MX2008008585A

MX2008008585A - 1, 3-oxazolidin-2-one derivatives useful as cetp inhibitors

Info

Publication number: MX2008008585A
Application number: MXMX/A/2008/008585A
Authority: MX
Inventors: Amjad Ali; Zhijian Lu; Peter J Sinclair; Cameron J Smith; Yiheng Chen; Hong Li
Original assignee: Amjad Ali; Yiheng Chen; Hong Li; Zhijian Lu; Merck & Co Inc; Peter J Sinclair; Cameron J Smith
Priority date: 2005-12-30
Filing date: 2008-06-27
Publication date: 2008-09-26

Abstract

Compounds having the structure of Formula I, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors, and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis. The compounds have 3 cyclic groups connected by single bonds, as for example triphenyl, which are attached directly to the ring of formula I or attached at the position B.

Description

CHOLESTEROL ESTER TRANSFER PROTEIN INHIBITORS FIELD OF THE INVENTION This invention relates to a class of chemical compounds that inhibit cholesterol ester transfer protein (CETP) and therefore have utility in raising HDL cholesterol, reducing LDL cholesterol, and in the treatment and prevention of atherosclerosis.

BACKGROUND OF THE INVENTION Atherosclerosis and its clinical consequences, coronary heart disease (CHD), stroke and peripheral vascular disease, represent a truly enormous burden for health care systems in the industrialized world. In the United States alone, approximately 13 million patients have been diagnosed with CHD, and more than half a million deaths are attributed to CHD each year. In addition, this amount is expected to increase over the next quarter of a century as obesity and diabetes continue to rise. It has long been recognized that in mammals, variations in circulating lipoprotein profiles correlate with the risk of atherosclerosis and CHD. The clinical success of HMG- inhibitors CoA reductase, especially statins, in the reduction of coronary events is based on the reduction of circulating low density lipoprotein cholesterol (LDL-C), levels that correlate directly with increased risk for atherosclerosis. Very recently, studies on epidemiology have shown an inverse relationship between high-density lipoprotein (HDL-C) cholesterol levels and atherosclerosis, leading to the conclusion that low serum HDL-C levels are associated with increased risk for CHD. Metabolic control of lipoprotein levels is a complex and dynamic procedure that involves many factors. An important metabolic control in man is cholesteryl ester transfer protein (CETP), a glycoprotein in plasma that catalyzes the movement of cholesteryl esters of HDL to lipoproteins containing apoB, especially VLDL (see Hesler, CB, et. al. (1987) Purification and characterization of human plasma protein cholesteryl ester transfer protein J. Biol. Chem. 262 (5), 2275-2282)). Under physiological conditions, the network reaction is a heterointerchange in which CETP carries triglyceride to HDL of apoB lipoproteins and transports HDL cholesterol ester to lipoprotein apoB. In humans, CETP plays a role in the transport of inverse cholesterol, the procedure by which cholesterol is returned to the liver from peripheral tissues. Intriguingly, many animals do not possess CETP, including animals that have high HDL levels and it is known which are resistant to coronary heart disease, such as rodents (see Guyard-Dangremont, V., et al., (1998) Phospholipid and cholesteryl ester transfer activities in plasma from 14 vertébrate species, Relation to atherogenesis susceptibility, Comp. Biochem. Physiol B Biochem Mol Biol. 120 (3), 517-525). Numerous epidemiological studies that correlate the effects of natural variation in CETP activity with respect to risk of coronary heart disease have been performed, including studies on a small number of known human null mutations (see Hirano, K.-l., Yamashita, S and Matsuzawa, Y. (2000) Pros and cons of inhibiting cholesteryl ester transfer protein, Curr Opin. Lipidol 11 (6), 589-596). These studies have clearly demonstrated 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 may be beneficial for humans by increasing HDL-C levels while reducing LDL levels. Despite the significant therapeutic advance represented by statins such as simvastatin (ZOCOR®), statins only achieve a risk reduction of approximately one third in the treatment and prevention of atherosclerosis and ensure atherosclerotic disease events. Currently, few pharmacological therapies are available that favorably increase the circulating levels of HDL-C. Certain Statins and some fibrates offer moderate HDL-C gains. Niacin, which provides the most effective therapy to increase HDL-C that has been clinically documented, suffers from compliance problems by the patient, due in part to side effects such as jet wash. An agent that surely and effectively increases HDL cholesterol levels may respond to a significant medical need but still not satisfied by offering a means of pharmacological therapy that can significantly improve circulating lipid profiles through a mechanism that is complementary to existing therapies . New classes of chemical compounds that inhibit CETP are being investigated in several pharmaceutical companies or are in clinical trials. Currently CETP inhibitors are not being commercialized. Clinical trials of Pfizer's CETP inhibitor, torcetrapib, were recently terminated due to increased mortality in patients who were using drugs during ongoing studies. New compounds are needed so that one or more pharmaceutical compounds can be found that are safe and effective. The novel compounds described therein are very potent CETP inhibitors.

BRIEF DESCRIPTION OF THE INVENTION The compounds having the formula I, including pharmaceutically acceptable salts of the compounds, are inhibitors of CETP, that have the utilities described below, where: B I I Y is selected from the group consisting of -C (= 0) - and - (CRR) -; X is selected from the group consisting of -O-, -NH-, -N (CrC5 alkyl) -, and - (CRR6) -; Z is selected from the group consisting of -C (= 0) -, -S (0) 2-, and - 9 9 C (= NR) -, wherein R is selected from the group consisting of H, -CN, and CrC5 alkyl optionally substituted with 1 -1 1 halogens; Each R is independently selected from the group consisting of H, C 1 -C 5 alkyl, and halogen, wherein C 1 -C 5 alkyl is optionally substituted with 1-11 halogens; B is selected from the group consisting of A1 and A2, where A1 has the structure: R1 and R6 are each selected from the group consisting of H, -C5 alkyl, halogen, and - (C (R) 2) nA2, wherein -alkyl of d-Cs is optionally substituted with 1 -1 1 halogens; R2 is selected from the group consisting of H, -C1-C5 alkyl, halogen, A1, and - (C (R) 2) nA2, wherein-C1-C5 alkyl is optionally substituted with 1-11 halogens; Where one of B and R2 is A1; and one of B, R1, R2, and R is A2 or - (C (R) 2) nA2; so that the compound of the formula I includes a group A1 and a group A2; A3 is selected from the group consisting of: (a) an aromatic ring selected from phenyl and naphthyl; (b) a phenyl ring fused to a non-aromatic 5-7 membered cycloalkyl ring, optionally comprising 1-2 double bonds; (c) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group, where the point of attachment of A3 to the phenyl ring to which A3 is attached is a carbon atom; and (d) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and -S (0) x- and optionally 1-2 doubles bonds, wherein the point of attachment of A3 to the phenyl ring to which A3 is attached is a carbon atom; wherein A3 is substituted with an A4 group and is optionally substituted with 1-4 Ra groups; A2 is selected from the group consisting of: (a) an aromatic ring selected from phenyl and naphthyl; (b) a phenyl ring fused to a non-aromatic 5-7 membered cycloalkyl ring, optionally comprising 1-2 double bonds; (c) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group; (d) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S and optionally 1-2 double bonds; and (e) a C3-C8-cycloalkyl ring optionally having 1-3 double bonds; wherein A2 is optionally substituted with 1-5 substituent groups independently selected from Ra; A4 is selected from the group consisting of: (a) an aromatic ring selected from phenyl and naphthyl; (b) a phenyl ring fused to a non-aromatic 5-7 membered cycloalkyl ring, optionally comprising 1-2 double bonds; (c) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group; and (d) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and -S (0) x- and optionally 1-2 doubles links; wherein when A4 is (a) an aromatic ring selected from phenyl and naphthyl; (b) a phenyl ring fused to a non-aromatic 5-7 membered cycloalkyl ring, optionally comprising 1-2 double bonds; (c) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group, where the point of attachment of the heterocyclic ring to A3 is an N atom of A4; or (d) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and -S (0) x- and optionally 1-2 doubles links; then A4 is optionally substituted with 1-5 Ra groups; and when A4 is a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group, wherein the point of attachment of the heterocyclic ring to A3 is a carbon atom of A4, then A4 is substituted with a group Re and is also optionally substituted with 1-4 groups independently selected from Ra; Each Ra is independently selected from the group consisting of -C C6 alkyl, -C2-C6 alkenyl, d-Ce alkylquinyl-C3-C8 cycloalkyl optionally having 1-3 double bonds, -O-C alkyl? -C6, -C2-C6alkenyl, -C2-C6alkynyl, -C3-C8cycloalkyl optionally having 1-3 double bonds, -C (= 0) d-C3alkyl, -C (= 0) C3-C8 cycloalkyl, -C (= 0) H, -C02H, -C02alkyl of C? -C6, -C (= 0) C4 alkyl, -OH, -NR3R4, -C (= 0) NR3R4, -N R3C (= 0) Oalkyl of C? -C6) -NR3C (= 0) NR3R4, -S (0) xalkyl of d-C6, -S (0) and NR3R4, -NR3S (0) and NR3R4, halogen, - CN, -NO2, and a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally also comprises a carbonyl group and optionally also comprises 1-3 double bonds, in where the point of attachment of said heterocyclic ring to the ring to which Ra is attached is a carbon atom, wherein said heterocyclic ring is optional ally substituted with 1-5 substituent groups independently selected from halogen, -C3-C3 alkyl, and -D3-C3 alkyl, wherein-C3 alkyl and -3C3 alkyl are optionally substituted with 1-7 halogens; wherein for compounds in which Ra is selected from the group consisting of -alkyl of d-Cß, -alkenyl of C2-C6, -alkynyl of C2-C6, -cycloalkyl of C3-C8 having optionally 1-3 double bonds , -Oalkyl of d-Cβ, -C 2 -C 6 -alkenyl, -C 2 -C 6 -alkynyl, -3-C 8 -cycloalkyl optionally having 1-3 double bonds, -C (= 0) -C alquilo-alkyl, -C ( = 0) C3-C8 cycloalkyl, -C02C-C6alkyl, -C (= 0) C6-C6-alkyl, -NR3C (= 0) C6-C6alkyl, and -S (0) -C6 C6alkyl, Ra is optionally substituted with 1-15 halogens and is optionally substituted with 1-3 substituent groups independently selected from (a) -OH, (b) -CN, (c) -NR3R4, (d) -C3-C8 cycloalkyl optionally having 1 -3 double bonds and optionally substituted with 1-15 halogens, (e) -O-C4-C4 alkyl optionally substituted with 1-9 halogens and optionally substituted with 1-2 substituent groups independently selected from -O-C2 alkyl and phenyl (f) -C3-C8 cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (g) -C02H, (h) -C (= 0) CH3, (i) -C02alkyl of d -C4 which is optionally substituted with 1-9 halogens, and (j) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3, -CF3, -OCH3, and -OCF3; Each Re is independently selected from the group consisting of -C2-C6 alkenyl, -C2-C6alkynyl, -C3-C8cycloalkyl optionally having 1-3 double bonds, -C2-C6Oalkenyl, -Oalkynyl C2-C6, -C3-C8-cycloalkyl optionally having 1-3 double bonds, -C (= 0) C-alkyl, -C (= 0) C3-C8 cycloalkyl, -C (= 0) H, -C02H, -C02alkyl of d-C6, -C (= 0) Salkyl of CrC6, -OH, -NR3R4, -C (= 0) NR R4, -NR3C (= 0) Oalkyl of C C6, -NR3C (= 0) NR3R4, -S (0) xalkyl of C? -C6, -S (0) and NR3R4, -NR3S (0) and NR3R4, -CN, -N02, and a heterocyclic ring of 5-6 members having 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally also comprising 1-3 double bonds, wherein the point of attachment of said heterocyclic ring to the ring to which Re is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen, -alkyl of d-C3, and -Oalkyl of d-C3, wherein -alkyl of C? -C3 and -Oalkyl of d-C3 are optionally substituted with 1-7 halogens; wherein for compounds in which Re is selected from the group consisting of -d-Cßalkenyl, d-Cßalkynyl, -3C8 cycloalkyl optionally having 1-3 double bonds, -C2-C6alkenyl , -C2-C6alkynyl, -3C8 cycloalkyl optionally having 1-3 double bonds, -C (= 0) dC6 alkyl, -C (= 0) C3-C8 cycloalkyl, - C02alkyl of C C6, -C (= 0) C4alkyl salt, -NR3C (= 0) O-alkyl of d-C6, and -S (0) xalkyl of d-Cß, Re is optionally substituted with 1-15 halogens and is optionally substituted with 1-3 substituent groups independently selected from (a) -OH, (b) -CN, (c) -NR3R4, (d) -C3-C8 cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (e) -C4 C4alkyl optionally substituted with 1-9 halogens and also optionally substituted with 1-2 substituent groups independently selected from -O-alkyl of d-C2 and phenyl, (f) -O-cycloalkyl of C3 -C8 that has optionally 1-3 double bonds and optionally substituted with 1-15 halogens, (g) -C02H, (h) -C (= 0) CH3, (i) -C02alkyl of d-C4 which is optionally substituted with 1-9 halogens , and (j) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3, -CF3, -OCH3, and -OCF3; n is 0 or 1; p is an integer of 0-4; x is O, 1 or 2; and it is 1 or 2; R3 and R4 are each independently selected from H, -alkyl of d-C5, -C (= 0) C1-C5 alkyl and -S (O) and alkyl of d-C5, wherein-C1-C5 alkyl in all cases is optionally substituted with 1-11 halogens; and R5 is selected from the group consisting of H, -OH, -C1-C5 alkyl, and halogen, wherein -alkyl of d-d is optionally substituted with 1-11 halogens. In the compounds of the formula I and in compounds described subsequently, the alkyl, alkenyl and alkynyl groups may be linear or branched, unless otherwise indicated.

