Hz, 1H), 7.60(br s, 1H), 7.33(dd, J=1.5 Hz, 8Hz, 1H), 6.25(s, 1H ), 5.85(d, J=8Hz, 1H), 3.76(dq, J=8Hz, 7Hz, 1H), 0.81(d, J=7Hz, 3H).

Example 91

trans-5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidine-2 - Ketone (racemic)

To 0.036g trans-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one, 0.024g (5-isopropyl -2-Methoxyphenyl)boronic acid and 0.04g of potassium carbonate in 2mL of acetone and 0.5mL of water were added 2mg of palladium acetate. The mixture was heated to reflux and stirred at this temperature for 1.5 hours. Acetone was removed by rotary evaporation and the residue was diluted with 10 mL of EtOAc and 10 mL of water. The aqueous phase was extracted with 10 mL EtOAc. The combined organic layers were washed with 10 mL of brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 10% EtOAc in hexanes, followed by a linear gradient of 10-100% EtOAc in hexanes over 10 CV off, the title compound was obtained. Mass spectrum (ESI) 394.2 (M+1). The ¹ H NMR signals overlap due to rotational enantiomerism.

¹ H NMR (500MHz, CDCl ₃ ): δ7.80, 7.78(s, 1H), 7.64, 7.63(d, J~8Hz, 1H), 7.35(d, J=7.5Hz, 1H), 7.27, 7.26( d, J-8Hz 1H), 7.00, 6.95(d, J=2.5Hz, 1H), 6.93, 6.92(d, J~8Hz, 1H), 5.87, 5.81(s, 1H), 5.16, 5.10(d, J～5Hz, 1H), 3.70-3.78(m, 3.5H), 3.49(m, 0.5H), 2.89(m, 1H), 1.24(m, 6H), 0.90, 0.70(d, J=6.5Hz, 3H).

Example 92

cis-5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidine-2 - Ketone (racemic)

Following the method described in Example 91, 0.046 g of cis-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one was used , the desired product was obtained. Mass spectrum (ESI) 394.2 (M+1). The ¹ H NMR signals overlap due to rotational enantiomerism.

¹ H NMR (500MHz, CDCl ₃ ): δ7.89, 7.88(s, 1H), 7.65, 7.64(d, J～7.5Hz, 1H), 7.34, 7.32(d, J～8Hz, 1H), 7.26( d, J=8.5Hz, 1H), 6.98, 6.86(d, J=2.5Hz, 1H), 6.91, 6.89(d, J~8Hz, 1H), 5.83, 5.75(s, 1H), 5.69, 5.61( d, J～8Hz, 1H), 3.75(s, 1.8H), 3.58-3.70(m, 2H), 3.32(m, 0.6H), 2.88(m, 1H), 1.23(m, 6H), 0.89, 0.71(d, J=6.5Hz, 3H).

Example 93

trans-3-[3,5-bis(trifluoromethyl)benzyl]-5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2 -yl]-4-methyl-1,3-oxazolidin-2-one (racemic)

To 30 mg trans-5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidine To a solution of -2-one in 1 mL of DMF at 0 °C was added 8 mg of sodium hydride. The mixture was stirred at room temperature for 10 minutes, then 32 mg of 3,5-bis(trifluoromethyl)benzyl bromide was added. The mixture was stirred at room temperature overnight, then diluted with 10 mL EtOAc and 10 mL water. The layers were separated and the aqueous phase was extracted with 5 mL EtOAC. The combined organic layers were washed with 5 mL of brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 4% EtOAc in hexanes, followed by a linear gradient of 4-100% EtOAc in hexanes over 10 CV, The title compound was obtained. Mass Spectrum (ESI) 620.2 (M+1). The ¹ H NMR signals overlap due to rotational enantiomerism.

¹ H NMR (500MHz, CDCl ₃ ): δ7.53-7.80(m, 5H), 7.33(d, J=8Hz, 1H), 7.21-7.29(m, 1H), 7.00, 6.76(d, J=2.5 Hz, 1H), 6.91, 6.86 (d, J = 8.5Hz, 0.4H), 5.15, 5.10 (d, J = 4.5 Hz, 1H), 4.80, 4.74 (d, J = 16Hz, 1H), 4.25, 4.21 (d, 16Hz, 1H), 3.76(s, 2H), 3.49(s, 1H), 3.43(m, 0.4H), 3.18(m, 0.5H), 2.77-2.98(m, 1H), 1.24(m , 3H), 1.16(m, 3H), 0.78, 0.61(d, J=6.5Hz, 3H).

Example 94

cis-3-[3,5-bis(trifluoromethyl)benzyl]-5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2 -yl]-4-methyl-1,3-oxazolidin-2-one (racemic)

Following the method described in Example 93, using 40 mg of cis-5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methanol 1,3-oxazolidin-2-one and 42 mg of 3,5-bis(trifluoromethyl)benzyl bromide to obtain the title compound. Mass Spectrum (ESI) 620.2 (M+1). ^{The 1} H NMR signals overlap due to rotational enantiomerism.

¹ H NMR (500MHz, CDCl ₃ ): δ7.82-7.94(m, 2H), 7.62-7.74(m, 3H), 7.39, 7.37(d, J～8Hz, 1H), 7.25, 7.17(br d, J=8.5Hz, 1H), 7.00, 6.78(s, 1H), 6.87, 6.84(d, J=8.5Hz, 1H), 5.59, 5.56(d, J=4.5Hz, 1H), 4.96(d, J =16Hz, 1H), 4.22, 4.11(d, J=16 Hz, 1H), 3.76(s, 2H), 3.58(s, 1H), 3.40(m, 0.4H), 2.85-3.00(m, 1H) , 2.78(m, 0.5H), 1.23(d, J=7 Hz, 3H), 1.06(m, 3H), 0.88, 0.69(d, J=6.5Hz, 3H).

Example 95

(4R,5R)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one Step A: (4S)-4- Benzyl-3-{(2R,3S)-3-hydroxy-3-[2-iodo-5-(trifluoromethyl)phenyl]-2-methylpropionyl}-1,3-oxazolidine -2-one

1.8 g of 5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde (Example 80, step A), 1.16 g of (4S)-4-benzyl - A mixture of 3-propionyl-1,3-oxazolidin-2-one, 0.048 g magnesium chloride, 1.40 mL triethylamine and 0.91 mL chlorotrimethylsilane in 10 mL EtOAc was stirred at room temperature for 24 hours, then filtered Filter through a 10 x 10 cm plug of silica gel, eluting with 400 mL _Et2O . The filtrate was concentrated and 10 mL of MeOH and 2 drops of trifluoroacetic acid were added. The solution was stirred at room temperature for 30 minutes and concentrated to a pale yellow oil. The residue was purified by flash chromatography on a Biotage Horizon, 65i column, eluting with 15 CV of 10% acetone in hexanes, to provide the title compound. Mass spectrum (ESI) 516.2 (M-OH).

¹ H NMR (500MHz, CDCl ₃ ): δ8.00(d, J=8.5Hz, 1H), 7.76(d, J=2Hz, 1H), 7.22-7.32(m, 4H), 7.07(br d, J =6.5Hz, 2H), 5.18(dd, J=6.5Hz, 7.5Hz, 1H), 4.67(m, 1H), 4.46(dq, J=6.5Hz, 7.5Hz, 1H), 4.17(t, J= 9Hz, 1H), 4.11(dd, J=3Hz, 9Hz, 1H), 3.97(d, J=8 Hz, 1H), 3.19(dd, J=7Hz, 13.5Hz, 1H), 2.57(dd, J= 9.5Hz, 13.5Hz, 1H), 1.34(d, J=7.5Hz, 3H)

Step B: (4R,5R)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

To 0.65 g (4S)-4-benzyl-3-{(2R,3S)-3-hydroxyl-3-[2-iodo-5-(trifluoromethyl)phenyl]-2-methylpropionyl To a solution of }-1,3-oxazolidin-2-one in 6 mL of 3:1 tetrahydrofuran-water at 0° C. was added a solution of 0.102 g of lithium hydroxide in 1.5 mL of water, followed by 0.554 mL of 30% aqueous hydrogen peroxide. The solution was stirred at 0 °C for 1 h at which time LC/MS analysis showed the absence of any starting material. To the cold solution was added 1.5M sodium sulfite solution (3.7 mL), then poured into a separatory funnel and extracted with 2 x 10 mL of dichloromethane. The combined _CH2Cl2 extracts were back extracted with 20 mL of 3:1 water- _saturated aqueous sodium bicarbonate. The combined aqueous layers were acidified (pH<1) with 6 N HCl and extracted with 4 x 10 mL EtOAc. The combined EtOAc extracts were washed with 10 mL of brine, dried over sodium sulfate, and concentrated. The residue was dissolved in 10 mL of toluene. Diphenylphosphoryl azide (0.315 mL) and 0.24 mL of triethylamine were added, and the mixture was stirred at 100° C. overnight, then cooled and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 40S column, eluting with 1 CV of 5% EtOAc in hexanes, followed by a linear gradient of 5-100% EtOAc in hexanes over 10 CV , the title compound was obtained. Mass spectrum (ESI) 372.1 (M+1).

¹ H NMR (500MHz, CDCl ₃ ): δ8.02 (d, J=8Hz, 1H), 7.61 (d, J=1.5Hz, 1H), 7.32 (dd, J=2Hz, 8Hz, 1H), 6.16( s, 1H), 5.39(d, J=4Hz, 1H), 3.76(dq, J=6Hz, 4.5Hz, 1H), 1.62(d, J=6Hz, 3H).

Analytical HPLC was performed on a Chiralpak AD 4.6 x 250 mm eluting with 4% ethanol in heptane at 0.75 mL/min ( _tR = 21.56 min for R, R; _tR = 18.00 min for S, S ), indicating 98% ee.

Example 96

(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1, 3-oxazolidin-2-one

To the 0 20 mg sodium hydride was added to the solution. The mixture was stirred at 0 °C for 10 minutes; then 94 mg of 3,5-bis(trifluoromethyl)benzyl bromide were added. The mixture was stirred at 0 °C for 10 min, then diluted with 10 mL EtOAc and 10 mL water. The layers were separated and the aqueous phase was extracted with 10 mL EtOAc. The combined organic phases were washed with 10 mL of brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25M column, eluting with 1 CV of 2% EtOAc in hexanes, followed by a linear gradient of 2-100% EtOAc in hexanes over 10 CV Elution afforded the title compound. Mass spectrum (ESI) 598.1 (M+1).

¹ H NMR (500MHz, CDCl ₃ ): δ8.00(d, J=8.5Hz, 1H), 7.77(s, 1H), 7.58(br s, 3H), 7.34(dd, J=1.5Hz, 8Hz, lH), 5.36(d, J=4Hz, lH), 4.89(d, J=16Hz, 1H), 4.31(d, J=16Hz, 1H), 4.48(dq, J=6Hz, 4Hz, 1H), 1.55 (d, J=6.5Hz, 3H).

Example 97

(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)bis Benzene-2-yl]-4-methyl-1,3-oxazolidin-2-one

Following the method described in Example 81, using 41 mg of (4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl-5-[2-iodo-5-(trifluoromethyl)benzene [0019]-4-methyl-1,3-oxazolidin-2-one and 17 mg of (5-isopropyl-2-methoxyphenyl)boronic acid to obtain the title compound. Mass spectrum (ESI) 620.4 (M+1). The ¹ H NMR signals overlap due to rotational enantiomerism.

¹ H NMR (500MHz, CDCl ₃ ): δ7.53-7.80(m, 5H), 7.33(d, J=8Hz, 1H), 7.21-7.29(m, 1H), 7.00, 6.76(d, J=2.5 Hz, 1H), 6.91, 6.86 (d, J=8.5Hz, 0.4H), 5.15, 5.10 (d, J=4.5Hz, 1H), 4.80, 4.74 (d, J=16Hz, 1H), 4.25, 4.21 (d, 16Hz, 1H), 3.76(s, 2H), 3 49(s, 1H), 3.43(m, 0.4H), 3.18(m, 0.5H), 2.77-2.98(m, 1H), 1.24( m, 3H), 1.16(m, 3H), 0.78, 0.61(d, J=6.5Hz, 3Hz).

Example 98

(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(tri Fluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one

Following the method described in Example 81, 38.5 mg of (4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl) )phenyl]-4-methyl-1,3-oxazolidin-2-one and 18 mg (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (Example 78) to obtain the title compound. Mass spectrum (ESI) 638.3 (M+1). The ¹ H NMR signals overlap due to rotational enantiomerism.

¹ HNMR (500MHz, CDCl ₃ ): δ7.55-7.80(m, 5H), 7.29(d, J=8Hz, 1H), 7.00, 6.77(d, J=8.5Hz, 1H), 6.68, 6.63(d , J-12Hz, 1H), 5.08, 5.04(d, J～5Hz, 1H), 4.81, 4.75(d, J=16Hz, 1H), 4.26, 4.23(d, 15.5Hz, 1H), 3.75(s, 2H), 3.50(s, 1H), 3.43(m, 0.5H), 3.12-3.24(m, 1.5H), 1.24, 1.22(d, J～5Hz, 3H), 1.17, 1.06(d, J=7Hz , 3H), 0.84, 0.70 (d, J=6Hz, 3H).

Example 99

(4S,5S)-5-[2-Iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one Step A: (4R)-4- Benzyl-3-{(25,3R)-3-hydroxy-3-[2-iodo-5-(trifluoromethyl)phenyl]-2-methylpropionyl}-1,3-oxazolidine -2-one

Following the procedure described in Example 95, Step A, using 0.72 g of 5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde (Example 80, Step A) , 0.466g (4R)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one, 0.02g magnesium chloride, 0.56mL triethylamine and 0.38mL chlorotrimethylsilane, obtained The title compound. Mass spectrum (ESI) 516.2 (M-OH).

¹ HNMR (500MHz, CDCl ₃ ): δ 8.00(d, J=8.5Hz, 1H), 7.76(d, J=2Hz, 1H), 7.22-7.32(m.4H), 7.07(br d, J=6.5 Hz, 2H), 5.18(dd, J=6.5Hz, 7.5Hz, 1H), 4.67(m, 1H), 4.46(dq, J=6.5Hz, 7.5Hz, 1H), 4.17(t, J=9Hz, 1H), 4.11(dd, J=3Hz, 9Hz, 1H), 3.97(d, J=8Hz, 1H), 3.19(dd, J=7Hz, 13.5Hz, 1H), 2.57(dd, J=9.5Hz, 13.5Hz, 1H), 1.34(d, J=7.5Hz, 3H).

Step B: (4S,5S)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

Following the procedure described in Step B of Example 95, using 0.214 g of (4R)-4-benzyl-3-{(25,3R)-3-hydroxy-3-[2-iodo-5-(trifluoromethyl )phenyl]-2-methylpropionyl}-1,3-oxazolidin-2-one, 0.034g lithium hydroxide, 0.16mL 30% hydrogen peroxide aqueous solution, 0.1mL diphenylphosphoryl azide and 0.072 mL of triethylamine to obtain the title compound. Mass spectrum (ESI) 372.1 (M+1).

¹ H NMR (500MHz, CDCl ₃ ): δ8.02 (d, J=8Hz, 1H), 7.61 (d, J=1.5Hz, 1H), 7.32 (dd, J=2Hz, 8Hz, 1H), 6.16( s, 1H), 5.39(d, J=4Hz, 1H), 3.76(dq, J=6Hz, 4.5Hz, 1H), 1.62(d, J=6Hz, 3H).

Analytical HPLC was performed on a Chiralpak AD 4.6 x 250 mm eluting with 4% ethanol in heptane at 0.75 mL/min ( _tR = 21.56 min for R, R; _tR = 18.00 min for S, S ), indicating 99% ee.

Example 100

(4S,5S)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1, 3-oxazolidin-2-one

Following the method described in Example 96, using 0.108 g of (4S,5S)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidine- 2-Keto, 23 mg sodium hydride and 107 mg 3,5-bis(trifluoromethyl)benzyl bromide afforded the title compound. Mass spectrum (ESI) 598.1 (M+1).

¹ HNMR (500MHz, CDCl ₃ ): δ8.00(d, J=8.5Hz, 1H), 7.77(s, 1H), 758(br s, 3H), 7.34(dd, J=1.5Hz, 8Hz, 1H ), 5.36(d, J=4Hz, 1H), 4.89(d, J=16Hz, 1H), 4.31(d, J=16Hz, 1H), 4.48(dq, J=6Hz, 4Hz, 1H), 1.55( d, J=6.5Hz, 3H)

Example 101

(4S,5S)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)bis Benzene-2-yl]-4-methyl-1,3-oxazolidin-2-one

Following the method described in Example 81, using 40 mg of (4S,5S)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl) Phenyl]-4-methyl-1,3-oxazolidin-2-one and 17 mg of (5-isopropyl-2-methoxyphenyl)boronic acid gave the title compound. Mass spectrum (ESI) 620.4 (M+1). The ¹ H NMR signals overlap due to rotational enantiomerism.

¹ H NMR (500MHz, CDCl ₃ ): δ7.53-7.80(m, 5H), 7.33(d, J=8Hz, 1H), 7.21-7.29(m, 1H), 7.00, 6.76(d, J=2.5 Hz, 1H), 6.91, 6.86 (d, J=8.5Hz, 0.4H), 5.15, 5.10 (d, J=4.5Hz, 1H), 4.80, 4.74 (d, J=16Hz, 1H), 4.25, 4.21 (d, 16Hz, 1H), 3.76(s, 2H), 3.49(s, 1H), 3.43(m, 0.4H), 3.18(m, 0.5H), 2.77-2.98(m, 1H), 1.24(m , 3H), 1.16(m, 3H), 0.78, 0.61(d, J=6.5Hz, 3Hz).

Example 102

(4R,5R)-5-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1 , 3-oxazolidin-2-one

According to the method described in Example 81, using 240 mg of (4R,5R)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidine-2 -ketone and 171 mg of (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (Example 78) afforded the title compound. Mass spectrum (ESI) 412.3 (M+1). The ¹ H NMR signals overlap due to rotational enantiomerism.

¹ H NMR (500MHz, CDCl ₃ ): δ7.79, 7.77(s, 1H), 7.64, 7.62(dd, J-2.5Hz, 8Hz, 1H), 7.32, 7.31(d, J-8Hz, 1H), 7.00, 6.95(d, J=8.5Hz, 1H), 6.70, 6.67(d, J=12Hz, 1H), 6.47, 6.43(s, 1H), 5.08, 5.04(d, J=5Hz, 0.1H), 3.68-3.80(m, 3.5H), 3.53(m, 0.5H), 3.21(m, 1H), 1.19-1.30(m, 6H), 0.95, 0.77(d, J=6Hz, 3H)

According to the method described in Example 96, from (4R,5R)-5-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2 -yl]-4-methyl-1,3-oxazolidin-2-one produced the compounds listed in Table 4:

Table 4

Example 111

((4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl )biphenyl-2-yl]methyl}-5-methylimidazolidin-2-ylidene)cyanamide

To (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N ² -{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl) yl)biphenyl-2-yl]methyl}propane-1,2-diamine (25.1 mg, 0.0424 mmol) in dichloroethane (1.5 mL) was added triethylamine (15 μL, 0.105 mmol) and diphenyl cyanoformimidate (13 mg, 0.053 mmol). The reaction was heated at 60 °C overnight, cooled to room temperature, filtered, and loaded directly onto a silica gel column for purification by flash chromatography, eluting with 10-40% EtOAc/hexanes, to afford ((4R,5S)-4- [3,5-bis(trifluoromethyl)phenyl]-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol Base}-5-methylimidazolidine-2-ylidene) cyanamide. _Rf = 0.20 (25% EtOAc/Hex). LCMS = 643.3 (M+1) ⁺ . ¹ HNMR (C ₆ D ₆ , 500MHz; atropisomers exist, some peaks overlap)

δ6.53-8.83(m, 10H), 3.61-4.91(m, 3H), 3.28-2.70(m, 5H), 1.14-1.25(m, 6H), -0.39--0.26(m, 3H).

The compounds in Table 5 were prepared following the general procedure described above:

table 5

Intermediate 1

(4S,5S)-5-(3,5-Difluorophenyl)-4-methyl-1,3-oxazolidin-2-one Step A: [(1S)-2-(3,5- Benzyl difluorophenyl)-1-methyl-2-oxoethyl]carbamate

To the solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (1.96 g, 7.36 mmol) in THF (9.4 mL) To the solution at -15°C was added isopropylmagnesium chloride (3.6 mL of a 2M solution in ether, 7.2 mmol). The reaction was stirred at -15°C for 15 minutes, then 3,5-difluorophenylmagnesium bromide (29.44 mL of a 0.5 M solution in THF, 14.72 mmol). The reaction was warmed to room temperature and stirred for 24 hours. The solution was then poured into saturated _NH4Cl (100 mL) and extracted with EtOAc (3 x 100 mL). The organic extracts were washed with water and brine (100 mL each), dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (15% EtOAc/hexanes) afforded benzyl [(1S)-2-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate ester. _Rf = 0.34 (15% EtOAc/Hex). LCMS = 342.3 (M+Na) ⁺ .

Step B: Benzyl [(1S,2S)-2-(3,5-difluorophenyl)-2-hydroxy-1-methylethyl]carbamate

To benzyl [(1S)-2-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate (1.35 g, 4.23 mmol) in THF (75 mL)- To the solution at 78°C was added 1-Selectride (6.35 mL of a 1M solution in THF, 6.35 mmol). After stirring at -78 °C for 1 h, the reaction was poured into 1N HCl (50 mL). The mixture was extracted with EtOAc (2 x 100 mL). The organic extracts were washed with water and brine (50 mL each), dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (5-40% EtOAc/hexanes) afforded [(1S,2S)-2-(3,5-difluorophenyl)-2-hydroxy-1-methylethyl] Benzyl carbamate (main product). LCMS = 322.3 (M+1) ⁺ .

Step C: (4S,5S)-5-(3,5-Difluorophenyl)-4-methyl-1,3-oxazolidin-2-one

Benzyl [(1S,2S)-2-(3,5-difluorophenyl)-2-hydroxy-1-methylethyl]carbamate (900 mg, 2.80 mmol) in THF (28.6 mL) To was added MeOH (14.3 mL) and 7.5N KOH (7.2 mL). The reaction was stirred at room temperature for 4 hours, then extracted with EtOAc (2 x 75 mL). The organic extracts were washed with water and brine (50 mL each), dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (10-75% EtOAc/hexanes) afforded (4S,5S)-5-(3,5-difluorophenyl)-4-methyl-1,3-oxazolidine -2-one. _Rf = 0.07 (25% EtOAc/Hex).

LCMS=214.3(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ6.89-6.93(m, 2H), 6.82(m, 1H), 6.24(bs, 1H), 5.01(d, J= 6.8 Hz, 1H), 3.79(m, 1H), 1.42(d, J=6.2Hz, 3H)

Intermediate 2

6-Chloro-5-fluoro-2-iodopyridin-3-ol

To a solution of 6-chloro-5-fluoropyridin-3-ol (307.8 mg, 2.08 mmol) in water (11 mL) was added Na ₂ CO ₃ (441 mg, 4.16 mmol) and I ₂ (549 mg, 2.08 mmol). After 2 hours, the reaction mixture was acidified to pH 3 with 1N HCl, diluted with EtOAc (100 mL), washed with aqueous NaHSO ₃ and brine (50 mL each). The organic layer was dried over sodium sulfate, filtered and concentrated to give 6-chloro-5-fluoro-2-iodopyridin-3-ol.

LCMS=273.9(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.11(d, J=8.5Hz, 1H), 5.47(d, J=1.4Hz, 1H).

Intermediate 3

2-Bromo-6-isopropenyl-3-methoxypyridine

To the tube was added 2-bromo-6-iodo-3-methoxypyridine (700 mg, 2.236 mmol), isopropenylboronic acid (212 mg, 2.460 mmol), DME (7.5 mL), EtOH (2.8 mL) and _1M Na Aqueous CO ₃ (5.6 mL). The mixture was degassed with nitrogen. Pd( _PPh3 ) ₄ (206mg, 0.179mmol) was added and the mixture was again degassed with nitrogen. The tube was sealed and heated at 80°C for 16 hours. The solution was then cooled to room temperature, diluted with EtOAc (100 mL), washed with saturated NaHCO ₃ and brine (50 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (0-15% EtOAc/hexanes) afforded 2-bromo-6-isopropenyl-3-methoxypyridine. _Rf = 0.38 (25% EtOAc/Hex).

LCMS=230.0(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.36(d, J=8.5Hz, 1H), 7.07(d, J=9.4Hz, 1H), 5.81(s, 1H ), 5.21(s, 1H), 3.92(s, 3H), 2.16(s, 3H)

Intermediate 4

2-iodo-3-methoxypyridine

To a solution of 2-iodopyridin-3-ol (45.3 mg, 0.205 mmol) in DMF (3 mL) was added Cs ₂ CO ₃ (334 mg, 1.030 mmol) and MeI (25 μL, 0.410 mmol). After 1 hour, the reaction was poured into water (10 mL), diluted with EtOAc (20 mL), washed with water (3 x 10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. 2-Iodo-3-methoxypyridine is obtained.

LCMS=236.1(M+1) ^{+ .1} H NMR (CDCl ₃ , 500MHz) δ8.00 (dd, J=1.4, 4.6Hz, 1H), 7.20 (dd, J=4.6, 8.0Hz, 1H), 7.00 (dd, 1.4, 8.3Hz, 1H), 3.90(s, 3H)

Intermediate 5

2-Bromo-6-iodopyridin-3-ol

To a solution _of 2-bromopyridin-3-ol (1.00 g, 5.80 mmol) in water (30 mL) was added _Na2CO3 (1.23 g, 11.60 mmol) and _I2 (1.53 g, 5.80 mmol). After 1 h, the reaction was treated with N HCl (20 mL), extracted with EtOAc (2 x 100 mL), washed with aqueous NaHSO ₃ and brine (50 mL each). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by flash silica gel chromatography (20-40% EtOAc/hexanes) afforded 2-bromo-6-iodopyridin-3-ol. _Rf = 0.44 (25% EtOAc/Hex).

LCMS=301.9(M+1) ⁺ . ¹ H NMR(CDCl ₃ , 500MHz)δ 7.56(d, J=8.3Hz, 1H), 6.99(d, J=8.3Hz, 1H), 5.65(s, 1H) .

Intermediate 6

1-(2-Bromo-1,3-thiazol-5-yl)ethanol

To a 0° C. solution of 2-bromo-5-formylthiazole (100.6 mg, 0.524 mmol) in THF (5 mL) was added MeMgBr (175 μL of a 3M solution in diethyl ether, 0.524 mmol). After 30 minutes, MeMgBr (50 μL of 3M in ether, 0.150 mmol) was heated. After 30 minutes, the reaction was poured into saturated _NH4Cl (20 mL). The mixture was extracted with EtOAc (50 mL), and the organic layer was washed with water and brine (25 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography (0-80% EtOAc/hexanes) afforded 1-(2-bromo-1,3-thiazol-5-yl)ethanol. _Rf = 0.13 (25% EtOAc/Hex).

LCMS=210.0(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) δ7.40(s, 1H), 5.12(q, J=6.4Hz, 1H), 1.59(d, J=6.4Hz, 3H).

Intermediate 7

4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-iodo-1,3-thiazole Step A: 4-({[tert-butyl(dimethyl)methyl silyl]oxy}methyl)-1,3-thiazole

To a solution of 1,3-thiazol-4-ylmethanol (311.4 mg, 2.7 mmol) in _CH2Cl2 (15 _mL ) was added _Et3N (1.9 mL, 13.6 mmol). The solution was cooled to -78°C and TBSOTf (776 μL, 3.38 mmol) was added. The reaction was warmed to room temperature and stirred for 1 hour. The reaction was then diluted with EtOAc (75 mL), washed with sat. NaHCO ₃ , brine, 1N HCl, and brine (20 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0-15% EtOAc/hexanes) to afford 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3- Thiazoles. _Rf = 0.28 (15% EtOAc/Hex).

LCMS=230.1(M+1) ^{+ .1} H NMR (CDCl ₃ , 600MHz) δ8.77(d, J=2.0Hz, 1H), 7.25(m, 1H), 4.93(d, J=1.1Hz, 2H ), 0.95(s, 9H), 0.12(s, 6H).

Step B: 4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-iodo-1,3-thiazole

To a solution of 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-thiazole (106.4 mg, 0.465 mmol) in THF (5 mL) at -78 °C was dropped Add n-BuLi (465 μL of a 1.6M solution in hexane, 0.744 mmol). The reaction was stirred at -78°C for 30 minutes, then cannulated with a solution of iodine (295 mg, 1.16 mmol) in THF (5 mL). The reaction was warmed to room temperature for 15 min, then poured into aqueous NaHSO ₃ (20 mL). The mixture was extracted with EtOAc (60 mL). The organic layer was washed with brine, saturated NaHCO ₃ , and brine (20 mL each), dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography (15% EtOAc/hexanes) afforded 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-iodo-1,3-thiazole. _Rf = 0.55 (15% EtOAc/Hex).

LCMS=356.0(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 600MHz) δ7.16(s, 1H), 4.86(s, 2H), 0.93(s, 9H), 0.10(s, 6H).

Intermediate 8

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1 , to a solution of 3-oxazolidin-2-one (975 mg, 1.633 mmol) in DMSO (16 mL) was added bis(pinacol)diboron (1.24 g, 4.899 mmol), [1,1′-di (Diphenylphosphino)-ferrocene]palladium(II) dichloride complex (1:1) with dichloromethane (133 mg, 0.1633 mmol) and KOAc (320 mg, 3.266 mmol). The mixture was degassed with nitrogen and heated at 80°C for 16 hours. The solution was then cooled to room temperature, diluted with EtOAc (200 mL) and washed with saturated NaHCO ₃ and brine (80 mL, respectively). The organic layer was dried over sodium sulfate, filtered through a plug of silica, and concentrated. Purification of the residue by reverse phase chromatography (C-18, 10-95% MeCN/water with 0.1% TFAA) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl) Phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-( Trifluoromethyl)benzyl]-1,3-oxazolidin-2-one.

LCMS=598.1(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.98(d, J=7.8Hz, 1H), 7.88(s, 1H), 7.78(s, 2H), 7.67(s , 1H), 7.57(d, J=7.8Hz, 1H), 5.68(d, J=7.5Hz, 1H), 5.01(d, J=15.6Hz, 1H), 4.76(d, J=15.5Hz, 1H ), 3.98-3.93(m, 1H), 1.35(d, J=6.9Hz, 12H), 0.77(d, J=6.7Hz, 3H).

Example 118

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl] Methyl}-4-methyl-1,3-oxazolidin-2-one

Add (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methanol to the tube Base-1,3-oxazolidin-2-one (52.5mg, 0.0879mmol), 3-isopropylphenylboronic acid (17.3mg, 0.106mmol), DME (370[mu]h), EtOH (120μL) and 1M _Na2CO3 in water (264 μL, 0.264 _mmol ). The mixture was degassed with nitrogen and then Pd(PPh ₃ ) ₄ (10.2 mg, 8.8×10 ⁻³ mmol) was added, and the mixture was degassed with nitrogen again. The tube was sealed and heated at 100°C for 2 hours. The solution was then cooled to room temperature, diluted with EtOAc (50 mL), washed with water and brine (15 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (0-15% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3'- isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf = 0.29 (15% EtOAc/hexanes).

LCMS=590.1(M+1) ^{+ .1} HNMR(CDCl ₃ , 500MHz) δ7.85(s, 1H), 7.72(s, 1H), 7.68(s, 2H), 764(d, J=8.0Hz, 1H), 7.44(d, J=8.0Hz, 1H), 7.39(t, J=7.6Hz, 1H), 7.29(d, J=7.8Hz, 1H), 7.15(bs, 1H), 7.11(bd, J=7.5Hz, 1H), 5.46(d, J=8.0Hz, 1H), 4.91(d, J=15.7Hz, 1H), 4.21(d, J=15.8Hz, 1H), 3.69(m, 1H) , 2.96(m, 1H), 1.26-1.28(m, 6H), 0.38(d, J=6.4Hz, 3H).

Example 119

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-3'-isopropenyl-4-(trifluoromethyl)biphenyl -2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Add (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3′-chloro-4′-fluoro-4-(trifluoromethyl) to the tube Biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Example 146) (30.2mg, 0.0504mmol), isopropenylboronic acid (27mg, 0.31mmol) , 1,1-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (5.5 mg, 8.4×10 ⁻³ mmol), THF (350 μL) and 1 M aqueous K ₂ CO ₃ (350 μL). The tube was degassed with nitrogen, sealed, and heated at 100°C for 5 hours. The solution was then cooled to room temperature, diluted with EtOAc (50 mL), washed with water and brine (15 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (0-15% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'- Fluoro-3'-isopropenyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. _Rf = 0.29 (15% EtOAc/Hex).

LCMS=606.2(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.86(s, 1H), 7.70(s, 3H), 7.64(d, J=8.0Hz, 1H), 7.42(d , J=8.0Hz, 1H), 7.23(dd, J=7.8, 2.0Hz, 1H), 7.12-7.17(m, 2H), 5.54(d, J=8.0Hz, 1H), 5.28(s, 1H) , 5.26(s, 1H), 4.90(d, J=15.8Hz, 1H), 4.18(d, J=15.8Hz, 1H), 3.78(m, 1H), 2.16(s, 3H), 0.47 (d, J=6.7Hz, 3H).

Example 120

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(1H-pyrrol-3-yl)-5-(trifluoromethyl Base) benzyl] -1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-{5-(trifluoromethyl)-2-[1-(triiso Propylsilyl)-1H-pyrrol-3-yl]benzyl}-1,3-oxazolidin-2-one (Example 149) (22.6 mg, 0.0326 mmol) in THF (2 mL) To the solution was added TBAF (65 μL of 1M in THF, 0.065 mmol). After 30 minutes, the reaction was treated with saturated _NH4Cl (5 mL). The mixture was extracted with EtOAc (35 mL), and the organic layer was washed with water and brine (15 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (25-60% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyll-4-methyl-3- [2-(1H-Pyrrol-3-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one. _Rf = 0.11 (25% EtOAc/Hex).

LCMS=537.1(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 600MHz) δ8.49(s, 1H), 7.85(s, 1H), 7.71(s, 2H), 7.64(s, 1H), 7.58 (d, J=S.1Hz, 1H), 7.51(d, J=8.0Hz, 1H), 6.88-6.91(m, 2H), 6.33(d, J=1.6Hz, 1H), 5.53(d, J =8.0Hz, 1H), 5.02(d, J=15.7Hz, 1H), 4.46(d, J=156Hz, 1H), 3.80(m, 1H).0.49(d, J=6.6Hz, 3H).

Example 121

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1-isopropyl-1H-pyrrol-3-yl)-5-(trifluoromethyl) Methyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(1H-pyrrol-3-yl)-5-(trifluoro To a solution of methyl)benzyl]-1,3-oxazolidin-2-one (6.8 mg, 0.0127 mmol) (Example 120) in DMSO (300 μL) was added powdered KOH (3.6 mg, 0.0643 mmol). After stirring for 15 minutes, 2-iodopropane (3.2 μL, 0.032 mmol) was added. After stirring at room temperature for 1.5 h, water (5 mL) _was added and the mixture was extracted first with _CH2Cl2 (2 x 15 mL) and then with EtOAc (2 x 15 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the residue by PTLC (25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1-isopropyl <RTIgt;-1H-pyrrol-3-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. _Rf = 0.33 (25% EtOAc/Hex).