DETAILED DESCRIPTION OF THE INVENTION In embodiments of the invention, the compound has the formula Ia, Ib or Id, including pharmaceutically acceptable salts. . the Ib Id In embodiments of the invention, the groups in the structures are as follows, independent of each other: Y is - (CRR1) -; R and R6 are each independently selected from the group consisting of H and -C1-C5 alkyl, wherein -alkyl of d-C5 is optionally substituted with 1-11 halogens; R1 is selected from the group consisting of H, -C1-C5 alkyl, and - (C (R) 2) nA2, wherein -alkyl of d-d is optionally substituted with 1-11 halogens; wherein one of B and R2 is A1; and one of B, R1, and R2 is A2 or - (C (R) 2) nA2; whereby the compound of formula I includes a group A1 and a group A2; A3 is selected from the group consisting of: (a) an aromatic ring selected from phenyl and naphthyl; (b) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group, where the point of attachment of A3 to the phenyl ring to which A3 is attached is a carbon atom; and (c) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and -S (0) x- and optionally 1-2 doubles bonds, wherein the point of attachment of A3 to the phenyl ring to which A3 is attached is a carbon atom; wherein A3 is substituted with an A4 group and is optionally substituted with 1-4 Ra groups. A2 is selected from the group consisting of: (a) an aromatic ring selected from phenyl and naphthyl; (b) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group; (c) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S and optionally 1-2 double bonds; Y (d) a C3-C8-cycloalkyl ring optionally having 1-3 double bonds; wherein A2 is optionally substituted with 1-5 substituent groups independently selected from Ra; Each Ra is independently selected from the group consisting of - dd alkyl, dd alkenyl, C3-C8 cycloalkyl optionally having 1-3 double bonds, - O-alkyl of d-, -C (= 0) C-alkyl ? -C6, -C (= 0) H, -C02H, -C02alkyl of C C6, -OH, -NR3R4, -NR3C (= 0) O-alkyl of C C6, -S (0) xalkyl of C C6, halogen, -CN, -N02, and a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally also comprising 1-3 doubles links, wherein the point of attachment of said heterocyclic ring to the ring to which Ra is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen, -alkyl d-C3 , and - C C3 alkyl, wherein -alkyl of dd and -Oalkyl of C C3 are optionally substituted with 1-7 halogens; wherein for compounds in which Ra is selected from the group consisting of -alkyl of d-C6, -alkenyl of d-, -cycloalkyl of C3-C8 having optionally 1-3 double bonds, -Oalkyl of d-C6l- C (= 0) d-C6 alkyl, -C02alkyl of C Ce, -NR3C (= 0) Oalkyl of dd, and -S (0) xalkyl of dd, Ra is optionally substituted with 1-15 halogens and is optionally substituted with a substituent group selected from (a) -OH, (b) -NR3R4, (c) -Dalkyl of dd optionally substituted with 1-9 halogens and optionally substituted with 1-2 substituent groups independently selected from -Oalkyl of d-C2 and phenyl, and (d) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3, -CF3, -OCH3, and -OCF3; Each Re is independently selected from the group consisting of-C2-C6 alkenyl, -C3-C8 cycloalkyl optionally having 1-3 double bonds, -C (= 0) d-C6 alkyl, -C (= 0) H, -C02H, -C02alkyl of dd, -OH, -NR3R4, -NR3C (= 0) O-alkyl of d-C6, -S (0) xalkyl of dd, -CN, -N02, and a heterocyclic ring of 5- 6 members having 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally also comprising 1-3 double bonds, wherein the point of attachment of said heterocyclic ring to the ring to which Re is bonded is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen, -dialkyl, and -Dalkyl, wherein -C3 alkyl and - O-alkyl dd are optionally substituted with 1-7 halogens; wherein for compounds in which Re is selected from the group consisting of-C2-C6 alkenyl, -C3-C8 cycloalkyl optionally having 1-3 double bonds, -C (= 0) dd alkyl, -C02alkyl C C6, -NR3C (= 0) O-alkyl of C C6, and -S (0) xalkyl of CrC6, Re is optionally substituted with 1-15 halogens and is optionally substituted with a substituent group selected from (a) -OH, (b) ) -NR3R4, (c) -CrCalkyl optionally substituted with 1-9 halogens and also optionally substituted with 1-2 substituent groups independently selected from -Oalkyl of C and phenyl, and (d) phenyl which is optionally substituted by 1- 3 groups independently selected from halogen, -CH3, -CF3, -OCH3, and -OCF3; p is an integer of 0-2; R3 and R4 are each independently selected from H and -alkyl of d-d, wherein -alkyl of d-d in all cases is optionally substituted with 1-11 halogens; R5 is selected from the group consisting of H, -OH, and -alkyl of d-d, wherein -alkyl of C d is optionally substituted with 1-11 halogens; Z is selected from the group consisting of -C (= 0) -, -S (0) -, and -C (= N-R9) -, wherein R9 is selected from the group consisting of H, -CN, and CH3; Each R is independently selected from the group consisting of H and Crd alkyl; R6 is selected from the group consisting of H and -alkyl of d-d, wherein d-d alkyl is optionally substituted with 1-5 halogens; R1 is selected from the group consisting of H, -alkyl of d-d, and - (C (R) 2) nA2, wherein -alkyl of d-d is optionally substituted with 1-5 halogens; R2 is selected from the group consisting of H, -Crd alkyl, A1, and - (C (R) 2) nA2, wherein -alkyl of d-d is optionally substituted with 1-5 halogens, wherein one of B and R2 is A1; and one of B, R1, and R2 is A2 or - (C (R) 2) nA2; whereby the compound of formula I includes a group A1 and a group A2; A3 is selected from the group consisting of: (a) phenyl; (b) a 5-6 membered aromatic heterocyclic ring having 1-2 heteroatoms independently selected from N, S, O, and -N (O) -, wherein the point of attachment of A3 to the phenyl ring to which A3 is attached is a carbon atom; and (c) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-membered aromatic heterocyclic ring having 1- 2 heteroatoms independently selected from O, N, and -S (0) x, wherein the point of attachment of A3 to the phenyl ring to which A3 is attached is a carbon atom; wherein A3 is substituted with an A4 group and is optionally substituted with 1-4 Ra groups; A2 is selected from the group consisting of: (a) phenyl; (b) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds; (c) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S; and (d) a C5-C6 cycloalkyl ring; wherein A2 is optionally substituted with 1-5 substituent groups independently selected from Ra; Each Ra is independently selected from the group consisting of -Crd alkyl, -C2-C4 alkenyl, cyclopropyl, -Dalkyl of dd, -C (= 0) dd alkyl, -C (= 0) H, -C02H, -C02alkyl of dd, -OH, -NR3R4, -NR3C (= 0) Oalkyl of dd, -S (0) xalkyl of dd, halogen, -CN, -N02, and a heterocyclic ring of 5-6 members having 1 -2 heteroatoms independently selected from N, S, and O, wherein the point of attachment of said heterocyclic ring to the ring to which Ra is attached to the ring is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen; wherein for compounds in which Ra is selected from the group consisting of -alkyl of dd, -alkenyl of C2-C, -Oalkyl of d-C2, -C (= 0) alkyl of dd, -C02alkyl of dd, - NR3C (= 0) Oalkyl of d-C4, and -S (0) xalkyl of C C2, the alkyl group of Ra is optionally substituted with 1-5 halogens and is optionally substituted with a substituent group selected from (a) -OH , (b) -NR3R4, (c) -OCH3 optionally substituted with 1-3 fluorine atoms and also optionally substituted with a phenyl group, and (d) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3, -CF3, -OCH3, and -OCF3; Each Re is independently selected from the group consisting of-C2-C4 alkenyl, cyclopropyl, -C (= 0) dd alkyl, -C (= 0) H, -C02H, -C02alkyl of dd, -OH, -NR3R4 , -NR3C (= 0) O-alkyl of d-C4, -S (0) xalkyl of CrC2, -CN, -N0, and a heterocyclic ring of 5-6 members having 1-2 heteroatoms independently selected from N, S, and O, wherein the point of attachment of said heterocyclic ring to the ring to which Re is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen; wherein for compounds in which Re is selected from the group consisting of-C-C-alkenyl, -C (= 0) dd alkyl, -C02C CrC4 alkyl, -NR3C (= 0) O-alkyl of d-C4, and -S (0) CrC2 xalkyl, the alkyl group of Re is optionally substituted with 1-5 halogens and is also optionally substituted with a substituent group selected from (a) -OH, (b) -NR3R4, (c) -OCH3 optionally substituted with 1-3 fluorine atoms and optionally substituted with a phenyl group; and (d) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3, -CF3, -OCH3, and -OCF3; p is an integer of 0-2; R3, R4 and R5 are each independently selected from H and -alkyl of d-d; In many modalities: the following definitions apply: X is -O-; Z is -C (= 0) -; Y is -CHR1, wherein R1 is selected from H and alkyl from d-d; R and R5 are H; R2 and B are selected from A1 and A2, where one of R2 and B is A1 and the other of R2 and B is A2¡. A2 is selected from the group consisting of phenyl, pyridyl, pyrazolyl, thienyl, 1,4-triazolyl and imidazolyl; A3 is selected from the group consisting of phenyl, thiazolyl and pyrazolyl; A4 is selected from the group consisting of phenyl, pyridyl, thiazolyl, pyrazolyl, 1,4-triazolyl, pyrimidinyl, piperidinyl, pyrrolidinyl and azetidinyl; A2 is optionally substituted with 1-3 substituents independently selected from halogen, -OCH3, -OCF3, and d-C3 alkyl optionally substituted with 1-3 halogens; A3 is substituted with an A4 group and is optionally substituted with 1-2 substituents independently selected from halogen, -OH, -OCH3, -OCF3, and d-d alkyl optionally substituted with 1-3 halogens; A4 is optionally substituted with 1-3 substituents independently selected from the group consisting of (a) -alkyl of dd optionally substituted with 1-3 halogens and optionally substituted with -OH, (b) -C2-C4 alkenyl optionally substituted with 1-3 halogens, (c) -C (= 0) dd alkyl optionally substituted with 1-3 halogen and optionally substituted with a group selected from -OH, -C02CH3l -C (= 0) CH3, -NR3R4, and -O-alkyl of d-C2enoOalkyl of dd, (d) -C (= 0) H, (e) - C02H, (f) -C02C1alkyl optionally substituted with a group selected from -C (= 0) C2alkyl, -OH, -C02CH3, -C02H, -NR3R4, and -Oalkyl of d-C2enoOalkyl of dd, ( g) -OH, (h) -S (0) xalkyl of C C2, (i) halogen, (j) -CN, (k) -N02, (I) -C (= 0) NR3R4, (m) - O-alkylnoalkyl of CrC2, (n) -Dalkyl of dd optionally substituted with 1-3 halogens, (o) -C (= O) O-alkyl of dd optionally substituted with 1-3 halogens and optionally substituted with a group selected from -OH, -C02CH3, -NR3R4, and -D-denoOalkyl of C C2, (p) -NR3C (= 0) C2 alkyl, (q) -NR3R4, and (r) -S (0) xNR3R4; provided that if A4 is a heterocyclic group connected to A3 through a ring carbon atom of A4, then at least one A4 solvent must be selected from Re, where Re is selected from the group consisting of (a) - dd alkyl substituted with -OH and optionally substituted with 1 -3 halogens, (b) -C2-C alkenyl optionally substituted with 1 -3 halogens, (c) -C (= 0) CrC2 alkyl optionally substituted with 1 -3 halogens and optionally substituted with a group selected from -OH, -C02CH3, -C (= 0) CH3, -NR3R4, and -Oalkyl of d-deneOalkyl of dd, (d) -C (= 0) H, ( e) -C02H, (0 -C02alkyl of dd optionally substituted with a group selected from -C (= 0) alkyl of d-C2, -OH, -C02CH3, -C02H, -NR3R4, and -Oalkyl of d-C2enoOalkyl of dd, (g) -OH, (h) -S (0) xalkyl of C C2, (i) -CN, (j) -N02, (k) -C (= 0) NR3R4, (I) -Okyl of C C2oenoalkyl of C C2, (m) -C (= 0) O-C2 alkyl optionally substituted with 1-3 halogens and optionally substituted with a group selected from -OH, -C02CH3, -NR3R4, and -D-denoOalkyl of C C2, (n) -NR3C (= 0) CrC2 alkyl, (o) -NR3R4; and (p) -S (0) xNR3R4; Ra is selected from halogen, -CH3, -CF3, -OCH3 and -OCF3; R3 and R4 are each independently selected from H and CH3; and x is 0, 1 or 2. In embodiments, B is A1 and R2 is A2. In modalities, B is A2 and R2 is A1. In modalities, A2, A3 and A4 are phenyl. In embodiments, each Ra is selected from the group consisting of (a) -alkyl of d-d which is optionally substituted with 1-5 fluorine atoms and is optionally substituted with a group selected from -OH, -OCH3, and -NR3R4; (b) -O-alkyl of d-d, which is optionally substituted with 1-3 fluorine atoms; (c) -C2-C4 alkenyl; (d) -alkyl d-d-O-alkyl of d-C2-phenol; (e) cyclopropyl; (f) -C (= 0) H; (g) -C02H; (h) -C02alkyl of d-d; (i) -OH; (j) -NR3R4; (k) -S (0) xalkyl of d-d; (I) halogen; (m) -CN; (n) -N02; and (o) a 5-6 membered heterocyclic ring comprising 1-2 atoms of oxygen that is optionally substituted with d-C2 alkyl. In other embodiments, the compound has the formula, including pharmaceutically acceptable salts thereof, wherein where one of B 1. Y. D B2 is and the other of B1 and B2 is Ar1 (Rc) u; Ar1 is selected from the group consisting of: (a) an aromatic ring selected from phenyl and naphthyl; (b) a phenyl ring fused to a non-aromatic 5-7 membered cycloalkyl ring, optionally comprising 1-2 double bonds; (c) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group; (d) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S and optionally 1-2 double bonds; and (e) a C3-C8 cycloalkyl ring having optionally 1-3 double bonds; Ar2 is selected from the group consisting of: (a) an aromatic ring selected from phenyl and naphthyl; (b) a phenyl ring fused to a non-aromatic 5-7 membered cycloalkyl ring, optionally comprising 1-2 double bonds; (c) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S and optionally 1-2 double bonds; and (d) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group; R1 is selected from the group consisting of H, -alkyl of d-d, and halogen, wherein -alkyl of d-d is optionally substituted with 1-1 halogens; R3 and R4 are each independently selected from H, - alkyl of d-d, -C (= 0) alkyl of d-d and -S (0) and alkyl of Crd, wherein -alkyl of d-d in all cases is optionally substituted with 1 -1 1 halogens; Each Ra, R, Rc and Rd is independently selected from the group consisting of - dd alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C8 cycloalkyl optionally having 1-3 double bonds, -Okyl of dd, -C2-C6alkenyl, -D-Oalkynyl, -3C8 cycloalkyl optionally having 1-3 double bonds, -C (= 0) dd alkyl, -C (= O) cycloalkyl C3-C8, -C (= 0) H, -C02H, -C02alkyl of dd, -C (= 0) Saltoyl of d-C6, -OH, -NR3R4, -C (= 0) NR3R4, -NR3C (= 0) O-alkyl of d-C6, -NR3C (= O) NR3R4, -S (O) xalkyl of C? -C6, -S (O) and NR3R4, -NR3S (0) and NR3R4, halogen, -CN, - N02, and a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally also comprising 1-3 double bonds, wherein the The point of attachment of said heterocyclic ring to the ring to which Ra, Rb, Rc or Rd is attached is a carbon atom, wherein said ring or heterocyclic is optionally substituted with 1-5 substituent groups independently selected from halogen, -alkyl of d-d, and -Oalkyl of d-d, wherein -alkyl of d-d and -Oalkyl of d-d are optionally substituted with 1 -7 halogens; wherein when Ra, Rb, Rc and Rd are selected from the group consisting of - d-d alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C3-C8 cycloalkyl optionally having 1-3 double bonds, -Dalkyl, -C2-C6alkenyl, -C2-C6alkynyl, -C3-C8 -cycloalkyl optionally having 1-3 double bonds, - C (= 0) alkyl of -d, -C (= 0) cycloalkyl of C3-C8, -C02alkyl of d-C6, -C (= 0) Salkyl of CrC6, -NR3C (= 0) Oalkyl of CrC6, and -S (0) xalkyl of C C6, then Ra, Rb, Rc and Rd are optionally substituted with 1-15 halogens and are optionally substituted with 1-3 substituent groups independently selected from (a) -OH, (b) -CN , (c) -NR3R4, (d) -C3-C8 cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (e) -Dalkyl optionally substituted with 1-9 halogens and optionally substituted with 1-2 substituent groups independently selected from -O-alkyl dd and phenyl, (f) -C3-C8-cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (g) -C02H, (h) -C (= 0 CH3, (i) -C02alkyl of C C4 which is optionally substituted with 1-9 halogens, and (j) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3, -CF3, -OCH, and -OCF3; Re is selected from the group consisting of-C2-C6 alkenyl, dd-alkynyl, -3-C8-cycloalkyl optionally having 1-3 double bonds, -Dalkyl, d-C-C6-alkyl, -O-cycloalkyl, C3-C8 having optionally 1-3 double bonds, -C (= 0) alkyl of dd, -C (= 0) C3-C8 cycloalkyl, -C (= 0) H, -C02H, -C02alkyl of dd, -C (= 0) Salkyl of dd, -OH, -NR3R4, -C (= 0) NR3R4, -NR3C (= 0) Oalkyl of d-C6, -NR3C (= 0) NR3R4, -S (0) xalkyl of d-C6, -S (0) and NR3R4, -NR3S (0) and NR3R4, -CN, -N02, and a heterocyclic ring of 5 -6 members having 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally also comprising 1-3 double bonds, wherein the point of attachment of said heterocyclic ring The ring to which Re is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen, -dialkyl, and -Dalkyl of dd, wherein -alkyl of dd and - O-alkyl dd are optionally substituted with 1-7 halogens; wherein when Re is selected from the group consisting of-C2-C6 alkenyl, dd-alkynyl, C3-C8-cycloalkyl optionally having 1-3 double bonds, -Dalkyl, dd -Oalkynyl, -O-cycloalkyl of C3-C8 having optionally 1-3 double bonds, -C (= 0) C6 alkyl, -C (= 0) C3-C8 cycloalkyl, -C02alkyl of dd, -C (= 0) Salkyl of dd , -NR3C (= 0) Oalkyl of dd, and -S (0) xalkyl of C d, then Re is optionally substituted with 1-15 halogens and is optionally substituted with 1-3 substituent groups independently selected from (a) -OH , (b) -CN, (c) -NR3R4, (d) -C3-C8 cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (e) -Dalkyl of dd optionally substituted with 1 -9 halogen and optionally substituted with 1-2 substituent groups independently selected from -O-alkyl of dd and phenyl, (f) -C3-C8-cycloalkyl which optionally has 1-3 double bonds and optionally substituted with 1-15 halogens, (g) -C02H, (h) -C (= 0) CH3, (i) -C0 alkyl of dd which is optionally substituted with 1-9 halogens , and (j) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3; p is an integer of 0-4; q is an integer of 0-4; u is an integer of 0-5; x is 0, 1 or 2; and y is 1 or 2; wherein when Ar2 is selected from the group consisting of: (a) an aromatic ring selected from phenyl and naphthyl; (b) a phenyl ring fused to a non-aromatic 5-7 membered cycloalkyl ring, optionally comprising 1-2 double bonds; (c) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S and optionally 1-2 double bonds; and (d) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group, wherein the point of attachment of the heterocyclic ring to the phenyl group to which the heterocyclic ring is attached is a heteroatom of the heterocyclic ring; then t is an integer of 0-5, and w is 0; and when Ar2 is a 5-6 membered heterocyclic ring having 1 -4 heteroatoms independently selected from N, S, O and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group, in where the point of attachment of the heterocyclic ring to the phenyl group to which the heterocyclic ring is attached is a carbon atom of the heterocyclic ring, then t is an integer of 0-4, and w is 1. Modalities of the compound having the formula , including pharmaceutically acceptable salts thereof: In embodiments, the compound has the formula If, including pharmaceutically acceptable salts thereof: In embodiments, the compound has the formula Ig, including pharmaceutically acceptable salts thereof: In embodiments, each Rd is independently selected from the group consisting of - dd alkyl, C2-C4 alkenyl, cyclopropyl, d-C4Oalkyl, -C (= 0) dd alkyl, -C (= 0) H, -C02H -C02alkyl of d-C4, -OH, -NR3R4, -NR3C (= O) O-alkyl of d-C4, -S (O) xalkyl of CrC2, halogen, -CN, -N02, and a heterocyclic ring of 5-6 members having 1-2 heteroatoms independently selected from N, S, and O, wherein the point of attachment of said heterocyclic ring to the ring to which Rd is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen; wherein when Rd is selected from the group consisting of-C4 alkyl, -C2-C alkenyl, cyclopropyl, -CO4 alkyl, -C (= 0) dd alkyl, -C02alkyl of dd, -NR3C ( = 0) O-alkyl of dd, and -S (0) xalkyl of dd, then the alkyl, alkenyl and cyclopropyl group of R is optionally substituted with 1 -5 halogens and is optionally substituted with a substituent group selected from (a) -OH , (b) -NR3R4, (c) -OCH3 optionally substituted with 1-3 fluorine atoms and optionally substituted with a phenyl group, and (d) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3, -CF3, -OCH3l and -OCF3 and t is a whole of 0-5. The embodiments may have the formula Ih, or a pharmaceutically acceptable salt thereof: lh In independent embodiments, including pharmaceutically acceptable salts: R1 is selected from the group consisting of H, and -alkyl of d-d, wherein -alkyl of d-d is optionally substituted with 1-11 halogens. R3 and R4 are each independently selected from H and -alkyl of d-d, wherein -alkyl of d-d in all cases is optionally substituted with 1-11 halogens. Each Ra, R and Rc is independently selected from the group consisting of -alkyl of d-d, -alkenyl of C2-C6, -cycloalkyl of C3-C8 having optionally 1-3 double bonds, -Dalkyl of dd, -C (= 0) alkyl of dd, -C (= 0) H, -C02H, -C02alkyl of d-C6, -OH, -NR3R4, -NR3C (= 0) O-alkyl C6, -S (0) xalkyl of d-C6, halogen, -CN, -N02, and a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S and Or, said heterocyclic ring optionally also comprising a carbonyl group and optionally also comprising 1-3 double bonds, wherein the point of attachment of said heterocyclic ring to the ring to which Ra is attached is a carbon atom, wherein said ring heterocyclic is optionally substituted with 1-5 substituent groups independently selected from halogen, dd alkyl, and dd-Oalkyl, wherein dd alkyl and Crd O-alkyl are optionally substituted with 1-7 halogens; wherein when Ra, Rb and Rc are selected from the group consisting of - dd alkyl, - C2-C6 alkenyl, - C3-C8 cycloalkyl optionally having 1-3 double bonds, - O-alkyl from dd, -C ( = 0) dd alkyl, -C02alkyl of dd, -NR3C (= 0) Oalkyl of d-C6, and -S (0) xalkyl of dd, then Ra, Rb and Rd are optionally substituted with 1-15 halogens and are optionally substituted with a substituent group selected from (a) -OH, (b) -NR3R4, (c) -Dalkyl of dd optionally substituted with 1-9 halogens and optionally substituted with 1-2 groups independently selected from -Oalkyl of dd and phenyl, and (d) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3.

Each Rd is independently selected from the group consisting of - dd alkyl, C2-C4 alkenyl, -Dalkyl of dd, -C (= 0) C2 alkyl, -C (= 0) H, -C02H -C02alkyl of CC, -OH, -NR3R4, -NR3C (= 0) O-alkyl of CrC4, -S (0) xalkyl of Crd, halogen, -CN, -N02 and a heterocyclic ring of 5-6 members having 1-2 heteroatoms independently selected from N, S, and O, wherein the point of attachment of said heterocyclic ring to the ring to which Ra is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen; where when Rd is selected from the group consisting of -alkyl of dd, -alkyl C2-C4, -Oalkyl of d-C2, -C (= 0) alkyl of dd, -C02alkyl of dd, -NR3C (= 0) Oalkyl of dd, and -S (0) xalkyl of C d, then the alkyl or alkenyl group of Rd is optionally substituted with 1-5 halogens and is optionally substituted with a group selected from (a) -OH, (b) -NR3R4, (c) -OCH3 optionally substituted with 1-3 fluorine atoms and optionally substituted with a phenyl group, and (d) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3, -CF3, -OCH3, and -OCF3. In modalities: p is an integer of 0-2. q is an integer of 0-2. t is an integer of 0-3. u is an integer of 0-2. x is O, 1 or 2 and is 1 or 2 In independent embodiments, including pharmaceutically acceptable salts R 1 is selected from H and -alkyl from d-d R 3 and R 4 are each independently selected from H and -alkyl from d-d Each Ra, Rb and Rc is independently selected from the group consisting of - dd alkyl, C2-C alkenyl, dd-Oalkyl, -C (= 0) C2 alkylene, -C (= 0) H, -C02H, -C02alkyl of d-C4, -OH, -NR3R4, -NR3C (= O) Oalqu? Lo of dd, -S (O) xalqu? Lo of CrC2, halogen, -CN, and -N02, wherein when Ra, Rb and Rc are selected from -alkyl of dC, -alkenyl of C2-C, -Oalkyl of C C2, -C (= 0) alkyl of dd, -C02alkyl of CrC4, -NR3C (= 0) O of C4, and -S (0) xalqu? Lo of dd, then the alkyl and alkenyl groups of Ra, Rb and Rc are optionally substituted with 1-5 halogens and are optionally substituted with a group selected from (a) -OH, (b) -NR3R4, (c) -OCH3 optionally substituted with 1-3 fluorine atoms and optionally substituted with a phenyl group, and (d) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3 Rd is selected from the group consisting of -alkyl of dd, -alkenyl of C2-C4, -NR3R4, -C (= 0) H, -C0 2H, -C02alkyl of d-C4, -OH, halogen, -CN, and -N02, wherein -alkyl of d-d and -alkenyl of C2-C4 in all uses are optionally substituted with 1 -5 fluorine atoms p is an integer of 1-2 q is an integer of 1-2 t is an integer of 0-3 u is an integer of 1 -2 x is 0, 1 or 2 In further embodiments, including pharmaceutically acceptable salts R1, R3 and R4 are each independently selected from H and CH3 Ra, Rb and Rc are each independently selected from the group consisting of -d3 alkyl, -Dalkyl, halogen and -OH, wherein -alkyl of dd and -Oalkyl of dd are optionally substituted with 1-3 F Rd is selected from the group consisting of -alkyl of dd, -NR3R4, -C02H, -C02alkyl of C C3, halogen, and -CN, wherein -alkyl of dd and -C02alkyl of C C3 are optionally substituted with 1 -3 F p is an integer of 1 -2 q is an integer of 1-2 t is an integer of 0-3 u is an integer of 1 -2 Definitions "Ac" is acetyl, which is CH3C (= 0) -. "Alkyl" means saturated carbon chains which may be linear or branched combinations thereof, unless the carbon chain is otherwise defined. Other groups having the prefix "ale", such as alkoxy and alkanoyl, may also be linear or branched or combinations thereof, unless the carbon chain is otherwise defined. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like. "Alkylene" groups are alkyl groups that are difunctional instead of monofunctional. For example, methyl is an alkyl and methylene group (-CH2-) is the corresponding alkylene group. "Alkenyl" means carbon chains containing at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. "Alkynyl" means carbon chains containing at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1 -pentinyl, 2-heptynyl and the like. "Cycloalkyl" means a saturated carbocyclic ring having from 3 to 8 carbon atoms, unless otherwise indicated (e.g., cycloalkyl can be defined as having one or more double bonds). The term also includes a cycloalkyl ring fused to an aryl group. Examples of cycloalkyl 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 means a monocyclic or bicyclic compound in which the rings are aromatic and which contains only carbon ring atoms. The term "aryl" may also refer to an aryl group that is fused to a cycloalkyl or heterocycle. The preferred "aryls" are phenyl and naphthyl. Phenyl is generally the most preferred aryl group. "EDC" is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. "Heterocyclyl," "heterocycle" and "heterocyclic" means a 5-6 membered ring completely or partially saturated or aromatic containing 1-4 heteroatoms independently selected from N, S and O, unless otherwise indicated. "Benzoheterocycle" represents a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 heteroatoms, each of which is O, N or S, wherein the heterocyclic ring may be saturated or unsaturated. Examples include indole, benzofuran, 2,3-dihydrobenzofuran and quinoline. "DIPEA" is diisopropyl-ethylamine.

"Halogen" includes fluorine, dorio, bromine and iodine. "HOBT" is 1-Hydroxybenzotriazole. "IPAC" is isopropyl acetate. "Me" represents methyl. "Weinreb amine" is N.O-dimethylhydroxylamine. The term "composition, "as in pharmaceutical composition, encompasses a product comprising the active ingredient (s), and the inert ingredient (s) that make up the vehicle, as well as any product that results, directly or indirectly, from the combination, complex formation or aggregation of any one or more of the ingredients, or dissociation of one or more of the ingredients, or other types of reactions or interactions of one or more of the ingredients. present invention encompasses any composition made by mixing a compound of the present invention and a pharmaceutically acceptable carrier The substituent "tetrazole" means a 2H-tetrazol-5-yl group and tautomers thereof.

Optical isomers - diastereomers - geometric isomers - tautomers The compounds of formula I may contain one or more asymmetric centers and therefore may occur as racemates, racemic mixtures, individual enantiomers, diastereomeric mixtures and individual diastereomers. The present invention includes all those isomeric forms of the compounds of the formula I and all mixtures of the compounds. When structures with a stereochemical representation are shown, other stereochemical structures are also included individually and collectively, such as enantiomers, diastereoisomers (where diastereomers are possible), and mixtures of d enantiomers and / or diastereomers, including racemic mixtures. Some of the compounds herein may contain olefinic double bonds, and unless otherwise specified, include both E and Z geometric isomers. Some of the compounds herein may exist as tautomers. An example is a ketone and its enol form, known as keto-enol tautomers. Individual tautomers as well as mixtures thereof are encompassed by 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 with chiral centers can be synthesized by stereospecific synthesis using optimally pure starting materials and / or reagents of known configuration. Some of the biphenyl and biaryl compounds of the present are observed as mixtures of atropoisomers (rotamers) in the spectra of NMR Individual atropoisomers as well as mixtures thereof sob encompassed by the compounds of this invention Salts The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable bases or toxic acids including organic or inorganic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous , lithium, magnesium, mangenic salts, manganous, potassium, sodium, zinc and the like Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. The salts in solid form can exist in more than one crystalline structure, and can also be in the form of hydrates Salts derived from organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-d? Benc? Let? Lend? Am? Na, diethylamine, 2-diethylaminoethanol, 2-d? Met? Lam? Noet anol, ethanolamma, ethylenediamine, N-ethyl-morpholine, N-ethylpipepdma, glucamma, glucosamine, histidine, hydrabamine, isopropylamino, sina, methylglucamine, morfohna, piperazine, pipepdine, polamine resins, procaine, pupnas, theobromo, tetylamine, tpmethylamine , tppropiloamine, tromethamine, and the like When the compound of the present invention is basic, the salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphor sulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. It will be understood that, as used herein, references to the compounds of formula I also include pharmaceutically acceptable salts.

Metabolites - Prodrugs Therapeutically active metabolites, wherein the metabolites as such fall within the scope of the claimed invention, are also compounds of the present invention. Prodrugs, which are compounds that are converted to the claimed compounds as they are administered to a patient or after they have been administered to a patient, are also compounds of this invention.

Utilities The compounds of the present invention are potent inhibitors of CETP. Therefore, they are also useful for treating diseases and conditions that are treated by CETP inhibitors. One aspect of the present invention provides a method for treating or reducing the risk of developing a disease or condition that can be treated or prevented by inhibiting CETP by administering a therapeutically effective amount of a compound of this invention to a patient in need of such treatment. A patient is a human or mammal, and is very often a human. A "therapeutically effective amount" is the amount of compound that is effective to obtain a desired clinical result in the treatment of a specific disease. Diseases or conditions that can be treated with compounds of this invention, or that the patient may have a reduced risk of developing as a result of being treated with the compounds of this invention, include atherosclerosis, peripheral vascular disease, dys-pheraemia, hyperbeta poproteinemia, hypoalpha poproteinemia, hypercholesterolemia, hypertriglyceridemia, fami al- hypercholesterolemia, cardiovascular disorders cular, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, vascular complications of diabetes, obesity, endotoxemia and metabolic syndrome The compounds of this invention are particularly effective in increasing HDL-C and / or increase the ratio of HDL-C to LDL-C Compounds are also effective in reducing LDL-C These changes in HDL-C and LDL-C may be beneficial in treating atherosclerosis, reducing or reversing the development of atherosclerosis, reducing the risk of developing atherosclerosis, or preventing atherosclerosis.

Administration and dose ranges Any suitable administration route can be used to provide a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like can be used. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like. Preferably, compounds of the formula I are administered orally. The effective dose of active ingredient used may vary depending on the particular compound used, the mode of administration, the condition being treated and the severity of the condition being treated. This dose can easily be achieved by one skilled in the art. When treating the diseases for which the compounds of the formula I are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dose of about 0.01 milligrams to about 100 milligrams per kilogram of the animal's body weight. or human, preferably given as a single daily dose or in divided doses two to six times a day, or in a sustained release form. In the case of a 70 kg human adult, the total daily dose will generally be from about 0 5 milligrams to about 500 milligrams. For a particularly potent compound, the dose for an adult human may be as low as 0 1 mg. The dosage regimen may be adjusted within of this interval or even outside this range to provide the optimal therapeutic response. Oral administration will usually be carried out using tablets. Examples of tablet doses 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 forms may also have the same doses (v gr, capsules) Pharmaceutical Compositions Another aspect of the present invention provides pharmaceutical compositions comprising a compound of the formula I and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention comprise a compound of the formula I or a pharmaceutically acceptable salt as an active ingredient., as well as a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic acids or bases. A pharmaceutical composition may also comprise a prodrug, or a pharmaceutically acceptable salt thereof, if a prodrug. Pharmaceutical compositions can also consist essentially of a compound of formula I and a pharmaceutically acceptable carrier without other therapeutic ingredients. The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend of the nature and severity of the conditions being treated and the nature of the active ingredient. They can be conveniently presented in unit dosage form and prepared by any of the methods well known in the pharmacy art. During practical use, the compounds of the formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier in accordance with conventional pharmaceutical compounding techniques. The vehicle can also take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media can be used, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations. , such as, for example, suspensions, elixirs and solutions; or vehicles such as starches, sugars, microcrystalline cellulose, diluents, agents granulants, lubricants, binders, disintegrating agents and the like in the case of solid oral preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously used. If desired, the tablets may be coated by standard aqueous or non-aqueous techniques. Said compositions and preparations should contain at least OJ percent active compound. The percentage of active compound in these compositions, of course, can vary and conveniently can be between about 2 percent to about 60 percent of the unit's weight. The amount of active compound in said therapeutically useful compositions is such that an effective dose will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or aspersion. The tablets, pills, capsules and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a unit dose 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, the 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 propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor. The compounds of the formula I can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. The 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 or dispersions. In all cases, the form must be sterile and must be fluid to the extent that it is easy to apply with a syringe. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), aerated mixtures thereof and vegetable oils.