LCMS=579.2(M+1) ^{+ .1} HNMR(CDCl ₃ , 500MHz)δ 7.85(s, 1H), 7.71(s, 2H), 7.61(s, 1H), 7.56(d, J=8.0Hz, 1H ), 7.50(d, J=8.0Hz, 1H), 6.83(t, J=2.1Hz, 1H), 6.79(t, J=2.5Hz, 1H), 6.24(t, J=2.3Hz, 1H), 5.49(d, J=8.0Hz, 1H), 5.04(d, J=15.5Hz, 1H), 4.48(d, J=15.6Hz, 1H), 4.27(m, 1H), 3.76(m, 1H), 1.48(d, J=6.6Hz, 6H), 0.49(d, J=6.6Hz, 3H).

Example 122

(4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-nitro-4-(trifluoromethyl)bis Benzene-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl ]Methyl}-4-methyl-1,3-oxazolidin-2-one (Example 143) (159.4 mg, 0.276 mmol) To a solution of HOAc (5 mL) was added _HNO3 (1.5 mL). After 45 minutes, additional _HNO3 (1.5 mL) was added. After 45 minutes, the reaction was poured into ice water (30 mL). The mixture was extracted with EtOAc (75 mL), washed with 1 N NaOH, saturated NaHCO ₃ and brine (25 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (8-40% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'- Methoxy-5'-nitro-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. _Rf = 0.11 (25% EtOAc/Hex).

LCMS=623.1(M+1) ^{+ .1} HNMR (CDCl ₃ , 500MHz, rotamers present) δ8.34(m, 1H), 8.10(m, 1H), 7.85(d, J=6.9Hz, 1H), 7.61 -7.71(m, 4H), 7.40(m, 1H), 7.11(m, 1H), 5.66(d, J=8.0Hz), 5.28(d, J=8.2Hz), 4.89-4.94(m, 1H) , 3.74-4.09(m, 5H), 0.61(d, J=6.6Hz), 0.47(d, J=6.5Hz).

Example 123

(4S, 5R)-3-{[5'-amino-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3,5-bis( Trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-5'-nitro-4-(trifluoromethyl) To a solution of biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Example 122) (48.2 mg, 0.077 mmol) in EtOAc (4 mL) was added _PtO2 (12 mg), the reaction was placed under an atmosphere of hydrogen (balloon) and stirred vigorously. After 45 minutes, the catalyst was removed by filtration through a plug of silica gel, washing with 100% EtOAc. Concentration of the filtrate afforded (4S,5R)-3-{[5'-amino-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5- [3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. _Rf = 0.20 (40% EtOAc/Hex). LCMS = 593.2 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz, rotamers exist)

δ 7.85(s, 1H), 7.60-7.70(m, 4H), 7.36(d, J=7.8Hz, 1H), 6.74-6.84(m, 2H), 6.56(s, 1H), 5.45-5.54(m , 1H), 4.82-4.87(m, 1H), 3.64-4.17(m, 2H), 3.70(s, 3H), 0.43-0.53(m, 3H).

Example 124

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylthio)-4-(trifluoromethyl Base) biphenyl-2-yl] methyl}-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-3-{[5′-amino-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3,5-di (Trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (Example 123) (40 mg, 0.0676 mmol) in CHCl ₃ (1 mL) had been degassed with nitrogen Dimethyl disulfide (10 μL, 0.101 mmol) and tert-butyl nitrite (16 μL, 0.135 mmol) were added to the solution. The reaction was stirred at room temperature for 30 minutes, then heated to reflux for 2 hours. The solution was cooled to room temperature and diluted with hexane (3 mL). The solution was loaded directly onto a silica gel column and eluted with 25% EtOAc/hexanes. Fractions containing the desired product were combined and repurified by silica gel chromatography eluting with 5-25% EtOAc/hexanes to afford (4S,5R)-5-[3,5-bis(trifluoromethyl) Phenyl]-3-{[2'-methoxy-5'-(methylthio)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1, 3-oxazolidin-2-one. _Rf = 0.52 (40% EtOAc/Hex). LCMS = 624.1 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 600 MHz, rotamers exist)

δ6.94-7.85(m, 9H), 5.58(d, J=8.1Hz), 5.25(d, J=7.8Hz), 4.94(d, J=15.8Hz), 4.85(d, J=15.7Hz), 3.65-4.12(m, 5H), 2.47(s), 2.44(s), 0.54(d, J=6.6Hz), 0.40(d, J=6.6Hz).

Example 125

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylsulfinyl)-4-(tri Fluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylthio)-4-(trifluoro Methyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Example 124) (32.5 mg, 0.0522 mmol) in CH ₂ Cl ₂ (5 mL) m-CPBA (14.6 mg, 77% purity, 0.0652 mmol) was added to the -60°C solution in the room. The reaction was warmed slowly to -20 °C, then diluted with EtOAc (35 mL), washed with aqueous NaHSO ₃ , brine, saturated NaHCO ₃ and brine (15 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (20-100% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methano Oxy-5'-(methylsulfinyl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. _Rf = 0.10 (75% EtOAc/Hex).

LCMS=640.1(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 600MHz) δ7.10-7.86(m, 9H), 4.87-5.59(m, 2H), 3.56-4.14(m, 5H), 2.79( s), 2.75(s), 2.73(s), 0.61(d, J=6.5Hz), 0.57(d, J=6.4Hz), 0.46(d, J=6.4Hz), 0.43(d, J=6.5 Hz).

Example 126

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylsulfonyl)-4-(trifluoro Methyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(methylthio)-4-(trifluoro Methyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Example 124) (7.8 mg, 0.013 mmol) in _CH2Cl2 (1 _mL ) m-CPBA (14 mg, 77% purity, 0.063 mmol) was added to the solution at 0°C. The reaction was stirred at room temperature for 30 min, then diluted with EtOAc (35 mL), washed with aqueous NaHSO ₃ , brine, saturated NaHCO ₃ and brine (15 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification of the residue by PTLC (50% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy -5'-(methylsulfonyl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. _Rf = 0.11 (40% EtOAc/Hex). LCMS = 656.2 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 600 MHz, rotamers exist)

δ7.99-8.02(m, 1H), 7.84-7.86(m, 1H), 7.75-7.78(m, 1H), 7.58-7.72(m, 4H), 7.38-7.42(m, 1H), 7.15-7.18 (m, 1H), 5.55(d, J=8.0Hz), 5.26(d, J=8.1Hz), 4.91-4.97(m, 1H), 3.63-4.03(m, 5H), 3.12(s), 3.10 (s), 0.62(d, J=6.6Hz), 0.48(d, J=6.6Hz)

Example 127

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(6-isopropenylpyridin-2-yl)-5-(trifluoromethyl) Benzyl]-4-methyl-1,3-oxazolidin-2-one

Step A: 2-Bromo-6-isopropenylpyridine

To the tube was added 2,6-dibromopyridine (100 mg, 0.422 mmol), isopropenylboronic acid (40 mg, 0.464 mmol), DME (1.5 mL), EtOH (500 μL) and 1 M aqueous sodium carbonate (1 mL, 1.0 mmol) . The mixture was degassed with nitrogen. Then Pd( _PPh3 ) ₄ (37 mg, 0.032 mmol) was added and the mixture was again degassed with nitrogen. The tube was sealed and heated at 100°C for 1 hour. The solution was then cooled to room temperature, diluted with EtOAc (50 mL), washed with water and brine (15 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (5% EtOAc/hexanes) afforded 2-bromo-6-isopropenylpyridine. _Rf = 0.45 (15% EtOAc/Hex).

LCMS=200.0(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.49(t, J=7.8Hz, 1H), 7.39(d, J=7.8Hz, 1H), 7.34(d, J =8.0Hz, 1H), 5.93(s, 1H), 5.32(m, 1H), 2.17(s, 3H).

Step B: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(6-isopropenylpyridin-2-yl)-5-(trifluoro Methyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To the tube was added 2-bromo-6-isopropenylpyridine (17.5 mg, 0.0878 mmol), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl -3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl] - 1,3-Oxazolidin-2-one (26.2 mg, 0.0439 mmol), DME (190 μL), EtOH (62 μL) and 1M aqueous sodium carbonate (100 μL, 0.1 mmol). The mixture was degassed with nitrogen. Then Pd(PPh ₃ ) ₄ (9 mg, 7.8×10 ⁻³ mmol) was added, and the mixture was again degassed with nitrogen. The tube was sealed and heated at 100°C for 2 hours. The solution was then cooled to room temperature, diluted with EtOAc (50 mL), washed with water and brine (15 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (5-25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(6 -isopropenylpyridin-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. _Rf = 0.15 (1 5% EtOAc/Hex).

LCMS=589.1(M+1) ^{+ .1} HNMR(CDCl ₃ , 500MHz) δ7.81-7.85(m, 2H), 7.74(s, 1H), 7.69-7.69(m, 3H), 7.58(d, J =8.0Hz, 1H), 7.53(d, J=7.7Hz, 1H), 7.34(d, J=7.6Hz, 1H), 5.94(s, 1H), 5.48(d, J=7.7Hz, 1H), 5.36(s, 1H), 5.06(d, J=16.0Hz, 1H), 4.47(d, J=16.1Hz, 1H), 3.91(m, 1H), 2.23(s, 3H), 0.50(d, J =6.6Hz, 3H).

Example 128

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(3-methoxy-6-methyl-1-oxopyridin-2-yl )-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(3-methoxy-6-methylpyridin-2-yl)-5- (Trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (Example 174) (7.6 mg, 0.0128 mmol) in CH ₂ Cl ₂ (1.3 mL) To the solution at °C was added m-CPBA (5.8 mg, 77% purity, 0.0256 mmol). The reaction was stirred at room temperature _for 1 h, then diluted with _CH2Cl2 (10 mL), washed with _{aqueous NaHSO3} , saturated _K2CO3 and brine (5 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification of the residue by PTLC (50% _Et2O / _CH2Cl2 ) afforded _the title compound.

R _f = 0.23 (50% Et ₂ O/CH ₂ Cl ₂ ), LCMS = 609.2 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) δ7.85 (s, 1H), 7.78 (d, J =7.7Hz, 1H), 7.70(s, 2H), 7.62(s, 1H), 7.53(d, J=7.8Hz, 1H), 7.32(d, J=8.9Hz, 1H), 7.04(d, J =9.2Hz, 1H), 5.74(d, J=8.3Hz, 1H), 4.88(d, J=14.8Hz, 1H), 4.11-3.96(m, 1H), 3.88(d, J=14.9Hz, 1H ), 3.86(s, 3H), 2.49(s, 3H), 0.65(d, J=6.6Hz, 3H).

Example 129

(4S,5R)-3-[2-(3-Amino-6-isopropylpyridin-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis(tri Fluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(6-isopropenyl-3-nitropyridin-2-yl)-5- (Trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (Example 177) (19.3 mg, 0.0305 mmol) in EtOH (300 μL) was added 10% Pd/C (5 mg). The reaction was placed under an atmosphere of hydrogen (balloon) and stirred vigorously. After 90 minutes, the mixture was loaded onto a PTLC plate and purified (30% EtOAc/hexanes, developed twice) to afford (4S,5R)-3-[2-(3-amino-6-isopropane Pyridin-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidine -2-one. _Rf = 0.63 (30% EtOAc/Hex, developed twice).

LCMS=606.2(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.84(s, 1H), 7.78(8, 1H), 7.72(d, J=8.0Hz, 1H), 7.69(s , 2H), 7.55(d, J=8.0Hz, 1H), 7.09-7.05(m, 2H), 5.53-5.52(m, 1H), 4.92(d, J=5.5Hz, 1H), 4.15-4.10( m, 1H), 3.89-3.78(m, 1H), 3.48(s, 2H), 3.00-2.95(m, 1H), 1.26-1.23(m, 6H), 0.44(d, J=5.1Hz, 3H) .

Example 130

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(3-chloro-6-isopropylpyridin-2-yl)-5-(tri Fluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To a solution of CuCl ₂ (9.3 mg) and tert-butyl nitrite (6.6 μL, 0.0559 mmol) in MeCN (300 μL) was added via cannula (4S,5R)-3-[2 -(3-Amino-6-isopropylpyridin-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4- Methyl-1,3-oxazolidin-2-one (Example 129) (16.9 mg, 0.0279 mmol). The reaction was heated at 60 °C for 1 h, then cooled to room temperature, diluted with EtOAc (20 mL), washed with water and brine (8 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification of the residue by PTLC (30% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(3-chloro- 6-isopropylpyridin-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. _Rf = 0.56 (30% EtOAc/Hex).

LCMS=625.1(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.85(s, 1H), 7.78(d, J=8.3Hz, 1H), 7.73-7.71(m, 2H), 7.68 (s, 2H), 7.53(d, J=7.8Hz, 1H), 7.24(d, J=8.2Hz, 1H), 5.55(d, J=7.7Hz, 1H), 5.05(d, J=15.4Hz , 1H), 3.97(d, J=15.4Hz, 1H), 3.88-3.82(m, 1H), 3.17-3.08(m, 1H), 1.30-1.32(m, 6H), 0.53(d, J=6.7 Hz, 3H).

Example 131

(4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-isopropenyl-1,3-thiazol-4-yl)-5-( Trifluoromethyl)benzyl 1-4-methyl-1,3-oxazolidin-2-one

Step A: 4-Bromo-2-isopropenyl-1,3-thiazole

To the tube was added 2,4-dibromothiazole (100 mg, 0.411 mmol), isopropenylboronic acid (39 mg, 0.452 mmol), DME (1.625 mL), EtOH (563 μL) and 1M aqueous sodium carbonate (1.03 mL, 1.03 mmol ). The mixture was degassed with nitrogen. Then Pd( _PPh3 ) ₄ (24mg, 0.0206mmol) was added and the mixture was again degassed with nitrogen. The tube was sealed and heated at 100°C for 2 hours. The solution was then cooled to room temperature, diluted with EtOAc (50 mL) and washed with water and brine (15 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (0-15% EtOAc/hexanes) afforded 4-bromo-2-isopropenyl-1,3-thiazole; NMR indicated the presence of impurities which were not removed. _Rf = 0.53 (15% EtOAc/Hex).

LCMS=206.0(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.13(s, 1H), 5.87(s, 1H), 5.33(d, J=1.3Hz, 1H), 2.21(s , 3H).

Step B: (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-[2-(2-isopropenyl-1,3-thiazol-4-yl)- 5-(Trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To the tube was added 4-bromo-2-isopropenyl-1,3-thiazole (20 mg, 0.097 mmol), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]- 4-Methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl )benzyl]-1,3-oxazolidin-2-one (29.4 mg, 0.0492 mmol), THF (340 μL), 1M K ₂ CO ₃ aqueous solution (340 μL) and 1,1-bis(di-tert-butylphosphine base) ferrocenepalladium dichloride (3.2 mg, 4.9 x 10 ^-3 mmol). The mixture was degassed with nitrogen. The tube was sealed and heated at 100°C for 1.5 hours. The solution was then cooled to room temperature, diluted with EtOAc (50 mL) and washed with water and brine (15 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (5-25% EtOAc/hexanes) followed by PTLC (90% _CH2Cl2 /hexanes) afforded (4S,5R)-5-[ _3,5 -bis( Trifluoromethyl)phenyl]-3-[2-(2-propenyl-1,3-thiazol-4-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1 , 3-oxazolidin-2-one. _Rf = 0.16 (15% EtOAc/Hex).

LCMS=595.1(M+1) ⁺ . ¹ HNMR(CD ₂ Cl ₂ , 500MHz) δ7.90(s, 1H), 7.64-7.76(m, 5H), 7.38(s, 1H), 5.89(s, 1H ), 5.60(d, J=8.1Hz, 1H), 5.37(d, J=1.2Hz, 1H), 4.99(d, J=16.0Hz, 1H), 4.66(d, J=16.0Hz, 1H), 3.94(m, 1H), 2.25(s, 3H), 0.59(d, J=6.4Hz, 3H).

Example 132

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(hydroxymethyl)-1,3-thiazol-2-yl]-5 -(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-({[tert-butyl(dimethyl)silyl]oxyl }methyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (embodiment 178)( To a solution of 54.0 mg, 0.0774 mmol) in THF (10 mL) at 0° C. was added TBAF (194 μL of a 1 M solution in THF, 0.194 mmol). The reaction was stirred at 0 °C for 30 min, then poured into saturated _NH4Cl (15 mL). The mixture was extracted with EtOAc (60 mL), and the organic layer was washed with water and brine (15 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (60% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-( Hydroxymethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. _Rf = 0.11 (40% EtOAc/Hex).

LCMS=585.1(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.85(s, 1H), 7.81(d, J=8.0Hz, 1H), 7.70-7.73(m, 4H), 7.36 (s, 1H), 5.52 (d, J = 8.0Hz, 1H), 5.39 (d, J = 15.3Hz, 1H), 4.81 (s, 2H), 4.55 (d, J = 15.3Hz, 1H), 3.87 (m, 1H), 0.69 (d, J=6.7Hz, 3H).

Example 133

2-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidine-3 -yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazole-4-carbaldehyde

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(hydroxymethyl)-1,3-thiazol-2-yl]- 5-(Trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (Example 132) (40.9 mg, 0.070 mmol) in CH ₂ Cl ₂ (5 mL) DMP (59.4mg, 0.140mmol) was added to the solution at 0°C. The reaction was warmed to room temperature and stirred for 45 minutes. Next the reaction was diluted with EtOAc (40 mL) and washed with 1N NaOH (2 x 15 mL) and brine (2 x 15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (50% EtOAc/hexanes) afforded 2-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4- Methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazole-4-carbaldehyde. _Rf = 0.24 (40% EtOAc/Hex).

LCMS=583.1(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ10.09(s, 1H), 8.33(s, 1H), 7.87(s, 2H), 7.82(d, J=8.2Hz , 1H), 7.79(s, 2H), 7.72, (d, J=8.1Hz, 1H), 5.70(d, J=8.0Hz, 1H), 5.13(d, J=16.0Hz, 1H, 4.83(d , J=16.0Hz, 1H), 4.23(m, 1H), 0.75(d, J=6.6Hz, 3H).

Example 134

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxyethyl)-1,3-thiazol-2-yl] -5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To 2-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidine- 3-yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazole-4-carbaldehyde (Example 133) (43.9 mg, 0.075 mmol) in _Et2O (7.5 mL) MeMgBr (30 μL of 3M solution in ether, 0.10 mmol) was added to the -40°C solution. The reaction was closely monitored by TLC and more MeMgBr was added dropwise until almost all the starting aldehyde was consumed. The reaction was then poured into saturated _NH4Cl (15 mL). The mixture was extracted with EtOAc (50 mL), and the organic layer was washed with water and brine (15 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (5-50% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4 -(1-Hydroxyethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. _Rf = 0.17 (40% EtOAc/Hex).

LCMS=599.1(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.70-7.86(m, 6H), 7.31-7.32(m, 1H), 5.53-5.55(m, 1H), 5.35- 5.41(m, 1H), 5.06(m, 1H), 4.57-4.62(m, 1H), 3.88(m, 1H), 1.61-1.63(m, 3H), 0.69(d, J=6.7Hz, 3H) .

Example 135

(4S,5R)-3-[2-(4-Acetyl-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis(tri Fluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxyethyl)-1,3-thiazol-2-yl ]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (Example 134) (31.0 mg, 0.052 mmol) in CH ₂ Cl ₂ (6 mL) DMP (55mg, 0.130mmol) was added to the solution at 0°C. The reaction was warmed to room temperature and stirred for 45 minutes. The reaction was then diluted with EtOAc (40 mL), washed with 1 N NaOH (2 x 15 mL) and brine (2 x 15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (40% EtOAc/hexanes) afforded (4S,5R)-3-[2-(4-acetyl-1,3-thiazol-2-yl)-5-(trifluoro methyl)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. _Rf = 0.26 (40% EtOAc/Hex).

LCMS=597.1(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 600MHz) δ8.27(s, 1H), 7.89(s, 1H), 7.77-7.82(m, 4H), 7.71(d, J= 7.9Hz, 1H), 5.68(d, J=7.9Hz, 1H), 5.22(d, J=16.3Hz, 1H), 4.85(d, J=16.4Hz, 1H), 4.08(m, 1H), 2.70 (s, 3H), 0.71 (d, J=6.6Hz, 3H).

Example 136

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxy-1-methylethyl)-1,3-thiazole -2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-3-[2-(4-acetyl-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis( Trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (Example 135) (38.1 mg, 0.064 mmol) in THF/heptane (1:1, 8 mL) MeMgBr (21 μL of a 3M solution in ether, 0.07 mmol) was added to the -40°C solution. The temperature was maintained at -40°C to -20°C and the reaction was closely monitored by TLC, and MeMgBr was added dropwise until almost all the starting ketone was consumed. The reaction was then poured into saturated _NH4Cl (15 mL). The mixture was extracted with EtOAc (50 mL), and the organic layer was washed with water and brine (15 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (10-60% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4 -(1-Hydroxy-1-methylethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidine- 2-keto. _Rf = 0.20 (40% EtOAc/Hex).

LCMS=613(M+1) ⁺ . ¹ H NMR(CD ₂ Cl ₂ , 500MHz) δ7.90(s, 1H), 7.85(d, J=8.0Hz, 1H), 7.77(s, 3H), 7.71 (d, J=8.3Hz, 1H), 7.32(s, 1H), 5.59(d, J=8.0Hz, 1h), 5.28(d, J=15.8Hz, 1H), 4.74(d, J=15.8Hz , 1H), 3.89(m, 1H), 3.01(bs, 1H), 1.63(s, 3H), 1.62(s, 3H), 0.64(d, J=6.5Hz, 3H).

Example 137

(4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(4-isopropenyl-1,3-thiazol-2-yl)-5-( Trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxyl-1-methylethyl)-1,3- Thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (Example 136) (9.5 mg, 0.015 mmol) in toluene ( To the solution in 4 mL) was added p-toluenesulfonic acid monohydrate (20 mg, 0.105 mmol). The reaction was heated at 80° C. for 30 min, then cooled to room temperature, diluted with EtOAc (35 mL), washed with saturated NaHCO ₃ and brine (15 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(4-iso propenyl-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. _Rf = 0.55 (40% EtOAc/Hex).

LCMS=595.1(M+1) ^{+ .1} HNMR(CD ₂ Cl ₂ , 500MHz) δ7.91(s, 1H), 7.78-7.83(m, 4H), 7.68(d, J=8.5Hz, 1H), 7.33(s, 1H), 5.95(d, J=0.9Hz, 1H), 5.66(d, J=8.0Hz, 1H), 5.24(m, 1H), 5.07(d, J=16.4Hz, 1H), 5.00(d, J=16.3Hz, 1H), 4.03(m, 1H), 2.17(s, 3H), 0.63(d, J=6.4Hz, 3H).

Example 138

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-3'-isopropyl-4-(trifluoromethyl)biphenyl -2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-3'-isopropenyl-4-(trifluoromethyl) To a solution of phen-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Example 119) (18.8 mg, 0.031 mmol) in EtOH (4.5 mL) was added 10 %Pd/C (15 mg). The reaction was placed under an atmosphere of hydrogen (balloon) and stirred vigorously. After 45 minutes, the catalyst was removed by filtration. The filtrate was concentrated and the residue was purified by flash silica gel chromatography eluting with 15% EtOAc/hexanes. Further purification by PTLC, eluting with 75% _CH2Cl2 /hexanes, afforded (4S,5R)-5- _[ 3,5-bis(trifluoromethyl)phenyl]-3-{[4'-Fluoro-3'-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. _Rf = 0.35 (15% EtOAc/Hex).

LCMS=608.2(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.86(s, 1H), 7.71(s, 1H), 7.70(s, 2H), 7.64(d, J=8.0Hz , 1H), 7.41(d, J=8.0Hz, 1H), 7.15(m, 1H), 7.08-7.12(m, 2H), 5.52(d, J=8.0Hz, 1H), 4.89(d, J= 15.7Hz, 1H), 4.18(d, J=15.8Hz, 1H), 376(m, 1H), 3.28(m, 1H), 1.25-1.29(m, 6H), 0.42(d, J=6.4Hz , 3H).

Example 139

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[5-(1-methoxyethyl)-1,3-thiazole-2- Base]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[5-(1-hydroxyethyl)-1,3-thiazol-2-yl ]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (Example 154) (13.2 mg, 0.0221 mmol) in THF (1 mL) To the solution was added NaHMDS (26.5 μL of 1M in THF, 0.0265 mmol) followed by MeI (1 drop). After 1.5 hours, additional NaHMDS (15 μL of 1 M in THF, 0.015 mmol) and MeI (1 drop) were added to the reaction. The reaction was warmed to room temperature for 20 minutes, then poured into saturated _NH4Cl (10 mL). The mixture was extracted with EtOAc (35 mL), and the organic layer was washed with water and brine (15 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (15-75% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[5 -(1-methoxyethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one . _Rf = 0.37 (40% EtOAc/Hex).

LCMS=613.0(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.87(s, 1H), 7.74-7.82(m, 5H), 7.67(d, J=8.0Hz, 1H), 6.63 -5.66(m, 1H), 5.08-5.14(m, 1H), 4.83-4.88(m, 1H), 4.64-4.68(m, 1H), 4.01-4.08(m, 1H), 3.34(m, 3H) , 1.60(d, J=6.4Hz, 3H), 0.69(d, J=6.7Hz, 3H).

Examples 140 and 141

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1,1-dioxide-1-benzothiophene-2-yl)-5- (Trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one and 2.2 mg (15%) of (4S,5R)-5-[3,5-bis(trifluoro Methyl)phenyl]-4-methyl-3-[2-(1-oxygen-1-benzothiophen-2-yl)-5-(trifluoromethyl)benzyl]-1,3- oxazolidin-2-one

To (4S, 5R)-3-[2-(1-benzothiophen-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis(trifluoromethyl) To a solution of phenyl]-4-methyl-1,3-oxazolidin-2-one (Example 150) (14.5 mg, 0.024 mmol) in _CH2Cl2 ( ₂ mL) was added m-CPBA (16 mg , 77% purity, 0.071 mmol). The reaction was stirred at room temperature for 3 hours, then diluted with EtOAc (40 mL), washed with aqueous NaHSO ₃ (15 mL), saturated NaHCO ₃ (15 mL) and brine (15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification of the residue by PTLC (25% EtOAc/hexanes, 2 eluents) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2 -(1,1-dioxide-1-benzothiophen-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one and 2.2 mg(15%)(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(1-oxygen-1-benzothiophene- 2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one. Data for 141: _Rf = 0.09 (25% EtOAc/Hex).

LCMS=636.2(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.96(d, J=8.0Hz, 1H), 7.83(s, 1H), 7.68-7.77(m, 5H), 7.63 (m, 1H), 7.57(m, 1H), 7.50(d, J=7.6Hz, 1H), 7.28(s, 1H), 5.75(d, J=8.0Hz, 1H), 5.21(d, J= 15.8Hz, 1H), 4.21(d, J=15.8Hz, 1H), 4.01(m, 1H), 0.70(d, J=6.7Hz, 3H).

Data for 140: _Rf = 0.06 (25% EtOAc/Hex).

LCMS=620.2(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.15-7.95(m, 11H), 5.72-5.75(m, 1H), 5.36(d, J=15.6Hz), 5.07 (d, J=15.8Hz), 4.41(d, J=16.0Hz), 4.22(d, J=15.8Hz), 3.88-4.08(m, 1H), 0.68(d, J=6.6Hz), 0.61( d, J=6.6Hz).

Example 142

(4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-( Trifluoromethoxy)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Step A: 2-(Bromomethyl)-1-nitro-4-(trifluoromethoxy)benzene

Fuming nitric acid (5 mL) was cooled to 0 °C and 3-(trifluoromethoxy)benzyl bromide (1 mL, 6.16 mmol) was added. After 15 minutes, the reaction was poured into ice water (100 mL) and extracted with EtOAc (200 mL). The organic layer was washed with water, saturated NaHCO ₃ and brine (75 g, respectively). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0-15% EtOAc/hexanes) to afford 2-(bromomethyl)-1-nitro-4-(trifluoromethoxy)benzene. _Rf = 0.54 (15% EtOAc/Hex).

¹ H NMR (CDCl ₃ , 500MHz) δ8.14(d, J=8.9Hz, 1H), 743(m, 1H), 731(m, 1H), 4.82(s, 2H).

Step B: (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-3-[2-nitro-5-(trifluoromethoxy)benzyl Base]-1,3-oxazolidin-2-one

To (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (840 mg, 2.68 mmol) in DMA ( To a solution in 25 mL) was added NaHMDS (2.68 mL of 1M in THF, 2.68 mmol). The reaction was stirred at room temperature for 5 minutes, then 2-(bromomethyl)-1-nitro-4-(trifluoromethoxy)benzene (967 mg, 3.22 mmol) in DMA (5 mL) was added via cannula . After 15 minutes, the reaction was poured into saturated _NH4Cl (50 mL). The mixture was extracted with EtOAc (150 mL), and the organic layer was washed with water and brine (40 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (5-25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3- [2-nitro-5-(trifluoromethoxy)benzyl]-1,3-oxazolidin-2-one. _Rf = 0.10 (15% EtOAc/Hex).

LCMS=533.2(M+1) ⁺ . ¹ H NMR(CDCl ₃ , 500MHz) δ8.16(d, J=8.9Hz, 1H), 7.92(s, 1H), 7.80(s, 2H), 7.44(s , 1H), 7.33(d, J=8.9Hz, 1H), 5.78(d, J=7.8Hz, 1H), 4.94(d, J=17.0Hz, 1H), 4.79(d, J=16.9Hz, 1H ), 4.25(m, 1H), 0.81(d, J=6.7Hz, 3H).

Step C: (4S,5R)-3-[2-Amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methanol Base-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-nitro-5-(trifluoromethoxy)benzyl] - To a solution of 1,3-oxazolidin-2-one (1.07 g, 2.01 mmol) in EtOAc (30 mL) was added _PtO2 (100 mg, 0.44 mmol). The reaction was placed under an atmosphere of hydrogen (balloon) and stirred vigorously. After 1 hour, the catalyst was removed by filtration, and the filtrate was concentrated. Purification by flash chromatography (5-40% EtOAc/hexanes) afforded (4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5 - bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. _Rf = 0.45 (40% EtOAc/Hex).

LCMS=503.2(M+1) ^{+ .1} HNMR(CDCl ₃ , 600MHz) δ7.89(s, 1H), 7.75(s, 2H), 7.03(dd.J=8.7, 2.0Hz, 1H), 6.90( d, J=2.1Hz, 1H), 6.67(d, J=8.7Hz, 1H), 5.67(d, J=8.5Hz, 1H), 4.73(d, J=15.4Hz, 1H), 4.35(bs, 2H), 4.09(d, J=15.4Hz, 1H), 4.04(m, 1H), 0.78(d, J=6.6Hz, 3H).

Step D: (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethoxy)benzyl]-4-methanol Base-1,3-oxazolidin-2-one

To (4S, 5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl- To a solution of 1,3-oxazolidin-2-one (582 mg, 1.16 mmol) in _CHCl3 (35 mL) was added tert-butyl nitrite (275 μL, 2.32 mmol). After 10 minutes, _I2 (736 mg, 2.9 mmol) was added. The reaction was stirred at room temperature for 30 minutes, then heated at 65 °C for 2 hours. The solution was then cooled to room temperature, diluted with EtOAc (150 mL), washed with aqueous NaHSO ₃ , water, brine, saturated NaHCO ₃ and brine (50 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash silica gel chromatography (2-15% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo -5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one. _Rf = 0.30 (15% EtOAc/Hex).

LCMS=614.1(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.89-7.91(m, 2H), 7.79(s, 2H), 7.23(m, 1H), 6.95(m, 1H) , 5.75(d, J=8.0Hz, 1H), 4.81(d, J=15.8Hz, 1H), 4.32(d, J=15.8Hz, 1H), 4.07(m, 1H), 0.78(d, J= 6.6Hz, 3H).

Step E: (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropyl-2'-methoxy- 4-(Trifluoromethoxy)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Add (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethoxy)benzyl]-4 to a microwave tube -Methyl-1,3-oxazolidin-2-one (41.6 mg, 0.0679 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (18 mg, 0.085 mmol), DME (305 μL), EtOH (100 μL) and 1M aqueous sodium carbonate (140 μL, 0.140 mmol). The mixture was degassed with nitrogen. Then Pd(PPh ₃ ) ₄ (4 mg, 3.4×10 ⁻³ mmol) was added and the mixture was again degassed with nitrogen. The tube was sealed and irradiated under microwave at 150°C and 200W for 10 minutes. The solution was then cooled to room temperature, diluted with EtOAc (40 mL), washed with water and brine (15 mL each). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (2-15% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'- Fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethoxy)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidine-2 -ketone. _Rf = 0.24 (15% EtOAc/Hex). LCMS = 654.3 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz, rotamers exist)

δ7.85(s, 1H), 7.69(s, 2H), 7.21-7.30(m, 4H), 6.95-7.00(m, 1H), 6.65-6.68(m, 1H), 5.59(d, J=8.0 Hz), 5.41(d, J=8.0Hz), 4.74-4.81(m, 1H), 3.75-4.09(m, 5H), 3.19(m, 1H), 1.16-1.27(m, 6H), 0.51(d , J=6.7Hz), 0.36(d, J=6.6Hz).

The compounds in Table 6 were prepared by the general method described above:

Table 6

The compounds in Table 7 were prepared by the general method described above:

Table 7

Intermediate 9

4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol

[2-iodo-5-(trifluoromethyl)phenyl]methanol (Example 69) (3.09g, 10.2mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl) Boronic acid (4.34 g, 20.5 mmol), (Ph ₃ P) ₄ Pd (1.42 g, 1.23 mmol) and Na ₂ CO ₃ (9.11 g, 85.9 mmol) in benzene/EtOH/H ₂ O (7:1:3, 250 mL) was heated to reflux under nitrogen for 24 hours. After cooling to room temperature, the _aqueous phase was separated and extracted with _CH2Cl2 (3 x 50 mL). The combined organic layers _were dried ( _Na2SO4 ) and concentrated in vacuo to afford crude product. This was purified by flash chromatography (Si, 65 x 200 mm, gradient 0-20% EtOAc in hexanes) to afford 4'-fluoro-5'-isopropyl-2'-methoxy-4 -(trifluoromethyl)biphenyl-2-yl]methanol. _Rf = 0.50 (20% EtOAc in hexanes).

¹ H NMR (500MHz, CDCl ₃ ) δ7.86(s, 1H), 7.59(d, J=6.7Hz, 1H), 7.30(d, J=7.9Hz, 1H), 6.99(d, J=8.6Hz , 1H), 6.68(d, J=12.0Hz, 1H), 4.52(br s, 1H), 4.46(br s, 1H), 3.73(s, 3H), 3.25-3.17(m, 1H), 1.82( br s, 1H), 1.24 (d, J=6.8Hz, 6H).