Combination Therapy The compounds of the invention (e.g., formula I and la-Ij) can be used in combination with other drugs which may also be useful in the treatment or alleviation of diseases or conditions for which the compounds of the formula I are useful. These other drugs can be administered, in one way and in an amount commonly used therefor, contemporaneously or sequentially with a compound of formula I. When a compound of formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing other drugs and the compound of formula I is preferred. However, combination therapy also includes therapies in which the compound of formula I and one or more other drugs are administered at different times. When oral formulations are used, the drugs can be combined in an individual combination tablet or other oral dosage form, or the drugs can be packaged together with separate tablets or other oral dosage forms. It is also contemplated that when used in combination with one or more other active ingredients, the compound of the present invention and the other active ingredients may be used in lower doses than when each is used individually. Therefore, the Pharmaceutical compositions of the present invention include those containing one or more other active ingredients, in addition to a compound of formula I. Examples of other active ingredients that can be administered in combination with a compound of this invention (e.g. formula I), and whether administered separately or in the same pharmaceutical composition, include, but are not limited to, other compounds that improve a patient's lipid profile, such as (i) HMG-CoA reductase inhibitors, (which they are generally statins, including lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, pitavastatin, and other statins), (ii) bile acid sequestrants (cholestyramine, colestipol, dialkylaminoalkyl derivatives of an interlaced dextran, Colestid®, LoCholest®, (iii) niacin and related compounds, such as nicotinic alcohol, nicotinamide, and nicotinic acid or a salt thereof. same, (iv) PPARa agonists, such as gemfibrozil and fenofibric acid derivatives (fibrates), including clofibrate, fenofibrate, bezafibrate, ciprofibrate and etofibrate, (v) cholesterol absorption inhibitors, such as stanol esters, beta-sitosterol , sterol glycosides such as tiqueside; and azetidinones, such as ezetimibe, (vi) acyl CoAxolesterol acyltransferase (ACAT) inhibitors, such as avasimibe and melinamide, and including selective inhibitors of ACAT-1 and ACAT-2 and double inhibitors, (vii) phenolic anti-oxidants, as probucol, (viii) inhibitors of microsomal triglyceride transfer secretion (MTP) / ApoB, (ix) anti-vitamin oxidants, such as vitamins C and E and beta carotene, (x) thyromimetics, (xi) LDL receptor inducers (low density lipoprotein), (xii) platelet aggregation inhibitors, eg, fibrinogen receptor antagonists glycoprotein llb / llla and aspirin, (xiii) vitamin B12 (also known as cyanocobalamin), (xiv) folic acid or a pharmaceutically acceptable salt or ester thereof, such as the sodium salt and the methylglucamine salt, (xv) ligands FXR and LXR, including both inhibitors and agonists, (xvi) agents that increase the expression of ABCA1 genes, and (xvii) transporters of ileal bile acid. Preferred classes of therapeutic compounds that can be used with the compounds of this invention for use in improving a patient's lipid profile (i.e., raising HDL-C and reducing LDL-C) include one or both of the statins and inhibitors of absorption of cholesterol. Particularly preferred are combinations of the compounds of this invention with simvastatin, ezetimibe, or both simvastatin and ezetimibe. Also preferred are combinations of compounds of this invention with statins other than simvastatin, such as lovastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin and ZD-4522. Finally, the compounds of this invention can be used with compounds that are useful for treating other diseases, such as diabetes, hypertension and obesity, as well as other anti-atherosclerotic compounds. These combinations can be used to treat one or more of such diseases as diabetes, obesity, atherosclerosis and dyslipidemia, or more than one of the diseases associated with metabolic syndrome. The combinations may exhibit synergistic activity to treat this disease, allowing the possibility of administering reduced doses of active ingredients, such as doses that might otherwise be sub-therapeutic. Examples of other active ingredients that can be administered in combination with a compound of this invention include, but are not limited to, compounds that are primarily antidiabetic compounds, including: (a) agonists and partial agonists of PAR gamma, including glitazones and non-glitazones ( e.g., pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, T-131, LY-300512, and LY-818; (b) biguanides such as metformin and phenformin; (c) protein tyrosine phosphatase inhibitors -1B (PTP-1 B); (d) dipeptidyl peptidase IV inhibitors (DP-IV), including vildagliptin, sitagliptin and saxagliptin; (e) insulin or insulin mimetics, such as for example insulin lispro, insulin glargine, suspension of zinc insulin and inhaled insulin formulations; (f) sulfonylureas, such as tolbutamide, glipizide, glimepiride, acetohexamide, chlorpropamide, glibenclamide and related materials; (g) a-glucosidase inhibitors (such as bosa, adiposine; camiglibosa; emiglitato; miglitol; voglibose; pradimicin-Q; and salbostatin); (h) double PPARa /? agonists, such as muragltazar, tesaglitazar, farglitazar and naveglitazar, (i) PPARa agonists such as GW501516 and those inferences in W097 / 28149; j) glucagon (k) GLP-1 receptor antagonists; GLP-1 derivatives; GLP-1 analogues, such as exendins, such as for example exenatide (Byetta); and non-peptidyl GLP-1 receptor agonists; (I) GIP-1; and (m) Insulin secretagogues that are not sulfonylureas, such as meglitinides (e.g., nateglinide and rapeglinide). These other active ingredients that can be used in combination with the present invention also include antiobesity compounds, including 5-HT inhibitors (serotonin), neuropeptide Y5 inhibitors (NPY5), melanocortin receptor agonists 4 (Mc4r), receptor antagonists. of cannabinoid 1 (CB-1) / inverse agonists, and ß3 adrenergic receptor agonists. These are listed in more detail later in this section. These other active ingredients also include active ingredients that are used to treat inflammatory conditions, such as aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids, azulfidine, and selective cyclooxygenase-2 inhibitors (COX-2), including etoricoxib, celecoxib, rofecoxib, and Bextra. Antihypertensive compounds can also be used advantageously in combination therapy with the compounds of this invention. Examples of antihypertensive compounds that can be used with the compounds of this invention include (1) angiotensin II antagonists, such as losarían; (2) Angiotensin converting enzyme inhibitors (ACE inhibitors), such as enalapril and captopril; (3) calcium channel blockers such as nifedipine and diltiazam; and (4) endothelial antagonists. The anti-obesity compounds can be administered in combination with the compounds of this invention, including: (1) growth hormone secretagogues and growth hormone receptor agonists / antagonists, such as NN703, hexarelin, and MK-0677; (2) tyrosine phosphatase-1 B protein inhibitors (PTP-1 B); (3) cannabinoid receptor ligands, such as CBL cannabinoid 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 agents, such as fenfluramine, dexfenfluramine, phentermine and sibutramine; (5) β3-adrenoreceptor agonists, such as AD9677 / TAK677 (Dainippon / Takeda), CL-316.243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, Trecadrine , Zeneca D7114, and SR 59119A; (6) pancreatic lipase inhibitors, such as or stat (Xenical®), Triton WR1339, RHC80267, pstatin, tetrahydrolipstatin, teasaponm, and diethylumbelifepho 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, SR-120562A, SR-120819A and JCF-104, (9) melamine concentrator hormone receptor (MCH) antagonists, (10) melanin concentrating hormone receptor antagonists 1 (MCH1 R), such as T-226296 (Takeda), (11) melanin-2 concentrating hormone receptor agonists / antagonists (MCH2R), (12) orex? Na-1 receptor antagonists, such as SB-334867 -A, (13) melanocortin agonists, such as Melanotan II, (14) other Mc4r agonists (melanocortin 4), such as CHIR86036 (Chiron), ME-10142, and ME-10145 ( Melacure), CHIR86036 (Chiron), PT-141, and PT-14 (Palatin), (15) 5HT-2 agonists, (16) 5HT2C agonists (serotonin 2C receptor), such as BVT933, DPCA37215, WAY161503, and R-1065, (17) galanin antagonists, (18) CCK agonists, (19) CCK-A agonists (cholecystokinin -A), such as AR-R 15849, Gl 181771, JMV-180, A-71378 , A-71623 and SR146131, (20) GLP-1 agonists, (21) corticotropin-releasing hormone agonists, (22) histamine-3 (H3) receptor modulators, (23) antagonists / agonists H-stannous receptor (H3) reverses, such as hyoperamide, N- (4-pentenyl) carbamate 3- (1 H-) Midazol-4-yl) propyl, clobenpropit, iodophenpropit, imoproxifan, and GT2394 (Gliatech); (24) inhibitors of β-hydroxysteroid dehydrogenase-1 (inhibitors of Hß-HSD-1), such as BVT 3498 and, BVT 2733, (25) inhibitors of PDE (phosphodiesterase), such as theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram and cilomilast; (26) Phosphodiesterase-3B (PDE3B) inhibitors; (27) transport inhibitors of NE (norepinephrine), such as GW 320659, depiramine, talsupram and nomifensin; (28) ghrelin receptor antagonists; (29) leptin, including recombinant human leptin (PEG-OB, Hoffman La Roche) and human recombinant methionyl leptin (Amgen); (30) leptin derivatives; (31) BRS3 agonists (bombesin receptor subtype 3) such as [D-Phe6, eta-Alai 1, Phe13, Nle14] Bn (6-14) and [D-Phe6, Phe13] Bn (6-13) propyl amide; (32) CNTF (ciliary neurotrophic factors), such as GI-181771 (GlaxoSmithKIine), SR146131 (Sanofi Synthelabo), butabindide, PD170.292, and PD 149164 (Pfizer); (33) derivatives of CNTF, such as axocin (Regeneron); (34) monoamine reabsorption inhibitors, such as sibutramine; (35) activators of UCP-1 (protein-1, 2 or 3), such as titanic acid, 4- [(E) -2- (5,6,7,8-tetrahydro-5,5,8, 8-tetramethyl-2-naphthalenyl) -1-propenyl] benzoic acid (TTNPB), and retinoic acid; (36) β-thyroid hormone agonists, such as KB-2611 (KaroBioBMS); (37) FAS (fatty acid synthase) inhibitors, such as Cerulenin and C75; (38) DGAT1 inhibitors (diacylglycerol acyltransferase 1); (39) DGAT2 inhibitors (diacylglycerol acyltransferase 2); (40) ACC2 inhibitors (acetyl-CoA carboxylase-2); (41) antagonists of glucocorticoid; (42) acyl-oestrogens, such as oleoyl-estrone; (43) dicarboxylate transporter inhibitors; (44) peptide YY, PYY 3-36, analogs, derivatives and peptide fragments YY such as BIM-43073D, BIM-43004C, (45) neuropeptide receptor agonists Y2 (NPY2) such as NPY3-36, N acetyl [ Leu (28.31)] NPY 24-36, TASP-V, and cyclo- (28/32) -Ac- [Lys28-Glu32] - (25-36) -pNPY; (46) neuropeptide Y4 agonists (NPY4) such as pancreatic peptide (PP); (47) Neuropeptide Y1 antagonists (NPY1) such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, and Gl-264879A; (48) Opioid antagonists, such as nalmefene (Revex ®), 3-methoxynaltrexone, naloxone and naltrexone; (49) glucose transporter inhibitors; (50) phosphate transporter inhibitors; (51) 5-HT inhibitors (serotonin); (52) beta-blockers; (53) Neurokinin-1 receptor antagonists (NK-1 antagonists); (54) clobenzorex; (55) cloforex; (56) clominorex; (57) clortermin; (58) cyclodexamine; (59) dextroamphetamine; (60) diffemethoxydine, (61) N-ethylamphetamine; (62) fenbutrazate; (63) fenisorex; (64) fenproporex; (65) fludorex; (66) fluminorex; (67) furfurylmethylamphetamine; (68) levamfetamine; (69) levofacetoperano; (70) mefenorex; (71) methamphepramone; (72) methamphetamine; (73) norpseudoephedrine; (74) pentorex; (75) phendimetrazine; (76) phenmetrazine; (77) picilorex; (78) phytopharma 57; (79) zonisamide, (80) aminorex; (81) anfechloral; (82) amphetamine; (83) benzfetamine; and (84) chlorentermine. The combination therapies described above that use the compounds of this invention may also be useful in the treatment of the metabolic syndrome. In accordance with a widely used definition, a patient who has metabolic syndrome is characterized as having three or more symptoms selected from the following group of five symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) high density lipoprotein cholesterol (HDL); (4) high blood pressure; and (5) elevated fasting glucose, which may be in the characteristic range of type 2 diabetes if the patient is also diabetic. Each of these symptoms is defined clinically in the third report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III) (Panel of Experts of the National Expert Program of the Adult Cholesterol Education Program (Adults Treatment Panel III, or PTA III) just published, National Institutes of Health, 2001, NIH Publication No. 01-3670. Patients with metabolic syndrome have an increased risk of developing the macrovascular and microvascular complications that were listed above, including atherosclerosis and coronary heart disease The combinations described above may alleviate more than one symptom of metabolic syndrome concurrently (eg, two symptoms, three symptoms, four symptoms, or the five symptoms ).

CETP test A continuous in vitro test to determine Cl50's to identify compounds that are inhibitors of CETP was performed based on a modification of the method described by Epps et al. using BODIPY®-CE as the lipid donor of cholesteryl ester and BODIPY®-TG as the triglyceride lipid donor. See Epps et al. (1995) Method for measuring the activities of cholesteryl ester transfer protein (lipid transfer protein), Chem. Phys. Lipids. 77, 51-63. The particles used in the test were created from the following materials by probe sonication essentially as described in Epps et al. Synthetic cholesteryl ester (CE) donor HDL particles contained DOPC (Dioleoyl Phosphatidyl Choline), BODIPY®-CE (Molecular Probes C-3927), triolein (a triglyceride), dabcildicethylamide, (a molecule not diffusible to reduce background fluorescence) and apoHDL . HDL particles donating synthetic triglyceride (TG) contained DOPC, BODIPY®-TG, and apoHDL. BODIPY ®-TG was synthesized at room temperature from diolein and the fatty acid analog containing BODIPY, 4,4-difluoro-5- (2-thienyl) -4-bora-3a, 4a-diaza-s- indaceno-3-dodecanoic (Molecular Probes) in methylene chloride in the presence of dicyclohexylcarbodimide. Dabcildicethylamide was made by heating dabcyl-n-succinimide with dicetylamine in DMF at 95 ° C overnight in the presence of diisopropylamino catalyst. The lipoproteins native to human blood were used as acceptor particles. Particles having a density of less than 1063 g / ml were harvested by ultracentrifugation. These particles include VLDL, IDL, and LDL. The particle concentrations were expressed in terms of protein concentration as determined by test of BCA (Pierce, E.U.A.). The paticles were stored at 4 ° C until used. The tests were carried out in 96-well plates with U bottom, Dynex Microfluor 2 (Cat # 7205). A test cocktail containing CETP, pH regulator 1X CETP (50 mM Tris, pH 7.4, 100 mM NaCl, 1 mM EDTA), 3% human serum, and half the final concentration of acceptor particles was used, and 100 μl of the test cocktail was added to each well of the plate. The test compounds in DMSO were added in a volume of 3 μl. The plate was mixed on a plate shaker and then incubated at 25 ° C for 1 hour. A second test cocktail containing donor particles, the remaining acceptor particles and pH regulator 1X CETP was prepared. 47 μl of the second test cocktail was added to the reaction wells to start the test. The tests were performed in a final volume of 150 μl. The EC transfer reactions were carried out as follows: final concentrations of materials were made: 2.5 ng / μl of donor EC particles, 7.5 ng / μl of acceptor particles (each expressed by protein content), pH regulator 1X CETP, 14-30 nM of recombinant human CETP (expressed in CHO cells and partially purified), and up to 2% DMSO when compounds are tested; the reactions were followed in a fluorescence plate reader (Molecular Devices Spectramax GeminiXS) fixed during a 45-minute kinetic operation at 25 ° C that reads the samples every 45 seconds at Ex = 480 nm, Em = 511 nm, with a filter cutting at 495 nm, medium photomultiplier tube attachment, calibration, and 6 readings / well. The transfer reactions of TG were performed as described above with the exception that 2.5 ng / ul of TG donor particles were used. The TG transfer was measured at an excitation wavelength of 538 nm while the emission was read at 568 nm every 45 seconds for 45 min at 37 ° C with a cut filter at 550 nm. The data were evaluated obtaining an initial velocity, expressed in units of relative fluorescence per second, for the pseudolinal portion of the curve, often 0-500 or 1000 sec. Comparison of sample rates with inhibitors to an uninhibited positive control (DMSO only) gave a percent inhibition. A graph of percent inhibition vs. log of the inhibitor concentration, fitted to a 4-parameter equation Sigmoidal 4 was used to calculate CI5o.

EXAMPLES The following schemes and examples are provided so that the invention will be more easily appreciated and understood. The starting materials are made using known procedures or as shown below. The examples should not be considered as limiting the invention in any way. The scope of the invention is defined by the appended claims. The compounds of this invention have a Cl50 value as measured for the EC transfer reaction, the reaction of TG transfer, or as described above less than or equal to 50 μM. Cl50 values of one or both reactions are generally in the range of 5 nM-15 μM, and are preferably in the range of 5 nM-5 μM, most preferably in the range of 5 nM-1 μM, most preferably still in the range of range of 5 nM-200 nM, and preferably still in the range of 5 nM-100 nM.

SCHEME 1 Intermediates 1-2, 1-3, 1-4, 1-5, 1-6 and 1-7 used in the present invention where Ra is as defined in the claims can be purchased or prepared as shown in Scheme 1. An appropriately substituted 2-haloaniline 1-1, wherein the halogen is preferably iodine or bromine is treated with CuCN in DMF at elevated temperature to give the corresponding 2-cyanoaniline 1-2. Alternatively, nitrile can be prepared by treatment of 1-1 with KCN and Cul in presence of a palladium (II) salt or in the presence of certain copper or nickel complexes (see: Smith, MB and March, J. "March's Advanced Organic Chemistry", 5th Ed., John Wiley and Sons, New York, pp. 867 (2001) and references therein). The iodides 1-3 are prepared by treatment of 1-2 with isoamyl nitrite, n-pentyl nitrite, t-butyl nitrite or the like in diiodomethane (see, e.g., Smith et al., J. Org. Chem. 55, 2543, (1990) and references cited therein). Alternatively, the iodide can be prepared first by forming diazonium using isoamyl nitrite, n-pentyl nitrite, t-butyl nitrite, sodium nitrite, nitrous acid or the like followed by heating in the presence of an iodide salt such as iodide. of copper, sodium iodide, potassium iodide, tetrabutylammonium iodide or the like. The hydrolysis of iodine-nitrile 1-3 is carried out using potassium hydroxide in isopropanol and water to give the acid iodine 1-4. Further reduction with borane, lithium aluminum hydride, lithium borohydride or the like in ether, tetrahydrofuran, dimethoxyethane or the like gives the 2-iodoalcohols 1-5. Intermediates 1-5 can be converted to benzyl bromides 1-6 using reagents such as triphenylphosphine and carbon tetrabromide in solvents such as dichloromethane or the like (see Smith, MB and March, J. "March's Advanced Organic Chemistry", 5th Ed. ., John Wiley and Sons, New York, pp. 518-199 (2001) and references therein). Intermediates 1-6 can also be converted to aldehydes 1-7 by treatment with Dess-Martin periodinane in dichloromethane or by Swern oxidation conditions, tetrapropyl ammonium perruthenate, pyridinium chlorochromate, sulfur trioxide-pyridine, or the like (see Smith, MB and March, J. "March's Advanced Organic Chemistry", 5th ed., John Wiley and Sons, New York, pp. 1167-1171 (2001) and references cited here) .

SCHEME 2 2-1 2-2 2-3 Intermediates 2-2 and 2-3 used in the present invention wherein Ra, Rb and Ar2 are as defined in the claims can be prepared as shown in scheme 2. 2-1 Benzyl alcohols can be purchased or prepared from according to the procedure outlined in the scheme 1. Intermediates 2-2 can be prepared by Suzuki reaction wherein 2-1 is coupled with an appropriately substituted arylboronic acid or aryl boronate ester in the presence of a palladium catalyst. The coupling reaction can be carried out using Pd (ll) acetate and potassium carbonate in refluxing aqueous acetone.

Alternatively, the reaction may use tetrakis (triphenylphosphino) palladium in a mixture of ethanol / toluene in the presence of sodium carbonate. Alternatively, as practiced by those skilled in the art, the reaction may utilize a number of palladium (0) compounds and palladium (II) salts in a number of solvents and in the presence of a variety of ligands, bases and promoters. , generally but not exclusively, with heating and / or microwave irradiation. Some appropriate reaction conditions can be found described in Miyaua et al., Chem. Rev. 95, 2457 (1995) and references cited within and as disclosed in Smith, MB and March, J. "March's Advanced Organic Chemistry", 5th Ed., John Wiley and Sons, New York, pp. 868-869 (2001) and citations therein. Compounds 2-3 are prepared from intermediates 2-2 as described in Scheme 1.

SCHEME 3 Intermediates 3-4 of the present invention wherein R1 and Ar1 are as defined in the claims can be prepared as shown in scheme 3. The treatment of an N-carbamoyl- (N-methoxy-N-methyl) amide of an amino acid 3-1 which can be purchased or prepared by known methods with a Grignard reagent or other organometallic reagent such as an organolithium gives the corresponding ketone 3-2. The reduction of the ketone with sodium borohydride or zinc borohydride in alcoholic solvents or THF or the like or with other reducing agents such as phenyl-dimethylsilane in THF gives alcohol 3-3 which can be cyclized to oxazolidinone 3-4 under base treatment such as KOH in solvents such as MeOH, EtOH or the like and THF, dioxane, dimethoxyethane or the like.

SCHEME 4 The compounds of the present invention 4-3 wherein R1, Ra, Rb, Ar1 and Ar2 are as defined in the claims can be prepared as shown in scheme 4. The oxazolidinones 4-2, prepared as shown in Schemes 3 can be alkylated with benzyl bromide 4-1 which is prepared as shown in scheme 1 using bases such as sodium hexamethyldisiliazide or sodium hydride in solvents such as tetrahydrofuran, dimethoxyethane, ethyl ether or the like to give the 4- products 3.

SCHEME 5 The compounds of the present invention 5-4 wherein R1, Ra, R, Ar1 and Ar2 are as defined in the claims can be prepared as shown in scheme 5. The oxazolidinones 5-2, prepared as shown in schemes 10 and 11 can be alkylated with benzyl bromide 5-1 which is prepared as shown in scheme 1 using bases such as sodium hexamethyldisiliazide or sodium hydride in solvents such as tetrahydrofuran, dimethoxyethane, diethyl ether or the like to give the products 5-3. Compounds 5-5 are then prepared by a Suzuki or Stille reaction or variation thereof using palladium-catalyzed cross-coupling of iodide 5-3 with an appropriately substituted aryl- or heteroaryl boronic acid, boronate ester or trialkyl- tin as described in Miyaua et al., Chem. Rev. 95, 2457 (1995) and references cited therein and as described in de Meijere, A. and Diedrich, F. "Metal-Catalyzed Cross Coupling Reactions" , 2nd Ed., WILEY-VCH Verlag GmbH & Co. KgaA, Weinheim (2004) and references cited therein. Alternatively, arylboronic acids or arylboronate esters can be prepared by treatment of aryl halide 5-3 with a suitable reagent such as a diborane silyl borane or stanyl borane or the like in the presence of a palladium catalyst or platinum catalyst or by metal exchange -halogen and treatment with a suitable boron electrophile as described in de Meijere, A. and Diedrich, F. "Metal-Catalyzed Cross Coupling Reactions", 2nd Ed., WILEY-VCH Verlag GmbH & amp;; Co. KgaA, Weinheim (2004), chapter 2. The aryl boron 5-4 reagent can be treated with an appropriately substituted aryl halide in the presence of a suitable palladium catalyst to give compounds 5-5.