Intermediate 10

2′-(Bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl

A solution of triphenylphosphine (3.11 g, 11.8 mmol) in anhydrous _CH2Cl2 (7 mL) was added via cannula to carbon tetrabromide (3.93 g, 11.8 _mmol ) and 4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol (3.38 g, 9.87 mmol) in anhydrous CH ₂ Cl ₂ ( 56mL) in a stirred solution. The reaction was warmed to room temperature. After 2 hours, the reaction mixture was concentrated in vacuo to afford crude product. This was purified by flash chromatography (Si, 65 x 200 mm, gradient 0-20% EtOAc in hexanes) to afford 2'-(bromomethyl)-4-fluoro-5-isopropyl-2 -Methoxy-4'-(trifluoromethyl)biphenyl.

¹ H NMR (500MHz, CDCl ₃ ) δ7.83(s, 1H), 7.61(d, J=8.0Hz, 1H), 7.35(d, J=8.0Hz, 1H), 7.15(d, J=8.6Hz , 1H), 6.72(d, J=12.0Hz, 1H), 4.43(br d, J=10.0Hz, 1H), 4.30(br d, J=10.2Hz, 1H), 3.76(s, 3H), 3.30 -3.22(m, 1H), 1.29(dJ=6.9Hz, 6H).

Intermediate 11

5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)bis Benzene-2-yl]methyl}-4,4-dimethyl-1,3-oxazolidin-2-one

Step A: Benzyl {2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate

N-methylmorpholine (682 mg, 741 μL, 6.74 mmol) and isobutyl chloroformate (460 mg, 441 μL, 3.37 mmol) were sequentially added to N-benzyloxycarbonyl-2-methyl Alanine (0.64 g, 2.69 mmol) in a stirred solution in _{anhydrous CH2Cl2} . The resulting cloudy mixture was stirred at 0 °C for 90 minutes. N,O-Dimethylhydroxylamine hydrochloride (316 mg, 3.24 mmol) was added in portions, and the mixture was warmed to room temperature and stirred for 3 hours. The _mixture was poured into 1N HCl (30 mL), extracted with _CH2Cl2 (3 x 40 mL). The combined extracts were washed with 1 N HCl (30 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Si, 40 x 160 mm, gradient 0-80% EtOAc in hexanes) to afford {2-[methoxy(methyl)amino]-1,1-dimethyl Benzyl-2-oxoethyl}carbamate. _Rf = 0.47 (50% EtOAc in hexanes). LCMS calcd = 303.1; found = 303.2 (M+Na) ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ7.37-7.29 (m, 5H), 5.82 (s, 1H), 5.09 (s, 2H), 3.60 (s, 3H), 3.18 (s, 3H), 1.60 ( s, 6H).

Step B: Benzyl (1,1-Dimethyl-2-oxoethyl)carbamate

Diisobutylaluminum hydride (1.77 mL, 1 M solution in toluene, 0.708 mmol) was added to {2-[methoxy(methyl)amino]-1,1-dimethyl at -78 °C under nitrogen In a stirred solution of benzyl-2-oxoethyl}carbamate (198.5 mg, 0.708 mmol) in anhydrous THF (7.1 mL). The reaction was stirred at -78°C for 4 hours. MeOH (100 μL) and 1N HCl (250 μL) were added and the reaction was allowed to warm to room temperature. The mixture was diluted with _Et2O (50 mL), washed with 1N HCl (2 x 50 mL), 50% saturated _NaHCO3 (50 mL), and water (50 mL), then dried ( _MgSO4 ) and concentrated in vacuo to afford (1 , Benzyl 1-dimethyl-2-oxoethyl)carbamate. _Rf = 0.40 (20% EtOAc in hexanes). LCMS calcd = 244.1; found = 244.1 (M+Na) ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ9.43(s, 1H), 7.38-7.30(m, 5H), 5.34(s, 1H), 5.09(s, 2H), 1.37(s, 6H).

Step C: Benzyl {2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1,1-dimethylethyl}carbamate

Ethylmagnesium bromide (1.63 mL, 1 M solution in THF, 1.63 mmol) was added dropwise to 1-iodo-3,5-bis(trifluoromethyl)benzene (608 mg, 317 μL, 1.79 mmol) in a stirred solution in anhydrous THF (1 mL). And the reaction was stirred for 30 minutes. The resulting solution was added to a stirred solution of benzyl (1,1-dimethyl-2-oxoethyl)carbamate (163.5 mg, 0.739 mmol) in anhydrous THF (1 mL) at -20 °C middle. The reaction was allowed to warm to room temperature over 3 hours. Sat. _NH4Cl (10 mL) and water (10 mL) were added, and the mixture was extracted with EtOAc (3 x 20 mL). The combined extracts _were dried ( _Na2SO4 ) and concentrated in vacuo to afford the crude product. It was purified by flash chromatography (Si, 25 x 160 mm, gradient 0-40% EtOAc in hexanes) to afford {2-[3,5-bis(trifluoromethyl)phenyl]-2 -Benzyl hydroxy-1,1-dimethylethyl}carbamate. _Rf = 0.40 (20% EtOAc in hexanes). LCMS calcd = 436.1; found = 436.0 (M+1) ⁺ .

¹ H NMR (600MHz, CDCl ₃ ) δ7.80(s, 1H), 7.77(s, 2H), 7.39-7.33(m, 5H), 5.12-5.08(m, 2H), 1.36(s, 1H), 4.90(d, J=4.4Hz, 1H), 4.81(s, 1H), 1.36(s, 3H), 1.23(s, 3H).

Intermediate 12

Benzyl [(1S)-2-(4-chloropyridin-2-yl)-1-methyl-2-oxoethyl]carbamate

A solution of 2-(dimethylamino)ethanol (471mg, 531mL, 5.28mmol) in anhydrous hexane (3.3mL) was cooled to -5°C, and n-butyllithium (1.6M in hexane solution in alkanes, 6.60 mL, 10.6 mmol). After 30 min at 0 °C, the solution was cooled to -78 °C and 4-chloropyridine (by adding a solution of the corresponding HCl salt (264 mg, 1.76 mmol) in _CH2Cl2 (20 mL) _was added dropwise via cannula Washed with saturated K ₂ CO ₃ (10 mL), then back extracted with CH ₂ Cl ₂ (2 x 20 mL), the organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated in vacuo) in hexane (3.3 mL). After 1 hour at -78 °C within the solution, the solution turned dark red. A solution of the electrophile was added via cannula by adding isopropylmagnesium chloride (2M in THF, 1.29 mL, 2.59 mmol) to {(1S)-2-[methoxy (Methyl)amino]-1-methyl-2-oxoethyl}carbamate (702 mg, 2.64 mmol) was prepared by a solution in anhydrous THF (3.5 mL) and stirring for 15 minutes). The reaction was allowed to warm slowly to room temperature overnight. Water (25 mL) and saturated _NH4Cl (50 mL) were added, and the mixture was extracted with EtOAc (3 x 50 mL). The combined extracts were dried ( _MgSO4 ) and concentrated in vacuo to afford crude product. It was purified by flash chromatography (Si, 40 x 160 mm, gradient 0-30% EtOAc in hexanes) to afford [(1S)-2-(4-chloropyridin-2-yl)-1- Benzyl methyl-2-oxoethyl]carbamate. _Rf = 0.46 (20% EtOAc in hexanes). LCMS calcd = 319.1; found = 319.3 (M+1) ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ8.58(d, J=5.0Hz, 1H), 8.04(s, 1H), 7.47(dd, J=5.2, 2.0Hz, 1H), 7.35-7.30(m, 5H), 5.78(s, 1H), 5.72(m, 1H), 5.11(m, 2H), 1.47(d, J=7.0Hz, 3H).

Intermediate 13

Benzyl [(1S)-1-methyl-2-oxo-2-(1,3-thiazol-2-yl)ethyl]carbamate

At -78°C under nitrogen, n-butyllithium (1.6M solution in hexane, 1.76mL, 2.83mmol) was added dropwise to 2-bromothiazole (462mg, 251μL, 2.82mmol) in anhydrous THF (13mL ) in the stirred solution, stirred for 45 minutes. Separately, isopropylmagnesium chloride (2M in THF, 0.94 mL, 1.99 mmol) was added to {(1S)-2-[methoxy(methyl)amino]- Benzyl 1-methyl-2-oxoethyl}carbamate (500 mg, 1.88 mmol) in a stirred solution in anhydrous THF (4 mL). The solution was stirred at -15°C for 15 minutes, and added dropwise to the above 2-lithiated thiazole solution at -78°C. The reaction was warmed to room temperature overnight, saturated _NH4Cl (20 mL) and water (10 mL) were added, and the mixture was extracted with EtOAc (3 x 30 mL). The combined extracts were washed with brine, dried ( _Na2SO4 ) and concentrated in _vacuo to afford the crude product. Purification by flash chromatography (Si, 25 x 160 mm, gradient 0-50% EtOAc in hexanes) gave [(1S)-1-methyl-2-oxo-2-(1, Benzyl 3-thiazol-2-yl)ethyl]carbamate. _Rf = 0.28 (20% EtOAc in hexanes). LCMS calcd = 291.1; found = 291.3 (M+1) ⁺ .

¹ H NMR (600MHz, CDCl ₃ ) δ8.03(s, 1H), 7.70(d, J=3.1Hz, 1H), 7.34-7.29(m, 5H), 5.79(d, J=6.6Hz, 1H) , 5.53-5.49(m, 1H), 5.14-5.08(m, 2H), 1.55(d, J=6.4Hz, 3H).

Intermediate 14

Benzyl [(1S)-1-methyl-2-(1-methyl-1H-imidazol-4-yl)-2-oxoethyl]carbamate

Benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (64 mg, 0.24 mmol) in _CH2Cl2 (1 _mL ) The solution was cooled to −20° C. under nitrogen, and isopropylmagnesium chloride (120 μL of a 2.0 M solution in THF) was added dropwise. The mixture was stirred at -20°C for 20 minutes. In a separate flask, ethylmagnesium bromide (480 μL of a 2.0M solution in diethyl ether) was added to 4-iodo-1-methyl-1-H-imidazole (109 mg, 0.48 mmol) in anhydrous solution in _CH2Cl2 ( _1.5 mL). The resulting mixture was stirred for 20 minutes, then the above solution was added slowly via cannula. The resulting solution was stirred overnight. Sat. NH ₄ Cl was added to the reaction solution, the mixture was diluted with water, and the aqueous phase was extracted with CH ₂ Cl ₂ (2×25 mL). _The combined organic extracts were dried ( _Na2SO4 ) and concentrated in vacuo. Purification of the residue by flash chromatography afforded benzyl [(1S)-1-methyl-2-(1-methyl-1H-imidazol-4-yl)-2-oxoethyl]carbamate. LCMS calcd = 288.14; found = 288.3 (M+1) ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ7.65(s, 1H); 7.47(s, 1H); 7.35-7.28(m, 5H); 5.93(d, J=6.9Hz, 1H); m, 1H); 5.13(s, 2H); 3.73(s, 3H); 1.26(d, J=7.1Hz, 3H).

Intermediate 15

Benzyl ((1S)-2-{1-[(benzyloxy)methyl]-1H-imidazol-2-yl}-1-methyl-2-oxoethyl)carbamate

Step A: 1-[(Benzyloxy)methyl]-1H-imidazole

A mixture of chloromethyl ether (4.3 mL, 29 mmol) and imidazole (6 g, 58 mmol) in acetonitrile (200 mL) was heated at reflux for 3.5 hours. Solvent was removed in vacuo. The resulting oily residue was partitioned between _CH2Cl2 (300 mL) and water (150 mL) _. The organic extract was then washed with water (2 x 150 mL), dried ( _Na2SO4 ) and concentrated in vacuo to afford 1-[( _benzyloxy )methyl]-1H-imidazole which was used without further purification. LCMS calculated = 189.10; found = 189.1 (M+1) ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ7.63(s, 1H); 7.40-7.30(m, 5H); 7.16(t, J=6.5Hz, 1H); 7.09(t, J=10.6Hz, 1H) ;5.34(s, 2H); 4.45(s, 2H).

Step B: Benzyl ((1S)-2-{1-[(benzyloxy)methyl]-1H-imidazol-2-yl}-1-methyl-2-oxoethyl)carbamate

To a solution of 1-[(benzyloxy)methyl]-1H-imidazole (706 mg, 3.75 mmol) in THF (4 mL) was added n-butyl lithium (2.3 mL 1.6 M in solution in hexane). The mixture was stirred at -78°C for 30 minutes. Benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (200 mg, 0.75 mmol) was dissolved at -15 °C under nitrogen. To a solution in THF (2 mL) was added isopropylmagnesium chloride (375 μL of a 2.0 M solution in THF). The resulting mixture was stirred at -15°C for 15 minutes. This mixture was added to the above solution via cannula at -78°C. The mixture was stirred at -78°C for about 3 hours, then gradually warmed to room temperature and stirred overnight. The mixture was treated with saturated _NH4Cl . The aqueous layer was extracted with _CH2Cl2 (3 _x 25 mL). The organic layers were combined _, dried ( _Na2SO4 ) and concentrated in vacuo. Purification of the residue by flash chromatography afforded ((1S)-2-{1-[(benzyloxy)methyl]-1H-imidazol-2-yl}-1-methyl-2-oxoethyl base) benzyl carbamate containing approximately 30% unreacted starting benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate. The mixture was used directly in the next step without further purification. LCMS calcd = 394.18; found = 394.2 (M+1) ⁺ .

Intermediate 16

2-bromo-4,5-dichloro-1-methyl-1H-imidazole

2-Bromo-4,5-dichloroimidazole (1 g, 4.6 mmol), methyl iodide (346 μL, 5.56 mmol), potassium carbonate (1.27 g, 9.2 mmol) and tetrabutylammonium bromide (148 mg, 0.46 mmol ) in acetonitrile (2 mL) was stirred vigorously at 70-80 °C for 1.0 h. After cooling to room temperature, the inorganic salts were filtered off and washed with acetonitrile. The filtrate was evaporated and the residue was purified by flash chromatography (Si) to afford 2-bromo-4,5-dichloro-1-methyl-1H-imidazole as a white solid. LCMS calcd = 230.89; found = 230.9 (M+1) ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ3.61(s, 3H).

Intermediate 17

4-iodo-1-methyl-1H-pyrazole

To a solution of 18-crown-6 (132 mg, 0.5 mmol) in _Et2O (8 mL) was added potassium tert-butoxide (616 mg, 5.5 mmol) under nitrogen. The mixture was stirred and 4-iodopyrazole (1 g, 5 mmol) was added in one portion at room temperature. The reaction was cooled to 0 °C and a solution of iodomethane (342 μL, 5.5 mmol) in Et2O ( ₂ mL) was added dropwise at 0 °C. The resulting mixture was warmed to room temperature and stirred overnight. The solution was then diluted with water and extracted with _Et2O (2 x 50 mL). The combined organic layers were washed with brine (45 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash chromatography afforded 4-iodo-1-methyl-1H-pyrazole. LCMS calcd = 208.96; found = 209.0 (M+1) ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ 7.52(s, 1H); 7.43(s, 1H); 3.95 (s, 3H).

Intermediate 18

3-iodo-1-methyl-1H-pyrazole

1-Methyl-1-H-pyrazol-3-amine (250 mg, 2.57 mmol) and tert-butyl nitrite (336 μL, 2.83 mmol) were heated to reflux in diiodomethane (5 mL) for 3 hours. Solvent and volatiles were removed in vacuo and the resulting residue (Si) was purified by flash chromatography to afford 3-iodo-1-methyl-1H-pyrazole. LCMS calcd = 208.96; found = 209.0 (M+1) ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ7.21(d, J=2.1Hz, 1H); 6.42(d, J=2.2Hz, 1H); 3.94(s, 3H).

Intermediates 19, 20

(4S, 5S)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4- Methyl-5-(1-methyl-1H-tetrazol-5-yl)-1,3-oxazolidin-2-one and (4S,5S)-3-{[4′-fluoro-5′ -Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-(2-methyl-2H-tetrazole-5 -yl)-1,3-oxazolidin-2-one

Step A: [(1S,2S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methyl-2-(1H-tetrazol-5-yl)ethyl] Benzyl carbamate and [{1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(2H-tetrazol-5-yl)ethyl base] benzyl carbamate

Benzyl ((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyano-1-methylethyl)carbamate (106.6mg, 0.306mmol ), triethylamine hydrochloride (211 mg, 1.53 mmol) and sodium azide (99.4 mg, 1.56 mmol) in anhydrous toluene (6 mL) was heated to reflux under nitrogen for 20 hours and kept at room temperature for 2 days. The reaction was diluted with 1N HCl (20 mL), extracted with EtOAc (3 x 20 mL). The combined extracts _were dried ( _Na2SO4 ) and concentrated in vacuo to afford the crude product. It was used without further purification. LCMS calculated = 392.2; found = 392.1 (M+1) ⁺ .

Step B: [(1S,2S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methyl-2-(1-methyl-1H-tetrazole-5- Base) ethyl] benzyl carbamate and [(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(2-methyl- Benzyl 2H-tetrazol-5-yl)ethyl]carbamate

(Trimethylsilyl)diazomethane (2M solution in hexane, 459 μL, 0.918 mmol) was added dropwise to [(1S,2S)-2-{[tert-butyl( Dimethyl)silyl]oxy}-1-methyl-2-(1H-tetrazol-5-yl)ethyl]benzyl carbamate and [{1S,2S)-2-{[tert-butyl The crude product of benzyl(dimethyl)silyl]oxy}-1-methyl-2-(2H-tetrazol-5-yl)ethyl]carbamate was dissolved in dichloromethane/methanol (3:2 , 5mL) in the solution. After 15 minutes, gas evolution had ceased and the reaction mixture was concentrated in vacuo to afford crude product. This was purified by flash chromatography (Si, 12 x 160 mm, gradient 0-70% EtOAc in hexanes) to afford [(1S,2S)-2-{[tert-butyl(dimethyl)formazan Silyl]oxy}-1-methyl-2-(1-methyl-1H-tetrazol-5-yl)ethyl]carbamate benzyl ester and [(1S,2S)-2-{[tert-butyl Benzyl(dimethyl)silyl]oxy}-1-methyl-2-(2-methyl-2H-tetrazol-5-yl)ethyl]carbamate, as regioisomer 2:1 mixture. LCMS calcd = 406.2; found = 406.2 (M+1) ⁺ .

Step C: Benzyl [(1S,2S)-2-hydroxy-1-methyl-2-(2-methyl-2H-tetrazol-5-yl)ethyl]carbamate and [(1S,2S) -2-Hydroxy-1-methyl-2-(1-methyl-1H-tetrazol-5-yl)ethyl]carbamate benzyl ester.

Tetrabutylammonium fluoride (1M in THF, 177 μL, 0.177 mmol) was added dropwise to [(1S,2S)-2-{[tert-butyl(dimethyl)silyl ]oxy}-1-methyl-2-(1-methyl-1H-tetrazol-5-yl)ethyl]benzyl carbamate and [(1S,2S)-2-{[tert-butyl( Dimethyl)silyl]oxy}-1-methyl-2-(2-methyl-2H-tetrazol-5-yl)ethyl]benzyl carbamate (2:1 of regioisomers The mixture, 65.2 mg, 0.161 mmol) was in a stirred solution in THF (2 mL). The reaction was stirred at 0° C. for 2 hours, diluted with sat. NH ₄ Cl (10 mL), extracted with EtOAc (3×30 mL). The combined extracts _were dried ( _Na2SO4 ) and concentrated in vacuo to afford the crude product. It was purified by flash chromatography (Si, 12 x 160 mm, gradient 0-80% EtOAc in hexanes) to afford [(1S,2S)-2-hydroxy-1-methyl-2-(2 -methyl-2H-tetrazol-5-yl)ethyl]benzyl carbamate and [(1S,2S)-2-hydroxy-1-methyl-2-(1-methyl-1H-tetrazole- 5-yl)ethyl]benzyl carbamate. 2-Methyl isomer (Intermediate 20): LCMS calcd. = 292.1; found = 292.1 (M+1) ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ7.33-7.29(m, 5H), 5.59(d, J=8.5Hz, 1H), 5.09-5.00(m, 5H), 4.49(m, 1H), 4.26( s, 3H), 1.07 (d, J=6.9Hz, 3H).

1-Methyl isomer (Intermediate 19): LCMS calculated = 292.1; found = 292.1 (M+1) ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ7.33-7.29 (m, 5H), 5.72 (s, 1H), 5.07 (m, 3H), 4.99 (m, 2H), 4.18 (m, 1H), 4.10 ( s, 3H), 1.24 (d, J=6.7Hz, 3H).

Example 196

(4S, 5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4- Methyl-5-pyridin-4-yl-1,3-oxazolidin-2-one

Step A: Benzyl [(1S)-1-methyl-2-oxo-2-pyridin-4-ylethyl]carbamate

Isopropylmagnesium chloride (1.6 mL, 1 M in THF, 3.23 mmol) was added dropwise to {(1S)-2-[methoxy(methyl)amino]-1- Benzyl methyl-2-oxoethyl}carbamate (Example 17, Step 1) (879 mg, 3.30 mmol) was in a stirred solution in anhydrous THF (4.2 mL). The reaction was stirred at -15 °C for 30 min, then dissolved by the dropwise addition of a solution of 4-pyridylmagnesium bromide in anhydrous THF (by adding ethylmagnesium bromide (6 mL, 2M in THF prepared by adding a solution of 4-iodopyridine (1.35 g, 6.60 mmol) in anhydrous THF (45 mL) and stirring for 30 minutes). The reaction was warmed to room temperature and stirred for 5 hours. 1N HCl (15 mL) was added to quench the reaction and the mixture was adjusted to basic pH with saturated NaHCO ₃ . _The mixture was extracted with EtOAc (2 x 50 mL) and _CH2Cl2 (3 x 50 mL). The EtOAc and _CH2Cl2 extracts were each washed with brine, dried ( _Na2SO4 ), combined and concentrated _in vacuo to afford _the crude product. Purification by flash chromatography (Si, 40 x 160 mm, gradient 0-100% EtOAc in hexanes) afforded [(2R)-1-methyl-2-oxo-2-pyridine-4 -Benzylethyl]carbamate as a colorless solid. _Rf = 0.33 (50% EtOAc/Hex). LCMS calcd = 285.1; found = 285.3 (M+1) ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ8.85(d, J=3.3Hz, 2H), 7.76(d, J=5.5Hz, 2H), 7.36-7.32(m, 5H), 5.70(d, J= 6.8Hz, 1H), 5.31-5.25(m, 1H), 5.13(s, 2H), 1.43(s, 3H).

Step B: Benzyl [(1S,2R)-2-hydroxy-1-methyl-2-pyridin-4-ylethyl]carbamate

Lithium aluminum tri-tert-butoxy hydride (964 mg, 3.79 mmol) was added to [(2R)-1-methyl-2-oxo-2-pyridin-4-ylethyl] at -78 °C under nitrogen Benzyl carbamate (539.1 mg, 1.90 mmol) in solution in anhydrous EtOH (40 mL). The reaction was stirred at -78°C for 2 hours. 2% Aqueous acetic acid was added to quench the reaction, and the mixture was adjusted to basic pH with saturated _NaHCO3 (ca. 50 mL). The mixture was extracted with EtOAc (3 x 100 mL), the combined extracts were washed with brine (50 mL), dried ( _Na2SO4 ) and concentrated in vacuo to afford the crude product _. Purification by flash chromatography (Si, 40 x 160 mm, gradient 0-100% EtOAc in hexanes) afforded [(1S,2R)-2-hydroxy-1-methyl-2-pyridine- Benzyl 4-ylethyl]carbamate as a colorless solid. _Rf = 0.49 (EtOAc). LCMS calcd = 287.1; found = 287.3 (M+1) ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ8.41(d, J=5.7Hz, 2H), 7.36-7.32(m, 7H), 5.27(d, J=7.4Hz, 1H), 5.10(s, 2H) , 4.89(s, 1H), 4.02(br s, 1H), 0.96(d, J=6.7Hz, 3H).

Step C: (4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl} -4-Methyl-5-pyridin-4-yl-1,3-oxazolidin-2-one

Sodium hydride (52.4 mg, 60% dispersion in mineral oil, 1.31 mmol) was added to [(1S,2R)-2-hydroxy-1-methyl-2-pyridine-4- Benzylethyl]carbamate (150 mg, 0.524 mmol) in anhydrous THF (6 mL). After stirring at room temperature for 30 minutes, 2-(bromomethyl)-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl (255 mg, 0.629 mmol) was added via cannula in Solution in anhydrous THF (3 mL). The reaction mixture was stirred overnight at room temperature. Sat. _NH4Cl (10 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined extracts _were dried ( _Na2SO4 ) and concentrated in vacuo to afford the crude product. It was purified by flash chromatography (Si, 25 x 160 mm, gradient 0-70% EtOAc in hexanes) to afford (4S,5R)-3-{[4'-fluoro-5'-isopropyl Base-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-pyridin-4-yl-1,3-oxazolidine-2 - Ketone, as a colorless oil. _Rf = 0.49 (EtOAc). LCMS calcd = 503.2; found = 503.3 (M+1) ⁺ . ¹ H NMR (600 MHz, CDCl ₃ , 1:1 mixture of atropisomers)

δ8.61(d, J=4.1Hz, 2H), 7.68(s, 0.5H), 7.61(s, 1H), 7.60(s, 0.5H), 7.33(dd, J=7.4, 3.8, Hz 1H) , 7.16(br s, 2H), 6.97(dd, J=17.8, 8.4Hz, 1H), 6.67(dd, J=12.0, 3.4Hz, 1H), 5.44(d, J=8.2Hz, 0.5H), 5.28(d, J=8.0Hz, 0.5H), 4.79(d, J=15.8Hz, 0.5H), 4.76(d, J=15.8Hz, 0.5H), 4.15-4.09(m, 1H), 3.88( d, J=15.8Hz, 0.5H), 3.79-3.70(m, 0.5H), 3.74(s, 3H), 3.23-3.17(m, 1H), 1.26-1.16(m, 6H), 0.52(d, J=6.5Hz, 1.5H), 0.38(d, J=6.5Hz, 1.5H).

Example 197

(4S, 5S)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4- Methyl-5-(4-methyl-1,3-thiazol-2-yl)-1,3-oxazolidin-2-one

Step A: Benzyl [(1S)-1-methyl-2-oxoethyl]carbamate

Dimethyl sulfoxide (1.01 g, 918 μL, 12.9 mmol) was added dropwise to oxalyl chloride (790 mg, 543 μL, 6.23 mmol) in dry _CH2Cl2 (12.6 _mL ) at -78 °C under nitrogen with stirring In the standing solution, the reaction was stirred for 15 minutes. A solution of [(1S)-2-hydroxy-1-methylethyl]carbamate (965 mg, 4.61 mmol) in anhydrous CH ₂ Cl ₂ (12.6 mL) was added dropwise via cannula, and the mixture was dissolved in Stir at -78°C for 30 minutes. Triethylamine (1.34 g, 1.85 mL, 13.2 mmol) was added and the reaction was allowed to warm to room temperature and stirred for 2 hours. Water (15 _mL ) was added and the aqueous phase was separated and extracted with _CH2Cl2 (3 x 15 mL). The combined organic extracts were washed with saturated NaHCO ₃ and brine, then dried (MgSO ₄ ) and concentrated in vacuo to afford benzyl [(1S)-1-methyl-2-oxoethyl]carbamate as free Color oil. _Rf = 0.75 (50% EtOAc in hexanes).

¹ H NMR (500MHz, CDCl ₃ ) δ9.58(s, 1H), 7.39-7.35(m, 5H), 5.39(br s, 1H), 5.15(s, 2H), 4.33(m, 1H), 1.40 (d, J=7.1Hz, 3H).

Step B: Benzyl [(1,S)-2-cyano-2-hydroxy-1-methylethyl]carbamate

Diethylaluminum cyanide (4.53 mL, 1M solution in toluene, 4.53 mmol) was added dropwise to [(1S)-1-methyl-2-oxoethyl]amino at -78 °C under nitrogen Benzyl formate (0.853 g, 4.12 mmol) was in a stirred solution in anhydrous toluene (33 mL). The mixture was stirred at -78°C for 6 hours, then allowed to warm to room temperature overnight. Sat. _NH4Cl (20 mL) and water (10 mL) were added, and the mixture was extracted with EtOAc (3 x 50 mL). The combined extracts _were dried ( _Na2SO4 ) and concentrated in vacuo to afford the crude product. Purification by flash chromatography (Si, 40 x 160 mm, gradient 0-40% EtOAc in hexanes) afforded [(1,S)-2-cyano-2-hydroxy-1-methyl Benzyl ethyl]carbamate as a 3:1 mixture of diastereomers. _Rf = 0.63 (50% EtOAc in hexanes). LCMS calcd = 257.1; found = 257.1 (M+1) ⁺ . ¹ H NMR (500MHz, CDCl ₃ ) major diastereomer:

δ7.39-7.31(m, 5H), 5.11(m, 2H), 4.60br(s, 1H), 3.96(m, 1H), 1.34(d, J=6.7Hz, 3H),

Minor diastereomer:

      δ7.39-7.31(m, 5H), 5.14(m, 2H), 4.50br(s, 1H), 4.10(m, 1H), 1.30(d, J=7.0Hz, 3H).

Step C: Benzyl ((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyano-1-methylethyl)carbamate

tert-Butyldimethylsilyl chloride (471 mg, 3.12 mmol) and imidazole (483 mg, 7.10 mmol) were sequentially added to [(1S)-2-cyano-2-hydroxy-1-methanol at room temperature under nitrogen. In a stirred solution of benzylethyl]carbamate ₍ 665 mg, 2.84 mmol) in anhydrous _CH2Cl2 (13 mL). The mixture was stirred overnight. Water (30 mL) was added and the mixture was extracted with _Et2O (3 x 30 mL). The combined extracts were dried ( _MgSO4 ) and concentrated in vacuo to afford crude product. This was purified by flash chromatography (Si, 40 x 160 mm, gradient 0-15% EtOAc in hexanes) to afford ((1S,2R)-2-{[tert-butyl(dimethyl)methano Silyl]oxy}-2-cyano-1-methylethyl)benzyl carbamate and ((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy} -benzyl 2-cyano-1-methylethyl)carbamate. (1S,2R)-diastereomer: _Rf = 0.29 (10% EtOAc in hexane). LCMS calcd = 349.2; found = 349.1 (M+1) ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ7.39-7.33(m, 5H), 5.16(d, J=12.1Hz, 1H), 5.07(d, J=12.1Hz, 1H), 4.89(brd, J= 6.6Hz, 1H), 4.68(br, d, 3.6Hz, 1H), 3.92(m, 1H), 1.31(d, J=6.7Hz, 3H), 0.91(s, 9H), 0.21(s, 3H) , 0.17(s, 3H).

(1S,2S)-diastereomer: _Rf = 0.24 (10% EtOAc in hexane). LCMS calcd = 349.2; found = 349.1 (M+1) ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ7.38-7.32 (m, 5H), 5.10 (s, 2H), 4.76 (br d, J=6.9Hz, 1H), 4.63 (br s, 1H), 4.00 ( m, 1H), 1.31(d, J=6.8Hz, 3H), 0.90(d, J=2.9Hz, 9H), 0.17(s, 3H), 0.08(s, 3H).

Step D: Benzyl ((1S,2S)-3-amino-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-3-thiopropyl)carbamate

Benzyl ((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyano-1-methylethyl)carbamate (115.6mg, 0.287mmol ), diethyl dithiophosphate (1 mL) and water (3 drops) was stirred overnight at room temperature. The reaction mixture was partitioned between saturated NaHCO ₃ (40 mL) and EtOAc (40 mL). The aqueous layer was separated and extracted with EtOAc (2 x 40 mL). The combined extracts _were dried ( _Na2SO4 ) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Si, 12 x 160 mm, gradient 0-40% EtOAc in hexanes) to afford ((1S,2S)-3-amino-2-{[tert-butyl(di Benzyl methyl)silyl]oxy}-1-methyl-3-thiopropyl)carbamate as a colorless oil. _Rf = 0.30 (20% EtOAc in hexanes). LCMS calcd = 383.2; found = 383.1 (M+1) ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ8.36(s, 1H), 7.87(s, 1H), 7.37-7.29(m, 5H), 5.13(m, 2H), 4.85(d, J=8.2Hz, 1H), 4.72(s, 1H), 4.47(m, 1H), 1.05(d, J=6.7Hz, 3H), 0.96(s, 9H), 0.08(s, 3H), 0.07(s, 3H).

Step E: Benzyl [(1S,2S)-2-hydroxy-1-methyl-2-(4-methyl-1,3-thiazol-2-yl)ethyl]carbamate

Benzyl ((1S, 2S)-3-amino-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-3-thiopropyl)carbamate (96.8 mg, 0.253 mmol) and chloroacetone (117 mg, 101 μL, 1.27 mmol) in anhydrous EtOH (5 mL) were heated at reflux under nitrogen for 20 hours, then stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo to obtain crude product. It was purified by flash chromatography (Si, 12 x 160 mm, gradient 0-100% EtOAc in hexanes) to afford [(1S,2S)-2-hydroxy-1-methyl-2-(4 -Benzyl methyl-1,3-thiazol-2-yl)ethyl]carbamate. _Rf = 0.44 (50% EtOAc in hexanes). LCMS calcd = 307.1; found = 307.1 (M+1) ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ7.31(m, 5H), 6.80(s, 1H), 5.49(br s, 1H), 5.06(m, 3H), 4.26-4.18(m, 1H), 2.38 (s, 3H), 1.09 (d, J=6.5Hz, 3H).

Step F: (4S,5S)-4-Methyl-5-(4-methyl-1,3-thiazol-2-yl)-1,3-oxazolidin-2-one

Benzyl [(1S,2S)-2-hydroxy-1-methyl-2-(4-methyl-1,3-thiazol-2-yl)ethyl]carbamate (53.4 mg, 0.174 mmol) in A solution in 7.5 N aqueous KOH (1 mL), MeOH (2 mL) and THF (4 mL) was stirred at room temperature overnight. The reaction mixture was acidified with 3N HCl and extracted with EtOAc (3 x 20 mL). The combined extracts were washed with brine, _dried ( _Na2SO4 ) and concentrated in vacuo to afford the product. LCMS calculated = 199.1; found = 199.1 (M+1) ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ6.92(s, 1H), 6.82(s, 1H), 5.91(d, J=8.2Hz, 1H), 4.39-4.35(m, 1H), 2.44(s, 3H), 0.95(d, J=6.4Hz, 3H).