SCHEMES 6 1. NaH, DMF 2- Br- (CR2) nAr1 Compounds 6-5 of the present invention wherein R1, Ra, Rb, Ar1 and Ar2 are as defined in the claims can be prepared as shown in the diagram 6. Benzyl alcohols 6-1 can be purchase or prepare in accordance with the procedure outlined in scheme 2. The 6-1 reaction with the Dess-Martin periodinane gives the 6-2 corresponding benzylaldehydes. Other methods to oxidize a group primary hydroxyl to an aldehyde can also be used, for example, Swern oxidation conditions, tetrapropyl ammonium perruthenate, pyridinium chlorochromate, sulfur trioxide-pyridine, or the like (see Smith, MB and March, J. "March's Advanced Organic Chemistry", 5th Ed., John Wiley and Sons, New York , pp. 1 167-1 171 (2001) and references cited therein). 2-Amino-1-phenylethanols 6-3 can be prepared from 6-2 by the corresponding silylated cyanohydrin by treatment with trimethylsilyl cyanide and catalytic zinc iodide followed by reduction with lithium-aluminum hydride or similar reducing agent. Alternatively, 2-amino-1-phenylethanols 6-3 can be prepared to look like 6-2 by the corresponding cyanohydrin by treatment with potassium cyanide followed by reduction. 2-Amino-1-phenylethanols 6-3 can be cyclized to oxazolidinones 6-4 using reagents such as phosgene (Y = CI), triphosgene (Y = OCCI3) or carbonyldiimidazole (Y = imidazole) with bases such as triethylamine, diisopropylethylamine or similar in solvents such as dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane or the like. Oxazolidinones 6-4 may be alkylated with alkyl, heteroalkyl, aryl or heteroaryl bromides using bases such as sodium hexamethyldisiliazide or sodium hydride in solvents such as tetrahydrofuran, dimethoxyethane, diethyl ether or the like to give products 6-5. Enantiopure products can be obtained by chiral chromatography.

SCHEME 7 Compounds 7-6 of the present invention wherein R 1, D Ra, Rb, Ar 1, and Ar 2 are as defined in the claims can be prepared as shown in Scheme 7. Aldehydes 7-1 can be purchased or prepared as outlined in scheme 1. Condensation of 7-1 with a nitroalkane gives the substituted nitroalcohols 7-2. This reaction can be catalyzed by aqueous bases such as sodium hydroxide or the like in solvents such as ethanol, methanol or the like. The nitro alcohols 7-2 they can reduce to aminoalcohols 7-3 with reducing agents such as Raney nickel, palladium on activated carbon, or platinum oxide in the presence of gaseous hydrogen and aqueous acid in alcoholic solvents such as methanol, ethanol or the like (See: Langer, O., et al., Bioorg, Med. Chem., 2001, 9, 677-694). Aminoalcohols 7-3 can be cyclized to oxazolidinones 7-4 using reactants such as phosgene (Y = CI), triphosgene (Y = OCCI3) or carbonyldiimidazole (Y = imidazole) with bases such as triethylamine, diisopropyloethylamine or the like in solvents such as dichloromethane , dichloroethane, tetrahydrofuran, dimethoxyethane or the like. Oxazolidinones 7-5 are prepared by a Suzuki or Stille reaction or variation thereof using cross coupling of palladium 7-4 catalyzed iodides with appropriately substituted aryl- or heteroaryl boronic acids, boronate esters or trialkyl tin compounds, as described in Miyaura et al., Chem. Rev. 95, 2457 (1995) and references cited within, and as described in 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. Oxazolidinones 7-5 can be alkylated with alkyl, heteroalkyl, aryl or heteroaryl bromides using bases such as sodium hexamethyldisiliazide or sodium hydride in solvents such as tetrahydrofuran, dimethoxyethane, diethyl ether or the like to give products 7-6. Enantiopure products can be obtained by chiral chromatography.

SCHEME 8 Compounds 8-5 of the present invention wherein R, R 1 Ra, A2, A3 and n are as defined in the claims can be prepared as shown in scheme 8. Aldehydes 8-1 can be purchased or prepared in accordance with the procedure delineated in scheme 1. The condensation of 8-1 with chiral α / - acyloxazolidinones gives the adducts of aldol 8-2, as described in Evans, DA ef a /., J. Am. Chem. Soc, 2002, 124, 392-3. The chiral α / - acyloxazolidinones can be purchased or prepared as described in Ager, D.J .; Alien, D.A .; Schaad, D.R. Synthesis 1996, 1283-5. Compounds 8-2 can be hydrolyzed to the corresponding acids and then treated with diphenyl phosphorazidate and a trialkylamine base to effect a rearrangement of Curtius, giving chiral oxazolidinones 8-3. The oxazolidinones 8-4 are prepared by a Suzuki or Stille reaction or variation thereof using palladium-catalyzed cross-coupling of 8-3 iodides with appropriately substituted aryl- or heteroaryl boronic acids, boronate esters or trialkyl-tin compounds, as described in Miyaura et al., Chem. Rev. 95, 2457 (1995) and references cited within, and as described in 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. The oxazolidinones 8-4 can be alkylated with alkyl, heteroalkyl, aryl or heteroaryl bromides using bases such as sodium hexamethyldisiliazide or sodium hydride in solvents such as tetrahydrofuran, dimethoxyethane, diethyl ether or the like to give the products 8-5. Alternatively, oxazolidinones 8-3 are alkylated with the appropriate bromides to give compounds 8-6, which are subjected to a Suzuki or Stille reaction or variation thereof with appropriately substituted aryl- or heteroaryl boronic acids, boronate esters or trialkyl-tin compounds to give the products 8-5.

INTERMEDIARY 1 2-Amino-5- (trifluoromethyl) benzonitrile A 2 liter flask was charged with 100 g (0.348 mol) of 4- amino-3-iodobenzotrifluoride, 40 g of CuCN and 750 ml of DMF. The mixture was heated and then refluxed for 1 hour. The reaction was cooled and evacuated in 3 l of water containing 300 ml of concentrated ammonium hydroxide. To the mixture was added 1 L of CH 2 Cl 2. The mixture was then filtered through Celite. The layers were separated and the aqueous layer was extracted again with CH2Cl2. The organic extracts were combined and the solvent was removed under reduced pressure. The residue was dissolved in 1.5 I of ether and the resulting solution was washed with 1 N ammonium hydroxide, aqueous sodium bisulfite, 1 N aqueous HCl and brine. The solution was dried over anhydrous MgSO 4 and filtered through a plug of silica gel containing a layer of MgSO 4 at the top. The plug was washed with 0.5 I of ether. The ether solutions were combined and concentrated to 750 ml and allowed to stand at room temperature. After 2 days the resulting solids were collected, washed with hexanes and dried under reduced pressure to give 2-amino-5- (trifluoromethyl) benzonitrile. 1 H NMR (CDCl 3, 500 MHz) d 7.68 (s, 1 H), 7.58 (d, J = 8.5 Hz, 1 H), 6 81 (d, J = 8.5 Hz, 1 H), 4.80 (br s, 2H).

INTERMEDIARY 2 2-Iodo-5- (trifluoromethyl) benzonitrile To a solution of 2-amino-5- (trifluoromethyl) benzonitrile (Intermediate 7, 15J g) and diiodomethane (24 ml) in acetonitrile (150 ml) at 35 ° C was added nitrite of f-butyl (21 ml) dropwise. The reaction was maintained at about 35 ° C during the addition. The reaction was aged for 30 min and then heated at 60 ° C for 30 minutes. The reaction mixture was cooled, diluted with ether and washed twice with water, twice with aqueous sodium bisulfite, water and then brine. The solution was dried over anhydrous MgSO, filtered through a plug of silica gel and then concentrated to give a red oil. The product was purified by silica gel chromatography eluting sequentially with hexanes, 3: 1 hexanes / CH 2 Cl 2 and 1: 1 hexanes / CH 2 Cl 2 to give 2-iodo-5- (trifluoromethyl) -benzonitrile. 1 H NMR (CDCl 3, 500 MHz) d 8.10 (d, j = 8.5 Hz, 1 H), 7.85 (d, j = 1.8 Hz, 1 H), 7.52 (dd, J = 8.5, 1.8 Hz, 1 H).

INTERMEDIARY 3 2-Vodo-5- (trifluoromethyl) benzoic acid. Potassium hydroxide (3.78 g, 0.0673 mol) was added to a stirred solution of 2-iodo-5- (trifluoromethyl) benzonitrile (Intermediate 8; 4 g; 0.0135 mol) in a 1: 1 solution of isopropanol: H20 (60 ml). The reaction was refluxed for 14 hr and then partitioned between H20 (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) and the combined extracts were washed with brine (50 ml), dried over MgSO 4, filtered and concentrated under vacuum to give 2-iodo-5- (trifluoromethyl) acid. ) benzoic as a yellow solid. LC-MS = 317.0 (M + 1) +. 1 H NMR (CDCl 3, 500 MHz): d 8.27 (d, J = 1.6 Hz, 1 H), 8.25 (d, J = 8.2 Hz, 1 H), 7.47 (dd, J = 8.2, 1.8 Hz, 1 H) .

INTERMEDIARY 4 [2-Iodo-5- (trifluoromethyl) phenemethanol Borane-THF (1.0M solution in THF, 94 mL, 94 mmol) was added to a stirred solution of 2-iodo-5- (trifluoromethyl) benzoic acid (Intermediate 3, 2.97 g; 9.4 mmoles) in THF (300 ml) at 0 ° C under N2. The reaction was heated to reflux for 90 min and then carefully quenched with 6N HCl until there was no evolution of gas. The reaction was diluted with H20 (250 mL) and extracted with EtOAc (3 x 250 mL). The combined extracts were washed with brine (300 ml), dried over MgSO, filtered and concentrated under vacuum. The crude material was purified by flash chromatography on silica gel (gradient of 0-25% EtOAc / hexanes) to give [2-iodo-5- (trifluoromethyl) phenyl] methanol as a white solid. LC-MS = 285.0 (M-17) +. 1 H NMR (CDCl 3, 500 MHz): d 7.97 (d, J = 8.3 Hz, 1 H), 7.79 (s, 1 H), 7.28 (d, J = 8.4 Hz, 1 H), 4.75 (s, 2 H) ).

INTERMEDIARY 5 2- (Bromomethyl) -1-vodo-4- (trifluoromethyl) benzene Carbon tetrahydromide (1.86 g, 5.6 mmol) and triphenylphosphine (1.47 g, 5.6 mmol) were successively added to a stirred solution of [2-Iodo-5- (trifluoromethyl) phenyl] methanol (Intermediate 10,1 J 3 g, 3.74 mmol) in CH 2 Cl 2 (25 ml) at 0 ° C under N 2. The reaction was stirred at room temperature for 48 hr. A second equivalent of carbon tetrabromide (1.2 g, 3.74 mmol) and triphenylphosphine (0.98 g, 3.74 mmol) was added and the reaction was stirred an additional 14 h. The solvent was removed under vacuum and the residue was purified by flash chromatography on silica gel (gradient of 0-25% EtOAc / hexanes) to give 2- (bromomethyl) -1-iodo-4- (trifluoromethyl) benzene as a clear oil. 1 H NMR (CDCl 3, 500 MHz): d 8.02 (d, j = 8.2 Hz, 1 H), 7.73 (d, j = 1.8 Hz, 1 H), 7.26 (dd, J = 8.3, 1.8 Hz, 1 H) 4.64 (s, 2 H).

INTERMEDIARY 6 (4S.5R) -5- [3,5-bs (trifluoromethyl) phenin-3-r2-vodo-5- (trifluoromethyl) -benzyl-4-methyl-1,3-oxazolidin-2-one (4S, 5R ) -5- [3,5-b / 's (trifluoromethyl) phenyl] -4-methyl-1,3-oxazolidin-2-one (400 mg, 1.28 mmol) was treated with NaH (60% in oil, 128 mg, 3.2 mmol) and 2- (bromomethyl) -1-iodo-4- (trifluoromethyl) benzene (Example 70, 466 mg, 1.28 mmoles) as described in example 66 to give (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. LC-MS = 598.0 (M + 1) +. 1 H NMR (CDCl 3, 500 MHz): d 8.06 (d, J = 8.2 Hz, 1 H), 7.93 (s, 1 H), 7.82 (s, 2 H), 7.61 (s, 1 H), 7.33 (dd) , J = 8.2, 1.4 Hz, 1 H), 5.79 (d, J = 7.8 Hz, 1 H), 4.91 (d, J = 16 Hz, 1 H), 4.40 (d, J = 16 Hz, 1 H) , 4.16-4.06 (m, 1 H), 0.83 (d, J = 6.4 Hz, 3 H).

INTERMEDIARY 7 (4S, 5R) -5- [3,5-Bis (trifluoromethyl) phenylh4-methyl-1,3-oxazolidin-2-one This intermediate is made directly from the CBZ-L-alanine chiral starting material by the route of 3 steps shown below.

The compound (4R, 5S) -5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-1,3-oxazolidin-2-one can be made by an analogous route starting from CBZ-D-alanine.

Step 1 CBZ-L-Alanine (6.5 kg, 28.5 moles), HOBT-hydrate (4.8 kg, 34.8 moles), Weinreb amine-HCl salt (3.4 kg, 36.2 moles) and THF (32 I) are charged to a clean flask under nitrogen. (The Weinreb amine is N, 0-dimethylhydroxylamine). The mixture is cooled to 0-10 ° C and then DIPEA (12.4 I) is slowly added at a temperature of less than 25 ° C. EDC-HCl (7 kg, 36.2 moles) is then added slowly with cooling at 15 ° -25 ° C. The suspension is aged overnight at 20 ° -25 ° C. The mixture is then cooled to 0 ° -10 ° C and 3N HCl (12 I) is added slowly. Then IPAC (32 I) is added and the layers are separated. The organic layer is washed once with HCl (13 I) and twice with 8% NaHCO 3 (13 I) (CAUTION: FOAMING). The organic layer is then concentrated under vacuum at about 15 1 to 50 ° C. The clear solution is slowly cooled to room temperature, allowing the product to crystallize. Then heptane (-70 I) is added slowly. The suspension is filtered, washed with heptane (18 L), and dried at room temperature over the filter vessel. The product is obtained with >99.9% ee as measured by chiral CLAR.

Step 2 The Weinreb amide of Step 1 (6 kg, 22.5 moles) and 3,5-bis (trifluoromethyl) bromobenzene (4.85 L, 28.1 moles) are dissolved in anhydrous THF (24 I). The solution is purged with nitrogen to remove oxygen. The water content should be < 500 ppm at this point. Atmospheric distillation can be carried out to azeotropically remove water if necessary. The solution is cooled to -10 ° C and iso-PrMgCI in THF (56.4 moles) is added slowly (2 hours) to the reaction via an addition funnel, maintaining a reaction temperature < -5 ° C. The solution is allowed to warm to 20 ° C and aged overnight at 20 ° C, until the amide is < 0.5 LCAP. The reaction is then cooled to -10X under nitrogen and slowly quenched for 2 hours in 5N HCl (14 I) which is maintained at 0-5 ° C. MTBE (12 I) is added and the biphasic mixture is stirred for 5 min. After heating to 20 ° -25 ° C, it is allowed to settle for 30 min, and then the layers are separated. The organic layer is washed with water twice (12 I). The organic layer is transferred under vacuum through a filter In-line PTFE of a miera in a distillation flask and then concentrated to -12 I under vacuum (internal temperature <40 ° C) at a minimum stirred volume. The solution is then azeotropically dried with toluene and it is collected at a stirred minimum volume again. The solution is used directly in the next step.

Step 3: Reduction of Ketone (step 2) to chiral oxazolidinone: The ketone from the previous step (6 kg) is heated to 50 ° C with 0.3 eq of AI (0-i-Pr) 3 (790 g) in 12 I of IPA and 18 I of toluene for 15.5 hours. The solution is cooled to room temperature, and solid KOH tablets (1.35 kg) are added slowly with vigorous stirring, while maintaining the temperature at < 25 ° C. After about 2 hours, when CLAR shows > 99.5% cyclization, 33 I of 1 N HCl solution is added to quench the reaction, which is maintained at < 25 ° C. If a solid waste layer forms, it must be filtered. The residue layer is racemic oxazolidinone, and the removal increases the enantiomeric excess. The organic layer is then washed, first with 36 I of 0.5N HCl, then with 6 liters of IPA combined with 45 I of water, and finally with 6 I of IPA combined with 36 I of water. The organic layer is transferred through an inline filter. The solvent is changed to heptane (target volume is -42 I) at -40 ° C until it is <2 v% toluene. Aging at room temperature during 2 hr gives Solid Intermediary 7.

INTERMEDIARY 8 2-methox? -4-fluoro-5- (2'-met? Lfen? L) boronic acid Step A 2-Fluoro-2'-met? Lb? Phen? L-4-yl methyl ether A mixture of 4-bromo-3-fluoroan? Sun, 2-met? Lfen? Lonic acid, tetrak? S (tpfen ? phosphate?) (5 mol%) and sodium carbonate (023 g, 2 1 mmol) in 20 ml of water / EtOH / toluene (1 2 4) was heated to reflux for 5 hr CCD (EtOAc hexane 12 98) showed that the reaction had ended The solvents were removed Water (10 ml) was added The organic layer was extracted with methylene chloride (3x 50 ml) The combined methylene chloride layers were washed with brine, and dried over sodium sulfate The title compound was obtained after purification with preparative CCD using 2% EtOAc in hexane as the eluent Step B 2-Fluoro-5-vodo-2'-met? Lb? Phen? L-4-? L methyl ester To a mixture of silver sulfate (0 34 g, 11.1 mmol), iodine (028 g, 11.1 mmol) in MeOH (10 mL) at room temperature, was added dropwise a solution of 2-fluoro-2'-meth? Lb? Phen? L-4-? Lmethyl ether? Previous co (024 g, 11.1 mmol) in MeOH (5 mL) The mixture was stirred at temperature environment for 4 hr until the color turned light yellow. The solid was filtered and the filtrate was concentrated. The residue was purified by column chromatography using hexane as the eluent to give the title compound.

Step C: 2-Methoxy-4-fluoro-5- (2'-methylphenyl) boronic acid To a solution of 2-fluoro-5-iodo-2'-methylbiphenyl-4-yl methyl ether (0 32 g0.93 mmole) in THF at -78 ° C, n-BuLi (0.48 ml, 1.22 mmole, 2.5M in hexane) was added dropwise by syringe. The solution was stirred at -78 ° C for 30 min. Triml borate (0.31 ml, 2.8 mmol) was added. Everything was stirred at -78 ° C for 3 hr. The reaction was quenched with a saturated solution of ammonium chloride. The mixture was extracted with EtOAc (3x 15 ml). The combined EtOAc layers were dried over sodium sulfate. The title compound was used when removing the solvent.

INTERMEDIARY 9 (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenin-4-methyl-3- [2- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) - 5- (Trifluoromethyl) benzyl-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 6, 0.75 g, 1.25 mmol), bis (pinacolato) diboro (339 mg, 1.5 mmol), 1, 1 '-bis (diphenylphosphino) ferrocene adduct palladium dichloride-dichloromethane (214 mg, 0.262 mmol), potassium acetate (257 mg, 2.616 mmol) and 1,4-dioxane (2.5 ml) were sealed in a microwave container. The reaction mixture was irradiated by microwave at 140 ° C for 20 minutes, then at 130 ° C for 30 minutes. The crude reaction was treated with brine followed by extractions with ethyl acetate. The combined extracts were dried over Na2SO4 followed by filtration and concentration under vacuum to give a dark oil. The mixture was used for the next step without purification.

INTERMEDIARY 10 2-Chloro-3'-iodo-4'-methox? B? Phen? L-4-carboxylate methyl Step A To methyl 4-methyl-3-chlorobenzoate A mixture of methyl 4-amino-3-chlorobenzoate (1.0 g, 5.4 mmol), n-pentyl nitrite (0.95 g, 8 1 mmol) and iodine (1.78 g) g, 7.0 mmol) was sed under reflux for 1 hr. The mixture was diluted with methylene chloride (30 ml) The purple solution was washed with saturated sodium thiosulfate solution, brine, and dried over sodium sulfate. The title compound was obtained after column chromatography using EtOAc. hexane / 2 98 as the eluent Step B Methyl 2-chloro-4'-methox? B? Phen-4-carboxylate A mixture of methyl 4-iodo-3-chlorobenzoate (1.20 g, 4.05 mmol) from step A, 4-methox acid? phenolboron? co (1.23 g, 8J mmoles), tetrak? s (tr? phen? lfosf? n) palad? o (0 23 g, 5 mol%) and sodium carbonate (0.94 g, 8 9 mmol) in 50 mL of water / EtOH / toluene (1: 2: 4) was heated to reflux overnight CCD (EtOAc / hexane / 1 9) showed that the reaction had ended The solvents were removed Water was added (30 g. ml) The organic layer was extracted with methylene chloride (3x 50 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after column chromatography using EtOAc hexane / 1 9 as the eluent. 1 H NMR (CDCl 3, 500 MHz) d 8 16 (d, J = 1.5 Hz, 1 H), 7 97 (dd, j = 8, 1.5Hz, 1 H), 7.43 (m, 3H), 7.01 (d, J = 6.5 Hz, 2H), 4.00 (s, 3H), 3.91 (s, 3H).

Step C: Methyl 2-chloro-3'-iodo-4'-methoxybiphenyl-4-carboxylate To a mixture of silver sulfate (0.97 g, 3J 1 mmol) and iodine (0.79 g, 3J 1 mmol) in MeOH ( 20 ml) at room temperature, a solution of methyl 2-chloro-4'-methoxy-benzyl-4-carboxylate (0.86 g, 3.1 1 mmol) in a 1: 1 mixture of MeOH / EtOAc (10 ml) was added. The mixture was sed at room temperature for 6 hr until the color of the reaction turned pale. The solid was filtered and the filtrate was concentrated. The title compound was obtained after column chromatography using EtOAc: hexane / 5: 95 as the eluent. 1 H NMR (CDCl 3, 500 MHz): d 8J 5 (d, j = 1.5 Hz, 1 H), 7.97 (d, j = 8, 2 Hz, 1 H), 7.89 (d, J = 2 Hz, 1 H), 7.46 (dd, J = 8.5, 2Hz, 1 H), 7.40 (d, J = 8 Hz, 1 H), 6.91 (d, J = 8 Hz, 1 H), 3.98 (s, 6H).

INTERMEDIARY 11 4'-methoxy-2-methyl-3 '- (4,4,5,5-tetramethyl-1,2,3-dioxaborolan-2-yl) biphenyl-4-carboxylic acid methyl 3'-iodo-4'-methoxy- 2-methylbiphenyl-4-carboxylate (500 mg, 1,308 mmol), bis (pinacolato) diboro (353 mg, 1.57 mmol), 1,1 '-bis (diphenylphosphino) ferrocene-palladium dichloride-dichloromethane adduct (214 mg, 0.262 mmol), potassium acetate (257 mg, 2616 mmol) and 1,4-dioxane (2.5 ml) were placed in a sealed tube and subjected to microwave irradiation at 140X for 20 minutes, then at 130C for 30 minutes. minutes The crude reaction was treated with brine followed by extractions with ethyl acetate. The combined extracts were dried over Na2SO4 followed by filtration and concentration under vacuum to give 4'-methoxy-2-methyl-3 '- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl. methyl biphenyl-4-carboxylate as a dark oil which was used in the next step without further purification. CL-EM cale. = 382.20; found = 383.41 (M + 1) +.