Step G: (4S,5S)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl} -4-methyl-5-(4-methyl-1,3-thiazol-2-yl)-1,3-oxazolidin-2-one

Sodium hydride (60% dispersion in mineral oil, 8.1 mg, 0.202 mmol) was added to (4S,5S)-4-methyl-5-(4-methyl-1,3 -Thiazol-2-yl)-1,3-oxazolidin-2-one (33.4 mg, 0.168 mmol) in a stirred solution in anhydrous THF (1 mL). The reaction was stirred for 15 minutes, then 2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl (81.0 mg, 0.202 mmol) in solution in anhydrous THF (2 mL). The reaction was stirred overnight at room temperature. Sat. _NH4Cl (10 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined extracts _were dried ( _Na2SO4 ) and concentrated in vacuo to afford the crude product. This was passed through flash chromatography (Si, 25 x 160 mm, gradient 0-70% EtOAc in hexane) and chiral HPLC (IA column, 20 x 250 mm, 5% i-PrOH in heptane) Purification afforded (4S,5S)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl }-4-methyl-5-(4-methyl-1,3-thiazol-2-yl)-1,3-oxazolidin-2-one. _Rf = 0.18 (20% EtOAc in hexanes). LCMS calcd = 523.2; found = 523.1 (M+1) ⁺ . ¹ H NMR (500 MHz, CDCl ₃ , 1:1 mixture of atropisomers)

δ7.68(s, 0.5H), 7.63(s, 0.5H), 7.59(d, J=8.0Hz, 1H), 7.32(d, J=7.9Hz, 1H), 6.99(d, J=8.5Hz , 0.5H), 6.95(d, J=8.5Hz, 0.5H), 6.88(s, 1H), 6.68(d, J=5.0Hz, 0.5H), 6.66(d, J=4.9Hz, 0.5H) , 5.70(d, J=8.3Hz, 0.5H), 5.55(d, J=8.2Hz, 0.5H), 4.72(d, J=15.9Hz, 0.5H), 4.64(d, J=15.9Hz, 0.5 H), 4.20(d, J=15.9Hz, 0.5H), 3.95(d, J=15.9Hz, 0.5H), 3.91-3.83(m, 1H), 3.75(s, 1.5H), 3.74(s, 1.5H), 3.23-3.15(m, 1H), 2.40(s, 3H), 1.26-1.18(m, 6H), 0.65(d, J=6.5Hz, 1.5H), 0.55(d, J=6.5Hz , 1.5H).

Following the general procedure described above, the compounds in Table 8 were prepared. Preparative Example 198 was used as a reference compound.

Table 8

Example 253, 254

(4S, 5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4- Methyl-5-[3-(methylsulfinyl)phenyl]-1,3-oxazolidin-2-one (Example 253) (45,5R)-3-{[4′-fluoro- 5'-isopropyl-2'-methoxy 4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-[3-(methylsulfonyl)phenyl ]-1,3-oxazolidin-2-one (Example 254)

Under nitrogen at 0°C, to (4S, 5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- Base] methyl}-4-methyl-5-[3-(methylthio)phenyl]-1,3-oxazolidin-2-one (Example 208) (25mg, 0.0457mmol) in anhydrous To a solution in dichloromethane (1.5 mL) was added dropwise a solution of 3-chloroperbenzoic acid (77%, 26 mg, 0.114 mmol) in _CH2Cl2 (0.5 _mL ). After the addition, the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was treated with saturated _Na2SO3 (15 _mL ). The aqueous layer was extracted with _Et2O (3 x 20 mL). The combined organic extracts were washed with sat. NaHCO ₃ , dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification of the crude product by flash chromatography (Si, 12 x 160 mm, gradient 0-60% EtOAc in hexanes) afforded (4S,5R)-3-{[4'-fluoro-5'-isopropyl Base-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-[3-(methylsulfinyl)phenyl]-1 , 3-oxazolidin-2-one and (45,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl -2-yl]methyl}-4-methyl-5-[3-(methylsulfonyl)phenyl]-1,3-oxazolidin-2-one. Example 253: LCMS calcd = 564.19; found = 564.3 (M+1) ⁺ . ¹ HNMR (500 MHz, CDCl ₃ , 1:1 mixture of atropisomers)

δ7.73(8,0.5H);7.66-7.52(m,4.5H);7.42(s,0.5H);7.40(s,0.5H);7.37(d,J=3.4Hz,0.5H);7.36 (d, J=3.5Hz, 0.5H); 7.02(d, J=8.4Hz, 0.5H); 6.99(d, J=8.4Hz, 0.5H); 6.71(d, J=3.1Hz, 0.5H) ; 6.69(d, J=2.9Hz, 0.5H); 5.59(d, J=5.9Hz, 0.5H); 5.57(d, J=5.9Hz, 0.5H); 5.42(t, J=8.4Hz, 1H ); 4.85(d, J=3.4Hz, 0.5H); 4.82(d, J=3.4Hz, 0.5H); 4.80(d, J=7.8Hz, 0.5H); 4.77(d, J=7.7Hz, 0.5H); 4.16(d, J=15.8Hz, 0.5H); 3.92(d, J=15.8Hz, 0.5H); 3.76(s, 3H); 3.85-3.72(m, 1H); 3.26-3.19( m, 1H); 2.73(d, J=4.7Hz, 3H); 1.30-1.26(m, 4.5H); 1.20(d, J=6.9Hz, 1.5H); 0.55(d, J=6.7Hz, 0.75 H); 0.52(d, J=6.7Hz, 0.75H); 0.41(d, J=4.0Hz, 0.75H); 0.39(d, J=4.1Hz, 0.75H).

Example 254: LCMS calcd = 580.17; found = 580.3 (M+1) ⁺ . ¹ H NMR (500 MHz, CDCl ₃ , 1:1 mixture of atropisomers)

δ7.95(s, 0.5H); 7.94(s, 0.5H); 7.81(s, 0.5H); 7.80(s, 0.5H); 7.73(s, 0.5H); 7.65-7.58(m, 3H) ;7.57(s, 0.5H); 7.38(d, J=3.5Hz, 0.5H); 7.36(d, J=3.8Hz, 0.5H); 7.02(d, J=8.4Hz, 0.5H); 6.99( d, J=8.4Hz, 0.5H); 6.72(s, 0.5H); 6.69(s, 0.5H); 5.58(d, J=8.1Hz, 0.5H); 5.42(d, J=8.0Hz, 0.5 H); 4.86(d, J=15.9Hz, 0.5H); 4.81(d, J=15.9Hz, 0.5H); 4.17(d, J=15.8Hz, 0.5H); 3.91(d, J=15.8Hz , 0.5H); 3.81-3.75(m, 1H); 3.78(s, 3H); 3.27-3.19(m, 1H); 3.07(s, 3H); 1.30-1.26(m, 4.5H); 1.21(t , J=8.7Hz, 1.5H); 0.53(d, J=6.5Hz, 1.5H); 0.39(d, J=65Hz, 1.5H).

Example 255

3-((4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl} -4-Methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde

(4S, 5R)-5-[3-(1,3-dioxan-2-yl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′ -Methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Example 210) (380mg, 0.647mmol ) in THF and 1N HCl (3:1) (4 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc, washed with sodium bicarbonate and brine. The organic layer was dried and concentrated in vacuo. Purification of the crude product (Si) by flash chromatography afforded 3-((4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoro Methyl)biphenyl-2-yl]methyl)-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde. LCMS calcd = 530.19; found = 530.4 (M+1) ⁺ . ¹ H NMR (500 MHz, CDCl ₃ , 1:1 mixture of atropisomers)

δ10.03(s, 1H); 7.88(s, 0.5H); 7.87(s, 0.5H); 7.77-7.52(m, 5H); 7.37(d, J=3.5Hz, 0.5H); 7.36(d , J=3.4Hz, 0.5H); 7.02(d, J=8.4Hz, 0.5H); 6.99(d, J=8.4Hz, 0.5H); 6.71(d, J=3.5Hz, 0.5H); 6.69 (d, J=3.4Hz, 0.5H); 4.17(d, J=15.8Hz, 0.5H); 6.98(d, J=15.8Hz, 0.5H); 3.78(s, 3H); 3.85-3.71(m , 1H); 3.26-3.19(m, 1H); 1.30-1.26(m, 4.5H); 1.19(d, J=6.9Hz, 1.5H); 0.53(d, J=6.6Hz, 1.5H); 0.40 (d, J=6.6Hz, 1.5H).

Example 256

(4S, 5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5- [3-(Hydroxy)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5 -[3-(Hydroxy

Under nitrogen atmosphere at 0°C, to 3-((4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl) A solution of phen-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde (12 mg, 0.023 mmol) in anhydrous EtOH (1 mL) NaBH ₄ powder (4.5 mg, 0.119 mmol) was added to NaBH 4 . The solution was warmed to room temperature and stirred for 1 hour. The mixture was treated with 2% HOAc and diluted with water. The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with saturated NaHCO ₃ (12 mL) and brine (12 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification of the crude product by flash chromatography afforded (4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl- 2-yl]methyl}-5-[3-(hydroxy)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl -2-yl]methyl}-5-[3-(hydroxyl. LCMS calculated = 532.0; found = 532.4 (M+1) ⁺ . ¹ H NMR (500 MHz, CDCl ₃ , 1 of the atropisomer :1 mixture)

δ7.73(s, 0.5H); 7.67(s, 0.5H); 7.64(s, 0.5H); 7.62(s, 0.5H); 7.42-7.32(m, 3H); 7.24(s, 1H); 7.15(s, 0.5H); 7.14(s, 0.5H); 7.01(d, J=8.4Hz, 0.5H); 6.98(d, J=8.5Hz, 0.5H); 6.71(s, 0.5H); 6.68(s, 0.5H); 5.51(d, J=8.1Hz, 0.5H); 5.37(d, J=8.0Hz, 0.5H); 4.81(d, J=15.9Hz, 0.5H); 4.74(d , J=16Hz, 0.5H); 4.73(s, 2H); 4.15(d, J=15.9Hz, 1H); 3.92(d, J=15.9Hz, 1H); 3.77(s, 3.0H); 3.74(H, 0.5H); 3.74-3.68(m, 0.5H); 3.25-3.18(m, 1H); 1.29-1.25(m, 4.5H); 1.19(d, J=6.9Hz, 1.5H); 0.53(d, J=6.4Hz, 1.5H); 0.40(d, J=6.4Hz, 1.5H).

Example 257

(4S, 5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5- [3-(1-Hydroxyethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

3-((4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl) To a solution of phen-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde (11 mg, 0.021 mmol) in THF (1 mL) was added Methylmagnesium bromide (30 μL of a 3.0M solution in ether). The mixture was stirred at -78°C for 2 hours. The mixture was treated with saturated _NH4Cl (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (15 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo to obtain the crude product. Purification (Si) by flash chromatography afforded (4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl) biphenyl-2-yl]methyl}-5-[3-(1-hydroxyethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. LCMS calcd = 546, 22; found = 546.4 (M+1) ⁺ . ¹ H NMR (500 MHz, CDCl ₃ , 1:1 mixture of atropisomers)

δ7.74(s, 0.5H); 7.67(s, 0.5H); 7.64(s, 0.5H); 7.63(s, 0.5H); 7.36(m, 3H); 7.24(s, 1H); 7.15( s, 0.5H); 7.14(s, 0.5H); 7.01(d, J=8.5Hz, 0.5H); 6.99(d, J=8.5Hz, 0.5H); 6.71(s, 0.5H); 6.68( s, 0.5H); 5.52(d, J=8.0Hz, 0.5H); 5.36(d, J=7.9Hz, 0.5H); 4.92(q, J=6.4Hz, 1H); 4.83(d, J= 15.7, 0.5H); 4.77 (d, J = 16.0, 0.5H); 4.16 (d, J = 15.5Hz, 0.5H); 3.92 (d, J = 15.5Hz, 0.5H); 3.77 (d, J = 7.1Hz, 3H); 3.81-3.68(m, 1H); 3.25-3.18(m, 1H); 1.64(br, s, 1H); 1.49(d, J=6.4Hz, 3H); , 4.5H); 1.19(d, J=6.9Hz, 1.5H); 0.53(d, J=6.5Hz, 1.5H); 0.40(d, J=6.5Hz, 1.5H).

Following the general procedure described above, the compounds in Table 9 were prepared:

Table 9

Example R LCMS(M+1) ⁺ 258 Et 560.4 259 n-Pr 574.4

Example 260

(4S, 5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4- Methyl-5-{3-[(methylamino)methyl]phenyl}-1,3-oxazolidin-2-one

To 3-((4S, 5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl }-4-Methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde (15 mg, 0.028 mmol) in 1,2-dichloroethane (1 mL) was added formaldehyde amine (1 mL of a 2.0 M solution in THF). The resulting mixture was treated with sodium triacetoxyborohydride (34.8 mg, 0.16 mmol) and AcOH (0.05 mL). The mixture was stirred at room temperature under nitrogen for 5 days. The reaction mixture was treated with 1N NaOH, and the aqueous layer was extracted with ether (3 x 15 mL). The ether extracts were washed with _brine , dried ( _Na2SO4 ) and concentrated in vacuo. Purification of the residue by flash chromatography (Si) afforded (4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl ) biphenyl-2-yl]methyl}-4-methyl-5-{3-[(methylamino)methyl]phenyl}-1,3-oxazolidin-2-one. LCMS calcd = 545.23; found = 545.4 (M+1) ⁺ . ¹ H NMR (500 MHz, CDCl ₃ , 1:1 mixture of atropisomers)

δ7.74(s, 0.5H); 7.67(s, 0.5H); 7.64(s, 0.5H); 7.62(s, 0.5H); 7.33(m, 3H); 7.20(s, 1H); 7.13( s, 0.5H); 7.12(s, 0.5H); 7.01(d, J=8.4Hz, 0.5H); 6.98(d, J=8.5Hz, 0.5H); 6.71(d, J=2.9Hz, 0.5 H); 6.68(d, J=2.8Hz, 0.5H); 5.51(d, J=8.1Hz, 0.5H); 5.37(d, J=8.0Hz, 0.5H); 4.82(d, J=15.9Hz , 0.5H); 4.75(d, J=15.9Hz, 0.5H); 4.16(d, J=15.9Hz, 0.5H); 3.92(d, J=15.9Hz, 0.5H); 3.77(m, 5.5H ); 3.70(t, J=6.6Hz, 0.5H); 3 25-3.18(m, 1H); 2.45(s, 3H); 1.93(br, s, 1H); 1.27(m, 4.5H); 1.19 (d, J=6.9Hz, 1.5H); 0.53(d, J=6.5Hz, 1.5H); 0.40(d, J=6.5Hz, 1.5H).

Example 261

(4S, 5R)-5-{3-[(Dimethylamino)methyl]phenyl}-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4- (Trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

To 3-((4S, 5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl }-4-Methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde (15 mg, 0.028 mmol) in EtOH (1 mL) was added dimethylamine (140 μL 2.0 M solution in MeOH) and titanium isopropoxide (79 μL, 0.28 mmol). The resulting white suspension was stirred overnight. Sodium borohydride (7.1 mg, 0.188 mmol) was added and the mixture was stirred overnight. The reaction was quenched by pouring the mixture into 2N aqueous ammonia (2 mL). The resulting inorganic precipitate was filtered off and washed with dichloromethane. The combined filtrates were extracted with dichloromethane (2 x 15 mL). The extracts were dried _{( Na2SO4} ) and concentrated in vacuo. Purification of the residue by flash chromatography (Si) afforded (4S,5R)-5-{3-[(dimethylamino)methyl]phenyl}-3-{[4'-fluoro-5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. LCMS calcd = 559.25; found = 559.4 (M+1) ⁺ . ¹ H NMR (500 MHz, CDCl ₃ , 1:1 mixture of atropisomers)

δ7.74(s, 0.5H); 7.67(s, 0.5H); 7.64(s, 0.5H); 7.62(s, 0.5H); 7.37-7.29(m, 3H); 7.18(s, 1H); 7.16(s, 0.5H); 7.13(s, 0.5H); 7.01(d, J=8.4Hz, 0.5H); 6.99(d, J=8.5Hz, 0.5H); 6.71(d, J=3.0Hz , 0.5H); 6.68(d, J=2.9Hz, 0.5H); 5.52(d, J=8.1Hz, 0.5H); 5.37(d, J=8.0Hz, 0.5H); 4.82(d, J= 15.9Hz, 0.5H); 4.77(d, J=16.0Hz, 0.5H); 4.15(d, J=16.0Hz, 0.5H); 3.91(d, J=15.9Hz, 0.5H); 3.76(s, 3H); 3.80-3.73(m, 0.5H); 3.72-3.68(m, 0.5H); 3.43(s, 2H); 3.25-3.18(m, 1H); 2.23(s, 6H); 4.5H); 1.19(d, J=6.9Hz, 1.5H); 0.53 (d, J=6.5Hz, 1.5H); 0.39(d, J=6.6Hz, 1.5H).

Example 262

(4S, 5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5- (1H-imidazol-2-yl)-4-methyl-1,3-oxazolidin-2-one

(4S, 5S)-5-{1-[(Benzyloxy)methyl]-1H-imidazol-2-yl}-3-{[4′-fluoro-5′-isopropyl-2′- Methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Example 244) (16.9mg, 0.028mmol ), 20% palladium hydroxide on carbon (8.3 mg) and 1 N HCl (28 uL) in MeOH (1 mL) was stirred overnight under hydrogen (balloon), then the mixture was filtered through celite and concentrated in vacuo. Purification of the crude product by flash chromatography afforded (4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl- 2-yl]methyl}-5-(1H-imidazol-2-yl)-4-methyl-1,3-oxazolidin-2-one. LCMS calcd = 492.18; found = 492.2 (M+1) ⁺ . ¹ H NMR (500 MHz, CDCl ₃ , 1:1 mixture of atropisomers)

δ7.71(s, 0.5H); 7.67(s, 0.5H); 7.65(s, 0.5H); 7.64(s, 0.5H); 7.37(d, J=3.2Hz, 0.5H); 7.35(d , J=3.3Hz, 0.5H); 7.09(d, 2H); 7.02(d, J=8.4Hz, 0.5H); 6.99(d, J=8.5Hz.0.5H); 6.72(d, J=4.3 Hz, 0.5H); 6.69(d, J=4.2Hz, 0.5H); 5.76(d, J=8.3Hz, 0.5H); 5.64(d, J=8.7Hz, 0.5H); 4.72(d, J =15.8Hz, 0.5H); 4.68(d, J=15.8Hz, 0.5H); 4.20(d, J=15.7Hz, 0.5H); 4.01(d, J=15.7Hz, 0.5H); 3.90(br , s, 1H); 3.79-3.72(m, 4H); 3.25-3.18(m, 1H); 1.28-1.22(m, 6H); 0.67(d, J=6.5Hz, 1.5H); J=6.5Hz, 1.5H).

Example 263

(4S, 5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4- Methyl-5-(1-oxypyridin-4-yl)-1,3-oxazolidin-2-one

Add m-chlorobenzoic acid (77%, 47.9mg, 0.214mmol) to (4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4 at 0°C -(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-pyridin-4-yl-1,3-oxazolidin-2-one (53.7,0.107mmol) in the absence of solution in water _CH2Cl2 (10.8 _mL ). After 15 minutes at 0°C, the reaction was stirred at room temperature for 3 hours. The reaction was diluted with _CH2Cl2 (40 _mL ), washed with _{saturated Na2SO3} (20 mL) and saturated _K2CO3 (2 x 20 _mL ). The organic layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford (4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoro Methyl)biphenyl-2-yl]methyl}-4-methyl-5-(1-oxypyridin-4-yl)-1,3-oxazolidin-2-one, as an oil. LCMS calcd = 519.2; found = 519.3 (M+1) ⁺ .

Example 264

4-((4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl} -4-methyl-2-oxo-1,3-oxazolidin-5-yl)pyridine-2-carbonitrile

Trimethylsilyl cyanide (39.9 mg, 54 μL, 0.402 mmol) was added to (4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′ at room temperature under nitrogen -Methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-(1-oxypyridin-4-yl)-1,3-oxazolidine- 2 _- Kone (37.9 mg, 0.0732 mmol) in a stirred solution in anhydrous _CH2Cl2 (2 mL). The reaction was stirred for 5 minutes and benzoyl chloride (20.5 mg, 17 μL, 0.146 mmol) was added. The reaction was stirred overnight at room temperature. ₅₀ % saturated _K2CO3 (10 mL) was added and _the mixture was diluted with _CH2Cl2 (20 mL). The aqueous layer was separated and extracted with _CH2Cl2 (2 _x 10 mL). The combined organic extracts _were dried ( _K2CO3 ) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Si, 12 x 160 mm, gradient 0-70% EtOAc in hexanes) to afford the product (11.6 mg, 30%) as a colorless oil. The product was resolved into its enantiomers by chiral HPLC (AD column, 20×250 mm, 10% i-PrOH in heptane) to give 4-((4S,5R)-3-{[4 '-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3 -oxazolidin-5-yl)pyridine-2-carbonitrile and 4-((4R,5S)-3-{[4′-fluoro-51-isopropyl-2′-methoxy-4-( Trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)pyridine-2-carbonitrile. _Rf = 0.72 (50% EtOAc in hexanes). LCMS calcd = 528.2; found = 528.3 (M+1) ⁺ . ¹ H NMR (500 MHz, CDCl ₃ , 1:1 mixture of atropisomers)

δ8.73(s, 1H), 7.67-7.59(m, 2H), 7.55(d, J=3.3Hz, 1H), 7.40(d, J=4.2Hz, 1H), 7.35(dd, J=7.8, 3.3Hz, 1H), 6.99(d, J=8.4Hz, 1H), 6.95(d, J=8.4Hz, 1H), 6.69(d, J=3.1Hz, 1H), 6.67(d, J=3.1Hz , 1H), 5.47(d, J=8.1Hz, 0.5H), 5.30(d, J=8.1Hz, 0.5H), 4.81(t, J=15.1Hz, 1H), 4.11(d, J=15.8Hz , 0.5H), 3.89(d, J=15.8Hz, 0.5H), 3.83-3.73(m, 1H), 3.76(s, 3H), 3.24-3.16(m, 1H), 1.27-1.17(m, 6H ), 0.54(d, J=6.5Hz, 1.5H), 0.39(d, J=6.5Hz, 1.5H).

Example 265

(4S, 5R)-5-(2-chloropyridin-4-yl)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl) Biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

(4S, 5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4 - A solution of methyl-5-(1-oxypyridin-4-yl)-1,3-oxazolidin-2-one (53.7 mg, 0.104 mmol) in phosphorus oxychloride (4 mL) was heated under nitrogen Reflux for 2 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, diluted with EtOAc (20 mL) and water (5 mL), and washed with saturated NaHCO ₃ (10 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers _were dried ( _Na2SO4 ) and concentrated in vacuo to afford crude product. Purification by flash chromatography (Si, 12 x 160 mm, gradient 0-70% EtOAc in hexanes) afforded the product as a colorless oil. The product was resolved into its enantiomers by chiral HPLC (AD column, 20×250 mm, 5% i-PrOH in heptane) to obtain (4S,5R)-5-(2-chloropyridine-4 -yl)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl -1,3-oxazolidin-2-one. _Rf = 0.17 (20% EtOAc in hexanes). LCMS calcd = 537.2; found = 537.3 (M+1) ⁺ . ¹ HNMR (500 MHz, CDCl ₃ , 1:1 mixture of atropisomers)

δ8.40(br s, 1H), 7.70(s, 0.5H), 7.63(s, 1.5H), 7 37(m, 1H), 7.24(br s, 1H), 7.10(br s, 1H), 7.01 (d, J=8.2Hz, 0.5H), 6.98(d, J=8.2Hz, 0.5H), 6.72-6.68(m, 1H), 5.44(d, J=8.1Hz, 0.5H), 5.29(d , J=8.1Hz, 0.5H), 4.81(t, J=16.9Hz, 1H), 4.14(d, J=15.9Hz, 0.5H), 3.91(d, J=15.9Hz, 0.5H), 3.81- 3.71(m, 1H), 3.76(s, 3H), 3.27-3.19(m, 1H), 1.29-1.19(m, 6H), 0.58(d, J=6.5Hz, 1.5H), 0.44(d, J =6.5Hz, 1.5H).

Example 266

(4S, 5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4- Methyl-5-(2-methylpyridin-4-yl)-1,3-oxazolidin-2-one

(4S, 5R)-5-(2-Chloropyridin-4-yl)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl )biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (20.9mg, 0.0389mmol), trimethylboroxine (14.7mg, 16μL, 0.116 A solution of mmol)Cs ₂ CO ₃ (38.0 mg, 0.117 mmol) and (Ph ₃ P) ₄ Pd (9.0 mg, 0.00778 mmol) in anhydrous 1,4-dioxane (1 mL) was heated to reflux overnight . The reaction mixture was filtered through a plug of celite, washing with EtOAc. The filtrate was concentrated in vacuo to obtain the crude product. Purification by flash chromatography (Si, 12 x 160 mm, gradient 0-70% EtOAc in hexanes) afforded the product as a colorless oil. Resolution of the product into its enantiomers by chiral BDPLC (AD column, 20×250 mm, 10% i-PrOH in heptane) afforded (4S,5R)-3-{[4′-fluoro -5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-(2-methylpyridine-4- base)-1,3-oxazolidin-2-one and (4R,5S)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl base) biphenyl-2-yl] methyl}-4-methyl-5-(2-methylpyridin-4-yl)-1,3-oxazolidin-2-one. _Rf = 0.22 (50% EtOAc in hexanes). LCMS calcd = 517.2; found = 517.1 (M+1) ⁺ . ¹ H NMR (500 MHz, CDCl ₃ , 1:1 mixture of atropisomers)

δ8.48(d, J=4.9Hz, 1H), 7.69(s, 0.5H), 7.61(s, 1H), 7.60(s, 0.5H), 7.33(m, 1H), 7.05(s, 1H) , 6.99-6.93(m, 2H), 6.69(d, J=3.2Hz, 1H), 6.66(d, J=3.2Hz, 1H), 5.40(d, J=8.1Hz, 0.5H), 5.24(d , J=8.1Hz, 0.5H), 4.79(d, J=15.9Hz, 0.5H), 4.74(d, J=15.9Hz, 0.5H), 4.13(d, J=15.9Hz, 0.5H), 3.89 (d, J=15.9Hz, 0.5H), 3.78-3.66(m, 1H), 3.75(s, 3H), 3.23-3.17(m, 1H), 2.56(s, 3H), 1.25-1.17(m, 6H), 0.53(d, J=6.5Hz, 1.5H), 0.39(d, J=6.5Hz, 1.5H).

The compounds in Table 10 were prepared following the general procedure described above:

Table 10

The compounds in Table 11 were prepared following the general procedure described above:

Table 11

The compounds in Table 12 were prepared following the general procedure described above:

Table 12

Example 281

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-2'-hydroxyl-5'-isopropyl-4-(trifluoromethyl) Methyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Step A: 4-Fluoro-2'-(iodomethyl)-5-isopropyl-4'-(trifluoromethyl)biphenyl-2-ol

In a sealed tube, mix [4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol (71.5 mg, 0.209 mmol) and A solution of iodine (610 mg, 2.40 mmol) in phenyltrimethylsilane (877 μL) was heated at 110° C. overnight. The reaction was cooled to room temperature, diluted with 1N HCl (10 mL), extracted with EtOAc (3 x 20 mL). _The combined extracts were washed with 10% _Na2S2O3 (20 mL), dried ( _Na2SO4 ) and concentrated _in vacuo to afford the _crude product. This was purified by flash chromatography (Si, 12 x 160 mm, gradient 0-20% EtOAc in hexanes) to afford 4-fluoro-2'-(iodomethyl)-5-isopropyl-4 '-(trifluoromethyl)biphenyl-2-ol. _Rf = 0.65 (20% EtOAc in hexanes).

¹ H NMR (500MHz, CDCl ₃ ) δ7.81(s, 1H), 7.60(d, J=7.9Hz, 1H), 7.34(d, J=7.9Hz, 1H), 7.10(d, J=8.3Hz , 1H), 6.69(d, J=11.1Hz, 1H), 4.82(s, 1H), 4.41(d, J=9.4Hz, 1H), 4.23(d, J=9.3Hz, 1H), 3.27-3.19 (m, 1H), 1.27 (br s, 6H).

Step B: 2-{[4-fluoro-2'-(iodomethyl)-5-isopropyl-4'-(trifluoromethyl)biphenyl-2-yl]oxy}tetrahydro-2H- pyran

Add p-toluenesulfonic acid (2.8 mg, 0.0145 mmol) to 4-fluoro-2'-(iodomethyl)-5-isopropyl-4'-(trifluoromethyl)biphenyl at room temperature under nitrogen -2-ol (63.4 mg, 0.145 mmol) and 3,4-dihydro-2H-pyran (60.8 mg, 66 μL, 0.723 mmol) in anhydrous CH ₂ Cl ₂ (7.2 mL), the The reaction was stirred for 3 days. The reaction mixture was diluted with saturated NaHCO ₃ (20 mL), and extracted with CH ₂ Cl ₂ (3×20 mL). The combined extracts _were dried ( _Na2SO4 ) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Si, 12 x 160 mm, gradient 0-20% EtOAc in hexanes) to afford 2-{[4-fluoro-2'-(iodomethyl)-5-iso Propyl-4'-(trifluoromethyl)biphenyl-2-yl]oxy}tetrahydro-2H-pyran. _Rf = 0.74 (10% EtOAc in hexanes).

¹ H NMR (500MHz, CDCl ₃ ) δ.75(s, 1H), 7.62(d, J=8.3Hz, 0.5H), 7.59(d, J=8.3Hz, 0.5H), 7.53(t, J= 7.3Hz, 0.5H), 7.41(s, 0.5H), 7.32(d, J=7.9Hz, 0.5H), 7.25(d, J=7.9Hz, 0.5H), 7.15(t, J=9.4Hz, 0.5H), 6.99(d, J=12.2Hz, 0.5H), 6.94(d, J=12.2Hz, 0.5H), 6.69(d, J=11.0Hz, 0.5H), 5.37(s, 0.5H) , 5.23(s, 0.5H), 5.13(s, 1H), 4.45(d, J=9.6Hz, 0.5H), 4.40(d, J=9.6Hz, 0.5H), 4.31(d, J=9.6Hz , 0.5H), 4.23(d, J=9.6Hz, 0.5H), 3.76(m, 0.5H), 3.66-3.54(m, 1.5H), 3.29-3.21(m, 1H), 1.68-1.44(m, 4H)1.32-1.26(m, 6H).

Step C: (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-2'-hydroxy-5'-isopropyl-4- (Trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Sodium hydride (60% dispersion in mineral oil, 1.9 mg, 0.0485 mmol) was added to (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl - 1,3-Oxazolidin-2-one in a stirred solution in anhydrous DMF (1 mL). The reaction was stirred for 30 minutes and 2-{[4-fluoro-2'-(iodomethyl)-5-isopropyl-4'-(trifluoromethyl)biphenyl-2-yl] was added via cannula Oxy}tetrahydro-2H-pyran (16.9 mg, 0.324 mmol) in anhydrous DMF (1 mL) and the reaction was stirred at room temperature overnight. The reaction was diluted with saturated _NH4Cl (10 mL) and water (5 mL), extracted with EtOAc (3 x 20 mL). The combined extracts _were dried ( _Na2SO4 ) and concentrated in vacuo to afford the crude product. A solution of the crude product and p-toluenesulfonic acid (0.6 mg, 0.00324 mmol) in MeOH (5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to obtain crude product. This was purified by flash chromatography (Si, 12 x 160 mm, gradient 0-35% EtOAc in hexanes) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl) Phenyl]-3-{[4'-fluoro-2'-hydroxyl-5'-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1 , 3-oxazolidin-2-one. _Rf = 0.33 (20% EtOAc in hexanes). LCMS calcd = 624.2; found = 624.3 (M+1) ⁺ . ¹ H NMR (500 MHz, CDCl ₃ , 1:1 mixture of atropisomers)

δ7.86(s, 1H), 7.67(m, 4H), 7.42(d, J=7.1Hz, 0.5H), 7.41(d, J=7.1Hz, 0.5H), 6.95(d, J=7.3Hz , 0.5H), 6.94(d, J=7.3Hz, 0.5H), 6.70(d, J=5.6Hz, 0.5H), 6.68(d, J=5.6Hz, 0.5H), 5.66(d, J= 8.0Hz, 0.5H), 5.36(d, J=8.1Hz, 0.5H), 4.93(d, J=15.8Hz, 0.5H), 4.88(d, J=15.8Hz, 0.5H), 4.18(d, J=15.8Hz, 0.5H), 4.00(d, J=15.8Hz, 0.5H), 3.87-3.83(m, 0.5H), 3.77-3.71(m, 0.5H), 3.22-3.14(m, 1H) , 1.77(br s, 1H), 1.27-1.17(m, 6H), 0.57(d, J=6.5Hz, 1.5H), 0.45(d, J=6.5Hz, 1.5H).

The compounds in Table 13 were prepared following the general procedure described above:

Table 13

Example 283

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-3'-hydroxyl-5'-isopropyl-2'-methoxy Base-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Step A: tert-butyl{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methoxy}dimethylformazan Silane

To [4'-fluoro-5'-isopropyl-2 '-Methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol (1.00 g, 2.93 mmol) in a stirred solution of anhydrous CH ₂ Cl ₂ (13.4 mL), and The reaction was stirred overnight. Water (50 mL) was added, and the mixture was extracted with EtOAc (3 x 50 mL). The combined extracts were dried ( _MgSO4 ) and concentrated in vacuo to afford crude product. Purification by flash chromatography (Si, 25 x 160 mm, 1% EtOAc in hexanes) afforded tert-butyl{[4'-fluoro-5'-isopropyl-2'-methoxy -4-(trifluoromethyl)biphenyl-2-yl]methoxy}dimethylsilane, a colorless oil. _Rf = 0.16 (1% EtOAc in hexanes). LCMS calcd = 457.2; found = 457.2 (M+1) ⁺ .

¹ H NMR (500MHz, CDCl ₃ ) δ7.94(s, 1H), 7.57(d, J=7.8Hz, 1H), 7.29(d, J=7.6Hz, 1H), 7.00(d, J=8.6Hz , 1H), 6.69(d, J=12.1Hz, 1H), 4.63(br s, 1H), 4.50(br s, 1H), 3.75(s, 3H), 3.29-3.21(m, 1H), 1.28( d, J=6.9Hz, 6H), 0.93(s, 9H), 0.03(s, 6H).

Step B: 2'-({[tert-butyl(dimethyl)silyl]oxy}methyl]-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoro Methyl)biphenyl-3-ol

n-Butyllithium (1.6M solution in hexane, 261 μL, 0.417 mmol) was added dropwise via syringe pump to tert-butyl{[4′-fluoro-5 '-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methoxy}dimethylsilane (200mg, 0.438mmol) in anhydrous THF (0.5mL ) in a stirred solution. After the addition was complete, the reaction was stirred at -78°C for 2 hours to obtain a purple solution. Trimethyl borate (43.4 mg, 47 μL, 0.417 mmol) was added dropwise, and the reaction was stirred at -78°C for 3 hours. The reaction mixture was warmed to 0 °C and acetic acid (25.1 mg, 24 μL, 0.626 mmol) was added rapidly, followed by dropwise addition of 30% aqueous hydrogen peroxide (52 μL, 0.459 mmol). The reaction was stirred at room temperature overnight, diluted with water (10 mL) and extracted with _Et2O (3 x 20 mL). The combined extracts were washed with 50% saturated _FeSO4 (20 mL), dried ( _Na2SO4 ) and concentrated in vacuo to afford the crude product _. Purification by flash chromatography (Si, 12 x 160 mm, gradient 0-100% EtOAc in hexanes) afforded 2'-({[tert-butyl(dimethyl)silyl]oxy }methyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl-3-ol. _Rf = 0.32 (10% EtOAc in hexanes). LCMS calcd = 473.1; found = 473.2 (M+1) ⁺ .

¹ H NMR (600MHz, CDCl ₃ ) δ7.95(s, 1H), 7.56(d, J=7.8Hz, 1H), 7.35(d, J=7.9Hz, 1H), 6.53(d, J=7.8Hz , 1H), 5.65(s, 1H), 4.68(br s, 1H), 4.54(br s, 1H), 3.42(s, 3H), 3.26-3.20(m, 1H), 1.25(d, J=6.9 Hz, 6H), 0.90(s, 9H), 0.02(s, 6H)

Step C: 4-Fluoro-2'-(hydroxymethyl)-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl-3-ol

tert-Butylammonium fluoride (1M in THF, 179 μL, 0.179 mmol) was added dropwise to 2′-({[tert-butyl(dimethyl)silyl]oxy}methyl )-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl-3-ol (76.8mg, 0.163mmol) was stirred in THF (2mL) solution, and the reaction was allowed to warm to room temperature overnight. Sat. _NH4Cl (10 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined extracts _were dried ( _Na2SO4 ) and concentrated in vacuo to afford the crude product. Purification by flash chromatography (Si, 12 x 160 mm, gradient 0-40% EtOAc in hexanes) gave 4-fluoro-2'-(hydroxymethyl)-5-isopropyl-2 -Methoxy-4'-(trifluoromethyl)biphenyl-3-ol. _Rf = 0.26 (20% EtOAc in hexanes).

¹ HNMR (600MHz, CDCl ₃ ) δ7.85(s, 1H), 7.63(d, J=7.9Hz, 1H), 7.41(d, J=8.0Hz, 1H), 6.53(d, J=7.7Hz, 1H), 4.50(br s, 1H), 4.47(s, 1H), 3.42(s, 3H), 3.25-3.19(m, 1H), 1.24(br s, 6H).

Step D: 2'-(Bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl-3-ol

A solution of triphenylphosphine (102.8 mg, 0.392 mmol) in anhydrous _CH2Cl2 ( ₂ mL) was added via cannula to carbon tetrabromide (130 mg, 0.392 mmol) and 4 at 0 °C under nitrogen. -Fluoro-2'-(hydroxymethyl)-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl-3-ol (58.5 mg, 0.163 mmol) in anhydrous CH ₂ Cl ₂ (2 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo to obtain crude product. This was purified by flash chromatography (Si, 12 x 160 mm, gradient 0-40% EtOAc in hexanes) to afford 2'-(bromomethyl)-4-fluoro-5-isopropyl-2 -Methoxy-4'-(trifluoromethyl)biphenyl-3-ol. _Rf = 0.55 (20% EtOAc in hexanes).

¹ H NMR (600MHz, CDCl ₃ ) δ7.84(s, 1H), 7.61(d, J=7.9Hz, 1H), 7.42(d, J=8.0Hz, 1H), 6.69(d, J=7.8Hz , 1H), 5.59(s, 1H), 4.50(d, J=9.6Hz, 1H), 4.39(d, J=9.7Hz, 1H), 3.47(s, 3H), 3.29-3.23(m, 1H) , 1.27 (d, J=6.9Hz, 6H).

Step E: 2-{[2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]oxy }tetrahydro-2H-pyran

3,4-Dihydro-2H-pyran (51.9 mg, 56 μL, 0.617 mmol) was added to p-toluenesulfonic acid (2.3 mg, 0.0123 mmol) and 2′-(bromomethyl)- 4-Fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl-3-ol (52.0 mg, 0.123 mmol) in anhydrous CH ₂ Cl ₂ (6.1 mL) , and the reaction was stirred overnight. The reaction mixture was diluted with _CH2Cl2 (45 mL), washed with saturated _NaHCO3 (5 mL) and 30% saturated _{Na2SO3 (} 5 mL), dried ( _Na2SO4 ) and concentrated in vacuo to obtain the crude _{product .} This was purified by flash chromatography (Si, 12 x 160 mm, gradient 0-40% EtOAc in hexanes) to afford 2-{[2'-(bromomethyl)-4-fluoro-5-iso Propyl-2-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]oxy}tetrahydro-2H-pyran. _Rf = 0.59 (20% EtOAc in hexanes).

¹ H NMR (600MHz, CDCl ₃ ) δ7.82(s, 1H), 7.60(d, J=7.0Hz, 1H), 7.41(d, J=8.0Hz, 1H), 6.67(d, J=7.8Hz , 1H), 5.77(s, 1H), 4.97(dd, J=4.9, 2.9Hz, 1H), 4.49(d, J=9.8Hz, 1H), 4.37(d, J=9.8Hz, 1H), 3.89 -3.87(m, 1H), 3.61-3.49(m, 1H), 3.46(s, 3H), 3.27-3.21(m, 1H), 1.89-1.83(m, 1H), 1.78-1.70(m, 1H) 1.64-1.48(m, 3H), 1.26(d, J=6.8Hz, 6H).

Step F: (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-3'-hydroxy-5'-isopropyl-2' -Methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Sodium hydride (60% dispersion in mineral oil, 14.7 mg, 0.368 mmol) was added to (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4- A stirred solution of methyl-1,3-oxazolidin-2-one (57.7 mg, 0.184 mmol) in anhydrous THF (2 mL). After 30 minutes, 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol (62.0 mg, 0.123 mmol) in anhydrous THF (2 mL), and the reaction mixture was stirred overnight. Sat. _NH4Cl (10 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined extracts _were dried ( _Na2SO4 ) and concentrated in vacuo to afford the crude product. Purification by flash chromatography (Si, 12 x 160 mm, gradient 0-40% EtOAc in hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl) Phenyl]-3-{[4'-fluoro-3'-hydroxy-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl} -4-Methyl-1,3-oxazolidin-2-one. _Rf = 0.25 (20% EtOAc in hexanes). LCMS calculated = 654.2; found = 654.2 (M+1) ⁺ . ¹ H NMR (500 MHz, CDCl ₃ , 1:1 mixture of atropisomers)

δ7.86(m, 1H), 7.73-7.63(m, 4H), 7.44(m, 1H), 6.55(d, J=7.6Hz, 0.5H), 6.52(d, J=7.7Hz, 0.5H), 5.71(br s, 1H), 5.60(d, J=8.0Hz, 0.5H), 5.54(d, J=8.0Hz, 0.5H), 4.87(d, J=16.0Hz, 0.5H), 4.72(d , J=16.1Hz, 0.5H), 4.23(d, J=16.1Hz, 0.5H), 3.98(d, J=15.9Hz, 0.5H), 3.93-3.85(m, 0.5H), 3 .77- 3.71(m, 0.5H), 3.51(s, 1.5H), 3 47(s, 1.5H), 3.25-3.17(m, 1H), 1.26-1.18(m, 6H), 0.58(d, J=6.5 Hz, 1.5H), 0.38(d, J=6.6Hz, 1.5H).

Example 284

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-2',3'-dihydroxy-5'-isopropyl-4 -(Trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Boron tribromide (17.4 mg, 6.6 μL, 0.0692 mmol) was added to (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3 at -78°C under nitrogen. -{[4'-fluoro-3'-hydroxy-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl)-4-methyl - a stirred solution _of 1,3-oxazolidin-2-one (22.6 mg, 0.0346 mmol) in anhydrous _CH2Cl2 (1 mL), and the reaction was stirred for 8 hours. The reaction was diluted with water (5 mL) and extracted with EtOAc (3 x 20 mL). The combined extracts _were dried ( _Na2SO4 ) and concentrated in vacuo to afford the crude product. It was purified by chiral HPLC (IA column, 20 x 250 mm, 15% i-PrOH in heptane) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl) Phenyl]-3-{[4'-fluoro-2',3'-dihydroxy-5'-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4- Methyl-1,3-oxazolidin-2-one. _Rf = 0.24 (20% EtOAc in hexanes). LCMS calcd = 640.2; found = 640.2 (M+1) ⁺ . ¹ H NMR (600 MHz, CDCl ₃ , 1:1 mixture of atropisomers)

δ7.85(s, 1H), 7.70-7.62(m, 4H), 7.41(m, 1H), 6.52(s, 0.5H), 6.51(s, 0.5H), 6.20(br s, 2H), 5.65 (d, J=7.9Hz, 0.5H), 5.38(d, J=8.0Hz, 0.5H), 5.00(d, J=15.5Hz, 0.5H), 4.92(d, J=15.6Hz, 0.5H, 4.15(d, J=15.5Hz, 0.5H), 4.02(d, J=15.6Hz, 0.5H), 3.88(t, J=6.7Hz, 0.5H), 3.77(t, J=6.7Hz, 0.5H ), 3.19-3.13(m, 1H), 1.26-1.17(m, 6H), 0.59(d, J=6.1Hz, 1.5H), 0.48(d, J=6.2Hz, 1.5H).

Intermediate 20

Step A: 2-(2-Fluoro-3,4-dimethoxyphenyl)propan-2-ol

Methylmagnesium chloride (3M solution in THF, 1.74 mL, 5.22 mmol) was added dropwise to 1-(2-fluoro-3,4-dimethoxyphenyl)ethanone ( J. Chem. Soc. Perkin Trans. 2 1994, 547-555) (646 mg, 3.26 mmol) in a stirred solution in heptane (3.1 mL) and THF (1.4 mL). The reaction was warmed to room temperature and stirred for 4 hours. 50% saturated _NH4Cl (20 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined extracts were dried ( _Na2SO4 ) and concentrated _in vacuo to afford 2-(2-fluoro-3,4-dimethoxyphenyl)propan-2-ol as a colorless oil. LCMS calcd = 197.1; found = 197.1 (M-OH) ⁺ .

¹ H NMR (600MHz, CDCl ₃ ) δ7.14(t, J=8.8Hz, 1H), 6.61(dd, J=8.8, 1.4Hz, 1H), 3.86(s, 3H), 3.83(s, 3H) , 2.56-2.25(br s, 1H), 1.58(s, 6H).

Step B: 2-Fluoro-1-isopropyl-3,4-dimethoxybenzene

10% palladium on carbon (69.8 mg) in 2-(2-fluoro-3,4-dimethoxyphenyl)propan-2-ol (698 mg, 3.26 mmol) in 5N HCl (0.7 mL) and EtOH ( The suspension in solution in 5.6 mL) was stirred overnight at room temperature under _H2 (15 psi). The mixture was filtered through a plug of celite and washed with EtOAc (-75 mL). The filtrate was washed with 50% saturated brine (10 mL), dried ( _MgSO4 ) and concentrated in vacuo to afford 2-fluoro-1-isopropyl-3,4-dimethoxybenzene.

¹ H NMR (500MHz, CDCl ₃ ) δ6.86(t, J=8.3Hz, 1H), 6.63(dd, J=8.7, 1.5Hz, 1H), 3.89(s, 3H), 3.84(s, 3H) , 3.19-3.11(m, 1H), 1.22(d, J=6.8Hz, 6H).

Step C: 1-Bromo-3-fluoro-2-isopropyl-4,5-dimethoxybenzene

Add bromine (80.6 mg, 26 μL, 0.504 mmol) to 2-fluoro-1-isopropyl-3,4-dimethoxybenzene (50.0 mg, 0.252 mmol) and potassium acetate (49.5 mg, 0.504 mmol) at room temperature ) in acetic acid (1 mL), and the reaction was stirred overnight. _The reaction was diluted with water (10 mL) and saturated _Na2SO3 (10 mL), and extracted with EtOAc (3 x 20 mL). The combined extracts were washed with saturated NaHCO ₃ (2 x 10 mL), dried (MgSO ₄ ) and concentrated in vacuo to afford 1-bromo-3-fluoro-2-isopropyl-4,5-dimethoxybenzene .

¹ HNMR (600MHz, CDCl ₃ ) δ6.86(d, J=2.0Hz, 1H, 3.87(s, 3H), 3.81(s, 3H), 3.43-3.34(m, 1H), 1.31-1.29(dd, J=7.1, 1.4Hz, 6H).

The compounds in Table 14 were prepared following the general procedure described above:

Table 14

Example 289

5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-(difluoromethyl)-2'-methoxy-4-(trifluoromethyl)biphenyl- 2-yl]methyl}-1,3-oxazolidin-2-one

Step A: 2'-({5-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-methanol Oxy-4'-(trifluoromethyl)biphenyl-3-carbaldehyde

5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one ( Example 66, 50 mg; 0.0858 mmol), 5-formyl-2-methoxyphenylboronic acid (46 mg; 0.257 mmol), tetrakis(triphenylphosphine)palladium(0) (12 mg; 0.0103 mmol) and sodium carbonate (74 mg) in benzene/ethanol/water (2.8/0.4/1.2 mL) was heated at reflux for 60 hours. The reaction was diluted with EtOAc (30 mL), washed sequentially with _H2O (10 mL) and brine (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-50% EtOAc/hexanes gradient) to afford 2'-({5-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-1 , 3-oxazolidin-3-yl}methyl)-6-methoxy-4'-(trifluoromethyl)biphenyl-3-carbaldehyde as a yellow oil. LCMS = 592.1 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz, mixture of atropisomers):

δ9.98(s, 1H), 7.99-7.96(m, 1H), 7.90(s, 1H), 7.75(s, 2H), 7.69-7.64(m, 2Hz), 7.53(s, 1H), 7.41- 7.38(m, 1H), 7.17-7.14(m, 1H), 5.37(t, J=8.2Hz, 1H), 4.59(d, J=15.3Hz, 1H), 4.37(d, J=15.6Hz, 1H ), 3.92(s, 3H), 3.67-3.64(m, 1Hz), 3.19-3.16(m, 1H).

Step B: 5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5'-(difluoromethyl)-2'-methoxy-4-(trifluoromethyl) Biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one

At 0°C, diethylaminosulfur trifluoride (22 μL, 0.1675 mmol) was added dropwise to 2′-({5-[3,5-bis(trifluoromethyl)phenyl]-2-oxo- 1,3-oxazolidin-3-yl}methyl)-6-methoxy-4′-(trifluoromethyl)biphenyl-3-carbaldehyde (Step A, 50 mg, 0.0838 mmol) in CH ₂ Cl ₂ (1 mL) in a stirred solution. The reaction was stirred at room temperature for 14 hours. _{The reaction was treated with water at 0 °C, diluted with CH2Cl2 (10 mL), washed with H2O ( 10} mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford 5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-(difluoromethane Base)-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one, a clear glass. LCMS = 594.2 (M-19) ⁺ . ¹ H NMR (Benzene-d ₆ , 500 MHz, mixture of atropisomers):

δ7.64(s, 1H), 7.38-7.36(m, 2H), 7.30-7.26(m, 2H), 7.14-7.11(m, 2H), 6.85(d, J=8Hz, 1H), 6.45(d , J=8.5Hz, 1H), 6.37-6.13(m, 1H), 4.46-4.38(m, 2H), 3.79-3.76(m, 1H), 3.21(s, 3H), 2.36(t, J=8.7 Hz, 1H), 2.05(t, J=8.4Hz, 1H).

This compound was separated into its enantiomers (5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[ 5'-(difluoromethyl)-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one and (5R )-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-(difluoromethyl)-2′-methoxy-4-(trifluoromethyl)bis phen-2-yl]methyl}-1,3-oxazolidin-2-one.

Example 290

5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-4,5'-bis(trifluoromethyl)-biphenyl-2-yl]methanol Base}-1,3-oxazolidin-2-one

Step A: 2-Iodo-1-methoxy-4-(trifluoromethyl)benzene

To a stirred solution of 2-methoxy-5-(trifluoromethyl)aniline (500 mg, 2.62 mmol) in _CH2Cl2 (10 mL) was added tert _- butyl nitrite (467 μL, 3.93 mmol). The reaction was stirred for 5 minutes, then iodine (1.3 g, 5.24 mmol) was added and heated at 70° C. for 2 hours. _The reaction was cooled, diluted with _CH2Cl2 (10 mL), washed with saturated _{Na2S2O3 (} 10 mL) and _brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (hexanes) to afford 2-iodo-1-methoxy-4-(trifluoromethyl)benzene as a pale yellow solid.

¹ H NMR (CDCl ₃ , 500MHz): δ8.05 (d, J=2Hz, 1H), 7.61 (dd, J=8.7, 1.8Hz, 1H), 6.89 (d, J=8.7Hz, 1H), 3.97 (s, 3H).

Step B: [2-Methoxy-5-(trifluoromethyl)phenyl]boronic acid

n-Butyllithium (1.6M solution in hexane, 456 μL, 0.729 mmol) was added dropwise to 2-iodo-1-methoxy-4-(trifluoromethyl)benzene ( Step A, 200 mg, 0.662 mmol) in a stirred solution in THF (1, 5 mL). The reaction was stirred at -78°C for 30 minutes, then triisopropyl borate (458 μL, 1.986 mmol) was added. The reaction was stirred at -78°C for an additional 2 hours and quenched with saturated _NH4Cl . The mixture was extracted with _CH2Cl2 , the organic phase was washed with _NaHCO3 (15 mL) and brine (15 _mL ), dried ( _Na2SO4 ), filtered and concentrated in vacuo to afford [2 _- methoxy-5- (Trifluoromethyl)phenyl]boronic acid which was used without purification.

Step C: 5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-4,5'bis(trifluoromethyl)-biphenyl-2-yl ]Methyl}-1,3-oxazolidin-2-one

5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one ( Example 66, 100 mg; 0.171 mmol) was treated with [2-methoxy-5-(trifluoromethyl)phenyl]boronic acid (Step B, 113 mg; 0.514 mmol), tetrakis(triphenylphosphine)palladium(0) (24 mg; 0.0206 mmol) and sodium carbonate (148 mg) were treated as described in Example 291 to afford 5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy Base-4,5′-bis(trifluoromethyl)-biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one, which is a clear glass. LCMS = 612.1 (M-19) ⁺ . ¹ HNMR (Benzene-d ₆ , 500 MHz, mixture of atropisomers):

δ7.61(s, 1H), 7.40-7.36(m, 1H), 7.31(s, 1H), 7.27-7.23(m, 4H), 6.74-6.72(m, 1H), 6.35(d, J=8.7 Hz, 1H), 4.42-4.32(m, 2H), 3.70(d, J=15.8Hz, 1H), 3.14(s, 3H), 2.28(t, J=8.7Hz, 1H), 1.98(t, J =8.2Hz, 1H)

This compound was separated into its enantiomers (5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[ 2′-Methoxy-4,5′-bis(trifluoromethyl)-biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one and (55)-5-[ 3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-4,5'-bis(trifluoromethyl)-biphenyl-2-yl]methyl}- 1,3-oxazolidin-2-one.

Intermediate 21

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1, 3-oxazolidin-2-one

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (400 mg, 1.28 mmol) was dissolved in NaH ( 60% dispersion in oil, 128 mg, 3.2 mmol) and 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (Example 70, 466 mg, 1,28 mmol) as in Example Workup as described in 66 afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl] -4-Methyl-1,3-oxazolidin-2-one as a white solid.

LCMS=598.0(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz): δ8.06(d, J=8.2Hz, 1H), 7.93(s, 1H), 7.82(s, 2H), 7.61( s, 1H), 7.33(dd, J=8.2, 1.4Hz, 1H), 5.79(d, J=7.8hz, 1H), 4.91(d, J=16Hz, 1H), 4.40(d, J=16Hz, 1H), 4.16-4.06(m, 1H), 0.83(d, J=6.4Hz, 3H).

Example 291

(4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-methoxy-5-methyl-3-thienyl)-5-( Trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

Step A: 3,5-Dibromo-2-methoxythiophene

To a stirred solution of 2-methoxythiophene (1 g, 8.76 mmol) in _CH2Cl2 (18 mL) was slowly added N _- bromosuccinimide (3.12 g, 17.52 mmol) at 0 °C. The reaction was warmed to room temperature and stirred for 14 hours. The reaction was cooled in an ice bath and filtered. The filtrate was washed with saturated NaHCO ₃ (2×25 mL). The aqueous layer was neutralized with 1N HCl and extracted with _CHCl3 (3 x 25 mL). The combined organic layers were washed with brine (25 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (hexanes) to afford 3,5-dibromo-2-methoxythiophene as a pale pink oil. LCMS = 272.9 (M+) ⁺ .

Step B: 3-Bromo-2-methoxy-5-methylthiophene

n-Butyllithium (2.0 M solution in pentane, 0.97 mL, 1.93 mmol) was added to 3,5-dibromo-2-methoxythiophene (Step A, 500 mg, 1.84 mmol) in a stirred solution in THF (5 mL). The reaction was stirred at -78°C for 1 hour, then methyl iodide (114 μL, 1.84 mmol) was added. The reaction was warmed to room temperature and stirred for 20 hours. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (15 mL) and _H2O (15 mL). The aqueous layer was extracted again (2 x 15 mL), the combined organic layers were washed with _H2O (15 mL) and brine (15 mL), dried ( _MgSO4 ), filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (hexanes) to afford 3-bromo-2-methoxy-5-methylthiophene as a yellow oil.

¹ HNMR (CDCl ₃ , 500MHz): δ6.44(s, 1H), 3.95(s, 3H), 2.41(s, 3H).

Step C: (2-Methoxy-5-methyl-3-thienyl)boronic acid

Under nitrogen, combine 3-bromo-2-methoxy-5-methylthiophene (Step B, 296 mg, 1.43 mmol) and triisopropyl borate (396 μL, 2.15 mmol) in toluene/THF (2.3/0.6 mL ) was cooled to -70°C. n-BuLi (2.0 M solution in pentane, 1.07 mL, 2.15 mmol) was added dropwise via syringe pump over 1 h. The reaction was stirred at -70°C for an additional 40 min with 2N HC. (2 mL) was treated at -20°C. The reaction was partitioned between EtOAc (15 mL) and _H2O (15 mL). The aqueous layer was extracted with EtOAc (10 mL); the combined organic layers were washed with brine (15 mL), dried (Na ₂ SO ₄ ), filtered, and concentrated in vacuo to afford (2-methoxy-5-methyl- 3-thienyl) boronic acid, as a yellow oil. The product was used without further purification.

Step D: (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-[2-(2-methoxy-5-methyl-3-thienyl)- 5-(Trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one

(4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1 , 3-Oxazolidin-2-one (Intermediate 21, 13 mg; 0.0219 mmol) with (2-methoxy-5-methyl-3-thienyl)boronic acid (Step C, 10.4 mg; 0.0657 mmol), Tetrakis(triphenylphosphine)palladium(0) (3 mg; 0.0026 mmol) and sodium carbonate (20 mg) were treated as described in Example 291 to afford (4S,5R)-5-[3,5-bis(tri Fluoromethyl)phenyl]-3-[2-(2-methoxy-5-methyl-3-thienyl)-5-(trifluoromethyl)benzyl]-4-methyl-1, 3-oxazolidin-2-one, a yellow glass.

LCMS=598.2(M+1) ⁺ . ¹ H NMR (benzene-d ₆ , 500MHz): δ7.75(s, 1H), 7.57(s, 1H), 7.31-29(m, 1H), 7.24(s , 2H), 7.12-7.10(m, 1H), 6.14(s, 1H), 4.96(d, J=16Hz, 1H), 4.57(d, J=8Hz, 1H), 3.99(d, J=15.8Hz , 1H), 3.30(s, 3H), 2.95-2.92(m, 1H), 2.05(s, 3H), -0.28(d, J=6.7Hz, 3H).

The compounds in Table 15 were prepared following the general procedure described above:

Table 15

Example 298

(4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-2'-methoxy-5'-(2-methyl-1 ,3-dioxolan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-1,3-oxazolidin-2-one

(4S, 5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1 , 3-oxazolidin-2-one (intermediate 21, 7.34g, 12.29mol), [4-fluoro-2-methoxy-5-(2-methyl-1,3-dioxolane Alk-2-yl)phenyl]boronic acid (5.5 g, 21.48 mol), tetrakis(triphenylphosphine)palladium(0) (1.7 g; 1.47 mol) and sodium carbonate (10 g) in benzene/EtOH/H ₂ O (203/29/86 mL) the mixture was heated to reflux for 14 hours. The reaction was treated with _H2O , partitioned between EtOAc (250 mL) and _H2O (75 mL). The aqueous layer was further extracted with EtOAc (3 x 200 mL). The combined extracts were washed with brine (100 mL), dried ( _MgSO4 ), filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4 '-Fluoro-2'-methoxy-5'-(2-methyl-1,3-dioxolan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl ]methyl}-4-1,3-oxazolidin-2-one, an amorphous solid. LCMS = 682.2 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz, mixture of atropisomers):

δ7.86(s, 1H), 7.71(S, 3H), 7.65-7.61(m, 1H), 7.37-7.34(m, 1H), 7.32-7.28(m, 1H), 6.75(dd, J=12.4 , 3.6Hz, 1H), 5.58(d, J=8.1Hz, 1H), 4.89(d, J=15.8Hz, 1H), 4.08-4.04(m, 2H), 3.91-3.76(m, 7H), 1.73 (d, J=10.5Hz, 3H), 0.4(d, J=6.5Hz, 3H).

Example 299

(4S, 5R)-3-{[5′-acetyl-4′-fluoro-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[ 3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-2'-methoxy-5'-(2-methyl- 1,3-dioxolan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-1,3-oxazolidin-2-one (8g , 0.0118 mol) in acetone (400 mL) was added p-toluenesulfonic acid monohydrate (670 mg, 0.0035 mol). The reaction was stirred at room temperature for 14 hours. The reaction was partitioned between EtOAc (250 mL) and saturated NaHCO ₃ (250 mL). The aqueous layer was further extracted with EtOAc (3 x 250 mL), the combined organic layers were washed with brine (200 mL), dried ( _MgSO4 ), filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,5R)-3-{[5'-acetyl-4'-fluoro-2'-methoxy-4 -(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidine-2 - Ketone, as a yellow solid. LCMS = 638.2 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz, mixture of atropisomers):

δ7.87(8, 1H), 7.81-7.79(m, 1H), 7.74(s, 1H), 7.70(s, 2H), 7.59(s, 1H), 7.39(d, J=8Hz, 1H), 6.80(d, J=12.8Hz, 1H), 5.27(d, J=8.2Hz, 1H), 4.97(d, J=15.3Hz, 1H), 4.04(d, J=15.5Hz, 1H), 3.94( s, 3H), 3.72-3.66(m, 1H), 2.67-2.64(m, 3H), 0.62(d, J=6.4Hz, 3H).

Example 300

(4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropenyl-2'-methoxy-4-( Trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Methylmagnesium iodide (29 μL, 0.085 mmol) was added dropwise to (4S,5R)-3-{[5′-acetyl-4′-fluoro-2′-methoxy-4-(trifluoro Methyl)biphenyl-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (30mg , 0.047 mmol) in ether (2 mL). The reaction was carefully heated to reflux for 4 hours. After addition of methylmagnesium iodide (63 μL, 0.19 mmol) and diethyl ether (1 mL), the reaction was refluxed for 3 hours. The reaction was treated with saturated _NH4Cl and extracted with EtOAc (3 x 25 mL). The combined extracts were washed with brine (25 mL), dried (Na ₂ SO ₄ ), filtered, and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4 '-Fluoro-5'-isopropenyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidine- 2-ketone is a clear glass. LCMS = 636.3 (M+1) ⁺ . ¹ H NMR (Benzene-d ₆ , 500 MHz, mixture of atropisomers):

δ7.59(s, 1H), 7.55(s, 1H), 7.35(d, J=8Hz, 1H), 7.30-7.27(m, 2H), 6.99-6.96(m, 2H), 6.45(d, J =12.9Hz, 1H), 5.32(d, J=16.9Hz, 1H), 5.16-5.15(m, 1H), 4.90(d, J=16.3Hz, 1H), 4.48(d, J=7.7Hz, 1H ), 3.70(d, J=6.4Hz, 1H), 3.16(s, 3H), 2.85-2.79(m, 1H), 2.12(s, 3H), -0.025(d, J=6.5Hz, 3H).

Example 301

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-([4′-fluoro-2′-hydroxy-5′-isopropenyl-4-(trifluoro Methyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropenyl-2'-methoxy-4- (Trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Example 300, 50 mg, 0.078 mmol) in DMF (450 μL) Lithium chloride (13.4 mg, 0.315 mmol) was added to the stirred solution. The vial was sealed and the reaction was heated at 160°C for 14 hours. 10% NaOH (10 mL) was added and the resulting solution was extracted with ether (3 x 10 mL). The aqueous layer was acidified with 3N HCl to pH~3 and re-extracted with diethyl ether (3 x 25 mL). The combined organic extracts were washed with brine (25 mL), dried ( _MgSO4 ), filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4 '-fluoro-2'-hydroxy-5'-isopropenyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidine-2- Ketone, a clear glass. LCMS = 622.1 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz, mixture of atropisomers):

δ7.90(s, 1H), 7.76-7.70(m, 4H), 7.48-7.45(m, 1H), 7.11-7.07(m, 1H), 6.75(d, J=11.7Hz, 1H), 5.71( d, J=7.8Hz, 1H), 5.59-5.56(m, 1H), 5.25-5.21(m, 2H), 4.81(d, J=15.4Hz, 1H), 4.04(d, J=15.6Hz, 1H ), 3.97-3.92(m, 1H), 2.13(s, 3H), 0.58(d, J=6.6Hz, 3H).

Example 302

(4S)-4-Benzyl-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl} -1,3-oxazolidin-2-one

A stirred suspension of sodium hydride (60% dispersion in oil, 37 mg, 0.926 mmol) in THF (1 mL) was dissolved with (S)- 4-Benzyl-2-oxazolidinone (33 mg, 0.185 mmol) was treated. The reaction was stirred for 20 minutes and 2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl (interm. 10, 50 mg, 0.124 mmol) in THF (1 mL). The reaction was stirred at room temperature for 60 hours. The reaction was treated with _H2O (1 mL), partitioned between EtOAc (25 mL) and _H2O (10 mL). The aqueous phase was further extracted with EtOAc (3 x 15 mL), the combined organic extracts were washed with brine (25 mL), dried ( _MgSO4 ) and concentrated in vacuo to afford the crude product. Purification by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) afforded (4S)-4-benzyl-3-{[4'-fluoro-5'-isopropyl-2'-methoxy -4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one, a clear glass. LCMS = 502.3 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz, mixture of atropisomers)

δ7.69-7.64(m, 1H), 7.58(s, 1H), 7.39-7.36(m, 1H), 7.29-7.24(m, 3H), 7.06(d, J=8.5Hz, 1H), 6.97- 6.91(m, 2H), 6.73(d, J=11.7, 1H), 4.79(d, J=15.8Hz, 1H), 4.30(d, J=15.8Hz, 1H), 4.08-4.05(m, 1H) , 3.99-3.97(m, 1H), 3.76(s, 3H), 3.65-3.58(m, 1H), 3.27-3.17(m, 1H), 2.81(dd, J=13.5, 4.1Hz, 1H), 2.45 -2.40(m, 1H), 1.30-1.4(m, 6H).

Example 303

(4S)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-(4 -Methylbenzyl)-1,3-oxazolidin-2-one

Step A: (2S)-2-Amino-3-(4-methylphenyl)propan-1-ol

A mixture of lithium aluminum hydride (254 mg, 6.696 mmol) in THF (20 mL) was heated at reflux for 1 h, then cooled in an ice bath. (S)-4-Methylphenylalanine (500 mg, 2.79 mmol) was added portionwise and the mixture was allowed to heat to reflux for 14 hours. Excess lithium aluminum hydride was decomposed by sequentially adding _H2O (1 mL), 10% aqueous NaOH (10 mL) and _H2O (2.5 mL). The mixture was filtered and the solid was washed with THF. The filtrate was concentrated in vacuo and the residue was dissolved in _CHCl3 (50 mL), washed with 5% aqueous NaOH (25 mL), _H2O (25 mL) and brine (25 mL), dried ( _MgSO4 ), filtered, and vacuum Concentration afforded (25)-2-amino-3-(4-methylphenyl)propan-1-ol as an off-white solid.

¹ H NMR (CD ₃ OD, 500MHz) δ7.13-7.09 (m, 4H), 3.52 (dd, J=10.7, 4.6Hz, 1H), 3.36 (dd, J=10.7, 6.9Hz, 1H), 3.04 -2.99(m, 1H), 2.73(dd, J=13.5, 6.2Hz, 1H), 2.53(dd, J=13.5, 7.7Hz, 1H), 2.30(s, 3H).

Step B: (4S)-4-(4-Methylbenzyl)-1,3-oxazolidin-2-one

(2S)-2-Amino-3-(4-methylphenyl)propan-1-ol (Step A, 460 mg, 2.79 mmol) in _CH2Cl2 (20 _mL ) was dissolved under nitrogen at 0 °C The stirred solution was treated with diisopropylethylamine (2.92 mL, 16.74 mmol) and triphosgene (414 mg, 1.39 mmol). The reaction was stirred at 0 °C for 3 hours. The reaction was treated with saturated _NaHCO3 (10 mL) and extracted with EtOAc (4 x 20 mL). The combined organic layers were washed with brine (25 mL), dried ( _MgSO4 ), filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-70% EtOAc/hexanes gradient) to afford (4S)-4-(4-methylbenzyl)-1,3-oxazolidin-2-one as white solid.

LCMS=192.2(M+1) ^{+ .1} H NMR (CDCl ₃ , 500MHz) δ7.17(d, J=8Hz, 2H), 7.09(d, J=7.7Hz, 2H), 5.39(br s, 1H ), 4.48(t, J=8.4Hz, 1H), 4.37(dd, J=8.6, 5.6Hz, 1H), 4.11-4.06(m, 1H), 2.86(d, J=7.1Hz, 2H), 2.36 (s, 3H).

Step C: (4S)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4 -(4-Methylbenzyl)-1,3-oxazolidin-2-one

(4S)-4-(4-Methylbenzyl)-1,3-oxazolidin-2-one (Step B, 14 mg, 0.074 mmol) was dissolved in sodium hydride (60% dispersion in oil, 6.2 mg, 0.154mmol) and 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl (intermediate 10, 25mg, 0.062 mmol) were treated as described in Example 305 to afford (4S)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)bis phen-2-yl]methyl}-4-(4-methylbenzyl)-1,3-oxazolidin-2-one as a clear gum. LCMS = 516.4 (M+1) ⁺ . 1H NMR (CDCl ₃ , 500MHz, mixture of atropisomers)

δ7.65-7.60(m, 1H), 7.53(s, 1H), 7.35-7.32(m, 1H), 7.06-7.20(m, 2H), 6.82-6.75(m, 2H), 6.69(d, J =11.7Hz, 1H), 4.67(d, J=15.8Hz, 1H), 4.06(d, J=15.8Hz, 1H), 4.04-4.00(m, 1H), 3.96-3.93(m, 1H), 3.73 (s, 3H), 3.55-3.48(m, 1H), 3.23-3.15(m, 1H), 2.63(dd, J=13.5, 3.6Hz, 1H), 2.35(d, J=13.5Hz, 1H), 2.29(s, 3H), 1.25-1.13(m, 6H).