INTERMEDIARY 12 (4 5f?) - 5-r2-vodo-5- (trifluoromethyl) phenin-4-methyl-1,3-oxazolidin-2-one Step A: 2-vodo-5- (trifluoromethyl) benzaldehyde To a solution of 2-iodo-5- (trifluoromethyl) benzonitrile (intermediate 2, 42 g) in CH 2 Cl 2 (300 ml) at -78 ° C was added a solution of DIBAL in CH 2 Cl 2 (175 ml, 1 M) for 30 minutes. A precipitate formed. The reaction was heated to 0 ° C. An additional 25 ml of the DIBAL solution was added dropwise over 30 minutes. The reaction was emptied into 200 ml of 2N aqueous HCl, diluted with ether and stirred 1 hour. The CCD analysis indicated that the imine was still present and an additional 100 ml of 2N aqueous was added and the reaction was stirred overnight. The imine was still present by the CCD analysis and 200 ml of aqueous 2N HCl was added and the mixture was stirred 2 hours. The layers were separated and the aqueous layer was extracted again with ether. The ether extracts were combined, washed with brine, dried over anhydrous MgSO 4, filtered and concentrated. The product was purified by silica gel chromatography eluting with 95: 5 hexanes / EtOAc to give 2-iodo-5- (trifluoromethyl) benzaldehyde as a white solid. H NMR (500 MHz, CDCl 3): d 10.00 (s, 1 H), 8.12 (s, 1 H), 8.1 1 (d, J = 8 Hz, 1 H), 7.53 (dd, J = 2 Hz, 8 Hz, 1 H).

Step B (4S) -4-benzyl-3-f (2 3S) -3-hydrox? -3J2-vodo-5- (tr? Fluoromet? L) phen? 1-2-met? Lpropane? l) -1, 3-oxazole? d? n-2-one A mixture of 1 8 g of 5 '-? Soprop? L-2'-methox? -4- (tr? Fluoromet? L) b? Phen? L-2-carbaldehyde (Step A), 16 g of (4S) -4-benzyl-3-prop? On? -1,3-oxazole? D? N-2-one, 0 048 g of magnesium chloride, 1 40 ml of tetylamine, and 0 91 ml of chlorotpmethylsilane in 10 ml of EtOAc was stirred ata for 24 h, then filtered through a plug of 10 x 10 cm silica gel, eluting with 400 ml of Et 2 O. The filtrate was concentrated, and 10 ml of MeOH was added together with 2 drops of tffluoroacetic acid This solution was stirred ata for 30 min and concentrated to a pale yellow oil The residue was purified by flash chromatography on a Biotage Hopzon column, 65 ?, eluting with 15 CV of 10% acetone in hexanes to provide 1 42 g (53%) of the title compound Mass Spectrum (ESI) 516 2 (M-OH) 1 H NMR (500 MHz, CDCl 3) d 8 00 (d, J = 8 5 Hz, 1 H), 7 76 (d, J = 2 Hz, 1 H), 7 22-7 32 (m 4H), 7 07 (br d, J = 6 5 Hz, 2 H), 5 18 (dd, J = 6 5 Hz, 7 5 Hz, 1 H), 4 67 (m, 1 H), 4 46 (dq, J = 6 5 Hz, 7 5 Hz, 1 H), 4 17 (t, J = 9 Hz, 1 H), 4 11 (dd, J = 3 Hz, 9 Hz, 1 H), 3 97 (d, J = 8 Hz, 1 H), 3 19 (dd, J = 7 Hz, 13 5 Hz, 1 H), 2 57 (dd, J = 9 5 Hz, 13 5 Hz, 1 H), 1 34 (d, J = 7 5 Hz, 3H) Step C (4 5f?) - 5- [2-iodo-5- (tr? Fluoromethyl) phen? N-4-methyl-1,3-oxazole? D? N-2-one To a solution at 0 ° C of 0.65 g of (4S) -4-benzyl-3-. { (2R, 3S) -3-hydroxy-3- [2-iodo-5- (tpfluoromethyl) phenol] -2-methylpropane? L} -1, 3-oxazolidin-2-one in 6 ml of 3 1 of tetrahydrofuran-water or 102 g of lithium hydroxide in 15 ml of water was added, then 0 554 ml of a 30% strength aqueous solution of hydrogen The solution was stirred 1 hr at 0 ° C, at which point the LC / MS analysis showed no starting material. A 1.5 M solution of sodium sulfite (3.7 ml) was added to the cold solution, which was then emptied into a separatory funnel and extracted with 2 x 10 ml of CH2Cl2. The combined CH2Cl2 extracts were again extracted with 20 ml of 3J of water-saturated aqueous NaHCO3 The combined aqueous layers were acidified (pH <1) with 6 N HCl and extracted with 4 x 10 ml of EtOAc The EtOAc extracts The combined extracts were washed with 10 ml of brine, dried over Na 2 SO 4, and concentrated. The residue was dissolved in 10 ml of toluene, Diphenylphosphopl azide (0 315 ml) and 0.24 ml of triethylamine were added and the mixture was stirred overnight at 100 ° C. ° C, 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 EtOAc in hexanes from 5 to 100% over 10 CV to provide 0302 g (67 %) of the title compound Mass Spectrum (ESI) 372 1 (M + 1) 1 H NMR (500 MHz, CDCl 3) d 8 02 (d, J = 8 Hz, 1 H), 7 61 (d, J = 1.5 Hz, 1 H), 7.32 (dd, J = 2 Hz, 8 Hz, 1 H), 6.16 (s, 1 H), 5.39 (d, J = 4 Hz, 1 H), 3.76 (dq, J = 6 Hz, 4.5 Hz, 1 H), 1.62 (d, J = 6 Hz, 3H). Analytical HPLC on 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) showed 98% e.e.

INTERMEDIARY 13 2"- (Bromomethyl) -4'-methoxy-2-methyl-4" - (trifluoromethyl) -1,1 ': 3', 1"-methylphenyl-4-carboxylic acid methyl ester Step A: Methyl 4'-methoxy-2-methylbiphenyl-4-carboxylate To methyl 4-bromo-3-methylbenzoate (92 g, 0.402 moles), (4-methoxyphenyl) boronic acid (61.1 g, 0.402 moles) , Na 2 CO 3 (85.2 g, 0.804 moles), and PdCl 2 (PPh 3) 2 (1410 mg, 2.01 mmol) was added EtOH (1.23 I) and water (0.61 I). The reaction was then heated at 80 ° C for 1 hour. The reaction was cooled to room temperature, 550 ml of water was added and the mixture was allowed to stand for 1 hour. The resulting solids were filtered and washed with a solution of EtOH and H20 (1: 1, 750 ml). The solids were ground using a mortar and pestle and then suspended in 250 ml of H20 at room temperature. environment for 1 hr, then filtered and washed with water (2x125 ml) and dried to give methyl 4'-methoxy-2-methylbiphenyl-4-carboxylate. 1 H NMR (CDCl 3, 400 MHz) d 7.95 (s, 1 H), 7.89 (d, J = 7.9 Hz, 1 H), 7.29 (d, J = 7.9 Hz, 1 H), 7.27 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 3.94 (s, 3H), 3.87 (s, 3H), 2.33 (s, 3H).

Step B: Methyl 3'-bromo-4'-methoxy-2-methylbiphenyl-4-carboxylate To a solution of methyl 4'-methoxy-2-methylbiphenyl-4-carboxylate (71.5 g, 0.279 moles) in acetonitrile (1.43 I) and water (572 ml) was added oxone (180.1 g, 0.293 moles). Then a solution of KBr (38.2 g, 0.321 mole) in water (143 ml) was added slowly over 30 minutes. The reaction was stirred for 2.5 hours, then water (715 ml) was added and the mixture was allowed to stand for 1 hour. The solids were filtered and washed as follows: with a solution of MeCN / water (1: 1, 350 ml, twice), water (700 ml, twice, then 350 ml) and dried to give 3'-bromo. Methyl 4'-methoxy-2-methylbiphenyl-4-carboxylate. 1 H NMR (CDCl 3, 400 MHz) d 7.94 (s, 1 H), 7.89 (d, J = 8.1 Hz, 1 H), 7.53 (d, J = 2.2 Hz, 1 H), 7.3-7.2 (m, 2H ), 6.97 (d, J = 8.4 Hz, 1 H), 3.96 (s, 3H), 3.94 (s, 3H), 2.32 (s, 3H).

Step C: 2"- (hydroxymethyl) -4'-methoxy-2-methyl-4" - (trifluoromethyl-1 J ': 3'J "-terphenyl-4-carboxylic acid methyl 3'-bromo-4 methyl-methoxy-2-methylbiphenyl-4-carboxylate (80.0 g, 0.239 mol), pinacol borane (72.8 g, 0.287 mol), Pd (dba) 2 (4120 mg, 7.17 mmol), P (Cy) 3 ( 2140 mg, 7.65 mmol), and KOAc (70.3 g, 0.717 mol) was added dioxane (1.2 L) .The reaction was heated to 80 ° C and stirred for 3 h.The reaction was then cooled to room temperature and filtered The solids were dissolved with EtOAc (800 ml), washed with brine (400 ml, twice), and concentrated.The residue was dissolved in THF (300 ml), and [2-chloro-5- ( trifluoromethyl) phenyl] methanol (47J g, 0.223 mole) and (f-Bu2P) 2-ferrocene PdCl2. A solution of K2C03 (83.7 g, 0.606 mole in water (214 ml) was added and the mixture was heated to 45 ° C. The mixture was stirred for 9 hours, the reaction was cooled to room temperature and diluted with EtOAc (428 ml), and washed with water (428 ml) and brine (4 ml). 28 ml) The organic material was added with 21.5 g of carbon (Darco KB - 100 mesh) and the mixture was stirred for 1 hour. The mixture was filtered, and the solid material was washed with EtOAc (428 ml). The filtrate was concentrated and then redissolved in MeOH (677 mL) and allowed to stand for 1 hour. To the mixture was added water (169 ml) for 2 hours, and then the mixture was allowed to stand for 1 hour. The resulting solids were washed with a solution of MeOH and water (4: 1, 170 ml, three times) and dried to give 2"- (hydroxymethyl) -4'-methoxy-2-methyl-4" - ( trifluoromethyl) -1, 1 ': 3', 1"-terphenyl-4-carboxylic acid methyl ester.

Step D: 2"- (bromomethyl) -4'-methoxy-2-methyl-4" - (trifluoromethyl) -1 J ': 3'J "-methylphenyl-4-carboxylic acid methyl ester To a solution of 0 ° C of 2"- (hydroxymethyl) -4'-methoxy-2-methyl-4" - (trifluoromethyl) -1 J ': 3', Methyl 1-methyl-methyl-4-carboxylate (1500 g, 3.49 mmol) in CH2Cl2 (14 mL) was added CBr4 (2.429 g, 7.33 mmol), and then a solution of triphenylphosphine (1830 g, 6.98 mmol) in CH2Cl2 (15 ml) The solution was warmed to room temperature and stirred for twelve hours, the reaction was concentrated, and the residue was purified by flash chromatography on silica gel (0 to 25% EtOAc / hexanes) to give 2". - (bromomethyl) -4'-methoxy-2-methyl-4"- (trifluoromethyl) -1 J ': 3'J" -terphenyl-4-carboxylic acid methyl ester. R, = 0.59 (50% EtOAc / hexanes). LC-MS = 494.8 (M + 1) +. H NMR (CDCl 3, 500 MHz) d 7.95 (s, 1 H), 7.89 (d, j = 8.0 Hz, 1 H), 7.80 (s, 1 H), 7.59 (d, j = 7.6 Hz, 1 H) , 7.40-7.33 (m, 3H), 7.21 (d, J = 2.3 Hz, 1 H), 7.06 (d, j = 8.5 Hz, 1 H), 4.44-4.39 (m, 2H), 3.93 (s, 3H) ), 3.82 (s, 3H), 2.37 (s, 3H).

INTERMEDIARY 14 (5R) -5-r3,5-bis (trifluoromethylphenyl-3J [4'-fluoro-5'-isopropyl-2'-methoxy-4- (trifluoromethyl) biphenyl-2-methyl) -4,4-dimethyl- 1,3-oxazolidin-2-one Step A: { Benzyl 2-fmethoxy (methyl) amino-1-J-dimethyl-2-oxoethyl) carbamic acid N-methylmorpholine (682 mg, 741 μl, 6.74 mmol) and isobutyl chloroformate (460 mg, 441 μl, 3.37 mmol) were added in turn to a stirred solution of N-carbobenzyloxy-2-methylalanine (0.64 g, 2.69 mmol) in dry CH 2 Cl 2 at 0 ° C under N 2. The resulting cloudy mixture was stirred at 0 ° C for 90 min. 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 hr. The mixture was washed in 1N HCl (30 ml) and extracted with CH2Cl2 (3 x 40 ml). The combined extracts were washed with 1 N HCl (30 ml), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 40 x 160 mm, gradient of 0-80% EtOAc in hexanes) to give. { 2- [Methoxy (methyl) amino] -1,2-dimethyl-2-oxoethyl-benzyl carbamate. Rf = 0.47 (50% EtOAc in hexanes). CL-EM cale. = 303J; found = 303.2 (M + Na) +. 1 H NMR (500 MHz, CDCl 3) d 7.37-7.29 (, 5H), 5.82 (s, 1 H), . 09 (s, 2H), 3.60 (s, 3H), 3.18 (s, 3H), 1.60 (s, 6H).

Step B: (1 J-dimethyl-2-oxoethyl) benzyl carbamate Diisobutylaluminum hydride (1.77 ml, 1 M solution in toluene, 0.708 mmol) was added to a stirred solution of. { 2- [Methoxy (methyl) amino] -1,1-dimethyl-2-oxoethyl} Benzyl carbamate (198.5 mg, 0.708 mmol) in dry THF (7.1 ml) at -78 ° C under N2. The reaction was stirred at -78 ° C for 4 h. MeOH (100 μl) and 1 N HCl (250 μl) were added and the reaction was allowed to warm to room temperature. The mixture was diluted with Et20 (50 ml) and washed with 1 N HCl (2 x 50 ml), 50% saturated NaHCO3 (50 ml) and water (50 ml), then dried (MgSO4) and concentrated vacuum to give (1, 1-dimethyl-2-oxoethyl) benzyl carbamate. Rf = 0.40 (20% EtOAc in hexanes). CL-EM cale. = 244.1; found = 244J (M + Na) +. 1 H NMR (500 MHz, CDCl 3) d 9.43 (s, 1 H), 7.38-7.30 (m, 5H), 5.34 (s, 1 H), 5.09 (s, 2H), 1.37 (s, 6H).

Step O (2J3,5-bis (trifluoromethylphenyl1-2-hydroxy-1 J-dimethylethylcarbamate benzyl ethylmagnesium bromide (1.63 ml, 1M in THF, 1.63 mmol) was added dropwise to a stirred solution of 1-iodine 3,5-bis (trifluoromethyl) benzene (608 mg, 317 μl, 1.79 mmol) in dry THF (1 ml) at room temperature under N2 and the reaction was stirred for 30 min.The resulting solution was added to a stirred solution of (1 J-dimethyl-2-oxoethyl) benzyl carbamate (163.5 mg, 0.739 mmol) in dry THF (1 ml) a -20 ° C and the reaction was allowed to warm to room temperature for 3 hr. NH CI saturated (10 ml) and water (10 ml) were added and the mixture was extracted with EtOAc (3 x 20 ml). The combined extracts were dried (Na2SO) and concentrated under vacuum to give the crude product. This was purified by flash chromatography (Si, 25 x 160 mm, gradient of 0-40% EtOAc in hexanes) to give. { 2- [3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-1,1-dimethylethyl} -benzyl carbamate. R = 0.40 (20% EtOAc in hexanes). CL-EM cale. = 436.1; found = 436.0 (M + 1) +. 1 H NMR (600 MHz, CDCl 3) d 7.80 (s, 1 H), 7.77 (s, 2 H), 7.39-7.33 (m, 5H), 5.12-5.08 (m, 2H), 1.36 (s, 1 H), 4.90 (d, J = 4.4 Hz, 1 H), 4.81 (s, 1 H), 1.36 (s, 3H) , 1.23 (s, 3H).

INTERMEDIARY 15 (4S, 5R) -4-Methyl-5-pyridin-4-yl-1,3-oxazolidin-2-one Step A: { (1 S) -2- [methoxy (methyl) amino-1-methyl-2-oxoethyl) benzyl carbamate CBZ-L-Alanine (6.5 kg, 28.5 moles), HOBT-hydrate (4.8 kg, 34.8 moles), (MeO) NH2CI (3.4 kg, 36.2 moles) and THF (32 I) were charged to a clean flask under nitrogen. The mixture was cooled to 0-10 ° C and diisopropylethylamine (12.4 I) was added slowly at a temperature of less than 20 ° C. EDC-HCl (7 kg, 36.2 moles) was added slowly with slight cooling at 15 ° -25 ° C. The suspension was aged overnight at 20 ° -25 ° C. The mixture was cooled to 0 ° -10 ° C and 3N HCl (13 I) was slowly added. Iopropyl acetate (45.5 I) was added and the layers separated. The organic layer was washed once with HCl (13 I) and twice with 8% NaHCO 3 (13 I). The organic layer was concentrated under vacuum at <20 I at 50 ° C. The clear solution was cooled slowly to room temperature, allowing the product to crystallize. Heptane (-70 I) was added slowly. The suspension was filtered, washed with heptane (18 L), and dried at room temperature over the filter vessel. It was obtained . { (1 S) -2- [methoxy (methyl) amino] -1-methyl-2-oxoethyl} benzyl carbamate with > 99.9% ee measured by chiral CLAR.

Step B: f (1 S) -1-methyl-2-oxo-2-pyridin-4-ylethyl] benzyl carbamate A solution of isopropylmagnesium chloride (1.6 ml, 1 M in THF, 3.23 mmol) was added dropwise to a stirred solution of. { (1 S) -2- [methoxy (methyl) amino] -1-methyl-2-oxoethyl} Benzyl carbamate (879 mg, 3.30 mmol) in dry THF (4.2 ml) at -15 ° C under N2. The reaction was stirred at -15 ° C for 30 min, then a suspension of 4-pyridylmagnesium bromide in dry THF (prepared by adding ethylmagnesium bromide (6 ml, 2M in THF, 6.00 mmol) to a stirred solution of 4-iodopyridine. (1.35 g, 6.60 mmol) in dry THF (45 ml) at room temperature under N2 and stirring for 30 minutes. min) was added dropwise by cannula. The reaction was allowed to warm to room temperature and was stirred for 5 hr. 1 N 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 CH 2 Cl 2 (3 x 50 ml). The extracted EtOAc and CH 2 Cl 2 were washed with brine separately, dried (Na 2 SO), combined and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 40 x 160 mm, gradient of 0-100% EtOAc in hexanes) to give [(2R) -1-methyl-2-oxo-2-pyridin-4-ylethyl] carbamate benzyl, as a colorless solid. Rf = 0.33 (50% EtOAc / hexanes). CL-EM cale. = 285.1; found = 285.3 (M + 1) +. H NMR (500 MHz, CDCl 3) d 8.85 (d, J = 3.3 Hz, 2H), 7.76 (d, J = 5.5 Hz, 2H), 7.36-7.32 (m, 5H), 5.70 (d, J = 6.8 Hz , 1H), 5.31-5.25 (m, 1 H), 5.13 (s, 2H), 1.43 (s, 3H).

Step C: [(1 Sl2f?) - benzyl 2-hydroxy-1-methyl-2-pyridin-4-iletincarbamate lithium-tri-fer-butoxyaluminium hydride (964 mg, 3.79 mmol) was added to a solution of [ Benzyl (2f?) - 1-methyl-2-oxo-2-pyridin-4-ylethyl] carbamate (539.1 mg, 1.90 mmol) in dry EtOH (40 mL) at -78X under N2. The reaction was stirred at -78X for 2 hr. 2% aqueous acetic acid was added to quench the reaction and the mixture was adjusted to basic pH with saturated NaHCO 3 (-50 ml). The mixture was extracted with EtOAc (3 x 100 ml) and the extracts The combined extracts were washed with brine (50 ml), dried (Na2SO) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 40 x 160 mm, gradient of 0-100% EtOAc in hexanes) to give [(1 S, 2R) -2-h? Drox? -1-met? L-2 p? r? din-4-? let? l] benzyl carbamate, as a colorless solid Rf = 0 49 (EtOAc) LC-MS cale = 287 1, found = 287 3 (M + 1) + 1 H NMR (500 MHz, CDCl 3) d 8 41 (d, J = 5 7 Hz, 2 H), 7 36-7 32 (m, 7 H), 5 27 (d, J = 7 4 Hz, 1 H), 5 10 (s, 2H), 4 89 (s, 1H), 4 02 (br s, 1 H), 0 96 (d, J = 6 7 Hz, 3H) Step D (4S.5ff) -4-Met? L-5-p? R? D? N-4-? L-1, 3-oxazole? D? N-2-one A solution of [(1 S, 2) -2-h? Drox? -1-met? L-2-p? Pd? N-4-ylethylcarbamate benzyl in KOH ac 7 5N / MeOH / THF (1 2 4, 7 ml) was stirred at room temperature overnight atmosphere The reaction was diluted with water (20 ml) and extracted with EtOAc (3 x 20 ml) The combined organic layers were dried (Na2SO4) and concentrated under vacuum to give (4S, 5R) -4-met ? l-5-phenol-1, 3-oxazole? d? n-2-one LC-MS cale = 179 1, found = 179 2 (M + 1) + INTERMEDIARY 16 Methyl 3-methyl-4- (4,4,5,5-tetramethyl-1,2-dioxaborolan-2-yl) benzoate A round bottom flask was charged with methyl 4-bromo-3-methylbenzoate ( 200 mg, 0.878 mmol), bis (pinacolato) diboro (277 mg, 1089 mmol), PdCI2 (dppf) CH2Cl2 (70 mg, 0.0873 mmol), KOAc (171 mg, 1.75 mmol), and DMSO (10 mL). The reaction was degassed with N2 and heated to 40X for 1 hour, 60X for 1 hour, and then 80X for 12 hours. The reaction was diluted with EtOAc (25 ml) and hexanes (75 ml) and the organics were washed with water (2 x 25 ml) and brine (50 ml). The organic layer was dried over Na 2 SO, filtered and concentrated. Purification of the residue by silica gel chromatography (0 to 15% EtOAc / hexanes) gave 3-methyl-4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl). methyl benzoate. 1 H NMR (CDCl 3, 500 MHz) d 7.82 (s, 1 H), 7.80 (s, 2 H), 3.91 (s, 3H), 2.57 (s, 3H), 1.35 (s, 12H).

INTERMEDIARY 17 4- (2-fluoro-4-methoxyphenyl) piperidine Step A: 1-benzyl-4- (2-fluoro-4-methoxyphenyl) piperidin-4-ol To a stirred and cooled (OX) solution of 4-bromo-3-fluoroanisole (1 g, 4.88 mmole) in anhydrous THF (7 mL) was added isopropylmagnesium chloride (2.0M in THF, 2.22 mL, 4.43 mmol) dropwise. The reaction was stirred at room temperature for 30 min and then cooled to OX. 1-Benzyl-4-piperidone (0.72 ml, 4.03 mmol) was added dropwise and the reaction was stirred at room temperature for 14 hr. The reaction was quenched with saturated NH4CI and partitioned between EtOAc (50 mL) and H20 (30 mL). The aqueous layer was extracted with EtOAc (3 x 50 ml) and the combined extracts were washed with brine (50 ml), dried (MgSO 4), filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient of 0-50% EtOAc / hexanes) to give 1-benzyl-4- (2-fluoro-4-methoxyphenyl) piperidin-4-ol as a light orange solid. . LC-MS = 315.9 (M + 1) +. 1 H NMR (CDCl 3, 500 MHz) d 7.38-7.31 (m, 5 H), 7.28-7.24 (m, 1 H), 6.66 (dd, J = 8.7, 2.5 Hz, 1 H), 6.61 (dd, J = 14.4, 2.5 Hz, 1 H), 3.79 (s, 3 H), 3.56 (s, 2 H), 2.77 (br d, J = 10.6 Hz, 2 H), 2.54-2.48 (m, 2 H), 2.31 -2.24 (m, 2 H), 1 84 (d, J = 12 3 Hz, 2 H) Step B 1-benzyl-4- (2-fluoro-4-methox? Phen?) -1, 2,3,6-tetrahydro-pyridine A stirred mixture of 1-benzyl-4- ( 2-fluoro-4-methox? Phen? L) p? Per? D? N-4-ol (step A, 300 mg, 0 952 mmol) and p-toluenesulfonic acid monohydrate (18 mg, 0 0952 mmol) in benzene (20 ml) was heated at 80X for 14 hr. An additional 100 mg of p-toluenesulfonic acid monohydrate was added and the reaction was heated at 80X for 1 hr. The reaction was partitioned between EtOAc (50 ml) and H20 (50 ml). aqueous was extracted with EtOAc (3 x 50 ml) and the combined extracts were washed with H2O (3 x 50 ml) and brine (50 ml), dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (gradient of 0-10% EtOAc / hexanes) to give 1-benzyl-4- (2-fluoro-4-methoxyphenol) 1, 2,3,6-tetrah ? drop? r? d? na as a yellow oil LC-MS = 297 9 (M + 1) + 1 H NMR (CDCl 3, 500 MHz) d 9 56 (br s, 1 H), 7 42-7 38 (m , 2 H), 7 34 (t, J = 7 3 Hz, 2 H), 7 28 (d, J = 7 3 Hz, 1 H), 7 17 (t, J = 8 7 Hz, 1 H), 6 64 (dd, J = 8 7, 2 5 Hz, 1 H), 6 59 (dd, J = 13 0, 2 5 Hz, 1 H), 5 91-5 89 (m, 1 H), 3 78 (s, 3 H), 3 66 (br s, 2 H), 3 18 (br s, 2 H), 2 71 (br s, 2 H), 2 54 (br s, 2 H) Step C 4- (2-fluoro-4-methox? Phen? L) p? Per? D? Na A solution of 1-benzyl-4- (2-fluoro-4-methox? Phen? L) 1, 2,3,6-tetrahydropmdine (step B, 117 mg, 0 393 mmol) in MeOH (10 ml) was treated with a catalytic amount of 10% Pd / C and the reaction was placed under an atmosphere of H2 (stirrer). Parr, 3 16 kg / cm2) for 48 hr The reaction was filtered through Ce te and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient of 0-100% EtOAc / hexanes) to give 4- (2-fluoro-4-methox? phen? l) p? per? d? na as a tan solid CL-MS = 210 1 (M + 1) + 1 H NMR (CDCb, 500 MHz) d 7 16 (t, J = 8 7 Hz, 1 H), 6 68 (dd, J = 8 7, 2 5 Hz, 1 H), 6 60 (dd, J = 12 3, 2 5 Hz, 1 H) , 3 78 (s, 3 H), 3 63 (d, J = 12 6 Hz, 2 H), 3 09-2 98 (m, 2 H), 2 18 (q, J = 12 1 Hz, 2 H ), 2 02 (d, J = 13 3 Hz, 2 H) INTERMEDIARY 18 [4- (2-fluoro-5-iodo-4-methox? Phen? L) p? Per? D? N-1-? Step A [4- (2-fluoro-4-methox? Phen? L) p? Per? D? N-1? -ethyl ethyl acetate To a stirred solution of 4- (2-fluoro-4-methox? Phen? l) p? per? d? na (40) mg; 0J 9 mmoles) in DMF (1 ml) under an atmosphere of N2 was added N, N-diisopropylethylamine (33 μl, 0J 9 mmoles), followed by ethyl bromoacetate (21 μl, 0J 9 mmoles). The resulting solution was stirred at room temperature for 2.5 hr. The reaction was partitioned between EtOAc (10 mL) and H20 (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 ml) and the combined extracts were washed with brine (10 ml), dried (Na 2 SO 4), filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient of 0-25% EtOAc / hexanes) to give ethyl [4- (2-fluoro-4-methoxyphenyl) piperidin-1-yl] acetate as a colorless oil. . LC-MS = 295.9 (M + 1) +. 1 H NMR (CDCb, 500 MHz) d 7J 4 (t, j = 8.7 Hz, 1 H), 6.65 (dd, J = 8.5, 2.5 Hz, 1 H), 6.58 (dd, J = 12.43, 2.5 Hz, 1 H ), 4.20 (q, J = 7.1 Hz, 2 H), 3.77 (s, 3 H), 3.26 (s, 2 H), 3.06 (d, J = 1 1 .4 Hz, 2 H), 2.80 (tt) , J = 12.1, 3.7 Hz, 1 H), 2.32 (t, J = 1 1.2 Hz, 2 H), 1.87 (qd, J = 12.3, 3.3 Hz, 2 H), 1.78 (d, j = 12.1 Hz, 2 H), 1 .29 (t, j = 7.1 Hz, 3 H).

Step B: ethyl [4- (2-fluoro-5-iodo-4-methoxyphenyl) piperidin-1-yl acetate) A mixture of ethyl [4- (2-fluoro-4-methoxyphenyl) piperidin-1-yl] acetate (step A, 21.6 mg, 0.073 mmol), iodine (45.6 mg, 0.J46 mmol) and silver sulfate (37 mg, 0.J46 mmol) in MeOH (1.5 mL) was stirred at room temperature for 2 hr. The reaction was filtered through Celite and the filtrate was concentrated under vacuum. The residue was redissolved in ether (25 ml) and washed with H20 (25 ml) The aqueous layer was extracted with ether (3 x 25 ml) and the combined extracts were washed with brine (25 ml), dried (MgSO), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient of 0-10% EtOAc / hexanes) to give [4- (2-fluoro-5-iodo-4-methox? phen? l) p? pepd? n-1-yl-acetate ethyl as a yellow oil LC-MS = 421 8 (M + 1) + 1 H NMR (CDCb, 500 MHz) d 7 61 (d, J = 8 3 Hz, 1 H), 6 45 (d, J = 11 9 Hz, 1 H), 4 21 (q, J = 7 1 Hz, 2 H), 3 84 (s, 3 H), 3 26 (s, 2 H), 3 05 (d, J = 11 2 Hz , 2 H), 2 80 (tt, J = 12 0, 3 9 Hz, 1 H), 2 33 (t, J = 10 6 Hz, 2 H), 1 87 (qd, J = 12 3, 3 2 Hz, 2 H), 1 78 (d, J = 12 1 Hz, 2 H), 1 29 (t, J = 7 1 Hz, 3 H) INTERMEDIARY 19 4- (2-fluoro-5-iodo-4-methox? Phen? L) p? Per? D? Na Step A 4- (2-Fluoro-4-methox? Phen? L) p? Pepd? Na-1-carboxy-tert-butyl A mixture of 4- (2-fluoro-4-methox? Phen? L) p? per? d? na (200 mg, 0.957 mmol) and N, Nd? soprop? let? lam? na (183 μl, 1053 mmol) was treated with di-butyl dicarbonate (230 mg, 1053 mmol). ) as described before to give 4- (2-fluoro-4-methox? phen? l) p? per? d? na-1-carboxy tert -butyl as a colorless oil LC-MS = 254 0 (M + 1-100 +44) + 1 H NMR (CDCl 3, 500 MHz) d 7 07 (t, J = 8 7 Hz, 1 H), 6 65 (dd, J = 8 5, 2 3 Hz, 1 H), 6 59 (dd , J = 12 3, 2 3 Hz, 1 H), 4 23 (br s, 2 H), 3 78 (s, 3 H), 2 91 (tt, J = 12 2, 3 2 Hz, 1 H) , 2 84-2 76 (m, 2 H), 1 79-1 75 (m, 2 H), 1 65-1 56 (m, 2 H), 1 48 (s, 9 H) Step B 4- (2-Fluoro-5-iodo-4-methox? Phen? L) p? Per? D? Na and 4- (2-fluoro-5-iodo-4-methox? Phen? L) p? tert-butyl per-d-na-1-carboxylate A stirred mixture of 4- (2-fluoro-4-methox? phen? l) p? pepd? na-1-carboxylic acid fer-butyl ester (step A) , 255 mg, 0 825 mmol) in MeOH (15 ml) was treated with iodine (345 mg, 1 107 mmol) and silver sulfate (281 mg, 1 107 mmol). The reaction was stirred at room temperature for 2 hr. it was filtered through Cehte and the filtrate was concentrated in vacuo. The residue was redissolved in ether (50 ml) and washed with H20 (50 ml). The aqueous layer was extracted with ether (3 x 50 ml) and the combined extracts were filtered. washed with brine (50 ml), dried (MgSO 4), filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient of 0-10% EtOAc / hexanes) to give 4- (2 -fluoro-5-iodo-4-methoxyphenol) p? pepd? na-1-carboxy-tert-butyl as a colorless glass The aqueous layer was then re-extracted with EtOAc (3 x 100 ml) and the combined extracts were dried (MgSO 4), filtered and the solvent was stirred under reduced pressure until a precipitate formed. This solid was collected by filtration and dried in a vacuum oven to give 4- (2-fluoro-5-iodo-4-methoxyphenyl) piperidine as an off-white solid. 4- (2-Fluoro-5-iodo-4-methoxyphenyl) piperidine-1-tert-butylcarboxylate: LC-MS = 379.7 (M + 1-100 + 44) +. 1 H NMR (CDCb, 500 MHz) d 7.54 (d, J = 8.3 Hz, 1 H), 6.55 (d, J = 12.2 Hz, 1 H), 4.23 (br s, 2 H), 3.85 (s, 3 H) ), 2.91 (tt, J = 12.3, 3.5 Hz, 1 H), 2.79 (t, J = 12.1 Hz, 2 H), 1.78-1.74 (m, 2 H), 1.59 (qd, J = 12.6, 4.1 Hz , 2 H), 1.48 (s, 9 H). 4- (2-fluoro-5-iodo-4-methoxyphenyl) piperidine: LCMS = 335.7 (M + 1) +. 1 H NMR (CDCb, 500 MHz) d 9.62 (br s, 1 H), 7.59 (d, J = 8.3 Hz, 1 H), 6.56 (d, J = 12.2 Hz, 1 H), 3.85 (s, 3 H) ), 3.64 (d, J = 12.1 Hz, 2 H), 3.06-3.97 (m, 3 H), 2.21-2.12 (m, 2 H), 2.05-2.00 (m, 2 H).

INTERMEDIARY 20 (4S, 5) -5-f3,5-Bis (trifluoromethyl) phenyl-3-f2- (2-bromobutanoyl) -5- (trifluoromethyl) benzyl-V-methyl-1,3-oxazolidin-2-one Step A: 2 - (((4S.5R) -5-f3.5-bis (trifluoromethylphenin-4-methyl-2-oxo-1Methyl 3-oxazolidin-3-yl) methyl) -4- (trifluoromethyl) benzoate Palladium acetate (11) (0J 09 g, 0.486 mmol), DPPF (0.269 g, 0.486 mmol), K2C03 (2.013 g, 14.57 mmoles) and Et 3 N (0.677 mL, 4.86 mmol) were added to a solution of (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl) -3- [2-iodo-5- (trifluoromethyl) benzyl] ] -4-methyl-1,3-oxazolidin-2-one (2.9 g, 4.86 mmol) in MeCN (30 mL) and MeOH (10 mL). The reaction mixture was purged with N2, the flask was capped and a CO balloon was fixed to it. After bubbling CO gas into the solution through a needle fixed to the balloon for 5 min, the mixture was heated under a balloon from CO to 70X during the night. The mixture was diluted with EtOAc (300 ml), filtered through Celite, then washed with water (3 x 50 ml), brine (1 x), dried (Na 2 SO 4), filtered and the solvent evaporated under empty. The residue was purified by flash chromatography on silica gel to give 2- ( { (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-2-oxo-1, 3 methyl-oxazolidin-3-yl.} methyl) -4- (trifluoromethyl) -benzoate. CL-EM cale. = 530.1; found = 529.9 (M + 1) +. 1 H NMR (500 MHz, CDC b) d 8.09 (d, J = 8.1 Hz, 1 H); 7.92 (s, 1 H); 7.82 (s, 2 H); 7.79 (s, 1 H); 7.69 (d, j = 8.1 Hz, 1 H); 5.75 (d, j = 7.8 Hz, 1 H); 5.10 (d, j = 16.2 Hz, 1 H); 4.81 (d, j = 16.2 Hz, 1 H); 4.19-4.1 1 (m, 1 H); 3. 99 (s, 3 H); 0.81 (d, J = 6.5 Hz, 3 H).

Step B: (4S.5?) - 5- [3,5-Bis (trifluoromethyl) phenin-3-y2- (hydroxymethyl) -5- (trifluoromethyl) bencip-4-methyl-1,3-oxazolidin-2- One to a solution of 2- ( { (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-2-oxo-1,3-oxazolidin-3-yl.} methyl) -4- (trifluoromethyl) benzoate (1.55 g, 2.93 mmol) in THF (65 ml) at OX under N2, 1 N Super hydride in THF (5.86 ml, 5.86 mmol) was added dropwise. The reaction was stirred at OX for 1 hr. More Super hydride was added to make the reaction complete. The reaction was carefully quenched with water and the aqueous layer was extracted with EtOAc (3 x). The combined organic layers were washed with brine, dried (Na2SO), filtered and the solvent was evaporated under vacuum. The residue was purified by flash chromatography on silica gel to give (4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl] -3- [2- (hydroxymethyl) -5- (trifluoromethyl) benzyl] -4-methyl-1,3-oxazolidin-2-one. CL-EM cale. = 502.1; found = 502.0 (M + 1) +. H NMR (500 MHz, CDC b) d 7.91 (s, 1 H); 7.78 (s, 2 H); 7.65 (t, J = 9.5 Hz, 2 H); 7.55 (s, 1 H); 5.72 (d, J = 8.1 Hz, 1 H); 5.09 (d, J = 15.5 Hz, 1 H); 4.86 (d, J = 3.7 Hz, 2 H); 4.29 (d, J = 15.5 Hz, 1 H); 4.06-4.00 (m, 1 H); 2.59 (s, 1 H); 0.82 (d, J = 6.6 Hz, 3 H).

Step C: 2J ((4S, 5R) -5J3,5-Bis (trifluoromethyl) phenyl-1,4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4- (trifluoromethyl) benzaldehyde A solution of (4S, 5ft) -5- [3,5-bis (trifluoromethyl) phenyl] -3- [2- (hydroxymethyl) -5- (trifluoromethyl) benzyl] -4-methyl-1,3-oxazolidin-2 -one (510 mg, 1017 mmol) in CH2CI2 (20 ml) at OX under N2, Dess-Martin periodinane (647 mg, 1526 mmol) was added in portions. The reaction was stirred at OX for 1 hr. The reaction was carefully quenched with saturated NaHC 3 3 and the aqueous layer was extracted with CH 2 Cl 2. The combined organic layers were washed with brine, dried (Na2SO4), filtered and the solvent was evaporated under vacuum. The residue was purified by flash chromatography on silica gel to give 2- ( { (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-2-oxo-1, 3 -oxazolidin-3-yl.} methyl) -4- (trifluoromethyl) benzaldehyde as a white solid. CL-EM cale. = 500.1; found = 500.0 (M + 1) +. 1 H NMR (500 MHz, CDC b) d 10.29 (s, 1 H); 8.04 (d, J = 7.8 Hz, 1 H); 7.93 (s, 1 H); 7.85 (d, J = 8.0 Hz, 1 H); 7.83 (s, 1 H); 7.82 (s, 2 H); 5.77 (d, J = 7.9 Hz, 1 H); 5.11 (d, J = 16.5 Hz, 1 H); 4.94 (d, J = 16.5 Hz, 1 H); 4.23-4.18 (m, 1 H); 0.84 (d, J = 6.5 Hz, 3 H).

Step D: (4S.5R) -5- [3,5-Bis (trifluoromethyl) phenyl-3- [2-butyryl-5- (trifluoromethyl) benzyl-1-4-methyl-1,3-oxazolidin-2- One to a solution of 2- ( { (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-2-oxo-1,3-oxazolidin-3-yl}. methyl) -4- (trifluoromethyl) benzaldehyde (654 mg, 1310 mmol) in toluene (25 ml) at -78X under N2, was added dropwise 2M n-Propylmagnesium chloride (0 655 mL, 1110 mmol) The reaction was stirred at -78X for 4 hr. The reaction was carefully quenched with water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and the solvent was evaporated under vacuum to give a mixture of products (4S, 5R) -5- [3,5-b? s (tr? fluoromet? l) phen? l] -3- [2-but? R? L-5- (tr? Fluoromet? L) benc? L] -4-met? L-1, 3-oxazol? D? N-2-one and by-product (4S, 5R) - 5- [3,5-b? S (tr? Fluoromet? L) phen? L] -3- [2- (hydro? Met? L) -5- (tr? Fluoromet? L) benc? L] -4-methanol -1,3-oxazole d-n-2-one with the ratio of 3 to 1 The mixture obtained above was dissolved in CH 2 Cl (50 ml) at OX under N 2 and periodominium was added in portions. Dess-Martin (834 mg, 1965 mmol) The reaction was stirred at OX for 1 hr. The reaction was carefully quenched with saturated NaHCO3 and extracted with CH2Cl2 (3x). The combined organic layers were washed with brine, dried (Na2S0 ), filtered and the solvent evaporated under vacuum The residue was purified by flash chromatography on silica gel to give (4S, 5f?) - 5- [3,5-b? s (tr? fluoromet? l) phen? I] -3- [2 -but? r? l-5- (tr? fluoromet? l) benc? l] -4-met? l-1, 3-oxazol? d? n-2-ona LC-MS cale = 542 1, found = 542 0 (M + 1) + 1 H NMR (500 MHz, CDCl 3) d 7 91 (s, 1 H), 7 81 (s, 2 H), 7 79 (d, J = 8 2 Hz, 2 H), 7 69 (d, J = 8 0 Hz, 1 H), 5 74 (d, J = 7 8 Hz, 1 H), 4 91 (d, J = 16 1 Hz, 1 H), 4 57 (d, J = 16 1 Hz, 1 H), 4 24-4 19 (m, 1 H), 3 01-2 89 (m, 2 H), 1 82-1 72 (m, 2 H), 1 03 (t , J = 7 4 Hz, 3 H), 0 80 (d, J = 6 5 Hz, 3 H) Step E: (4S, 5f?) - 5J3,5-Bis (trif) uoromethyl) phenin-3J2J2-bromobutanoyl) -5- (trifluoromethyl) benzyl-1-4-methyl-1,3-oxazolidin-2-one To one solution of (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -3- [2-butyryl-5- (trifluoromethyl) benzyl] -4-methyl-1,3-oxazolidin-2-one ( 300 mg, 0.554 mmole) in CHCb (3 ml) at OX under N2, a solution of bromine (0.030 ml, 0.582 mmole) in CHCl3 (2 ml) was added dropwise. The reaction was stirred at 0X for 1 hr. The reaction mixture was evaporated under vacuum. The residue was purified by flash chromatography on silica gel to give (4S, 5?) - 5- [3,5-bis (trifluoromethyl) phenyl] -3- [2- (2-bromobutanoyl) -5- (trifluoromethyl) benzyl] -4-methyl-1,3-oxazolidin-2-one as a white solid. CL-EM cale. = 622.0; found = 621.7 (M + 1) +. 1 H NMR (500 MHz, CDCl 3, 1: 1 mixture of atropoisomers) d 7.91 (s, 1 H); 7.85 (d, J = 5.1 Hz, 1 H); 7.83-7.77 (m, 2.5 H); 7.74-7.69 (m, 1.5 H); 5.79 (d, J = 7.8 Hz, 0.5 H); 5.74 (d, J = 7.9 Hz, 0.5 H); 5.06-4.92 (m, 2 H); 4.57 (d, J = 16.4 Hz, 0.5 H); 4.47 (d, J = 16.0 Hz, 0.5 H); 4.24-4.16 (m, 1 H); 2.35-2.25 (m, 1 H); 2.19-2.09 (m, 1 H); 1.18-1.16 (m, 3 H); 0.80 (d, J = 6.6 Hz, 1.5 H); 0.78 (d, J = 6.6 Hz, 1.5 H).

INTERMEDIARY 21 4- (Methyl aminocarbonothioyl) -3-methylbenzoate Step A: Methyl 4-cyano-3-methylbenzoate To a microwave tube, methyl 4-bromo-3-methylbenzoate (100 mg, 0.437 mmol), Pd (Ph3P) 4 (25.2 mg, 0.022 mmol) was added, Zn (CN) 2 (51.3 mg, 0.437 mmol) and DMF (2 ml). The mixture was flushed with N2 and seatightly. The reaction mixture was exposed to microwave irradiation at 150X for 5 min. The mixture was diluted with EtOAc and washed with water. The organic layer was dried (Na 2 SO 4), filtered and the solvent evaporated under vacuum. The residue was purified by flash chromatography on silica gel to give methyl 4-cyano-3-methylbenzoate. CL-EM cale. = 176.1; found = 176.1 (M + 1) +. 1 H NMR (500 MHz, CDCl 3) d 8.02 (s, 1 H); 7.95 (d, J = 8.1 Hz, 1 H); 7.71 (d, J = 8.0 Hz, 1 H); 7.29 (s, 1 H); 3.98 (s, 3 H); 2.64 (s, 3 H).

Step B: Methyl 4- (aminocarbonothioyl) -3-methylbenzoate To a solution of methyl 4-cyano-3-methylbenzoate (36 mg, 0.205 mmol) in 1,4-dioxane (0.5 ml) and water (0.500 ml) , sulfur was added sodium acid (0.019 ml, 0.616 mmol) and triethylamine hydrochloride (170 mg, 1.233 mmol). The reaction mixture was heated at 55 ° C overnight. The reaction was allowed to cool and water was added. The mixture was extracted with EtOAc. The combined organic layers were dried (Na 2 SO), filtered and the solvent was evaporated under vacuum to give the product as a yellow solid. CL-EM cale. = 210.1; found = 210.2 (M + 1) +. 1 H NMR (500 MHz, CDC b) 7.86 (s, 1 H); 7.84 (d, J = 8.1 Hz, 1 H); 7.42 (d, J = 7.9 Hz, 1 H); 7.16 (s, 2 H); 3.93 (s, 3 H); 2.51 (s, 3 H).

INTERMEDIARY 22 2'.4'-difluoro-2-methyl-5 '- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) biphenyl-4-carboxylic acid methyl ester Step A: Methyl 5'-amino-2 ', 4'-difluoro-2-methylbiphenyl-4-carboxylate 5-bromo-2,4-difluoroaniline (500 mg, 2.40 mmol), 3-methyl-4- (Methyl 4,4,5,5-tetramethyl-1,2-dioxaborolan-2-yl) benzoate (intermediate 16, 797 mg, 2.88 mmol), sodium carbonate (2.40 ml, ac., 2M, 2.88 mmoles), adduct of 1,1 '-bis (diphenylphosphino) ferrocene-palladium dichloride-dichloromethane (196 mg, 0.24 mmol) and ethanol (15 ml) were heated in an 80X oil bath for 3 hours then allowed to cool at room temperature overnight. The volatiles were removed under reduced pressure. The residue from the retentate was treated with DCM / brine / Na2SO4 / filtration / concentration to give a dark oil. The resulting oil was purified by flash chromatography (Si02, Biotage 40 + M cartridge). The column was eluted by a gradient mixture from 0% to 40% EtOAc / hexanes. The related fractions were combined and concentrated in vacuo to give the title compound. CL-EM (ESI) cale. = 277.09; found = 278.03 (M + 1) +.

Step B: methyl 2 ', 4'-difluoro-5'-iodo-2-methylbiphenyl-4-carboxylate methyl 5'-Amino-2', 4'-difluoro-2-methylbiphenyl-4-carboxylate (step A, 500 mg, 1.80 mmol), 3-methylbutyl nitrite (317 mg, 2.71 mmol), iodine (549 mg, 2.16 mmol) and chloroform (15 ml) were refluxed in an oil bath for 5 hours, then it was allowed to cool to room temperature overnight. Crude product from the reaction was purified by flash chromatography (Si02, Biotage 40 + M cartridge) was eluted with a gradient mixture of EtOAc / hexanes. The related fractions were combined and concentrated in vacuo to give the title compound. CL-EM (ESI) cale. = 387.98; found = 388.92 (M + 1) +.