The compounds in Table 16 were prepared following the general procedure described above:

Table 16

Example 317

(4S, 5S)-4-benzyl-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol Base}-5-methyl-1,3-oxazolidin-2-one

Step A: tert-butyl [1(S)-1-benzyl-2-oxopropyl]carbamate

N-(tert-butoxycarbonyl)-N-methoxy-N-methyl-1-phenylalaninamide (500 mg, 1.62 mmol) was dissolved in THF (3 mL) at -15 °C under nitrogen. The stirred solution was treated with methylmagnesium bromide (540 [mu]L, 1.62 mmol). The reaction was stirred at -15°C for 15 minutes, then methylmagnesium bromide (1.08 mL, 3.24 mmol) was added dropwise. The reaction was stirred at room temperature for 14 hours and treated with 1N HCl (5 mL). The mixture was partitioned between _H2O (15 mL) and EtOAc (20 mL), and the aqueous layer was extracted with additional EtOAc (2 x 20 mL). The combined organic layers were washed with _H2O (20 mL) and brine (20 mL), dried ( _Na2SO4 ), filtered and concentrated in vacuo _. The crude product was purified by flash silica gel chromatography to afford tert-butyl [1(S)-1-benzyl-2-oxopropyl]carbamate as a white solid.

LCMS=164.2 (M-BOC) ^{+ .1} H NMR (CDCl ₃ , 500MHz) δ7.34-7.26 (m, 3H), 7.18 (d, J=7.1Hz, 2H), 5.15 (br s, 1H), 4.59-4.56(m, 1H), 3.14-2.99(m, 2H), 2.16(s, 3H), 1.44(s, 9H).

Step B: tert-butyl [(1S)-1-benzyl-2-hydroxypropyl]carbamate

[1(S)-1-Benzyl-2-oxopropyl]carbamate tert-butyl ester (Step A, 150 mg, 0.57 mmol) was stirred in anhydrous MeOH (5 mL) at -20 °C The solution was treated with sodium borohydride (44.2 mg, 1.169 mmol). The reaction was stirred at -20 °C for 1 h, treated with _H2O (1 mL) and concentrated in vacuo. The residue was dissolved in EtOAc (25 mL), washed sequentially with _H2O (15 mL) and brine (15 mL), dried ( _Na2SO4 ), filtered and concentrated in vacuo _. The crude product was purified by preparative TLC eluting with 15% acetone/hexanes to give [(1S,2R)-1-benzyl-2-hydroxypropyl]carbamate tert-butyl ester (45 mg) and [ (1S,2S)-tert-butyl 1-benzyl-2-hydroxypropyl]carbamate as a white solid. [(1S,2R)-1-Benzyl-2-hydroxypropyl]carbamate tert-butyl ester:

LCMS=166.2(M-BOC) ⁺ . ¹ H NMR(CDCl ₃ , 500MHz) δ7.34-7.31(m, 2H), 7.26-7.23(m, 3H), 4.81(br s, 1H), 3.83(dq , J=6.4, 2.7Hz, 1H), 3.71-3.69(m, 1H), 2.90(d, J=7.3Hz, 2H), 1.43(s, 9H), 1.22(d, J=6.5Hz, 3H) .

[(1S,2S)-1-Benzyl-2-hydroxypropyl]carbamate tert-butyl ester

LCMS=166.2(M-BOC) ⁺ . ¹ H NMR(CDCl ₃ , 500MHz) δ7.34-7.31(m, 2H), 7.26-7.23(m, 3H), 4.58(br s, 1H), 3.3.93 -3.85(m, 2H), 2.90(dd, J=14.2, 5Hz, 1H), 2.82-2.73(m, 1H), 1.40(s, 9H), 1.25(d, J=6.4Hz, 3H).

Step C: (4S,5S)-4-Benzyl-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2- Base]methyl}-5-methyl-1,3-oxazolidin-2-one

[(1S,2S)-1-Benzyl-2-hydroxypropyl]carbamate tert-butyl ester (Step B, 39 mg, 0.148 mmol) was dissolved in sodium hydride (60% dispersion in oil, 12 mg, 0.309 mmol ) and 2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl (intermediate 10, 50mg, 0.123mmol) as implemented Workup as described in Example 305 afforded (4S,5S)-4-benzyl-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl ) biphenyl-2-yl]methyl}-5-methyl-1,3-oxazolidin-2-one, a clear glass. LCMS = 516.4 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz, mixture of atropisomers)

δ7.68(d, J=11.5Hz, 1H), 7.66-7.63(m, 1H), 7.39-7.36(m, 1H), 7.28-7.23(m, 3H), 7.07(d, J=8.5Hz, 1H), 6.94(d, J=6.9Hz, 2H), 6.73(d, J=4.8Hz, 1H), 4.81(d, J=16Hz, 1H), 4.38(d, J=16.1Hz, 1H), 4.28 -4.23(m, 1H), 3.78(s, 3H), 3.29-3.17(m, 2H), 2.81(dd, J=13.3, 3.9Hz, 1H), 2.38-2.28(m, 1H), 1.29-1.13 (m, 6H), 0.98 (d, J=6.2Hz, 3H).

Example 318

(4S, 5R)-4-benzyl-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol Base}-5-methyl-1,3-oxazolidin-2-one

[(15,25)-1-Benzyl-2-hydroxypropyl]carbamate tert-butyl ester (Example 317, Step B, 39 mg, 0.148 mmol) was dissolved in sodium hydride (60% dispersion in oil, 12mg, 0.309mmol) and 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl (intermediate 10, 50mg, 0.123 mmol) were treated as described in Example 305 to afford (4S,5R)-4-benzyl-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-( Trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-1,3-oxazolidin-2-one, a clear glass, LCMS=516.4(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz, mixture of atropisomers)

δ7.64-759(m, 2H), 7.33-7.30(m, 1H), 7.28-7.21(m, 2H), 7.16(s, 1H), 7.00-6.91(m, 3H), 6.67(d, J =3Hz, 1H), 4.70(d, J=2.7Hz, 1H), 4.52-4.47(m, 1H), 3.95(d, J=15.8Hz, 1H), 3.70(s, 3H), 3.68-3.62( m, 1H), 3.24-3.18(m, 1H), 2.72-2.53(m, 2H), 1.28-1.21(m, 6H), 1.19(d, J=6.8Hz, 3H).

Example 319

(4R)-4-Benzyl-3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3- oxazolidin-2-one

The title compound was prepared from (R)-4-benzyl-2-oxazolidinone (49 mg, 0.27 mmol) and 2-(bromomethyl)-1-iodo-4-( Trifluoromethyl)benzene (100 mg, 0.27 mmol) gave the title compound as a colorless oil. _Rf = 0.35 (15% EtOAc/Hex). LCMS 484(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) (atropisomers exist)

δ7.72(br s 1H), 7.65(br s, 1H), 7.42(m, 1H), 7.32-7.22(m, 3H), 7.08(m, 1H), 6.90-6.84(m, 3H), 4.81 (d, J=15.8Hz, 1H), 4.35(d, J=15.8Hz), 4.28(t, J=8.7Hz, 1H), 3.96-3.92(m, 3H), 3.78(s, 3H), 3.62 -3.52(m, 1H), 2.94-2.86(m, 1H), 2.82(dd, J=9.4, 3.9Hz, 1H), 2.42(dd, J=9.6, 3.9Hz), 1.26(s, 3H), 1.10(s, 3H).

Example 320

Example 322 was prepared from (S)-4-benzyl-5,5-dimethyl-2-oxazolidinone (10 mg, 0.05 mmol) and 2-(bromomethyl) according to the method described in Example 14 -5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl (20 mg, 0.05 mmol) to give the title compound as a colorless oil. LCMS 512(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) (atropisomers exist)

δ7.72(br s 1H), 7.31(br s, 1H), 7.12-7.02(m, 2H), 6.85-6.82(m, 3H), 6.45-6.35(m, 4H), 4.61(d, J= 15.8Hz, 1H), 4.21(d, J=15.8Hz), 3.21(s, 2H), 3 16(s, 3H), 2.62-2.52(m, 1H), 2.42-2.18(m, 1H), 1.98 (m, 2H), 1.22(d, J=7.1Hz), 1.05(d, J=7.1Hz), 0.98(s, 3H), 0.88(s, 3H).

Example 321

(4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[4'-fluoro-5'-isopropyl]-2'-methoxy-4- (Trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-pyrrolidin-2-one

Step A: Ethyl 3-[3,5-bis(trifluoromethyl)phenyl]acrylate

To a solution of NaH (60% suspension in oil, 168 mg, 4.96 mmol) in THF (3 mL) was added triethyl phosphonoacetate (0.5 mL, 2.52 mmol) at 0 °C under nitrogen. The reaction was stirred at 0 °C for 30 minutes and 3,5-bis(trifluoromethyl)benzaldehyde (609 mg, 2.52 mmol) was added. The reaction was warmed to room temperature, stirred for an additional 2 hours, then concentrated in vacuo. The residue was diluted with EtOAc (20 mL), washed with _H2O , brine, dried over magnesium sulfate, concentrated, and purified by flash chromatography eluting with 10% EtOAc/hexanes to afford the title compound as white solid. LCMS 313(M+1) ⁺ .

Step B. Methyl 3-[3,5-bis(trifluoromethyl)phenyl]-4-nitropentanoate

Ethyl 3-[3,5-bis(trifluoromethyl)phenyl]acrylate (170 mg, 0.54 mmol) and nitromethane (736 uL, 10.29 mmol) were dissolved in tetrabutylammonium hydroxide solution (1.0 M in MeOH solution, 1.5 mL), the mixture was heated to reflux for 3 h, diluted with 10% aqueous ammonium chloride (10 mL) and extracted with EtOAc (4 x 30 mL). The combined organic extracts were washed with 10% ammonium chloride (20 mL), dried over magnesium sulfate, and concentrated in vacuo to give the crude product. Purification by flash chromatography using 10% EtOAC/hexanes afforded methyl 3-[3,5-bis(trifluoromethyl)phenyl]-4-nitropentanoate as colorless Oil.

¹ HNMR (CDCl ₃ , 500MHz) δ7.82(br s 1H), 7.64(br s, 2H), 4.91(m, 1H), 3.91(m, 1H), 3.61(s, 3H), 2.82(m, 2H), 1.42(d, J=6.7Hz, 3H).

Step C: 4-[3,5-Bis(trifluoromethyl)phenyl]-5-methylpyrrolidin-2-one

A suspension of Raney nickel (50% w/v slurry in water, 200 mg) was added to methyl 3-[3,5-bis(trifluoromethyl)phenyl]-4-nitrovalerate in anhydrous solution in EtOH (5 mL), the resulting mixture was stirred at room temperature under a balloon of hydrogen overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to remove EtOH. Purification of the residue by flash chromatography using 75% EtOAC/hexanes afforded threo-4-[3,5-bis(trifluoromethyl)phenyl]-5-methylpyrrolidine-2- Ketone and erythro-4-[3,5-bis(trifluoromethyl)phenyl]-5-methylpyrrolidin-2-one as white solids. Threo-diastereomers:

LCMS 353 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.82 (br s 1H), 7.64 (br s, 2H), 5.72 (br s, 1H), 3.85 (m, 1H), 3.31(dd, J=8.9, 8.2Hz, 1H), 2.61(dd, J=8.9, 8.2Hz, 1H), 1.34(d, J=6.1Hz, 3H).

Erythro-diastereomers:

LCMS 353 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.82 (br s 1H), 7.64 (br s, 2H), 5.76 (br s, 1H), 4.20 (m, 1H), 3.90(m, 1H), 2.81(dd, J=8.5, 8.2Hz, 1H), 2.73(dd, J=8.5, 8.2Hz, 1H), 0.88(d, J=6.7Hz, 3H).

Step D: (4R,5S)-4-[3,5-Bis(trifluoromethyl)phenyl]-1-{[4'-fluoro-5'-isopropyl]-2'-methoxy -4-(Trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-pyrrolidin-2-one

To a stirred suspension of NaH (60% in oil, 4.4 mg, 0.11 mmol) in THF (3 mL) was added erythro-4-[3,5-bis( A solution of trifluoromethyl)phenyl]-5-methylpyrrolidin-2-one (16 mg, 0.051 mmol) in THF (1 mL). The resulting mixture was stirred at 0°C for 30 minutes, then 2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl (16 mg , 0.051 mmol). After 3 hours, the reaction was diluted with 15 mL EtOAc and 5 mL _H2O . The layers were separated and the organic phase was washed with _H2O , brine, dried ( _MgSO4 ) and concentrated. The residue was purified by flash chromatography using 10% EtOAC/hexanes to provide the title compound as a colorless oil. LCMS 636(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) (atropisomers exist)

¹ H NMRδ7.82(br s1H), 7.80(br s, 1H), 7.45-7.36(m, 3H), 7.32-7.22(m, 3H), 7.08(d, J=10.1Hz, 1H), 6.60( m, 1H), 5.05(m, 1H), 4.01(d, J=15.5Hz), 3.78(s, 3H), 3.71-3.52(m, 2H), 3.24(m, 1H), 1.32-1.20(m , 6H), 0.56(d, J=6.4Hz, 3H).

This compound was separated into its two enantiomers (4R,5S)-4-[3,5-di( Trifluoromethyl)phenyl]-1-{[4'-fluoro-5'-isopropyl]-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl }-5-Methyl-pyrrolidin-2-one and (4S, 5R)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[4′-fluoro-5′- isopropyl]-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-pyrrolidin-2-one.

The compounds in Table 17 were prepared following the general procedure described above:

Table 17

Example 327

(4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-6-methyl Base-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Step A: [2,6-Dimethyl-4-(trifluoromethyl)phenyl]amine

2,6-dibromo-4-trifluoromethylaniline (1.00g, 3.14mmol), trimethylboroxine (1.16ml, 1.04g, 8.33mmol), potassium carbonate (1.15g, 8.33mmol) and a catalytic amount (10%) of Pd(PPh ₃ ) ₄ in DMF (5 ml) was heated at 90° C. for 14 hours. Water (10ml) was added. The mixture was extracted with ethyl acetate (3 x 20ml). The combined EtOAc layers were washed with brine and dried over sodium sulfate. Purification by flash column using EtOAc:hexanes (1:9) as eluent afforded the title compound as a colorless oil.

¹ H NMR (CDCl ₃ , 500MHz): δ7.28(s, 1H), 7.22(s, 1H), 3.88(br s, 2H), 2.21(s, 6H).

Step B: 2-iodo-1,3-dimethyl-5-(trifluoromethyl)benzene

A mixture of the title compound from Step A (0.27g, 1.43mmol), n-amyl nitrite (0.50g, 2.86mmol) and _I2 (0.72g, 2.86mmol) in chloroform (10ml) was refluxed for 1 hour. The mixture was diluted with dichloromethane (20ml) and washed with saturated sodium thiosulfate solution and brine. The organic layer was dried over sodium sulfate. Purification by flash column eluting with hexanes afforded the title compound as a pale yellow liquid.

¹ H NMR (CDCl ₃ , 500MHz) δ7.31(s, 2H), 2.58(s, 6H).

Step C: 1-(Bromomethyl)-2-iodo-3-methyl-5-(trifluoromethyl)benzene

A mixture of the title compound from Step B (0.26 g, 0.87 mmol), NBS (0.154 g, 0.87 mmol) and a catalytic amount of AEBN in _CCl4 was refluxed for 6 hours. TLC (hexanes) indicated the presence of a mixture of starting materials and new spots. After additional AIBN was added, the reaction was refluxed for an additional 2 hours. No changes were observed. The reaction mixture was cooled to room temperature and the solvent was removed. Purification by preparative TLC using hexane as eluent afforded the title compound as a white solid, along with starting material.

¹ H NMR (CDCl ₃ , 500MHz): δ7.54(s, 1H), 7.42(s, 1H), 4.67(s, 2H), 2.60(s, 3H)

Step D. (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-[2-iodo-3-methyl-5-(trifluoromethyl)benzyl] -4-Methyl-1,3-oxazolidin-2-one

To a solution of oxazolidinone (0.058 g, 0.186 mmol) in THF (5 ml) from example xx, step xx was added NaH at 0°C. The mixture was stirred at 0°C for 30 minutes. A solution of benzyl bromide from Step C (0.064 g, 0.169 mmol) in THF (5 mL) was added via syringe. The mixture was then stirred at room temperature for 12 hours. The reaction was treated with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (3 x 15ml). The combined EtOAc layers were washed with brine and dried over sodium sulfate. Purification by preparative TLC plate using EtOAc:hexane = 1:9 as eluent afforded the title compound.

¹ HNMR (CDCl ₃ , 500MHz): δ7.92(s, 1H), 7.82(s, 2H), 7.49(s, 1H), 7.38(s, 1H), 5.77(d, J=8Hz, 1H), 4.93(d, J=16Hz, 1H), 4.45(d, J=16Hz, 1H), 4.05(m, 1H), 2.60(s, 3H), 0.81(d, J=6.5Hz, 3H).

Step E: (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropyl-2'-methoxy- 6-Methyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

The title compound from step D (0.07g, 0.11mmol), 2-methoxy-4-fluoro-5-isopropylphenylboronic acid (0.036g, 0.17mmol), sodium carbonate (0.024g, 0.23mmol) ) and a catalytic amount of Pd( _PPh3 ) ₄ in a 2:1:4 EtOH/ _H2O /toluene mixture was heated at reflux for 3 hours. The solvent was removed and the aqueous layer was extracted with dichloromethane (3 x 20ml). The combined dichloromethane layers were washed with brine and dried over sodium sulfate. Purification by preparative TLC plate using EtOAc:hexane = 1:9 as eluent afforded the title compound. The two diastereotropic isomers of the title compound were separated by chiral OD column using EtOH/n-heptane as eluent. Isomer A (eluted faster):

¹ H NMR (CDCl ₃ , 500MHz): δ7.89(s, 1H), 7.75(s, 2H), 7.52(s, 2H), 6.85(d, J=8.5Hz, 1H), 6.71(d, J =12Hz, 1H), 5.63(d, J=8Hz, 1H), 4.71(d, J=16Hz, 1H), 3.93(m, 1H), 3.87(d, J=16Hz, 1H), 3.72(s, 3H), 3.22(m, 1H), 2.09(s, 3H), 1.26(m, 6H), 0.53(d, J=6.5Hz, 3H); LC-MS(M+1): 652.3.

Isomer B (slower eluting):

¹ H NMR (CDCl ₃ , 500MHz): δ7.89(s, 1H), 7.73(s, 2H), 7.53(s, 2H), 6.90(d, J=8.5Hz, 1H), 6.73(d, J =12Hz, 1H), 5.60(d, J=8Hz, 1H), 4.69(d, J=15.5Hz, 1H), 3.88(m, 1H), 3.86(d, J=15.5Hz, 1H), 3.76( s, 3H), 3.22(m, 1H), 2.11(s, 3H), 1.23(m, 6H), 0.48(d, J=6.5Hz, 3H); LC-MS(M+1): 652.3.

Example 328

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-chloro-4'-fluoro-5'-isopropyl-2'-methoxy -4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

Step A. [2-Chloro-6-methyl-4-(trifluoromethyl)phenyl]amine

2-Bromo-6-chloro-4-trifluoromethylaniline (1.00g, 3.64mmol), trimethylboroxine (0.66ml, 0.59g, 4.47mmol), potassium carbonate (1.00g, 7.30mmol) and a catalytic amount (10%) of Pd(PPh ₃ ) ₄ in DMF (5 ml) was heated at 90° C. for 14 hours. Water (20ml) was added. The mixture was extracted with ethyl acetate (3 x 50ml). The combined EtOAc layers were washed with brine and dried over sodium sulfate. Purification by flash column using EtOAc:hexanes (1:9) as eluent afforded the title compound as a colorless oil.

¹ H NMR (CDCl ₃ , 500MHz): δ7.43(s, 1H), 7.24(s, 1H), 4.38(br s, 2H), 2.22(s, 3H).

Step B [2-Chloro-6-(iodomethyl)4-(trifluoromethyl)phenyl]amine

A mixture of the title compound from Step A (0.67g, 3.20mmol), n-amyl nitrite (0.75g, 6.41mmol) and I2 (1.05g, 4.17mmol) in chloroform (10ml) was refluxed for 1 hour. The mixture was diluted with dichloromethane (20ml) and washed with saturated sodium thiosulfate solution and brine. The organic layer was dried over sodium sulfate. Purification by flash column using hexane as eluent afforded 2-iodo-3-chloro-4-trifluoromethylbenzyl iodide.

¹ H NMR (CDCl ₃ , 500MHz): δ7.60(s, 2H), 4.65(s, 2H).

Step C. (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-[3-chloro-2-iodo-5-(trifluoromethyl)benzyl]- 4-Methyl-1,3-oxazolidin-2-one

To a solution of oxazolidinone (0.058 g, 0.186 mmol) in THF (5 ml) from example xx, step xx was added NaH at 0°C. The mixture was stirred at 0°C for 30 minutes. A solution of 2-iodo-3-chloro-4-trifluoromethylbenzyl iodide from Step B (0.226 g, 0.51 mmol) in THF (5 mL) was added via syringe. The mixture was stirred at room temperature for 3 hours. The reaction was treated with saturated ammonium chloride solution and the mixture was extracted with ethyl acetate (3 x 20ml). The combined EtOAc layers were washed with brine and dried over sodium sulfate. Purification by flash column using EtOAc:Hexane = 1:9 as eluent afforded the title compound. LC-MS (M+1): 432.0.

Step D: (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[6-chloro-4'-fluoro-5'-isopropyl-2'- Methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

The title compound from Step C (0.10 g, 0.16 mmol), 2-methoxy-4-fruoro-5-isopropylphenylboronic acid (0.067 g, 0.32 mmol), sodium carbonate (0.034 g, 0.32 mmol) ) and a catalytic amount of Pd( _PPh3 ) ₄ in a 2:1:4 EtOH/ _H2O /toluene mixture was heated at reflux for 4 hours. The solvent was removed and the aqueous layer was extracted with methyl chloride (3 x 15ml). The combined dichloromethane layers were washed with brine and dried over sodium sulfate. Purification by preparative TLC plate using EtOAc:hexane = 1:9 as eluent afforded the title compound. The two diastereotropic isomers of the title compound were separated by a chiral AD column using i-PrOH/n-heptane. Isomer A (eluted faster):

¹ H NMR (CDCl ₃ , 500MHz): δ7.91(s, 1H), 7.75(s, 3H), 7.61(s, 1H), 6.92(d, J=8.5Hz, 1H), 6.73(d, J =12Hz, 1H), 5.64(d, J=8Hz, 1H), 4.72(d, J=16Hz, 1H), 3.95(d, J=16Hz, 1H), 3.93(m, 1H), 3.78(s, 3H), 3.22(m, 1H), 1.23(m, 6H), 0.55(d, J=7Hz, 3H); LC-MS(M+1): 672.1.

Isomer B (slower eluting):

¹ H NMR (CDCl ₃ , 500MHz): δ7.89(s, 1H), 7.75(s, 1H), 7.73(s, 2H), 7.62(s, 1H), 6.98(d, J=8.5Hz, 1H ), 6.74(d, J=12Hz, 1H), 5.61(d, J=8.5Hz, 1H), 4.72(d, J=16Hz, 1H), 3.91(d, J=16Hz, 1H), 3.87(m , 1H), 3.79(s, 3H), 3.22(m, 1H), 1.22(m, 6H), 0.48(d, J=6.5Hz, 3H); LC-MS(M+1): 672.1.

Intermediate 22

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-fluorobenzyl)-4-methyl-1,3-oxazolidine -2-one

At 0°C, to (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (2.0g, 6.39 To a solution of mmol) in THF (40 mL) was added NaH (285 mg, 60 w/w% suspension in mineral oil, 7.13 mmol, 1.1 eq.) in one portion. The resulting foamy mixture was stirred in an ice bath. THF (50 mL) was added to the reaction. The mixture was stirred at 0°C for 30 minutes. A solution of 2-bromo-5-fluorobenzyl bromide (1.712 g, 6.39 mmol) in THF (20 mL) was added. The resulting mixture was stirred and cooled for 30 minutes, then allowed to warm to room temperature. The reaction was complete in 3 hours. Monitoring by LC-MS. The reaction was treated with saturated aqueous ammonium chloride (80 mL). Volatile components were removed in vacuo. The crude mixture was extracted with EtOAc and dried over sodium sulfate. The resulting clear gel was purified by silica (Biotage 40+M cartridge, EtOAc/hexanes, gradient). The title compound was obtained as a clear oil.

LC-MS: 500.09(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.88(s, 1H), 7.79(s, 2H), 7.55(dd, J=8.8, 5.2Hz, 1H) , 7.17(dd, J=8.7, 4.5Hz, 1H), 6.95(m, 1H), 5.74(d, J=8.0Hz, 1H), 4.83(d, J=15.8, 1H), 4.54(d, J =16.0Hz, 1H), 4.11(m, 1H), 0.80(d, J=6.6Hz, 3H)

Example 329

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4,4'-difluoro-5'-isopropyl-2'-methoxybis Benzene-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-fluorobenzyl)-4-methyl-1,3-oxazole To a solution of alkan-2-ones (1.0 g, 2.0 mmol) in 1,4-dioxane (6 mL) was added (4-fluoro-5-isopropyl-2-methoxyphenyl) Boronic acid (509mg, 2.4mmol), [1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) dichloride (82mg, 5mol%) and aqueous potassium hydroxide (1.3mL, 3M , 2eq.). The reaction mixture was purged with nitrogen and sealed in a microwave container. The reaction vessel was subjected to microwave irradiation at 150° C. for 40 minutes. The crude mixture was worked up with water. Use to evaporate the volatile materials. The resulting mixture was extracted with EtOAc. The combined extracts were dried over sodium sulfate. The resulting purple residue was purified by silica (Biotage 40+M cartridge, eluting with EtOAc/hexanes, gradient; 5%-25%). The title compound was obtained as a clear solid. LC-MS: 588.23 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) 6:4 mixture of rotamers

δ7.85(s, 1H), 7.69(s, 2H), 7.16-7.21(m, 1.5H), 7.04-7.13(m, 1.5H), 6.96(dd, J=14.3, 8.80Hz, 1H), 6.65(d, J=10.0Hz, 1H), 5.59(d, J=8.0Hz, 0.6H), 5.43(d, J=8.0Hz, 0.4H), 4.85(d, J=15.8Hz, 0.6H) , 4.82(d, J=15.8Hz, 0.4H), 4.02(d, J=15.8Hz, 0.6H), 3.85(m, 0.6H), 3.76-3.81(m, 0.8H), 3.75(s, 1.8 H), 3.73(s, 1.2H), 3.19(m, 1H), 1.14-1.26(m, 6H), 0.56(d, J=6.6Hz, 1.2H), 0.38(d, J=6.6Hz, 1.8 h)

Intermediate 23

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-chloro-4-fluorobenzyl)-4-methyl-1,3-oxazolidine -2-one

At 0°C, to (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (1.0g, 3.19 To a solution of mmol)/THF (40 mL) was added NaH (153 mg, 60 w/w% suspension in mineral oil, 3.83 mmol, 1.2 eq.) in one portion. The resulting foamy mixture was stirred in an ice bath for 30 minutes, then 2-chloro-4-fluorobenzyl chloride (572 mg, 3.19 mmol) was added. The resulting mixture was stirred at 0°C for 30 minutes and allowed to warm to room temperature overnight. The reaction did not proceed at room temperature and was warmed in a 60°C oil bath for 20 hours. An aliquot showed the reaction to go to completion. This was treated with aqueous _NH4Cl (50 mL). Volatile materials were evaporated. The resulting mixture was extracted with EtOA. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to a yellow oil. The oil was purified by silica (Biotage 40+M cartridge, eluting with EtOAc/hexanes, gradient; 5%-40%). The title compound was obtained as a colorless glass.

LC-MS: 456.12(M+1) ⁺ . ¹ H MR(CDCl ₃ , 500MHz) δ7.89(s, 1H), 7.77(s, 2H), 7.46(dd, J=8.7, 6.0Hz, 1H) , 7.17(dd, J=8.4, 2.5Hz, 1H), 7.03(m, 1H), 5.68(d, J=8.2Hz, 1H), 4.83(d, J=15.6, 1H), 4.36(d, J =15.3Hz, 1H), 4.06(m, 1H), 0.79(d, J=6.4Hz, 3H).

Example 330

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4′,5-difluoro-5′-isopropyl-2′-methoxybis Benzene-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-chloro-4-fluorobenzyl)-4-methyl-1,3-oxazole To a solution of alkan-2-ones (100 mg, 0.22 mmol) in 1,4-dioxane (1 mL) was added (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (55.8mg, 0.26mmol), palladium(II) acetate (10mg, 20mol%), potassium hydroxide aqueous solution (147μL, 3M, 2eq.) and tri-tert-butylphosphine (13.4mg, 0.066mmol, 30mol%, 10 % w/w hexane solution). The reaction mixture was purged with nitrogen and sealed in a microwave vessel. The reaction vessel was subjected to microwave irradiation at 140° C. for 40 minutes. LC-MS indicated formation of the desired product. This was treated with water (50 mL). Volatile materials were evaporated. The resulting mixture was extracted with EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to an oil. After two purifications by using silica gel and a reverse phase prep-HPLC, the title compound was obtained LC-MS: 588.25 (M+1) ⁺ .

Intermediate 24

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-chloro-6-fluorobenzyl)-4-methyl-1,3-oxazolidine -2-one

At 0°C, to (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (1.0g, 3.19 To a solution of mmol) in THF (40 mL) was added NaH (153 mg, 60 w/w% suspension in mineral oil, 3.83 mmol, 1.2 eq.) in one portion. The resulting foamy mixture was stirred in an ice bath for 30 minutes, then benzyl chloride (572 mg, 3.19 mmol) was added. The resulting mixture was stirred at 0°C for 30 minutes, then warmed to 60°C for 30 hours. An aliquot showed about 10% of the starting (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidine-2- ketone. The reaction was cooled and treated with saturated _NH4Cl (50 mL). Volatile materials were evaporated. The resulting mixture was extracted with EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to a yellow oil. After purification over _SiO2 (Biotage 40+M, eluting with EtOAc/hexanes, gradient; 5%-40%), the title compound was obtained as a colorless glass.

LC-MS: 456.11(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.87(s, 1H), 7.77(s, 2H), 7.22-7.34(m, 2H), 7.01-7.09( m, 1H), 5.62(d, J=8.2Hz, 1H), 5.01(dd, J=14.8, 2.0Hz, 1H), 4.45(d, J=14.6Hz, 1H), 3.91(m, 1H), 0.81(d, J=6.4Hz, 3H).

Example 331

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3,4'-difluoro-5'-isopropyl-2'-methoxybis Benzene-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-chloro-6-fluorobenzyl)-4-methyl-1,3-oxazole To a solution of alkan-2-ones (327 mg, 0.72 mmol) in 1,4-dioxane (4 mL) was added (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (228mg, 1.08mmol), palladium(II) acetate (33mg, 20mol%), potassium hydroxide (588μL, 3M, 2.5eq.) and tri-tert-butylphosphine (44mg, 0.22mmol, 30mol%, 10%w /w hexane solution). The resulting reaction mixture was purged with nitrogen and sealed in a microwave vessel. The reaction vessel was subjected to microwave irradiation at 135° C. for 50 minutes. LC-MS indicated a starting/product ratio of about 55:45. Reaction conditions (μw 50 min at 135° C.) were reapplied to the reaction mixture. LC-MS trace assays indicated no reaction progression from the second irradiation. Palladium(II) acetate (33 mg, 20 mol%), potassium hydroxide (588 μL, 3M, 2.5 eq.) and tri-tert-butylphosphine (44 mg, 0.22 mmol, 30 mol%, 10% w/ w hexane solution). The reaction mixture was reapplied to reaction conditions (135°C μw for 1 hour) LC-MS showed no significant progress of the reaction. The reaction mixture was treated with water. Volatile materials were evaporated. The resulting mixture was extracted with EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to a yellow oil. The oil was dissolved in DMSO and purified twice by reverse phase prep-HPLC (column: Kromasil, 100-5C18, 100×21.1 mm) with 10%-90% H ₂ O (0.1% TFA, v/v) /MeCN (0.1% TFA, v/v) elution. The resulting glass was purified on a prep-TLC plate eluting with 100% dichloromethane to afford the title compound. LC-MS: 588.21 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) 1:1 mixture of rotamers

δ7.83(s, 1H), 7.67(s, 1H), 7.65(s, 1H), 7.32-7.41(m, 1H), 7.09-7.16(m, 1H), 6.96-7.06(m, 1H), 6.64 -6.70(m, 1H), 5.47(d, J=8.0Hz, 0.5H), 5.19(d, J=7.8Hz, 0.5H), 4.96(d, J=14.9Hz, 0.5H), 4.80(d , J=15.1Hz, 0.5H), 4.31(d, J=15.1Hz, 0.5H), 3.91(d, J=15.1Hz, 0.5H), 3.78(s, 1.5H), 3.75(s, 1.5H ), 3.62-3.69(m, 1H), 3.15-3.26(m, 1H), 1.14-1.25(m, 6H), 0.54(d, J=6.6Hz, 1.5H), 0.33(d, J=6.4Hz , 1.5H).

Example 332

Step A: 2-Bromo-5-nitrophenyl)methanol

Methyl 2-bromo-5-nitrobenzoate (10 g, 38.46 mmol) was dissolved in THF (100 mL), and cooled to internal temperature = -15～-10°C. To this mixture was added diisobutylaluminum hydride solution (1.0 M in toluene, 57 mL, 57 mmol) slowly, keeping the internal temperature <0 °C. The resulting mixture was stirred at room temperature for 1 h, then treated with aqueous _NH4Cl (150 mL). The crude mixture was diluted with EtOAc (100 mL), then filtered. The volatiles were removed under reduced pressure, then extracted with EtOA (200 mL x 2). The combined extracts were dried over sodium sulfate, filtered and evaporated to an oil. The resulting oil was purified by silica (Biotage 65i, EtOAc/hexanes, gradient; 10%-15%). The title compound was obtained as a crystalline yellow solid.

¹ H NMR (CDCl ₃ , 500MHz) δ8.44(d, J=2.74Hz 1H), 8.02(dd, J=8.7, 2.8Hz.1H), 7.72(d, J=8.7, 1H), 4.83(s , 3H).

Step B: 1-Bromo-2-(bromomethyl)-4-nitrobenzene

To a solution of 2-bromo-5-nitrophenyl)methanol (4.746g, 20.45mmol) in anhydrous dichloromethane (150mL) at 0°C was added triphenylphosphine (6.43g, 24.5mmol) and tetra Carbon bromide (8.15 g, 24.5 mmol). The mixture was stirred at 0°C for 30 minutes, then at 20°C for 1 hour. TLC indicated complete consumption of starting material. Volatile materials were removed under reduced pressure. The resulting oil was purified by silica (Biotage 4OM, eluting with EtOAc/hexanes, gradient) to afford the title compound as a colorless solid.

¹ H NMR (CDCl ₃ , 500MHz) δ8.33(d, J=2.74Hz 1H), 8.03(dd.J=8.7, 2.5Hz.1H), 7.78(d, J=8.7,1H), 4.63(s , 3H).