Step C: 2'.4'-Difluoro-2-methyl-5 '- (4,4,5,5-tetramethyl-1,2-dioxaborolan-2-yl) biphenyl-4-carboxylic acid methyl 2', 4'-difluoro- Methyl 5'-iodo-2-methylbiphenyl-4-carboxylate (step B, 1551 g, 4.55 mmole), bis (pinacolato) diboron (1385 g, 5.46 mmole), potassium acetate (0.892 g, 9.09 mmole), adduct of IJ '-bis (diphenylphosphino) ferrocene-palladium dichloride-dichloromethane (0.743 g, 0.909 mmol) and 1,4-dioxane (10 ml) were placed in a sealed tube and heated in a microwave oven at 140X for 30 minutes. min. Plot of LC-MS from the reaction aliquot indicated the formation of the de-brominated by-product and the desired borate / boronic acid. Crude product from the reaction was diluted with ethyl acetate and filtered. The filtrate was treated with brine, extracted with ethyl acetate, dried over Na 2 SO 4, filtered and evaporated to give a dark mixture as a crude mixture of the title compound, to be used as such for the next step.

CL-EM (ESI) cale. = 388.17; found = 389.11 (M + 1) +.

INTERMEDIARY 23 The triaryl tosylate shown above is made by the following multi-step procedure: Biaryldichlorobenzyl alcohol 1 A 100 I flask equipped with overhead stirrer, thermocouple, nitrogen inlet, dropping funnel and a steam vessel was charged with 30 I of DMF, 8 I of GMP water, 5000 g of benzyl alcohol starting material and 4458 g of potassium acetate. The mixture was degassed by splashing with nitrogen and then placed under nitrogen. PdCI2 (DTBPF) (64.8 g) was charged to the reaction mixture, and the batch was heated to 40-45 ° C. (DTBPF is 1, 1 '-bis (di-re-butylphosphino) ferrocene).

A 20 I flask equipped with overhead agitator and nitrogen inlet was charged with 10 I of DMF and 41 14 g of dichlorophenylboronic acid. The solution was degassed by splashing with nitrogen and placed under nitrogen. This solution was slowly transferred to the reaction using a dropping funnel for about 1 hr. The reaction was monitored by CLAR and completed in apox. 2 hr. After the reaction was complete, toluene (20 I) and 0.2 M acetic acid (20 I) were added to the reaction mixture. The two phase mixture was transferred to a 170 I cylinder. Toluene (20 I) and 0.2 M acetic acid (20 I) were added to the reaction flask, and this mixture was also transferred to the 170 I cylinder. separated, and the organic layer (upper) was washed with 10% by weight of aqueous sodium chloride (2 x 40 I) and then with GMP water (40 I). The organic phase was then filtered through a pad of silica gel (3 kg), and the silica gel was rinsed with additional toluene (2 x 20 I) until all the product was recovered. The toluene solution was batch-concentrated to a volume of 20 I and then flushed with 2 x 50 I portions of heptane. The volume of the batch was adjusted to 60 L, and the batch was heated to completely dissolve any precipitated product. The batch was seeded with crystals from previous batches and allowed to cool to room temperature overnight. The mixture was cooled to 0 ° C and filtered. The wet cake was rinsed with cold heptane (0 ° C, 15 I) and dried under nitrogen and vacuum in the funnel, yielding the desired biarylbenzyl alcohol.

Biarylbenzyl benzoate 2 A 100 I flask equipped with overhead agitator, thermocouple, nitrogen inlet, dropping funnel and a steam vessel was charged with 51 I of toluene, 4869 ml of triethylamine, 5100 g of biarylbenzyl alcohol 1 from the previous step, and 102 g of 4-dimethylaminopyridine (DMAP). The solution was cooled to 0 ° C. Benzoyl chloride (2120 ml) was slowly added to the batch from a dropping funnel for approx. 1 hr. The addition is exothermic. After the addition was complete, the batch was heated to room temperature. A thick white suspension formed. The reaction was monitored by HPLC and completed approximately 2 hours after warming to room temperature. Aqueous HCl (1.0 M, 20 I) was added to the reaction flask, and the batch was transferred to a 100 I extractor. The lower aqueous layer was separated, and the batch was washed sequentially with 2 x 12 I of HCl 1.0 M and then with 2 x 12 I of water GMP. The toluene solution was dried over anhydrous sodium sulfate and then filtered through a concreted glass funnel. The toluene solution was concentrated in batches at a volume of 10 L, and then 51 I of heptane was added while maintaining the temperature at 40-45 ° C. The batch was allowed to cool to room temperature overnight. The lot then it was cooled to -5 ° C and filtered. The wet cake was rinsed with cold heptane (-5 ° C, 16 I) and dried in the funnel under nitrogen and then under vacuum, giving biarylbenzyl benzoate 2.

Boronic acid 3 A 3 liter round-bottomed flask equipped with a mechanical stirrer, thermocouple, and addition funnel was charged with 100 g of solid 4-iodo-3-methylbenzoic acid methyl ester and 100 μl of dry THF. The mixture was cooled to -25 ° C, and 218 ml of i-PrMgCI (2M in THF) were added dropwise during 25 min while the internal temperature was maintained at < -15 ° C. The lot was maintained at < -10 ° C for 1 hr after the addition of the Grignard reagent. Analysis of a hydrolyzed aliquot showed more than 97% deiodination. Then, the reaction was cooled to about -20 ° C and quenched with trimethyl borate (77 g). The reaction of trimethyl borate is exothermic. The temperature was increased to about -4 ° C during the addition of the trimethyl borate for a time of about 3 min. The resulting solution was aged for 1 hr at < 0 ° C. The batch was then cooled to about -20 ° C and further quenched with 1.0 I of H3P04 1 M. This extinction was also exothermic, raising the temperature to 3 ° C at the end of the extinction. The batch was aged at room temperature overnight. The THF was then removed by distillation at < 45 ° C under reduced pressure. The product suspension was allowed to cool to room temperature, and then filtered. The cake was washed with water (3 X 500 ml) and toluene (2 X 250 ml) and then dried under vacuum with nitrogen blanket for 18 hr to give the boronic acid 3 as an off-white crystalline solid.

Triaryl benzoate 4 The catalyst was first made in a dry box filled with nitrogen by charging bis (acetonitrile) palladium dichloride (107 mg) and 1,2-bis (di-tert-butylphosphinomethyl) benzene (292 mg) in a vessel equipped with a bar agitation. Then acetonitrile (35 ml) was charged. The resulting suspension was stirred at room temperature for ~ 2 hr before being used. A 100 ml Schlenk vessel equipped with a stir bar, nitrogen / vacuum inlet, and septum was charged with boronic acid 3 (6.79 g, 35.3 mmolese) and biaryl 2 benzoate (9.45 g). The flask was purged with nitrogen and transferred to a dry box. The catalyst suspension which was done as described in the previous paragraph after the Schlenk container was loaded in the dry box. The vessel in which the catalyst suspension was made was rinsed with acetonitrile (5 ml); the rinse was also transferred into the Schlenk container. Aqueous K3P04 (15.0 g of 50% w / w K3P04, 7.5 g of K3P04) was charged to the slurry in the Schlenk container in the dry box at room temperature. The Schlenk container was sealed, it was removed from the dry box, and fixed to a nitrogen sparger. The resulting biphasic mixture was stirred and heated for 22 hr in an oil bath which was maintained at 55X, at which time the amount of remaining unreacted biaryl benzoate was 1.7% relative to the triaryl benzoate product by analysis of CLAR. Acetonitrile (40 ml) was added at ~ 30X, and the lower aqueous layer was separated. The aqueous layer was re-extracted with acetonitrile (3 ml), and this extract was combined with the main organic layer. The reaction mixture was concentrated at -40% of the original volume while maintaining an external temperature and pressure of 40-42X and 190-200 mbar. The batch was cooled to ~30X, and the organic layer was filtered through a glass funnel concretely directly into the crystallization vessel. The reaction vessel was rinsed with CH3CN (17 ml), and the rinses were filtered in the reaction vessel. Once the batch cooled, it was observed that triaryl benzoate 4 began to crystallize rapidly. The rapid crystallization mixture, which was in a 100 ml 3-necked round bottom flask equipped with a mechanical stirrer, Nitrogen inlet / sparger, and addition funnel, was diluted with 43 ml of additional CH3CN, giving a ~6 ml test of CH3CN / g of triaryl benzoate product. Water (25 ml) was added over 60 min. At room temperature to the slurry to yield -27 vol.% Of water (relative to CH.sub.3 CN). The suspension was stirred at room temperature until the concentration of triaryl benzoate in the supernatant reached about 5.5 g / L by HPLC analysis (aging overnight). The batch was cooled in an ice bath to ~2X and stirred for about 2 hours, at which time the concentration of triaryl benzoate 4 in the supernatant reached -1.6 g / L. The suspension was filtered in a concreted funnel and the cake was washed with 46 ml of 75:25 v / v cold CH3CN: water, which was used as a displacement wash. The triaryl benzoate cake was dried under vacuum and a nitrogen box at room temperature until a constant weight was obtained.

Triaryl alcohol (5) 2 kg of solid triaryl benzoate (4) and dry methanol (20 l) were added. A sprinkled subsurface of the suspension with Nitrogen with stirring was carried out for 5 min. Sodium methoxide (30 wt% solution in MeOH, 210 ml) was added to the suspension, and the reaction mixture was aged to T.A. until it was < 0J5% starting triaryl benzoate (approximately 3-4 hr). The reaction mixture became homogeneous about 1 hr before the end of the reaction. 5M HCl (250 ml) was added, followed by toluene (10 l) and water (15 l). The phases were separated, and the organic layer was washed once with water (10 I). The batch was then concentrated to remove water and residual methanol. The triaryl alcohol 5 was used in the next step without further purification.

Triaryl tosylate 6 A 75 I round bottom flask equipped with overhead stirrer, nitrogen inlet, thermocouple and dropping funnel was charged with 1490 g of triaryl alcohol 5 in toluene (22.2 I). TsCI (1232 g) was added to the solution and stirred, followed by a solution of triethylamine (1197 ml), DABCO (19.3 g) and toluene (2.5 I) by means of an addition funnel over a period of 3 minutes. The internal temperature rose to 32X. The reaction was monitored by CLAR, reaching a conversion of > 99.7% in 2 hr.

Once the starting triaryl alcohol was consumed, the solution was filtered through a pad of silica gel (1700 g, Merck Grade 9385), whereby the cloudy suspension became a clear solution. The filter cake was washed with 5.0 I of toluene, and the combined washings were added to a 100 I reactor / extractor. The stirred solution was mixed with 6.0 I of 10% w / w NaHS04 (900 g in 9.0 I water GMP) and stirred vigorously. The phases were divided, and the aqueous phase was cut (pH = 1). The organic layer (upper) was washed with GMP water (2 x 9.0 I), and the aqueous layers were separated. The pH values of the 2 washes were 1 and 4, respectively. The organic layer was concentrated to an oil and dissolved in 10-14 volumes of 3-7% toluene in heptane. The organic compounds were heated until the solution became clear and homogeneous (between 60-80X, depending on the concentration of toluene), and then cooled slowly to t.a. Seeding of the solution (with seeds obtained from previous batches) was conducted at 50X, and crystal growth was observed immediately. After cooling to t.a. during the night, the mother liquor was decanted, and the crystals were washed with 10.0 I of 10% toluene / heptane followed by 6.0 I of heptane. The bright white solid was dried for 72 hr under vacuum in a nitrogen box, giving tosylate 6.

EXAMPLE 1 (4S.5?) - 5-f3,5-bis (tr? Fluoromet? L) phen? Ll-3 - ([6'-methox? -4- (tr? Fluoromet? D-1.1 '3M "-terfen ? l-2-? llmet? l) -4-met? l-1, 3-oxazol? d? n-2-one Step A (4S, 5R) -5-f3,5-b? S (tr? Fluoromet? L) phen? Ll-3Jf5'-bromo-2'-methox? -4- (tr? Fluoromet? L) b? Phen? L- 2-? Pmet? L) -4-met? L-1, 3-oxazol? D? N-2-one A mixture of (4S, 5f?) - 5- [3,5-b? S (tr? fluoromet? l) phen? l] -3- [2-iodo-5- (tpfluoromethyl) benc? l] -4-meth? -1,3-oxazole? d? n-2-one (6 80 g, 11 39 mmol), 2-methox? -5-bromo-phenolboron? Co acid (3 00 g, 1299 mmol), and sodium carbonate (2 65 g, 25.0 mmol) in 200 ml of a mixture 1 Water of 2% EtOH toluene was stirred at room temperature for 30 min. A catalytic amount of tetrak? S (tr? Phen? Lfosf? N) palladium (0 66 g, 5 mol%) was added. The mixture was stirred under reflux for 24 hr CCD (CH2CI2 hexane / 1 1) showed no starting material The solvents were removed Water (100 ml) was added The mixture was extracted with methylene chloride (3x100 ml) The combined methylene chloride layers were washed with brine and dried over sodium sulfate. The title compound was obtained after column chromatography using CH 2 Cl 2 hexane / 6 4 as the eluent 1 H NMR (CDCl 3, 500 MHz) d mixture 1 1 of atropoisomers 7 88 (s, 1 H), 7 74 (s, 1 H), 7 72 (s, 1 H), 7 67 (t, J = 7 Hz , 1 H), 7 62 (s, 1 H), 7 54 (m, 1 H), 7 37-7 42 (m, 1 H), 7 31-7 34 (m, 1 H), 6 90- 6 93 (m, 1 H), 5 63 (d, J = 8 Hz, 0 5H), 5 25 (d, J = 8 Hz, 0 5H), 4 98 (d, J = 15 5 Hz, 0 5H ), 4 88 (d, J = 16 Hz, 0 5H), 4 12 (d, J = 15 5 Hz, 0 5H), 3 88 (d, J = 16 5 Hz, 0 5H), 3 84 (s) , 3H), 3 81 (s, 3H), 3 73 (m, 1 H), 0 59 (d, J = 6 5 Hz, 1 5H), 0 45 (d, J = 6 5 Hz, 1 5H) Step B (4S.5ffl-5- [3,5-bis (trifluoromethyl) phenn-3- (f6'-methoxy-4- (trifluoromethyl-1, r: 3'J "-terphenyl-2-inmetl) -4-methyl-1, 3-oxazolidin-2-one A mixture of the title compound from step A (0.05 g, 0.076 mmol), phenylboronic acid (0.014 g, 0J 1 mmol), tetrakis (triphenylphosphine) palladium (5%) molar) and sodium carbonate (0.018 g, 0J7 mmole) in 7 ml of water / EtOH / toluene (1: 2: 4) was heated to reflux for 4 hr.CCD (CH2Cl2: hexane / 1: 1) showed that the The solvent was removed and water (30 ml) was added The organic compound was extracted with methylene chloride (3x 40 ml) The combined methylene chloride layers were washed with brine and dried over sodium sulfate. The title compound was obtained after preparative CCD using CH2Cl2: hexane / 6: 4 as the eluent.1H NMR (CDCl3, 500 MHz): d 1: 1 mixture of artopoisomers 7.86 (s, 0.5H), 7.84 ( s, 0.5H), 7.26-7.71 (m, 10H), 7J0 (dd, J = 8.5, 3Hz, 1 H), 6.96 (t, J = 7.5 Hz, 1 H), 6.86 (d, J = 9 Hz, 1 H), 5.57 (d, J = 8 Hz, 0.5H), 5.10 (d, J = 7.5 Hz, 0.5H), 5.05 (d, J = 16 Hz, 0.5H), 4.92 (d , J = 16 Hz, 0.5H), 4J9 (d, J = 15.5 Hz, 0.5H), 3.99 (d, J = 16 Hz, 0.5H), 3.90 (s, 1.5H), 3.88 (s, 1.5H ), 3.72 (m, 1 H), 0.564 (d, J = 6.5Hz, 1.5H), 0.40 (d, J = 6.5 Hz, 1.5H). LC-MS (M + 1): 654.3. The following compounds (Table 1) were prepared using the same procedure as in Example 1.

TABLE 1 EXAMPLE 21 fifteen Step A (4S.5R) -5- [3,5-bis (trifluoromethinophen-3- (2'-methoxy-5 '- (4,4,5,5-tetramethyl-1,2,3-dioxaborolan-2-yl) -4- (trifluoromethyl) ) biphenyl-2-inmethyl) -4-methyl-1,3-oxazolidin-2-one (4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl] -3- { [5, -bromo-2'-methoxy-4- (trifluoromethyl) biphenyl-2-yl] methyl.} -4-methyl-1,3-oxazolidin-2-one (500 mg, 0.762 mmol), bis (pinacolato) diboro (388 mg, 1.53 mmol), adduct of 1,1 '-bis (diphenylphosphino) ferrocene-palladium dichloride-dichloromethane (150 mg, 0J 84 mmol), potassium acetate (150 mg, 1.53 mmol) and 1.4 dioxane (5 ml) were sealed in a microwave vessel.The reaction mixture was irradiated by microwave at 140X for 40 minutes, additional diborum bis (pinacolato) (388 mg, 1.53 mmol) was added followed by microwave irradiation at 140X for 20 minutes, then additional potassium acetate (150 mg, 1.53 mmol) was added followed by microwave irradiation at 140X for 20 minutes, the crude of the reaction was treated with water.

The resulting product was extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated to give a dark solid. The solid was purified by reverse phase preparative HPLC (column: Kromasil 100-5C18, 100 x 21.1 mm) eluting with a gradient mixture of MeCN / H20 to give (4S, 5R) -5- [3,5-bis ( trifluoromethyl) phenyl] -3-. { [2'-methoxy-5 '- (4,4,5,5Jetramethyl-1, 3,2-dioxaborolan-2-yl) -4- (trifluoromethyl) biphenyl-2-yl] methyl} -4-methyl-1,3-oxazolidin-2-one as a dark oil. CL-EM cale. = 703.22; found = 704.47 (M + 1) +.

Step B 2"- (((4S.5R) -5- [3,5-bis (trifluoromethyl) fenin-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4'-methoxy-2-methyl- 4"- (trifluoromethyl) -1 J ': 3'J" Jerphenyl-4-methyl carboxylate A mixture of (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -3-. [2'-methoxy-5 '- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -4- (trifluoromethyl) biphenyl-2- il] methyl} -4-methyl-1, 3-oxazolidin-2-one (60 mg, 0.085 mmol), methyl 4-bromo-3-methylbenzoate (29 mg, 0J28 mmol), 1,1 '-bis (diphenylphosphino) adduct ferrocene-palladium dichloride-dichloromethane (28 mg, 30%), aqueous potassium hydroxide (57 μL, 3M, 0J71 mmol) and 1,4-dioxane (1 mL) was placed in a sealed tube and subjected to irradiation by microwave at 140X for 15 minutes. The crude reaction was purified by preparative CCD on SiO2 (eluted with 30% EtOAc in hexanes) to give 2"- (. {(4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl]] 4-methyl-2-oxo-1,3-oxazolidin-3-yl.} Methyl) -4'-methoxy-2-methyl-4"- (trifluoromethyl) -1,1 ': 3'J" - methyl terphenyl-4-carboxylate as a solid foam LC-MS cale = 725.18; found = 726.49 (M + 1) +. The 1 H NMR signals are duplicated due to atropoisomerism. 1 H NMR (CDCl 3, 500 MHz) 7.94 (d, J = 8.5 Hz, 1 H), 7.88 - 7.83 (m, 2 H), 7.71 (s, 0.5 H), 7.69 (s, 0.5 H), 7.68 - 7.60 ( m, 2H), 7.45 - 7.39 (m, 2H), 7.38, 7.37 (d, J = 2 Hz, 1 H), 7.28 (d, J = 8 Hz, 0.5H), 7.24 (d, J = 8 Hz , 0.5H), 7.14 (d, J = 2 Hz, 1 H), 7.07 (t, J = 8 Hz, 1 H), 5.58 (d, J = 8.5 Hz, 0.5H), 5.28 (d, J = 8 Hz, 0.5H), 4.96 (d, J = 10 Hz, 0.5H), 4.93 (d, J = 9.5 Hz, 0.5H), 4.16 (d, J = 15.5 Hz, 0.5H), 3.96 (d, J = 16 Hz, 0.5H), 3.92 (s, 3H), 3.86 (s, 3H), 3.82 - 3.93 (m, 1 H), 2.37 (s, 1.5H), 2.31 (s, 1 .5H), 0.54 (d, J = 6.5 Hz, 1.5H), 0.42 (d, J = 6.5 Hz, 1.5H).

EXAMPLE 22 (4S, 5f?) - 5-f3.5-b1s (trifluoromethyl) phen-3 - ([6'-chloro-2"-methyl-4- (trifluoromethyl) -1 J ': 3 'J' Jerphenyl-2-ylmethyl) -4-methyl-1,3-oxazolidin-2-one Step A (4S.5f?) - 5- [3,5-bis (trifluoromethyl) phenyl-3-f [2'-chloro-5'-nitro-4- (trifluoromethyl) biphenyl-2-illmethyl) -4-methyl- 1,3-oxazolidin-2-one A mixture of (4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl] -3- [2-iodo-5- (trifluoromethyl) -benzyl] -4 -methyl-1,3-oxazolidin-2-one (1.0 g, 1.68 mmol), 2-chloro-5-nitrophenylboronic acid (0.67 g, 3.3 mmol), tetrakis (triphenylphosphine) palladium (97 mg, 5 mol%) and Sodium carbonate (0.39 g, 3.68 mmol) in 50 mL of water / EtOH / toluene (1: 2: 4) was heated to reflux for 4 hr. CCD (CH2Cl2: hexane / 1: 1) showed that the reaction was complete. The solvents were removed. Water (30 ml) was added. The organic compound was extracted with methylene chloride (3x 40 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after column chromatography using CH2Cl2: hexane / 6: 4 as the eluent. 1 H NMR (CDCl 3, 500 MHz): d 1: 1 mixture of rotamers 8.16-8.31 (m, 1 H), 8.21 (d, J = 2.5 Hz, 1 / 2H), 8J6 (d, J = 2.5 Hz, 1 / 2H), 7.90 (s, 1 H), 7.71 -7.78 (m, 5H), 7.42-7.46 (m, 1 H), 5.66 (d, J = 4.5 Hz, 1 / 2H), 5.64 (d, J = 4.5 Hz, 1 / 2H), 4.93 (d, J = 15.5 Hz, 1 / 2H), 4.79 (d, J = 16 Hz, 1 / 2H), 4.03 (d, J = 16Hz, 1 / 2H), 3.94 (m, 1 H), 3.91 (d, J = 15.5 Hz, 1 / 2H), 0.70 (d, J = 6.5 Hz, 1.5H), 0.64 (d, J = 6.5 Hz, 1.5H).