Step C: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-nitrobenzyl)-4-methyl-1,3 -oxazolidin-2-one

At 0°C, to (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (5.3g, 16.95 To a solution of mmol) in THF (100 mL) was added NaH (746 mg, 60 w/w% suspension in mineral oil, 18.65 mmol, 1.1 eq.) in one portion. The resulting foamy mixture was stirred in an ice bath. THF (100 mL) was added to the reaction. The mixture was stirred at 0°C for 30 minutes. A solution of 1-bromo-2-(bromomethyl)-4-nitrobenzene (5.0 g, 16.95 mmol) in THF (25 mL) was added. The resulting mixture was stirred and cooled for 30 minutes, then allowed to warm to room temperature. The reaction was complete in 1.5 hours. The reaction was treated with saturated aqueous _NH4Cl (100 mL). The crude mixture was extracted with EtOAc and dried over sodium sulfate. The resulting clear gel was purified by silica (Biotage 4OM cartridge, EtOAc/hexanes, gradient, 25%-45%). The title compound was obtained as a crystalline solid.

LC-MS: 529.11(M+1) ^{+ .1} HNMR (CDCl ₃ , 500MHz) δ8.24(d, J=2.5Hz, 1H), 8.07(dd, J=8.7, 2.8Hz, 1H), 7.91( s, 1H), 7.79-7.83(m, 3H), 5.82(d, J=7.8Hz, 1H), 4.82(d, J=16.2Hz, 1H), 4.44(d, J=16.3, 1H), 4.11 -4.20(m, 1H), 0.84(d, J=6.6Hz, 3H).

Step D: (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-[(4'-fluoro-5'-isopropyl-2'-methoxy- 4-nitrobiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-nitrobenzyl)-4-methyl-1,3- To a solution of oxazolidin-2-one (3.877 g, 7.35 mmol) in a mixture of toluene (24 mL): ethanol (12 mL): water (6 mL) was added (4-fluoro-5-isopropyl-2-methoxy phenyl)boronic acid (2.337g, 11.03mmol), tetrakis(triphenylphosphine)palladium(0) (425mg, 5mol%) and sodium carbonate (1.56g, 14.72mmol). The resulting mixture was bubbled with nitrogen, and then heated in an oil bath at 90°C for 10 hours. An aliquot showed complete consumption of starting material. The reaction was treated with brine. The resulting mixture was extracted with EtOAc and dried over sodium sulfate. The resulting glassy mixture was purified by silica (Biotage 4OS cartridge, EtOAc/hexanes, gradient). The title compound was obtained as a crystalline solid. LC-MS: 615.26 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) 1:1 mixture of rotamers

δ8.31(s, 1H), 8.20-8.26(m, 1H), 7.86(s, 1H), 7.70(s, 2H), 7.39-7.43(m, 1H), 6.96-7.01(m, 1H), 6.67-6.72(m, 1H), 5.64(d, J=8.0Hz, 0.5H), 5.48(d, J=8.0Hz, 0.5H), 4.90(d, J=16.3Hz, 0.5H), 4.86( d, J=16.3Hz, 0.5H), 4.10-4.16(m, 0.5H), 3.84-3.94(m, 1.5H), 3.77(s, 1.5H), 3.75(s, 1.5H), 3.15-3.26 (m, 1H), 1.15-1.29(m, 6H), 0.57(d, J=6.6Hz, 1.5H), 0.40(d, J=6.6Hz, 1.5H).

Example 333

(4S, 5R)-3-[(4-amino-4'-fluoro-5'-isopropyl-2'-methoxybiphenyl-2-yl)methyl]-5-[3,5- Bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4'-fluoro-5'-isopropyl-2'-methoxy-4- A solution of nitrobiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (1.94 g, 3.16 mmol) in methanol (20 mL) was applied with _H2 (40 psi. , Parr shaker) at 20°C for 1.5 hours. LCMS indicated traces of starting material. The crude mixture was filtered through a bed of celite (521). The filtrate was evaporated in vacuo to give a glassy product. LC-MS: 585.32 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) 1:1 mixture of rotamers

δ7.83(s, 1H), 7.67(s, 2H), 6.93-7.06(m, 2H), 6.87(s, 0.5H), 6.72-6.82(m, 1.5H), 5.57(d, J=8.0 Hz, 0.5H), 5.36(d, J=8.0Hz, 0.5H), 4.77(d, J=5.5Hz, 0.5H), 4.74(d, J=6.5Hz, 0.5H), 3.95(d, J =15.5Hz, 0.5H), 3.75-3.86(m, 1.5H), 3.73(s, 3H), 3.12-3.24(m, 1H), 1.11-1.29(m, 6H), 0.47(d, J=6.5 Hz, 1.5H), 0.29 (d, J=6Hz, 1.5H).

Example 334

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4'-fluoro-5'-isopropyl-2'-methoxy Biphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-3-[(4-amino-4'-fluoro-5'-isopropyl-2'-methoxybiphenyl-2-yl)methyl]-5-[3,5 - To a solution of bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (526 mg, 0.90 mmol) in bromoform (2.5 mL) was added tert-butyl nitrite Ester (186 mg, 1.80 mmol). The resulting mixture was stirred at 80°C for 20 minutes. An aliquot showed complete reaction. The crude reaction product was purified by silica gel chromatography to afford the title compound as a yellow glass. LC-MS: 650.09 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) 1:1 mixture of rotamers

δ7.85(s, 1H), 7.69(s, 2H), 7.60(s, 0.5H), 7.48-7.53(m, 1.5H), 7.07-7.11(m, 1H), 6.93-6.99(m, 1H ), 6.62-6.67(m, 1H), 5.59(d, J=8.0Hz, 0.5H), 5.39(d, J=7.0Hz, 0.5H), 4.82(d, J=6.5Hz, 0.5H), 4.75(d, J=6.5Hz, 0.5H), 3.98(d, J=16.0Hz, 0.5H), 3.76-3.85(m, 1.5H), 3.75(s, 1.5H), 3.74(s, 1.5H) ), 3.13-3.23(m, 1H), 1.13-1.29(m, 6H), 0.52(d, J=6.5Hz, 1.5H), 0.34(d, J=7.0Hz, 1.5H).

Example 335

(4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-cyclopropyl-4'-fluoro-5'-isopropyl-2'-methanol Oxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4'-fluoro-5'-isopropyl-2'-methoxy 1,4-dioxane (0.5 mL) Cyclopropylboronic acid (10mg, 0.19mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (82mg, 8mol%), bis(tri tert-butylphosphine) palladium(0) (10 mg, 13 mol%) and aqueous potassium hydroxide (78 μL, 3M, 1.5 eq.). The reaction mixture was purged with nitrogen and sealed in a microwave container. Microwave irradiation was applied to the reaction at 150°C for 30 minutes. An aliquot showed complete consumption of starting material. The crude reaction product was worked up with water. The resulting mixture was extracted with EtOAc, dried over sodium sulfate. Purification using two preparative TLC plates using 20% EtOAc in hexanes and 5% EtOAc in dichloromethane as eluents gave the title compound as a glass. LC-MS: 610.26 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) 1:1 mixture of rotamers

δ7.84(s, 1H), 7.65-7.70(m, 2H), 7.21(s, 0.5H), 7.08-7.14(m, 1.5H), 6.95-7.04(m, 2H), 6.61-6.67(m , 1H), 5.52(d, J=8.5Hz, 0.5H), 5.27(d, J=8.0Hz, 0.5H), 4.85(d, J=15.5Hz, 0.5H), 4.81(d, J=15.5 Hz, 0.5H), 4.00(d, J=15.5Hz, 0.5H), 3.69-3.81(m, 4.5H), 3.13-3.24(m, 1H), 1.90-1.99(m, 1H), 1.12-1.30 (m, 6H), 0.98-1.15(m, 2H), 0.71-0.77(m, 2H), 0.48(d, J=6.5Hz, 1.5H), 0.29(d, J=6.5Hz, 1.5H).

Example 336

(4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-( Methylthio)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-3-[(4-amino-4'-fluoro-5'-isopropyl-2'-methoxybiphenyl-2-yl)methyl]-5-[3,5 - To a solution of bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (200 mg, 0.34 mmol) in dimethyl disulfide (2 mL) was added tert-nitrite Butyl ester (70 mg, 0.68 mmol). The resulting mixture was stirred at 80°C for 30 minutes. An aliquot showed complete reaction. Purification using two preparative TLC plates using 20% EtOAc in hexanes and 10% EtOAc in dichloromethane as eluents respectively gave the title compound as a glass. LC-MS: 616.21 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) 1:1 mixture of rotamers

δ7.84(s, 1H), 7.67(s, 2H), 7.35(s, 0.5H), 7.22-7.28(m, 1.5H), 7.12-7.19(m, 1H), 6.94-7.02(m, 1H ), 6.61-6.68(m, 1H), 5.55(d, J=8.0Hz, 0.5H), 5.31(d, J=9.5Hz, 0.5H), 4.85(d, J=16.0Hz, 0.5H), 4.83(d, J=15.5Hz, 0.5H), 3.99(d, J=15.5Hz, 0.5H), 3.69-3.81(m, 4.5H), 3.12-3.24(m, 1H), 2.54, (s, 1.5H), 2.53(s, 1.5H), 1.11-1.27(m, 6H), 0.50(d, J=6.5Hz, 1.5H), 0.31(d, J=7.0Hz, 1.5H).

Example 337

(4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-( Methylsulfonyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4- (Methylthio)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (156 mg, 0.25 mmol) in dichloromethane (3 mL) was added 3-Chloroperbenzoic acid (175 mg, 1.01 mmol). The resulting mixture was stirred at 20°C for 1 hour. An aliquot showed complete reaction. The crude reaction product was partitioned between water and dichloromethane. The organic layer was separated and dried over sodium sulfate. Purification using three preparative TLC plates using 50% EtOAc in hexanes, 20% EtOAc in dichloromethane and dichloromethane as eluents gave the title compound as a glass. LC-MS: 648.29 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) 1:1 mixture of rotamers

δ7.99(s, 0.5H), 7.92-7.96(m, 1.5H), 7.86(s, 1H), 7.70(s, 2H), 7.42-7.46(m, 1H), 6.96-7.00(m, 1H ), 6.69(d, J=12Hz, 1H), 5.64(d, J=8.0Hz, 0.5H), 5.45(d, J=8.0Hz, 0.5H), 4.93(d, J=6.0Hz, 0.5H ), 4.90 (d, J=6.5Hz, 0.5H), 4.09(d, J=16Hz, 0.5H), 3.88(d, J=16Hz, 0.5H), 3.80-3.88(m, 1H), 3.78( s, 1.5H), 3.75(s, 1.5H), 3.16-3.25(m, 1H), 3.14(s, 1.5H), 3.13(s, 1.5H), 1.22-1.28(m, 6H), 0.57( d, J=6.5Hz, 1.5H), 0.38(d, J=6.5Hz, 1.5H).

Example 338

2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl} Methyl)-4'-fluoro-5'-isopropyl-2'-methoxybiphenyl-4-carbonitrile

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4'-fluoro-5'-isopropyl-2'-methoxy Diphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (100mg, 0.15mmol) in N,N-dimethylformamide (1.5mL) Copper(I) cyanide (17 mg, 0.19 mmol) was added to the solution. The resulting reaction mixture was purged with nitrogen and sealed in a microwave vessel. Microwave irradiation was applied to the container at 150° C. for 30 minutes. LC-MS indicated only bromide starting material was present. Tetrakis(triphenylphosphine)palladium(0) (10 mg, 6 mol%) was added to the reaction mixture, and microwave irradiation was again applied at 150° C. for 30 minutes. An aliquot showed formation of the desired product and all starting bromide had been consumed. The crude reaction product was partitioned between water and hexanes. The aqueous phase was back extracted with ether. The combined extracts were dried over sodium sulfate. Purification using two preparative TLC plates developed with 20% EtOAc in hexanes and 4% EtOAc in dichloromethane gave the title compound as a glass. LC-MS: 595.03 (MH+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) 1:1 mixture of rotamers

δ7.86(s, 1H), 7.61(S, 0.5H), 7.67-7.71(m, 2.5H), 7.64-7.68(m, 1H), 7.32-7.36(m, 1H), 6.98(d, J =8.5Hz, 0.5H), 6.95(d, J=8.5Hz, 0.5H), 6.68(d, J=12Hz, 1H), 5.62(d, J=8.0Hz, 0.5H), 5.46(d, J =8.0Hz, 0.5H), 4.85(d, J=16.0Hz, 0.5H), 4.80(d, J=16.0Hz, 0.5H), 4.06(d, J=16Hz, 0.5H), 3.79-3.86( m, 1H), 3.70-3.78(m, 3.5H), 3.16-3.24(m, 1H), 3.75(s, 1.5H), 3.16-3.25(m, 1H), 3.14(s, 1.5H), 3.13 (s, 1.5H), 1.15-1.27 (m, 6H), 0.54 (d, J=7.0H2, 1.5H), 0.37 (d, J=6.5Hz, 1.5H)

Example 339

(4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4'-fluoro-5'-isopropyl-2'-methoxy-4-methyl ylbiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4'-fluoro-5'-isopropyl-2'-methoxy 1,4-dioxane (1 mL) To a solution of trimethylboroxine (39 mg, 0.31 mmol), Pd(PPh ₃ ) ₄ (15 mg, 10 mol%) and potassium carbonate (35 mg, 0.25 mmol) were added. The resulting reaction mixture was purged with nitrogen and sealed in a microwave vessel. Microwave irradiation was applied to the container at 130° C. for 15 minutes. The crude mixture was diluted with brine and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate. Purification using two preparative TLC plates developed with 20% EtOAc in hexanes and dichloromethane gave the title compound as a glass. LC-MS: 584.08 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) 1:1 mixture of rotamers

δ7.84(s, 1H), 7.65-7.70(m, 2H), 7.29(s, 0.5), 7.18-7.22(m, 1.5H), 7.10-7.15(m, 1H), 7.01(d, J= 8.0Hz, 0.5H), 6.98(d, J=8.5Hz, 0.5H), 6.66(d, J=5.0Hz, 0.5H), 6.64(d, J=5.5Hz, 0.5H), 5.54(d, J=8.5Hz, 0.5H), 5.31(d, J=8.0Hz, 0.5H), 4.82(d, J=15.5Hz, 1H), 4.02(d, J=15Hz, 0.5H), 3.71-3.82( m, 5H), 3.15-3.24(m, 1H), 2.42(s, 1.5H), 2.41(s, 1.5H), 1.13-1.27(m, 6H), 0.48(d, J=6.5Hz, 1.5H ), 0.31(d, J=6.5Hz, 1.5H).

Example 340

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4'-fluoro4-isopropenyl-5'-isopropyl-2'-methoxy ylbiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4'-fluoro-5'-isopropyl-2'-methoxy 1,4-dioxane (0.5 mL) (2-Chloro-5-isopropylphenyl)boronic acid (10mg, 0.12mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride were added to the solution of (2.4mg, 5mol%) and aqueous potassium hydroxide solution (40μL, 3M, 2eq.). The reaction mixture was purged with nitrogen and sealed in a microwave container. Microwave irradiation was applied to the reaction at 140°C for 20 minutes. The crude mixture was worked up with water and EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to afford crude product. This was purified by preparative TLC plate eluting with 20% EtOAc in hexanes to afford the title compound. LC-MS: 610.04 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) 1:1 mixture of rotamers

δ7.84(s, 1H), 7.64-7.70(m, 2H), 7.56(s, 0.5), 7.45-7.50(m, 1.5H), 7.18-7.23(m, 1H), 7.02(d, J= 9.0Hz, 0.5H), 6.99(d, J=8.5Hz, 0.5H), 6.67(d, J=7.0Hz, 0.5H), 6.64(d, J=5.5Hz, 0.5H), 5.52(d, J=8.0Hz, 0.5H), 5.43(d, J=8.5Hz, 1H), 5.26(d, J=8.0Hz, 0.5H), 5.13-5.17(m, 1H), 4.91(d, J=15.0 Hz, 0.5H), 4.86(d, J=15.5Hz, 0.5H), 4.04(d, J=15.5Hz, 0.5H), 3.83(d, J=15.5, 0.5H), 3.70-3.78(m, 3H), 3.14-3.25(m, 1H), 2.18-2.22(m, 3H), 1.14-1.29(m, 6H), 0.50(d, J=6.5Hz, 1.5H), 0.31(d.J=6.5Hz, 1.5H).

Example 341

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4'-fluoro-4,5'-diisopropyl-2'-methoxybis Benzene-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one

Give (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4′-fluoro-4-isopropenyl-5′-isopropyl-2′- A solution of methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (15 mg, 0.025 mmol) in methanol (1 mL) was applied with _H2 (balloon atmosphere ) overnight at 20°C. The crude mixture was filtered through a syringe filter. The filtrate was evaporated in vacuo and purified by preparative TLC plate developed with 20% EtOAc in hexanes to afford the title compound. LC-MS: 612 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) 1:1 mixture of rotamers

δ7.84(s, 1H), 7.64-7.68(m, 2H), 7.30(s, 0.5), 7.20-7.27(m, 1.5H), 7.13-7.17(m, 1H), 7.02(d, J= 8.5Hz, 0.5H), 6.99(d, J=8.0Hz, 0.5H), 6.65(d, J=6.0Hz, 0.5H), 6.63(d, J=6.0Hz, 0.5H), 5.52(d, J=8.0Hz, 0.5H), 5.25(d, J=8.0Hz, 1H), 4.87(d, J=15.5Hz, 0.5H), 4.82(d, J=15.5Hz, 0.5H), 4.03(d , J=15.0Hz, 0.5H), 3.81(d, J=15.0Hz, 0.5H), 3.69-3.77(m, 4II), 3.14-3.24(m, 1H), 2.92-3.02(m, 1H), 1.14-1.33(m, 12H), 0.48(d, J=6.5Hz, 1.5H), 0.30(d, J=7.0Hz, 1.5H.

Intermediate 25

(4S,5R)-3-(5-Amino-2-bromobenzyl)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidine -2-one

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-nitrobenzyl)-4-methyl-1,3- A mixture of oxazolidin-2-one (614 mg, 1.17 mmol), tin(II) chloride dehydrate (1.314 g, 5.823 mmol) and ethanol (3 mL) was stirred at 20°C for 36 hours. The crude reaction product was worked up with water. The resulting mixture was extracted with EtOAc and dried over sodium sulfate. After _SiO2 purification (Biotage 40+M, gradient, 0%-35% EtOAc in hexanes), the title compound was obtained as a glass.

LC-MS: 499.05(M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500MHz) δ7.88(s, 1H), 7.77(s, 2H), 7.31(d, J=8.5, 1H), 6.77( d, J=2.7, 1H), 6.54(dd, J=8.5, 2.7Hz, 1H), 5.69(d, J=8.0Hz, 1H), 4.77(d, J=15.3, 1H), 4.29(d, J=15.3Hz, 1H), 4.05-4.12(m, 1H), 0.79(d, J=6.4Hz, 3H).

Intermediate 26

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-bromo-5-(methylthio)benzyl]-4-methyl-1,3 -oxazolidin-2-one

To (4S, 5R)-3-(5-amino-2-bromobenzyl)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazole To a solution of alkan-2-ones (457 mg, 0.92 mmol) in dimethyl disulfide (4 mL) was added tert-butyl nitrite (182 μL, d=0.867, 1.38 mmol). The resulting mixture was stirred at 80°C for 1 hour. An aliquot showed complete reaction. Purification by preparative TLC plate using 25% EtOAc in hexanes gave the title compound as a glass. LC-MS: 529.71 (M+1) ⁺ .

Example 342

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-chloro-4′-fluoro-5′-isopropyl-4-(methylthio Base) biphenyl-2-yl] methyl}-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-bromo-5-(methylthio)benzyl]-4-methyl-1, To a solution of 3-oxazolidin-2-one (60 mg, 0.114 mmol) in 1,4-dioxane (1 mL) was added (2-chloro-4-fluoro-5-isopropylphenyl ) boronic acid (10mg, 0.12mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (28mg, 30mol%) and aqueous potassium hydroxide solution (95μL, 3M, 2eq.). The reaction mixture was purged with nitrogen and sealed in a microwave container. Microwave irradiation was applied to the reaction at 150°C for 30 minutes. The crude mixture was worked up with water and EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to afford crude product. This was purified by preparative TLC plate to afford the title compound. LC-MS: 619.95 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) 1:1 mixture of rotamers

δ7.83-7.88(m, 1H), 7.72(s, 1H), 7.68(s, 1H), 7.30-7.35(m, 1H), 7.24-7.29(m, 1H), 7.11-7.19(m, 2.5H ), 7.04-7.07(m, 0.5H), 5.62(d, J=8.2Hz, 0.5H), 5.24(d, J=8.0Hz, 0.5H), 4.87(d, J=15.3Hz, 0.5H) , 4.70(d, J=15.8Hz, 0.5H), 3.79-3.98(m, 2H), 3.18(m, 1H), 2.55(s, 1.5H), 2.54(s, 1.5H), 1.20-1.29( m, 6H), 0.53(d, J=6.4Hz, 1.5H), 0.47(d, J=6.6Hz, 1.5H).

Example 343

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(2'-chloro-5'-isopropyl-4-nitrobiphenyl-2-yl )methyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-nitrobenzyl)-4-methyl-1,3- To a solution of oxazolidin-2-one (950 mg, 1.80 mmol) in a mixture of toluene (5.2 mL):ethanol (2.6 mL):water (1.3 mL) was added (2-chloro-5-isopropylphenyl)boronic acid (325mg, 1.64mmol), tetrakis(triphenylphosphine)palladium(0) (188mg, 10mol%) and sodium carbonate (346mg, 3.26mmol). The resulting mixture was heated in an 80 °C oil bath for 12 hours. The crude reaction product was evaporated to dryness. The resulting residue was worked up by a mixture of water and EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to afford a crude product which was purified by _SiO2 (Biotage 40+S cartridge, EtOAc/hexanes, gradient) to afford the title compound. LC-MS: 601.19 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) 1:1 mixture of rotamers

δ8.31-8.30(m, 1H), 8.24-8.28(m, 1H), 7.85-7.89(m, 1H), 7.68-7.76(m, 2H), 7.42-7.48(m, 2H), 7.26-7.30 (m, 1H), 7.04-7.11(m, 1H), 5.74(d, J=7.8Hz, 0.5H), 5.58(d, J=8.0Hz, 0.5H), 4.92(d, J=15.8Hz, 0.5H), 4.76(d, J=16.2Hz, 0.5H), 3.97-4.04(m, 1.5H), 3.82(dt, J=8.0, 6.6Hz, 0.5H), 2.89-2.99(m, 1H) 1.22-1.29(m, 6H), 0.60(d, J=6.4Hz, 1.5H), 0.52(d, J=6.6Hz, 1.5H).

Example 344

(4S, 5R)-3-[(4-Amino-2'-chloro-5'-isopropylbiphenyl-2-yl)methyl]-5-[3,5-bis(trifluoromethyl) Phenyl]-4-methyl-1,3-oxazolidin-2-one

(4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(2'-chloro-5'-isopropyl-4-nitrobiphenyl-2- A solution of methyl)-4-methyl-1,3-oxazolidin-2-one (425 mg, 0.71 mmol) in methanol (10 mL) was applied at 20° C. with H ₂ (40 psi., Parr shaker )6 hours. The crude mixture was filtered through a bed of celite (521). The filtrate was evaporated in vacuo to give a glass. Purification by preparative TLC plate developed with 20% EtOAc in hexanes afforded the title compound. LC-MS: 571.22 (M+1) ⁺ . ¹ HNMR (CDCl ₃ , 500MHz) 6:4 mixture of rotamers

δ7.82-7.86(m, 1H), 7.65-7.71(m, 2H), 7.34-7.38(m, 1H), 7.11-7.17(m, 2H), 7.02-7.06(m, 1H), 6.76-6.82 (m, 1H), 6.68-6.74(m, 1H), 5.58(d, J=8.0Hz, 0.4H), 5.51(d, J=8.2Hz, 0.6H), 4.82(d, J=15.3Hz, 0.6H), 4.70(d, J=15.6Hz, 0.4H), 3.69-4.00(m, 4H), 2.84-2.94(m, 1H), 1.19-1.28(m, 6H), 0.45(d, J= 6.6Hz, 1.2H), 0.40(d, J=6.6Hz, 1.8H).

Example 345

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-2'-chloro-5'-isopropylbiphenyl-2-yl) Methyl]-4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-3-[(4-amino-2′-chloro-5′-isopropylbiphenyl-2-yl)methyl]-5-[3,5-bis(trifluoromethyl )Phenyl]-4-methyl-1,3-oxazolidin-2-one (100 mg, 0.175 mmol) in bromoform (0.5 mL) and dichloromethane (1 mL) was added tert-butyl nitrite Ester (23 μL, d=0.867, 90% pure, 0.193 mmol). The resulting mixture was stirred at 50°C for 1 hour. An aliquot showed complete reaction. The reaction crude was deposited on 2 preparative TLC plates and eluted with dichloromethane to afford the title compound. LC-MS: 635.80 (M+1) ⁺ . ¹ HNMR (CDCl ₃ , 500MHz) 6:4 mixture of rotamers

δ7.84-7.88(m, 1H), 7.67-7.74(m, 2H), 7.60-7.63(m, 1H), 7.51-7.57(m, 1H), 7.38-7.42(m, 1H), 7.19-7.23 (m, 1H), 7.11-7.16(m, 1H), 7.09(d, J=2.3Hz, 0.6H), 7.03(d, J=2.3Hz, 0.4H), 5.66(d, J=8.0Hz, 0.4H), 5.55(d, J=8.0Hz, 0.6H), 4.86(d, J=15.6Hz, 0.6H), 4.70(d, J=15.6Hz, 0.4H), 3.77-4.00(m, 2H ), 2.87-2.95(m, 1H), 1.20-1.28(m, 6H), 0.53(d, J=6.6Hz, 1.2H), 0.45(d, J=6.4Hz, 1.8H)

Example 346

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(2′-chloro-4-cyclopropyl-5′-isopropylbiphenyl-2- Base) methyl] -4-methyl-1,3-oxazolidin-2-one

To (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-2'-chloro-5'-isopropylbiphenyl-2-yl )Methyl]-4-methyl-1,3-oxazolidin-2-one (27 mg, 0.043 mmol) in 1,4-dioxane (1 mL) was added cyclopropylboronic acid (9mg, 0.10mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.4mg, 30mol%) and aqueous potassium hydroxide (42μL, 3M, 3eq .). The reaction mixture was purged with nitrogen and sealed in a microwave container. Microwave irradiation was applied to the reaction at 120°C for 20 minutes. The crude mixture was worked up with water and EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to afford crude product. This was purified by preparative TLC plate eluting with 20% EtOAc in hexanes to afford the title compound. LC-MS: 595.99 (M+1) ⁺ . ¹ H NMR (CDCl ₃ , 500 MHz) 6:4 mixture of rotamers

δ7.82-7.86(m, 1H), 7.66-7.72(m, 2H), 7.36-7.40(m, 1H), 7.21-7.23(m, 0.5H), 7.11-7.19(m, 3H), 7.01- 7.08(m, 1.5H), 5.58(d, J=8.0Hz, 0.4H), 550(d, J=8.0Hz, 0.6H), 4.88(d, J=15.1Hz, 0.6H), 4.71(d , J=15.6Hz, 0.4H), 3.76-3.95(m, 2H), 2.84-2.95(m, 1H), 1.92-2.00(m, 1H), 1.18-1.29(m, 6H), 1.00-1.07( m, 2h), 0.71-0.82(m, 2H), 0.47(d, J=6.6Hz, 1.2H), 0.42(d, J=6.6Hz, 1.8H)

According to the method described in Example 96, from (4R,5R)-5-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)-biphenyl- 2-yl]-4-methyl-1,3-oxazolidin-2-one The compounds described in Table 18 were prepared.

Table 18

Example 360

(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[5'-isopropyl-2'-(trifluoromethoxy)-4-(trifluoromethyl) Methyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one

To 80mg (4R, 5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl- To a solution of 1,3-oxazolidin-2-one in 2 mL of benzene, 1 mL of water and 0.5 mL of ethanol was added 100 mg of 5-isopropyl-2-(trifluoromethoxy)phenylboronic acid, 0.15 mL of 2M carbonic acid Aqueous sodium solution and 21 mg Pd(PPh ₃ ) ₄ . A reflux condenser was attached and the mixture was heated to 100°C. The mixture was stirred at 100 °C for 24 hours, then diluted with 10 mL EtOAc and 10 mL water. The phases were separated, and the aqueous phase was extracted with 10 mL EtOAc. The combined organic phases were washed with 10 mL of brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25M column, eluting with 1 CV of 2% EtOAc in hexanes, followed by a linear gradient of 2-100% EtOAc in hexanes over 10 CV . Repurification of the product using the same conditions afforded the title compound. Mass spectrum (ESI) 674.4 (M+1).

Following the general procedure described above, the compounds listed in Table 19 were prepared.

Table 19

Intermediate 27

(4R,5R)-4-Ethyl-5-[2-iodo-5-(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one

Step A: (4S)-4-Benzyl-3-butyryl-1,3-oxazolidin-2-one

To a -78°C solution of S-benzyl-oxazolidinone in 15 mL THF was added n-BuLi followed by butyryl chloride over about 1 min. The mixture was stirred at -78°C for 30 minutes, then allowed to warm to room temperature over about 30 minutes. Excess acid chloride was worked up by adding 3 mL of saturated aqueous _NH4Cl , then most of the solvent was removed by rotary evaporation. The residue was diluted with 17 mL of saturated aqueous _NH4Cl and 30 mL _{of CH2Cl2} . The phases were separated and the aqueous phase was extracted with ₂₀ mL _CH2Cl2 . The combined organic extracts were washed with 20 mL _of 1N NaOH solution and 20 mL of brine, dried ( _Na2SO4 ) and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 40M column, eluting with 1 CV of 2% EtOAc in hexanes, followed by a linear gradient of 2 → 100% EtOAc in hexanes over 10 CV . The residue was stored in the freezer overnight, during which time the residue crystallized. The resulting solid was triturated with hexanes, filtered, and dried under high vacuum. Mass spectrum (ESI) _178.2 ( _MC3H7CO ).

Step B: (4S)-4-Benzyl-3-((2R)-2-{(S)-Hydroxy[2-iodo-5-trifluoromethyl)phenyl]methyl}butyryl)-1 , 3-oxazolidin-2-one

Following the procedure described in Example 95, Step A, from 5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde (Example 80, Step A) and ( 4S)-4-Benzyl-3-butyryl-1,3-oxazolidin-2-one yielded the title compound. Mass spectrum (ESI) 530.1 (M-OH).

Step C: (4R,5R)-4-Ethyl-5-[2-iodo-5-(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one

Following the procedure described in Example 95, step B, from (4S)-4-benzyl-3-((2R)-2-{(S)-hydroxy[2-iodo-5-(trifluoromethyl)benzene [Ethyl]methyl}butyryl)-1,3-oxazolidin-2-one afforded the title compound. Mass spectrum (ESI) 386.2 (M+1).

Intermediate 28

(4R,5R)-4-Benzyl-5-[2-iodo-5-(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one

Step A: (4S)-4-Benzyl-3-(3-phenylpropionyl)-1,3-oxazolidin-2-one

The title compound was prepared from S-benzyl-oxazolidinone and hydrocinnamoyl chloride as described in Intermediate 27, Step A. Mass Spectrum (ESI) 178.2 (M-PhC2H4CO).

Step B: (4S)-4-Benzyl-3-{(2R,3S)-2-benzyl-3-hydroxy-3-[2-iodo-5-(trifluoromethyl)phenyl]propionyl }-1,3-oxazolidin-2-one

Following the procedure described in Example 95, Step A, from 5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde (Example 80, Step A) and ( 4S)-4-Benzyl-3-(3-phenylpropanoyl)-1,3-oxazolidin-2-one yielded the title compound. Mass spectrum (ESI) 592.3 (M-OH).

Step C: (4R,5R)-4-Benzyl-5-[2-iodo-5-(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one

Following the procedure described in Example 95, Step B, from (4S)-4-benzyl-3-{(2R,3S)-2-benzyl-3-hydroxy-3-[2-iodo-5-(tri Fluoromethyl)phenyl]propionyl}-1,3-oxazolidin-2-one afforded the title compound. Mass spectrum (ESI) 448.2 (M+1).

Following the general procedure described above, the compounds listed in Table 20 were prepared.

Table 20

Example 372

Preparation of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-([4'-fluoro-5'-isopropyl-2'-methoxy-4- Another method for (trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Example 73)

The compound of Example 73 can be prepared by the method shown below:

Step 1: Suzuki coupling reaction of boronic acid 1 with aryl chloride 2

_A 3M _K2CO3 solution _was made by adding 4.71 kg of solid _K2CO3 to 10.3 L of water. Cooling was applied to maintain the solution at 20-25°C. THF (12 L), aryl chloride 2 (2.69 _kg ) and boronic acid 1 (2.74 kg) prepared in Example 78 were added to the _K2CO3 , followed by a 1 L THF wash. A 1.00/1.00 ratio of 1/2 was confirmed using HPLC analysis. The solution was degassed by purging with nitrogen for 70 minutes. The solid catalyst 1,1-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (42 g) was added followed by a degassed THF wash (1.5 L). The organic layer turned dark brown immediately. The biphasic mixture was cooled at 36°C-40°C with vigorous stirring. HPLC indicated complete conversion (15-18 hours), the mixture was cooled to room temperature and the aqueous layer was removed. Heptane (25.6 L) and water (25.6 L) were added to the organic layer, and the layers were separated. The organic layer was washed with water (19 L). The organic layer was treated with 680 g Darco KB-B at room temperature for 60 minutes, filtered through solka-floc, washed with 10% THF/heptane (-15 L). The solvent was changed to heptane (-35 L) at about 45-50 °C until <0.5 v% THF remained. Additional heptane was added to bring the total volume to about 45-50 L. If a bed of crystals did not form, the solution was seeded with crystals from a previous preparative run. The slurry was cooled slowly to room temperature and then to -15°C. After aging at -15°C for 1-2 hours, LC of the supernatant indicated a loss of -2 g/l product in the supernatant, and the slurry was filtered and washed with cold heptane (-25 L) to afford compound 3.

Step 2: Chlorination of 3 to 4:

To a solution of bisarylate 3 (3.4 kg) in DMF (17 L) kept at 10°C was added thionyl chloride (940 ml) and the mixture was allowed to warm to room temperature. The mixture was aged until >99.8% converted chlorine as determined by HPLC. Water (3.4 L) was then added. Seed crystals (1 wt%) were added, the mixture was aged for 30 minutes, then 5.1 L of water was added slowly over 1 hour. The solid was filtered, washed first with 20 L of 1:1 DMF:water, then 3 x 20 L of water. The solid product 4 was dried at 20°C until <0.1 wt% water remained.

Step 3: Alkylation of the product of Example 17 with compound 4 to give the product of Example 73:

The chiral intermediate (4S, 5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidine-2 prepared in Example 17 was - The ketone was dissolved in DMF (2.8 kg in 32.7 L) and cooled to -15°C. Then 2.0M NaHMDS (3.92 L, 1.05 eq) was added over 1.5 hours followed by biaryl chloride 4 in DMF (2.8 kg). The mixture was warmed to +12°C and aged until complete conversion. 5N HCl (3.4 L) was then added, followed by 16 L of 10% IPAC/heptane and 34 L of water, maintaining the temperature at 10°C-20°C. The layers were separated, and the organic layer was washed twice with 14 L of 1:1 DMF:water, then twice with 14 L of water. The organic layer was analyzed for yield, then filtered through 2.4 kg of silica gel to remove excess oxazolidinone to <0.5%. The silica gel was washed with 5% IPAC/heptane. The combined organic solutions were distilled to remove IPAC to <1%. The warm heptane solution was then slowly transferred to the 20°C heptane solution containing 10 wt% seed crystals. The slurry was cooled to -20°C and filtered. The filter cake was washed with cold heptane and dried to obtain the compound originally prepared in Example 73.

Intermediate 29

(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-3-nitro-5-(trifluoromethyl)phenyl]-4- Methyl-1,3-oxazolidin-2-one

(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl Add 1,3-oxazolidin-2-one to 2 mL of fuming nitric acid in batches. The reaction mixture was stirred overnight at room temperature and then heated at 75°C for 4 hours. The reaction mixture was cooled and added dropwise to a rapidly stirring mixture of 10 mL of water and 10 mL of EtOAc. The phases were separated and the organic phase was washed with 10 mL of saturated NaHCO ₃ and brine respectively, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 5% EtOAc in hexanes, followed by a linear gradient of 5 → 100% EtOAc in hexanes over 10 CV. , the title compound was obtained. Mass spectrum (ESI) 643 (M+1).

Example 373

(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[4'-fluoro-5'-isopropyl-2'-methoxy-6-nitro -4-(Trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one

Following the method described in Example 81, 48 mg of (4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-3-nitro-5-( Trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one and 48 mg (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (Example 78), two atropisomers were obtained, which could be separated by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 5% EtOAc in hexane, followed by 5→100% EtOAc in hexane The mixture in alkanes was eluted with a linear gradient of 10CV to obtain hindered isomer A [mass spectrum (ESI) 683.4 (M+1)] and hindered isomer B [mass spectrum (ESI) 683.3 (M+1) ].

Example 374

(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[4'-fluoro-5'-isopropyl-2'-methoxy-6-iodo- 4-(Trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one (Hindered Isomer A)

To 17mg (4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[4'-fluoro-5'-isopropyl-2'-methoxy-6- Nitro-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one, hindered isomer A (Example 373) in 1 mL EtOAc 5 mg of PtO ₂ (Adam's catalyst) was added to the solution in . The reaction mixture was purged with hydrogen and then stirred under a balloon of hydrogen for 2 h at which time LC/MS analysis indicated mostly nitroso product. The reaction mixture was filtered through celite, washed with EtOAc, the filtrate was concentrated and left under reaction conditions overnight. The reaction mixture was filtered through celite, washed with EtOAc, and the filtrate was concentrated. The residue was dissolved in 0.5 mL CH ₂ I ₂ and 6 μL tert-butyl nitrite was added. The reaction mixture was stirred at 80°C for 1.5 hours. The reaction mixture was purified by preparative thin layer chromatography on a 1000 [mu]M plate eluting with 20% EtOAc in hexanes to afford the title compound. Mass spectrum (ESI) 764.3 (M+1).

Example 375

(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[4'-fluoro-5'-isopropyl-2'-methoxy-6-iodo- 4-(Trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one (Hindered Isomer B)

To 70mg (4R, 5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-3-nitro-4-(trifluoromethyl)phenyl]- To a solution of 4-methyl-1,3-oxazolidin-2-one (Intermediate 30) in 1 mL of EtOH was added 124 mg of _SnCl2 . The reaction mixture was stirred at room temperature overnight; then another 60 mg of _SnCl2 was added, and the mixture was heated to 80°C and stirred overnight. _The reaction mixture was concentrated and the residue was partitioned between 10 mL _CH2Cl2 and 10 mL 1N NaOH. The aqueous _phase was extracted with 2 _x 10 mL _CH2Cl2 , the combined organic phases were dried ( _Na2SO4 ) and concentrated. Following the procedure described in Example 81, using the residue from this reduction and 70 mg of (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (Example 78), the corresponding biphenyl was obtained. Benzene compound, a mixture of hindered isomers. This mixture was dissolved in 0.5 mL _CH2I2 and 14 μL tert-butyl nitrite _was added. The reaction mixture was stirred at 80 °C for 1.5 h, then cooled, applied directly to two 1000-μM TLC plates, and eluted with 20% EtOAc in hexanes to afford approximately equivalent amounts of the title compound The hindered isomers A and B. Mass Spectrum (ESI) 764.2 (M+1).

Intermediate 31

4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde

Following the procedure described in Example 81, using 200 mg of 2-iodo-5-(trifluoromethyl)benzaldehyde (Example 80, Step A) and 170 mg of (4-fluoro-5-isopropyl-2-methoxy phenyl)boronic acid (Example 78) to obtain the title compound. Mass spectrum (ESI) 341.3 (M+1).

Intermediate 32

5-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1-(4-methoxybenzyl)imidazole alkan-2-one

Step A: [4'-Fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl][(4-methoxybenzyl)amino] Acetonitrile

To a solution of 203 mg 4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde (intermediate 31) in _{2 mL} CH2Cl2 100 μL of TMSCN was added, followed by 1 mg of ZnI ₂ . The mixture was stirred at room temperature for 30 minutes. p-Methoxybenzylamine (157 μL) in 2 mL of MeOH was added and the mixture was heated at reflux for 1.5 hours. The reaction mixture was cooled and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25M column, eluting with 1 CV of 2% EtOAc in hexanes, followed by a linear gradient of 2 → 100% EtOAc in hexanes over 10 CV , the title compound was obtained. Mass Spectrum (ESI) 487.2 (M+1).

Step B: 5-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1-(4-methoxybenzyl base) imidazolidin-2-one

To 100mg [4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl][(4-methoxybenzyl)amino]acetonitrile Add 620 _μL of 1 M LiAlH4 in _Et2O to the 0 °C solution in 4 mL THF. The cooling bath was removed and the mixture was stirred at room temperature for 45 minutes. The mixture was recooled to 0 °C and treated dropwise carefully with 24 μL of water, 24 μL of 15% aqueous NaOH and 60 μL of water. The solid was filtered, washed with _Et2O , and the filtrate was concentrated. The residue _was dissolved in 2 mL _CH2Cl2 and cooled to 0 °C. Triethylamine (55 μL) was added followed by triphosgene (32 mg). The mixture was stirred at 0°C for 45 minutes. The reaction mixture was partitioned between 10 mL EtOAc and 10 mL water. The aqueous phase was extracted with 10 mL of EtOAc, the combined organic layers were washed with 10 mL of brine, dried ( _Na2SO4 ) and concentrated _. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 15% EtOAc in hexanes, followed by a linear gradient of 15 → 100% EtOAc in hexanes over 10 CV , the title compound was obtained. Mass spectrum (ESI) 517.3 (M+1).

Example 376

1-[3,5-bis(trifluoromethyl)benzyl]-4-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl -2-yl]imidazolidin-2-one

Step A: 1-[3,5-Bis(trifluoromethyl)benzyl]-4-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl ) biphenyl-2-yl]-3-(4-methoxybenzyl) imidazolidin-2-one

To 19mg 5-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1-(4-methoxybenzyl ) to a solution of imidazolidin-2-one (Intermediate 32) in 1 mL of DMF at 0 °C was added 3 mg of NaH (60% dispersion in oil). The solution was stirred at 0°C for 10 minutes, then 8 μL of 3,5-bis-trifluoromethylbenzyl bromide was added, and the mixture was stirred at 0°C for 3 hours. The reaction mixture was treated with a drop of water, then filtered and purified by reverse phase HPLC [Waters XTerra C8 19 x 50 mm column with 90% water (0.1% TFA) - 100% acetonitrile (0.1% TFA) at a flow rate of 20 mL/min. Elution for 5.15 minutes, hold for 1.45 minutes, then 90% water for 0.5 minutes] afforded the title compound. Mass spectrum (ESI) 743.2 (M+1).

Step B: 1-[3,5-Bis(trifluoromethyl)benzyl]-4-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl ) biphenyl-2-yl] imidazolidin-2-one

15mg 1-[3,5-bis(trifluoromethyl)benzyl]-4-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl) A solution of biphenyl-2-yl]-3-(4-methoxybenzyl)imidazolidin-2-one in 0.5 mL TFA was stirred overnight at room temperature. The reaction mixture was concentrated and then purified by reverse phase HPLC [Waters XTerra C8 19×50 mm column, eluting with 90% water (0.1% TFA)-100% acetonitrile (0.1% TFA) at a flow rate of 20 mL/min for 5.15 minutes, Hold for 1.45 minutes, then elute with 90% water for 0.5 minutes] to give the title compound. Mass spectrum (ESI) 623.4 (M+1).

Example 377

1-Benzyl-4-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]imidazolidin-2-one

Step A: 1-Benzyl-4-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-3-(4 -Methoxybenzyl)imidazolidin-2-one

Following the procedure described in Example 379, Step A, using 31 mg of 5-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl] -1-(4-Methoxybenzyl)imidazolidin-2-one (Intermediate 32) and 9 μL of benzyl bromide afforded the title compound. Mass spectrum (ESI) 607.5 (M+1).

Step B: 1-Benzyl-4-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]imidazolidine-2- ketone

Following the procedure described in Example 379, Step B, using 5 mg of 1-benzyl-4-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl -2-yl]-3-(4-methoxybenzyl)imidazolidin-2-one, the title compound was obtained. Mass spectrum (ESI) 487.4 (M+1).

Claims (21)

1. formula I compound or pharmaceutically acceptable salt thereof

Wherein:

Y is selected from-C (=O)-and-(CRR ¹)-;

X is selected from-O-,-NH-,-N (C ₁-C ₅Alkyl)-and-(CRR ⁶)-;

Z is selected from-C (=O)-,-S (O) ₂-and-C (=N-R ⁹)-, be R wherein ⁹Be selected from H ,-CN and-C ₁-C ₅Alkyl, described alkyl is optional to be replaced by 1-11 halogen;

Each R be independently selected from H ,-C ₁-C ₅Alkyl and halogen, wherein-C ₁-C ₅Alkyl is optional to be replaced by 1-11 halogen;

B is selected from A ¹And A ², A wherein ¹Have following structure:

R ¹And R ⁶Be independently selected from respectively H ,-C ₁-C ₅Alkyl, halogen and-(C (R) ₂) _nA ², wherein-C ₁-C ₅Alkyl is optional to be replaced by 1-11 halogen;

R ²Be selected from H ,-C ₁-C ₅Alkyl, halogen, A ¹With-(C (R) ₂) _nA ², wherein-C ₁-C ₅Alkyl is optional to be replaced by 1-11 halogen;

Wherein B and R ²In the middle of have one to be A ¹And B, R ¹, R ²And R ⁶In the middle of have one to be A ²Or-(C (R) ₂) _nA ²This pattern I compound comprises a group A ¹With a group A ²

A ³Be selected from:

(a) be selected from the aromatic ring of phenyl and naphthyl;

(b) with the optional non-aromatics cycloalkyl ring condensed benzyl ring of 5-7 unit that comprises 1-2 two keys;

(c) 5-6 unit heterocycle, described heterocycle have 1-4 be independently selected from N, S, O and-N (O)-heteroatoms, and optional 1-3 two keys and carbonyl, the wherein A of comprising ³Be connected with A ³The tie point of benzyl ring be carbon atom; With

(d) comprise benzheterocycle with the heterocyclic fused benzyl ring of 5-6 unit, described heterocycle have 1-2 be independently selected from O, N and-S (O) _x-heteroatoms, and optional have 1-2 two key, wherein A ³Be connected with A ³The tie point of benzyl ring be carbon atom;

A ²Be selected from:

(a) be selected from the aromatic ring of phenyl and naphthyl;

(b) with the optional non-aromatics cycloalkyl ring condensed benzyl ring of 5-7 unit that comprises 1-2 two keys;

(c) 5-6 unit heterocycle, described heterocycle have 1-4 be independently selected from N, S, O and-N (O)-heteroatoms, and optional 1-3 two keys and the carbonyl of comprising;

(d) comprise benzheterocycle with the heterocyclic fused benzyl ring of 5-6 unit, described heterocycle has 1-2 heteroatoms that is independently selected from O, N and S, and optionally has 1-2 two keys; With

(e) optional have 1-3 two keys-C ₃-C ₈Cycloalkyl ring;

A wherein ³And A ²Optional respectively by the individual R that is independently selected from of 1-5 ^aSubstituting group replace;

Each R ^aBe independently selected from-C ₁-C ₆Alkyl ,-C ₂-C ₆Alkenyl ,-C ₂-C ₈Alkynyl, optional have 1-3 two keys-C ₃-C ₈Cycloalkyl ,-OC ₁-C ₆Alkyl ,-OC ₂-C ₆Alkenyl ,-OC ₂-C ₆Alkynyl, optional have 1-3 two keys-OC ₃-C ₈Cycloalkyl ,-C (=O) C ₁-C ₆Alkyl ,-C (=O) C ₃-C ₈Cycloalkyl ,-C (=O) H ,-CO ₂H ,-CO ₂C ₁-C ₆Alkyl ,-C (=O) SC ₁-C ₆Alkyl ,-OH ,-NR ³R ⁴,-C (=O) NR ³R ⁴,-NR ³C (=O) OC ₁-C ₆Alkyl ,-NR ³C (=O) NR ³R ⁴,-S (O) _xC ₁-C ₆Alkyl ,-S (O) _yNR ³R ⁴,-NR ³S (O) _yNR ³R ⁴, halogen ,-CN ,-NO ₂With 5-6 unit heterocycle, described heterocycle has 1-4 heteroatoms that is independently selected from N, S and O, and described heterocycle is also optional to be comprised carbonyl and optionally comprise 1-3 two keys, wherein said be connected with R ^aThe tie point of ring be carbon atom, wherein said heterocycle optional by 1-5 be independently selected from halogen ,-C ₁-C ₃Alkyl and-OC ₁-C ₃The substituting group of alkyl replaces, wherein-and C ₁-C ₃Alkyl and-OC ₁-C ₃Alkyl is optional to be replaced by 1-7 halogen;

Wherein for R wherein ^aBe selected from-C ₁-C ₆Alkyl ,-C ₂-C ₆Alkenyl ,-C ₂-C ₆Alkynyl, optional have 1-3 two keys-C ₃-C ₈Cycloalkyl ,-OC ₁-C ₆Alkyl ,-OC ₂-C ₆Alkenyl ,-OC ₂-C ₆Alkynyl, optional have 1-3 two keys-OC ₃-C ₈Cycloalkyl ,-C (=O) C ₁-C ₆Alkyl ,-C (=O) C ₃-C ₈Cycloalkyl ,-CO ₂C ₁-C ₆Alkyl ,-C (=O) SC ₁-C ₆Alkyl ,-NR ³C (=O) OC ₁-C ₆Alkyl and-S (O) _xC ₁-C ₆The compound of alkyl, R ^aOptional replaced, and optionally be independently selected from following substituting group replacement by 1-3 by 1-15 halogen: (a)-OH, (b)-CN, (c)-NR ³R ⁴, (d) optional have 1-3 two keys and optional by 1-15 halogen replacement-C ₃-C ₈Cycloalkyl (e) is optionally replaced by 1-9 halogen and optionally is independently selected from-OC by 1-2 is individual ₁-C ₂The substituting group of alkyl and phenyl replaces-OC ₁-C ₄Alkyl, (f) optional have 1-3 two keys and optional by 1-15 halogen replacement-OC ₃-C ₈Cycloalkyl, (g)-CO ₂H, (h)-C (=O) CH ₃, (i) optional by 1-9 halogen replacement-CO ₂C ₁-C ₄Alkyl and (j) optional by 1-3 be independently selected from halogen ,-CH ₃,-CF ₃,-OCH ₃With-OCF ₃The phenyl that replaces of group;

Condition is: when B is A ¹, X and Y are-CH ₂-, Z is-C (=O)-, and R ²Be to have substituent R in the 4-position ^aPhenyl, R wherein ^aBe to choose substituted as mentioned above-OC wantonly ₁-C ₆During alkyl, then at R ²On do not have other R ^aSubstituting group, wherein R ^aBe selected from-OH ,-OC ₁-C ₆Alkyl ,-OC ₂-C ₆Alkenyl ,-OC ₂-C ₆Alkynyl and optional have 1-3 two keys-OC ₃-C ₈Cycloalkyl, all these groups are optional to be substituted as mentioned above,

N is 0 or 1;

P is the integer of 0-4;

X is 0,1 or 2;

Y is 1 or 2;

R ³And R ⁴Be independently selected from respectively H ,-C ₁-C ₅Alkyl ,-C (=O) C ₁-C ₅Alkyl and-S (O) _yC ₁-C ₅Alkyl, wherein in all cases ,-C ₁-C ₅Alkyl is optional to be replaced by 1-11 halogen; And R ⁵Be selected from H ,-OH ,-C ₁-C ₅Alkyl and halogen, wherein-C ₁-C ₅Alkyl is optional to be replaced by 1-11 halogen.

2. the compound of claim 1, wherein said compound is selected from the compound or pharmaceutically acceptable salt thereof with formula Ia, Ib and Id:

With

3. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein:

Y is-(CRR ¹)-;

R and R ⁶Be independently selected from respectively H and-C ₁-C ₅Alkyl, wherein-C ₁-C ₅Alkyl is optional to be replaced by 1-11 halogen;

R ¹Be selected from H ,-C ₁-C ₅Alkyl and-(C (R) ₂) _nA ², wherein-C ₁-C ₅Alkyl is optional to be replaced by 1-11 halogen;

Wherein B and R ²In the middle of have one to be A ¹And B, R ¹And R ²In the middle of have one to be A ²Or-(C (R) ₂) _nA ²This pattern I compound comprises a group A ¹With a group A ²

A ³Be selected from:

(a) be selected from the aromatic ring of phenyl and naphthyl;

(b) 5-6 unit heterocycle, described heterocycle have 1-4 be independently selected from N, S, O and-N (O)-heteroatoms, and optional 1-3 two keys and carbonyl, the wherein A of comprising ³Be connected with A ³The tie point of benzyl ring be carbon atom; With

(c) comprise benzheterocycle with the heterocyclic fused benzyl ring of 5-6 unit, described heterocycle have 1-2 be independently selected from O, N and-S (O) _x-heteroatoms, and optional have 1-2 two key, wherein A ³Be connected with A ³The tie point of benzyl ring be carbon atom;

A ²Be selected from:

(a) be selected from the aromatic ring of phenyl and naphthyl;

(b) 5-6 unit heterocycle, described heterocycle have 1-4 be independently selected from N, S, O and-N (O)-heteroatoms, and optional 1-3 two keys and the carbonyl of comprising;

(c) comprise benzheterocycle with the heterocyclic fused benzyl ring of 5-6 unit, described heterocycle has 1-2 heteroatoms that is independently selected from O, N and S, and optionally has 1-2 two keys; With

(d) optional have 1-3 two keys-C ₃-C ₈Cycloalkyl ring;

A wherein ³And A ²Optional by the individual R that is independently selected from of 1-4 ^aSubstituting group replace;

Each R ^aBe independently selected from :-C ₁-C ₆Alkyl ,-C ₂-C ₆Alkenyl, optional have 1-3 two keys-C ₃-C ₈Cycloalkyl ,-OC ₁-C ₆Alkyl ,-C (=O) C ₁-C ₆Alkyl ,-C (=O) H ,-CO ₂H ,-CO ₂C ₁-C ₆Alkyl ,-OH ,-NR ³R ⁴,-NR ³C (=O) OC ₁-C ₆Alkyl ,-S (O) _xC ₁-C ₆Alkyl, halogen ,-CN ,-NO ₂With 5-6 unit heterocycle, described heterocycle has 1-4 heteroatoms that is independently selected from N, S and O, and described heterocycle is also optional to be comprised carbonyl and optionally comprise 1-3 two keys, wherein said heterocycle be connected with R ^aThe tie point of ring be carbon atom, wherein said heterocycle optional by 1-5 be independently selected from halogen ,-C ₁-C ₃Alkyl and-OC ₁-C ₃The substituting group of alkyl replaces, wherein-and C ₁-C ₃Alkyl and-OC ₁-C ₃Alkyl is optional to be replaced by 1-7 halogen; Wherein for R wherein ^aBe selected from-C ₁-C ₆Alkyl ,-C ₂-C ₆Alkenyl, optional have 1-3 two keys-C ₃-C ₈Cycloalkyl ,-OC ₁-C ₆Alkyl ,-C (=O) C ₁-C ₆Alkyl ,-CO ₂C ₁-C ₆Alkyl ,-NR ³C (=O) OC ₁-C ₆Alkyl and-S (O) _xC ₁-C ₆The compound of alkyl, R ^aOptional replaced, and optionally be selected from following substituting group replacement by 1 by 1-15 halogen: (a)-OH, (b)-NR ³R ⁴, (c) optionally replaced by 1-9 halogen and optionally be independently selected from-OC by 1-2 is individual ₁-C ₂The substituting group of alkyl and phenyl replaces-OC ₁-C ₄Alkyl and (d) phenyl, described phenyl optional by 1-3 be independently selected from halogen ,-CH ₃,-CF ₃,-OCH ₃With-OCF ₃Group replace; Condition is: when B is A ¹, X and Y are-CH ₂-, Z is-C (=O)-, and R ²Be to have substituent R in the 4-position ^aPhenyl, R wherein ^aBe to choose substituted as mentioned above-OC wantonly ₁-C ₆During alkyl, then at R ²On do not have other R ^aSubstituting group, wherein R ^aBe-OH or optional substituted as mentioned above-OC ₁-C ₆Alkyl;

P is the integer of 0-2;

R ³And R ⁴Be independently selected from respectively H and-C ₁-C ₅Alkyl, wherein in all cases ,-C ₁-C ₅Alkyl is optional to be replaced by 1-11 halogen; And

R ⁵Be selected from H ,-OH and-C ₁-C ₅Alkyl, wherein-C ₁-C ₅Alkyl is optional to be replaced by 1-11 halogen.

4. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein:

Y is-(CRR ¹)-;

Z is selected from-C (=O)-,-S (O) ₂-and-C (=N-R ⁹)-, be R wherein ⁹Be selected from H ,-CN and CH ₃Each R is independently selected from H and C ₁-C ₂Alkyl;

R ⁶Be selected from H and-C ₁-C ₃Alkyl, wherein C ₁-C ₃Alkyl is optional to be replaced by 1-5 halogen;

R ¹Be selected from H ,-C ₁-C ₃Alkyl and-(C (R) ₂) _nA ², wherein-C ₁-C ₃Alkyl is optional to be replaced by 1-5 halogen;

R ²Be selected from H ,-C ₁-C ₃Alkyl, A ¹With-(C (R) ₂) _nA ², wherein-C ₁-C ₃Alkyl is optional to be replaced by 1-5 halogen;

B and R ²In the middle of have one to be A ¹And B, R ¹And R ²In the middle of have one to be A ²Or-(C (R) ₂) _nA ²This pattern I compound comprises a group A ¹With a group A ²

A ³Be selected from:

(a) phenyl;

(b) 5-6 unit heterocycle, described heterocycle have 1-2 be independently selected from N, S, O and-N (O)-heteroatoms, A wherein ³Be connected with A ³The tie point of benzyl ring be carbon atom; With

(c) comprise benzheterocycle with 5 yuan of aromatic heterocycle condensed benzyl rings, described heterocycle have 1-2 be independently selected from O, N and-S (O) _x-heteroatoms, A wherein ³Be connected with A ³The tie point of benzyl ring be carbon atom;

A ²Be selected from:

(a) phenyl;

(b) 5-6 unit heterocycle, described heterocycle have 1-4 be independently selected from N, S, O and-N (O)-heteroatoms, and optionally comprise 1-3 two keys;

(c) comprise benzheterocycle with 5 yuan of heterocyclic fused benzyl rings, described heterocycle has 1-2 heteroatoms that is independently selected from O, N and S; With

(d)-C ₅-C ₆Cycloalkyl ring;

A wherein ³And A ²Optional respectively by the individual R that is independently selected from of 1-4 ^aSubstituting group replace;

Each R ^aBe independently selected from-C ₁-C ₄Alkyl ,-C ₂-C ₄Alkenyl, cyclopropyl ,-OC ₁-C ₂Alkyl ,-C (=O) C ₁-C ₂Alkyl ,-C (=O) H ,-CO ₂C ₁-C ₄Alkyl ,-OH ,-NR ³R ⁴,-NR ³C (=O) OC ₁-C ₄Alkyl ,-S (O) _xC ₁-C ₂Alkyl, halogen ,-CN ,-NO ₂With 5-6 unit heterocycle, described heterocycle has 1-2 heteroatoms that is independently selected from N, S and O, wherein said heterocycle be connected with R ^aThe tie point of ring be carbon atom, wherein said heterocycle is optional to be replaced by 1-5 substituting group that is independently selected from halogen;

Wherein for R wherein ^aBe selected from-C ₁-C ₄Alkyl ,-C ₂-C ₄Alkenyl ,-OC ₁-C ₂Alkyl ,-C (=O) C ₁-C ₂Alkyl ,-CO ₂C ₁-C ₄Alkyl ,-NR ³C (=O) OC ₁-C ₄Alkyl and-S (O) _xC ₁-C ₂The compound of alkyl, R ^aAlkyl optional replaced by 1-5 halogen, and optionally be selected from following substituting group replacement by one: (a)-OH, (b)-NR ³R ⁴, (C) optionally replaced by 1-3 fluorine atom, and optional by a phenyl replacement-OCH ₃And (d) phenyl, described phenyl optional by 1-3 be independently selected from halogen ,-CH ₃,-CF ₃,-OCH ₃With-OCF ₃Group replace; Condition is: when B is A ¹, X and Y are-CH ₂-, Z is-C (=O)-, and R ²Be to have substituent R in the 4-position ^aPhenyl, R wherein ^aBe to choose substituted as mentioned above-OC wantonly ₁-C ₂During alkyl, then at R ²On do not have other R ^aSubstituting group, wherein R ^aBe selected from-OH or optional substituted as mentioned above-OC ₁-C ₂Alkyl;

P is the integer of 0-2; And

R ³, R ⁴And R ⁵Be independently selected from H and-C ₁-C ₃Alkyl.

5. the compound or pharmaceutically acceptable salt thereof of claim 4, wherein

A ³Be selected from phenyl, thienyl, imidazolyl, pyrryl, pyrazolyl, pyridyl, N-oxidation-pyridyl, thiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, benzothienyl, benzothienyl-S-oxide compound and benzothienyl-S-dioxide; And

A ²Be selected from phenyl, thienyl, imidazolyl, thiazolyl, pyrryl, pyrazolyl, 1,2,4-triazolyl, tetrazyl, benzodioxole base, pyridyl, N-oxidation-pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, cyclopentyl, cyclohexyl and THP trtrahydropyranyl.

6. the compound or pharmaceutically acceptable salt thereof of claim 5, wherein

X is selected from-O-,-NH-and-N (C ₁-C ₃Alkyl)-; And

Z is-C (=O)-.

7. the compound or pharmaceutically acceptable salt thereof of claim 4, wherein

A ²And A ³It all is phenyl; And

R ^aBe selected from-C ₁-C ₄Alkyl, described alkyl is optional to be replaced by 1-5 fluorine atom, and optionally is selected from-OH and-OCH by one ₃Group replace; Optional by 1-3 fluorine atom replacement-OC ₁-C ₂Alkyl;-C ₂-C ₄Alkenyl; By a group-NR ³R ⁴Replace-C ₁-C ₂Alkyl;-C ₁-C ₂Alkyl-O-C ₁-C ₂Alkyl-phenyl; Cyclopropyl;-C (=O) H;-OH;-NR ³R ⁴-S (O) _xC ₁-C ₂Alkyl; Halogen;-CN;-NO ₂With comprise 1-2 Sauerstoffatom and optional quilt-C ₁-C ₂The 5-6 unit heterocycle that alkyl replaces;

Have the condition identical with claim 4.

8. the compound of claim 7, wherein said compound has formula Ii or its pharmacologically acceptable salt:

Wherein

R ⁷Be selected from Cl and-CF ₃

Each R ^bBe independently selected from-C ₁-C ₃Alkyl ,-OCH ₃And F;

R ¹Be selected from H and-C ₁-C ₂Alkyl;

R ^cBe selected from halogen ,-CH ₃,-CF ₃With-CN;

Q is 2 or 3; And

T is the integer of 0-2.

9. the compound of claim 7, wherein said compound has formula Ij or its pharmacologically acceptable salt:

Wherein

R ⁷Be selected from Cl and-CF ₃

Each R ^bBe independently selected from-C ₁-C ₃Alkyl ,-OCH ₃And F;

R ¹Be selected from H and-C ₁-C ₂Alkyl;

R ^cBe selected from halogen ,-CH ₃,-CF ₃With-CN;

Q is 2 or 3; And

T is the integer of 0-2.

10. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein

A ³Be phenyl, described phenyl is optional by 1-4 substituent R ^aReplace, wherein R ^aBe independently selected from-C ₁-C ₅Alkyl ,-OC ₁-C ₃Alkyl ,-CO ₂C ₁-C ₃Alkyl ,-CO ₂H, halogen ,-NR ³R ⁴,-C (=O) C ₁-C ₃Alkyl ,-C (=O) H ,-C (=O) NR ³R ⁴,-SC ₁-C ₃Alkyl ,-C ₂-C ₃Alkenyl ,-CN ,-NO ₂With 1,2,4- di azoly, wherein all that occur-C ₁-C ₃Alkyl and-C ₁-C ₅Alkyl is optional to be replaced by 1-6 substituting group that is independently selected from 1-5 halogen and one-OH group; And-C ₂-C ₃Alkenyl is optional to be replaced by 1-3 halogen;

A ²Be selected from phenyl, cyclohexyl and 5-6 unit heterocycle, described heterocycle have 1-2 be independently selected from O, N, S and-N (O)-heteroatoms, and optionally comprise 1-3 two key, wherein A ²Optional by individual following substituting group the replacement :-C that is independently selected from of 1-2 ₁-C ₄Alkyl ,-OC ₁-C ₃Alkyl ,-NO ₂,-CN ,-S (O) _xC ₁-C ₃Alkyl ,-NHS (O) ₂C ₁-C ₃Alkyl ,-NR ³R ⁴,-NR ³C (=O) R ⁴,-C ₂-C ₃Alkenyl ,-C (=O) NR ³R ⁴, halogen and pyridyl, wherein in all cases, C ₁-C ₃Alkyl, C ₁-C ₄Alkyl and C ₂-C ₃Alkenyl is optional to be replaced by 1-3 halogen, and condition is, when B is A ¹, X and Y are-CH ₂-, Z is-C (=O)-, and R ²Be to have substituent R in the 4-position ^aPhenyl, R wherein ^aBe to choose substituted as mentioned above-OC wantonly ₁-C ₃During alkyl, then at R ²On do not have other R ^aSubstituting group, wherein R ^aBe substituted as mentioned above-OC ₁-C ₂Alkyl; R ³And R ⁴Be independently selected from respectively H and-C ₁-C ₃Alkyl; And

P is 0-2.

11. the compound or pharmaceutically acceptable salt thereof of claim 10, wherein

A ¹Be

R wherein ⁷And R ⁸Be independently selected from respectively H, halogen ,-NR ³R ⁴,-C ₁-C ₃Alkyl ,-OC ₁-C ₃Alkyl ,-CN ,-NO ₂And pyridyl, wherein in all cases, C ₁-C ₃Alkyl is optional to be replaced by 1-3 halogen; And

A ²Be selected from phenyl, pyridyl and cyclohexyl, wherein A ²Choose wantonly by 1-2 and be independently selected from-C ₁-C ₄Alkyl ,-OC ₁-C ₃Alkyl ,-NO ₂The substituting group of ,-CN and halogen replaces, wherein the C in all use ₁-C ₄Alkyl and C ₁-C ₃Alkyl is optional to be replaced by 1-3 halogen, and condition is, when B is A ¹, X and Y are-CH ₂-, Z is-C (=O)-, and R ²Be to have substituent R in the 4-position ^aPhenyl, R wherein ^aBe to choose wantonly by 1-3 halogen to replace-OC ₁-C ₃During alkyl, then at R ²On do not have other R ^aSubstituting group, wherein R ^aBe to choose wantonly by 1-3 halogen to replace-OC ₁-C ₃Alkyl.

12. the compound or pharmaceutically acceptable salt thereof of claim 11, wherein

A ¹Be

R ⁷Be selected from H, halogen ,-NR ³R ⁴,-C ₁-C ₃Alkyl ,-OC ₁-C ₃Alkyl ,-CN ,-NO ₂And pyridyl, wherein in all cases, C ₁-C ₃Alkyl is optional to be replaced by 1-3 halogen; And R ⁸Be selected from H, halogen ,-CH ₃,-CF ₃,-OCH ₃With-OCF ₃

13. comprise the compound or pharmaceutically acceptable salt thereof of claim 1 and the pharmaceutical composition of pharmaceutically acceptable carrier.

14. the compound of claim 4, wherein said compound are selected from following compounds or its pharmacologically acceptable salt:

With

15. the compound of claim 4, wherein said compound are selected from the have formula compound or pharmaceutically acceptable salt thereof of (a)-(c):

(a)

Wherein R is selected from

(b)

Wherein R is selected from

(c)

Wherein R is selected from

16. the compound of claim 4, wherein said compound are selected from following compounds or its pharmacologically acceptable salt:

17. the compound of claim 4, wherein said compound are selected from the have formula compound or pharmaceutically acceptable salt thereof of (a)-(k):

(a)

Wherein for compound (1)-(6), A ³, A ²Be selected from Z:

(b)

A wherein ³Be selected from:

(c)

Wherein for compound (1)-(6), A ³And A ²Be selected from:

(d)

Wherein R is selected from:

With

(e)

Wherein R is Et or n-Pr;

(f)

Wherein for compound (1)-(4), R and A ³Be selected from:

(g)

Wherein R is selected from:

With

(h)

A wherein ²Be selected from:

With

(i)

Wherein R is selected from:

With

(j)

A wherein ³Be selected from:

With With

(k)

Wherein for compound (1)-(3), A ³, R ₂And R ₃Be selected from:

18. an atherosclerotic method for the treatment of among the patient who needs treatment, described method comprises the compound or pharmaceutically acceptable salt thereof to the claim 1 of described patient's drug treatment significant quantity.

19. one kind raises and needs the method for the HDL-C among the patient of treatment, comprises the compound or pharmaceutically acceptable salt thereof to the claim 1 of described patient's drug treatment significant quantity.

20. the compound or pharmaceutically acceptable salt thereof of claim 1 is used for the treatment of application in the atherosclerotic medicine in production.

21. a pharmaceutical composition, described composition comprise the compound or pharmaceutically acceptable salt thereof, pharmaceutically acceptable carrier of claim 1 and one or more are selected from following activeconstituents:

(i) HMG-CoA reductase inhibitor;

(ii) bile acid chelating agent;

(iii) nicotinic acid and related compound;

(iv) PPAR alfa agonists;

(v) cholesterol absorption inhibitor;

(vi) acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor;

(vii) phenol antioxidant;

(viii) microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitor;

(ix) antioxidant vitamin;

(x) intend the Tiroidina medicine;

(xi) LDL (low-density lipoprotein) receptor inducer;

(xii) anticoagulant;

(xiii) vitamin B12 (also being called Vitral);

(xiv) folic acid or its pharmacologically acceptable salt or ester;

(xv) FXR and LXR part;

(xvi) promoting agent of raising ABCA1 genetic expression; With

(xvii) ileal bile acid carrier.