Step B (4S, 5ft) -5J3,5-bis (trifluoromethyl-3-phenyl-3J [2'-chloro-5'-vodo-4- (trifluoromethyl) biphenyl-2-methyl) -4-methyl-1,3-oxazolidin-2- One To a solution of the title compound from step A (1 J4 g, 1.82 mmol) in EtOH (20 ml) at room temperature was added SnCl2.H20 (5 eq). The solution was stirred at room temperature for 4 h. CCD (CH2Cl2: hexane / 1: 1) showed that the reaction was over. EtOAc (50 ml) was added. The mixture was washed with water (2x20 ml), brine, and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was diluted with chloroform (30 ml). N-pentyl nitrite (0.36 ml, 2.73 mmol) and iodine (0.55 g, 2 J8 mmol) were added. The mixture was stirred under reflux for 1 hr. The mixture was diluted with methylene chloride (30 ml). The purple solution was washed with saturated sodium thiosulfate solution, brine, and dried over sodium sulfate. The title compound was obtained after column chromatography using EtOAc hexane / 2 98 as the eluent H NMR (CDCb, 500 MHz) d a mixture of 1 1 of artopoisomers 7 90 (s, 1 H), 7 77 (s, 1 H), 7 70 -7 75 (m, 4H), 7 65 (d, J = 2 5 Hz, 1 / 2H), 7 61 (d, J = 2 5 Hz, 1 / 2H), 7 40 (m, 1 H), 7 28 (m, 1 H), 5 66 (d, J = 8 Hz, 1 / 2H), 5 64 (d, J = 8 Hz, 1 / 2H), 4 85 (d, J = 15 5 Hz, 1 / 2H), 4 82 (d, J = 14 Hz, 1 / 2H), 4 02 (d, J = 16 Hz, 1 / 2H), 3 96 (m, 1 / 2H), 3 95 (d, J = 15 5 Hz, 1 / 2H), 3 79 (m, 1 / 2H), 0 64 (d, J = 6 5 Hz, 1 5 H), 0 57 (d, J = 6 5 Hz, 1 5H ) Step C (4S.5f?) - 5- [3,5-b? S (tr? Fluoromet? L) phen? Ll-3JI6'-chloro-2"-met? L-4- (tr? Fluoromet? L ) -1 J '3'J "Jerfen? L-2-? Llmet? L) -4-met? L-1, 3-oxazol? D? N-2-one A mixture of the title compound of step B ( 0 064 g, 0 9 mmol), 2-met? Lfen? Lboron? Co acid (0 018 g, 0 14 mmol), tetrak? S (tr? Phen? Lfosf? N) paladin (10 mg, 5% molar) and sodium carbonate (0 048 g, 0 45 mmol) in 7 ml of water / EtOH / toluene (1 2 4) was heated at reflux for 2 hr CCD (CH 2 Cl 2 hexane / 8 2) showed that the reaction was over The solvents were removed Water (10 ml) was added The organic compound was extracted with methylene chloride (3x 20 ml) The combined methylene chloride layers were washed with brine, and dried over sodium sulfate The title compound was obtained after purification with preparative CCD using 18% EtOAc in hexane as the eluent H NMR (CDCl 3, 500 MHz) d 1 1 mixture of atropoisomers 7 89 (s, 1 H), 7.72 (m, 3H), 7.60 (d, J = 1.5 Hz, 0.5H), 7.67.59 (d, J = 1.5 Hz, 0.5H), 7.48 (m, 1 H), 7.38 (m, 1 H), 7.21-7.32 (m, 4H), 7J4 (d, J = 7.5 Hz, 0.5H), 7.10 (t, J = 7.5 Hz, 0.5H), 6.87 (t, J = 7.5 Hz, 0.5H), 6.80 (d, J = 7.5Hz, 0.5H), 5.62 (t, J = 8.0 Hz, 1 H), 5.00 (d, J = 15.5 Hz, 0.5H), 4.83 (d, J = 16 Hz, 0.5H), 4J2 (d, J = 16 Hz, 0.5H), 4.02 (d, J = 15.5 Hz, 0.5H), 3.95 (m, 0.5H), 3.87 (m, 0.5H), 2.33 (s, 1.5H), 2.33 (s, 1.5H), 0.61 (d, J = 6.5 Hz, 1.5H), 0.57 (d, J = 6.5 Hz, 1.5H). LC-MS (M +): 672.2.

EXAMPLE 23 The following compound was prepared using the procedures described above (LC / MS 730.4): This compound (Example 23) has also been made by the following procedure from intermediates 7 and 23: The chiral oxazolidinone (intermediate 7) (1 35 kg) and dry DMF (30 8 I) were added to a 100 I flask. After cooling to -15 to -20X, NaHMDS (1 96 I of 2M solution) was added and the mixture was aged 15-30 min. The tpapltosylate (intermediate 23.2 kg) in DMF was added to the sodium salt resulting from the oxazohdmone, and the mixture was allowed to warm from 0 to 5X After the tilapia tosylate was consumed, 2 44 I of 5M HCl were added, followed by 22 I of 20% heptane / ethyl acetate Finally, water was slowly added (11 I) The layers were separated and then the organic layer was washed with DMF water twice and then with water twice. The organic layer was tested for yield and then filtered through a plug of silica gel to remove excess oxazolidinone. The solution was then changed from solvent to methanol for subsequent steps EXAMPLE 24 2"- (4S, 5f?) - 5-f3.5-bis (trifluoromethyl) phenin-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4" - Chloro-4'-methoxy-2-methyl-1 J ': 3'J "-terphenyl-4-carboxylic acid methyl ester Step A 1-Bromo-2- (bromomethyl) -4-chlorobenzene A mixture of 2-bromo-5-chloro-toluene (2.00 g, 9.75 mmole), NBS (2.08 g, 11.7 mmole) and catalytic amount of AIBN in tetrachloride of carbon (50 ml) was heated and refluxed for 4 h. CCD (EtOAc: hexane / 5: 95) showed no starting material. The mixture was filtered and the filtrate was concentrated. The title compound was obtained as a white solid (2.20 g) after column chromatography using EtOAc: hexane / 5: 95 as the eluent. 1 H NMR (CDCl 3, 500 MHz) d 7.53 (d, j = 9.0 HzJ H), 7.47 (d, J = 2.5 Hz, 1 H), 7.18 (dd, J = 8.5, 2.5 Hz, 1 H), 4.60 ( s, 2H).

Step B (4S.5f?) - 5- | 3.5-bis (trifluoromethyl) phenin-3- (2-bromo-5-chlorobenzyl) -4-methyl-1,3-oxazolidin-2-one To a solution of ( 4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-1, 3-oxazolidin-2-one (0.050 g, 0J6 mmol) in THF (1 ml) at OX was added NaH (7.6 mg, 0J9 mmol, 60%). The mixture was stirred at OX for 30 min.

The title compound of step A (0.059 g, 0.21 mmol) was added. All was stirred at 0X for 1 hr and was heated at room temperature for 4 hr. The reaction was quenched with saturated ammonium chloride. The organic compound was extracted with ethyl acetate (3 x 15 ml). The combined ethyl acetate layers were washed with brine and dried over sodium sulfate. The title compound was obtained after purification by preparative CCD using EtOAc: hexane / 2: 8 as the eluent. 1 H NMR (CDCl 3, 500 MHz) d 7.92 (s, 1 H), 7.82 (s, 2 H), 7.55 (d, J = 8.5 Hz, 1 H), 7.43 (d, J = 2.5 Hz, 1 H), 7.23 (d, J = 8.5, 2.5 Hz, 1 H), 5.77 (d, J = 8.0 Hz, 1 H), 4.86 (d, J = 16.0 Hz, 1 H), 4.36 (d, J = 16.0 Hz, 1 H), 4.11 (m, 1 H), 0.82 (d, J = 6.5 Hz, 3H).

Step C 2"- ( { (4S, 5) -5- [3,5-bis (trifluoromethyl) phen'n-4-methyl-2-oxo-1,3-oxazolidin-3-yl | methyl) -4"-chloro-4'-methoxy-2-methyl-1 J ': 3M" Jerphenyl-4-carboxylic acid methyl A mixture of the title compound of step B (0.068 g, 0.13 mmol), 4'- methyl methoxy-2-methyl-3 '- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) biphenyl-4-carboxylate (intermediate 11) (0.075 g, 0.19 mmol) , tetrakis (triphenylphosphine) palladium (15 mg, 5 mol%) and sodium carbonate (0.07 g, 0.65 mmole) in 7 ml of water / EtOH / toluene (1: 2: 4) was heated to reflux for 5 h. CCD (EtOAc: hexane / 1: 3) showed that the reaction was over. The solvents were removed. Water (10 ml) was added. The organic compound was extracted with methylene chloride (3x 20 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after purification with preparative CCD using 10% EtOAc in hexane as the eluent. 1 H NMR (CDCl 3, 500 MHz): d 1: 1 mixture of atropoisomers 7.96 (d, J = 9 Hz, 1 H), 7.88 (m, 2H), 7.72 (s, 1 H), 7.65 (s, 1 H), 7.49 (d, J = 2Hz, 0.5H), 7.39 (m , 2H), 7.36 (d, J = 2Hz, 0.5H), 7.24-7.28 (m, 2H), 7.15 (m, 1 H), 7.70 (m, 1 H), 5.62 (d, J = 8Hz, 0.5 H), 5.52 (d, J = 8Hz, 0.5H), 4.91 (t, J = 16Hz, 1H), 4.08 (d, J = 15.5 Hz, 0.5H), 3.95 (s, 3H), 3.88 (s) , 3H), 3.87 (d, J = 16 Hz, 0.5H), 3.84 (m, 1 H), 2.39 (s, 1.5H), 2.33 (s, 1.5H), 0.56 (d, J = 7Hz, 1.5 H), 0.43 (d, J = 6.5Hz, 1.5H).

EXAMPLE 25 The title compound was obtained according to the procedure outlined in Example 24 starting from (4S, 5R) -5- [3,5-bis (chloro) phenyl] -4-methyl-1,3-oxazolidin-2- ona 1 H NMR (CDCl 3, 500 MHz): d 1: 1 mixture of atropisomers 7.96 (d, J = 6.5 Hz, 1 H), 7.89 (dd, J = 8, 1 Hz, 1 H), 7.45 (m, 2 H) , 7.34-7.40 (m, 3H), 7.22-7.31 (m, 2H), 7.13 (d, J = 2.5Hz, 0.5H), 7.12 (d, J = 2.5Hz, 0.5H), 7.01-7.07 (m , 2H), 5.45 (d, J = 8.5 Hz, 0.5H), 5.20 (d, J = 8 Hz, 0.5H), 4.88 (d, J = 16 Hz, 0 5H), 4.83 (d, J = 15.5 Hz, 0.5H), 4.08 (d, J = 15.5 Hz, 0.5H), 3.95 (s, 3H), 3.87 (s, 3H), 3.85 (d, J = 16 Hz, 0.5H), 3.75 (m, 1 H), 2.38 (s, 1.5H), 2.33 (s, 1.5H), 0.58 (d, J = 6.5 Hz, 1.5H), 0.44 (d, J = 6 Hz, 1.5H). LC-MS (M + 1): 626.38.

EXAMPLE 26 2"J [(4S, 5f?) - 5- (3,5-d? Chlorophen? N-4-met? L-2-oxo-1,3-oxazole? D? N -3? Nmet? L) - 4'-methox? -2-met? L-4"- (tr? Fluoromet? L) -1, 1 '3'J" -terfen? L-4-carboxylic acid methyl ester ((4S, 5 /? ) -5- (3,5-d? Chlorophen? L) -3- [2-iodo-5- (tr? Fluoromet? L) benc? L] -4-met? L-1,3-oxazole? D ? n-2-one (100 mg, 0 1886 mmol), 4'-methox? -2-met? l-3 '- (4,4,5,5-tetramet? l-1, 3,2-d ? oxaborolan-2-? l) b? phen? l-4-carboxylic acid methyl ester (108 mg, 0 283 mmoles), adduct of 1 J '-b? s (d? phen? lfosf? no) ferrocene- d) palladium chloride-dichloromethane (46 mg, 0 056 mmol), aqueous sodium carbonate (190 μL, 2M, 0 380 mmol) and 1,4-d-oxano (2 mL) were placed in a sealed tube and subjected to microwave irradiation at 130X for 30 minutes and then at 135X for 15 minutes to complete the reaction. The crude reaction mixture was purified by preparative CCD on S02 (sequentially eluted with 30% ethyl acetate in hexanes, 70 % from dichloromethane in hexanes and then 80% dichloromethane in hexanes) to give 2"- { [(4SI5R) -5- (3,5-dichlorophenyl) -4-methyl-2-oxo-1,3-oxazolidin-3 -yl] methyl.}. 4'-methoxy-2-methyl-4"- (trifluoromethyl) -1 J ': 3'J" -methylphenyl-4-carboxylic acid methyl ester as a white solid. = 657.13; found = 658.46 (M + 1) +. The 1 H NMR signals are duplicated due to atropoisomerism 1 H NMR (CDCl 3, 500 MHz) d 7.94 (d, J = 7 Hz, 1 H), 7.87 (d, J = 8.5 Hz, 1 H), 7.70 (s, 0.5H), 7.65 - 7.61 (m, 1.5H), 7.47 - 7.36 (m, 3H), 7.32 (d, J = 2 Hz, 0.5H), 7.29 - 7.23 (m, 1.5H), 7.11 (dd, J = 6.3, 2.0 Hz, 1 H), 7.08 -7.02 (m, 1.5H), 7.00 (dd, J = 8.3, 2.0 Hz, 0.5H), 5.41 ( d, J = 8.5 Hz, 0.5H), 5J6 (d, J = 8.0 Hz, 0.5H), 4.91 (d, J = 16 Hz, 0.5H), 4.85 (d, J = 16.5 Hz, 0.5H), 4J7 (d, J = 16 Hz, 0.5H), 3.98 - 3.90 (m, 3.5H), 3.856, 3.851 (s, 3H), 3.74 -3.66 (m, 1 H), 2.36, 2.32 (s, 3H) , 0.55 (d, J = 7 Hz, 1.5H), 0.43 (d, J = 6 Hz, 1.5H).

EXAMPLE 27 Step A (4S, 5R) -5J3,5-bis (trifluoromethyl) phenin-3- (2-bromo-5-fluorobenzyl) -4-methyl-1,3-oxazolidin-2-one To a solution of (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-1,3-oxazolidin-2-one (2.0 g, 6.39 mmol) in THF (40 ml) at 0X was added NaH (285 mg, 60% p / p in mineral oil, 7.13 mmoles, 1.1 eq.) In one portion. The resulting foam mixture was stirred in an ice bath. Additional THF (50 ml) was added in the reaction. The mixture was stirred at 0X for 30 min. 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 cold for 30 min and then allowed to warm to room temperature. The reaction was completed in 3 hours. The reaction was quenched with NH 4 Cl (aq, sat., 80 ml). The volatiles were removed under vacuum. The crude mixture was extracted with EtOAc and dried over Na2SO4. The residue was purified by flash chromatography on Si02 (Biotage 40 + M cartridge, EtOAc / hexane, gradient). (4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl] -3- (2-bromo-5-fluorobenzyl) -4-methyl-1,3-oxazolidin-2-one was obtained as a clear oil. LC-MS: 500.09 (M + 1) +. 1 H NMR (CDCl 3, 500 MHz) d 7.88 (s, 1 H), 7.79 (s, 2 H), 7.55 (dd, J = 8.8, 5.2 Hz, 1 H), 7.17 (dd, J = 8.7, 4.5 Hz, 1 H), 6.95 (m, 1 H), 5.74 (d, J = 8.0 Hz, 1 H), 4.83 (d) , J = 15.8, 1 H), 4.54 (d, J = 16.0 Hz, 1 H), 4.11 (m, 1 H), 0.80 (d, J = 6.6 Hz, 3H).

Step B (4S.5f?) - 5-f3.5-b? S (tr? Fluoromet? L) phen? N-3-y (5'-bromo-4-fluoro-2'-methox? B? Phen? L -2-? L) met? Ll-4-met? L-1, 3-oxazol? D? N-2-one (4S, 5R) -5- [3,5-b? S (tr? Fluoromet? l) phenol] -3- (2-bromo-5-fluorobenzyl) -4-met? -1,3-oxazole? d? n-2-one (600 mg, 1.2 mmoles), acid (5-bromo-2-methox? Phen?) Boron? Co (319 mg, 1 38 mmol), aqueous sodium carbonate solution (1 27 ml, 2M, 2 54 mmol), toluene (3.5 ml) and ethanol (400 μl) were mixed and stirred at room temperature for 45 minutes followed by the addition of tetrak? s (tr? phen? lfosf? n) paladin (0) (87 mg, 4 5 mol%) The mixture The resulting reaction was heated in a 90X oil bath for 24 hours to complete the reaction. The crude reaction was diluted with brine and extracted with ethyl acetate. The combined extracts were dried over Na2SO4 followed by filtration and concentration under vacuum to give a dark oil The crude oil was purified by reverse phase preparative HPLC (Kromasil 100-5C18, 100x21 1 mm) eluting with a mixture of gradients of MeCN (0 1% TFA, v / v) / H20 (0 1% TFA, v / v) giving (4S, 5f?) - 5- [3,5-b? S (tr? Fluoromet? L) phen? L] -3 - [(5'-bromo-4-fluoro-2'-methox? B? Phen? L-2? ) met? l] -4-met? l- 1, 3-oxazol? d? n-2-ona LC-MS cale = 607 04, found = 607 98 (M + 1) + Step C (4S.5R) -5-f3.5-b? S (tr? Fluoromet? L) phen? N-3-f (4-fluoro-6'-methox? -2"-met? L-1 J '3'J "Jerfen? L-2-? L) met? Ll-4-met? L-1,3-oxazol? D? N-2-one (4S, 5R) -5- [3,5-b ? s (tr? fluoromet? l) phen? l] -3 - [(5'-bromo-4-Jouro-2'-methox? b? phen? l-2-? l) met? l] -4-met? l-1, 3-oxazole? d? n-2-one (50 mg, 0 082 mmol), acid (2-met? lfen? l) boron? co (22 mg, 0 165 mmol), adduct of 1 J'-b? s (d? phen? lfosf? no) ferrocene-d? palladium chloride-dichloromethane ( 20 mg, 0 024 mmol), aqueous potassium hydroxide (55 μl, 3M, 0 165 mmol) and 1,4-dioxane (1 ml) were placed in a sealed tube and subjected to microwave irradiation at 140X for 20 minutes to complete the reaction The crude reaction mixture was purified by preparative CCD on S02 (eluted with 20% ethyl acetate in hexanes) to give (4S, 5f?) - 5- [3,5-b? s (tr? fluoromet? l) phen? l] -3 - [(4? uoro-6'-methox? -2"-met? l-1, 1 '3'J" Jerfen? l-2-? l) met? l] -4-met? -1-l, 3-oxazole? d? n-2-one as a colorless glass LC-MS cale = 617 18, found = 618 16 (M + 1) + The 1 H NMR signals are duplicates due to atropoisomepsmo 1 H NMR (CDCI 3, 500 MHz) d 7 84 (s, 1 H), 7 68 (s, 1 H), 7 62 (s, 1 H), 7 36 - 7 32 (m, 1 H ), 7 30 - 7 22 (m, 4H), 7 22 - 7 18 (m, 1 5H), 7 18 -7 14 (m, 0 5H), 7 14 - 7 11 (m, 1 H), 7 11 - 7 05 (m, 1 H), 7 02 (t, J = 8 0 Hz, 1 H), 5 58 (d, J = 8 5 Hz, 0 55 H), 5 28 (d, J = 8 Hz, 0 45 H), 4 90 (d, J = 3 5 Hz, 0 45 H), 4 09 (d, J = 15 5 Hz, 0 45H), 3 88 (d, J = 16.5 Hz, 0 55H), 3 844, 3 838 (s, 3H), 3 82 - 3 75 (m, 1 H), 2 32, 2 56 (s, 3H), 0 52 (d, J = 6 5 Hz, 1 35H), 0 38 (d, J = 6 5 Hz, 1 65H) EXAMPLE 28 (4S.5R) -5-f3.5-bis (trifluoromethyl) phenin-3 - ([6'-fluoro-2"-methyl-4- (trifluoromethyl) -1 J ': 3'J" Jerphenyl-2- illmethyl) -4-methyl-1,3-oxazolidin-2-one Step A (4S.5R) -5-f3.5-bis (trifluoromethyl) phenyl-3 - ([5'-bromo-2'-fluoro-4- (trifluoromethyl) -biphenyl-2-ylmethyl) -4-methyl-1 , 3-oxazolidin-2-one (4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl] -3- [2-iodo-5- (trifluoromethyl) -benzyl) -4-methyl-1 , 3-oxazolidin-2-one (500 mg, 0.837 mmol) was mixed with acid (5-bromo-2-fluorophenyl) boronic acid (211 mg, 0.963 mmol), toluene (5 ml), ethanol (278 μl) and aqueous sodium carbonate solution (2M, 0.89 ml, 1.78 mmol). The resulting mixture was stirred at 20X for 30 min followed by the addition of tetrakis (triphenylphosphine) palladium (0) (43.5 mg, 0.0376 mmol, 4.5 mol%). The reaction mixture was heated in a 90X oil bath for 40 hours to complete the reaction. The resulting crude mixture was purified by flash chromatography (Si02, Biotage 40 + M cartridge). The column was eluted by a mixture of ethyl acetate / hexanes. The related fractions were combined and concentrated in vacuo to give (4S, 5 /?) - 5- [3,5-bis (trifluoromethyl) phenyl] -3-. { [5'-bromo-2'-fluoro-4- (trifluoromethyl) biphenyl-2-yl] methyl} -4-methyl-1,3-oxazolidin-2-one. CL-EM cale. = 645.02; found = 645.94 (M + 1) +.

Step B (4S.5R) -5-r3.5-bis (trifluoromethylphenyl-3- (6'-fluoro-2"-methyl-4- (trifluoromethyl) -1, r: 3'J" Jerphenyl-2-inmethyl ) -4-methyl-1, 3-oxazolidin-2-one (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -3- { [5'-bromo-2'Jluoro- 4- (trifluoromethyl) biphenyl-2-yl] methyl.} -4-methyl-1,3-oxazolidin-2-one (79 mg, 0.123 mmol), (2-methylphenyl) boronic acid (25 mg, 0.882 mmol) ), adduct of 1, 1 '-bis (diphenylphosphino) ferrocene-palladium dichloride-dichloromethane (10 mg, 0.0122 mmol), aqueous potassium hydroxide (82 μl, 3M, 0.246 mmol) and 1,4-dioxane (1 ml) ) were placed in a sealed tube and subjected to microwave irradiation at 140X for 15 minutes to complete the reaction.The crude reaction mixture was purified by preparative CCD on Si02 ( eluted with 30% ethyl acetate in hexanes) to give (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -3-. { [6'-Fluoro-2"-methyl-4- (trifluoromethyl) -1, r: 3 ', 1" Jerphenyl-2-yl] methyl} -4-methyl-1, 3-oxazolidin-2-one as a clear glass. CL-EM cale. = 655.16; found = 656.11 (M + 1) +. 1 H NMR signals are duplicated due to 1 H NMR atropoisomerism (CDCI 3, 500 MHz) d 7.86 (s, 1 H), 7.73 (s, 1 H), 7.72 -7.66 (m, 2 H), 7.48 (d, J = 8 Hz, 1 H), 7.41 - 7.36 (m, 1 H), 7.29 - 7.23 (m, 4H), 7J 9 - 7.23 (m, 3H), 5.56 (br s, 1 H), 4.96 (br s, 1 H), 4J3 (br d, J = 46.5 Hz, 1 H), 3.83 (br d, J = 43.5 Hz, 1 H), 2.29 (s, 3 H), 0.56, 0.51 (br s, 3 H). (4 $, 5f?) - 5-f3,5-bis (trifluoromethyl) phen-3-. { r4'Jluoro-6'-methoxy-2"-methyl-4- (trifluoromethyl) -1 J ': 3'J" Jerphenyl-2-illmethyl) -4-methyl-1,3-oxazolidin-2-one A mixture of ( 4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -3- [2-iodo-5- (trifluoromethyl) -benzyl] -4-methyl-1,3-oxazolidin-2-one (0.050 g, 0.084 mmole), 2-methoxy-4-fluoro-5- (2'-methylphenyl) boronic acid (excess), tetrakis- (triphenylphosphine) palladium (5 mol%) and sodium carbonate (19.5 mg, 0J8 mmole) in 7 ml of water / EtOH / toluene (1: 2: 4) was heated to reflux for 4 hr. CCD (CH2Cl2: hexane / 1: 1) showed that the reaction was over. The solvents were removed. Water (10 ml) was added. The organic compound was extracted with methylene chloride (3x 10 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after column chromatography using CH2Cl2: hexane / 6: 4 as the eluent. LC-MS (M + 1): 686.1.

EXAMPLE 30 Acid 2"- ( { (4S.5R) -5-f3,5-bis (trifluoromethyl) phenan-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4 ' -methoxy-2-methyl-4"- (trifluoromethyl) -1.1 ': 3'.1" -terphenyl-4-carboxylic acid 2"- ( { (4S, 5R) -5- [3,5-bis ( trifluoromethyl) phenyl] -4-methyl-2-oxo-1, 3- oxazolidin-3-yl} methyl) -4'-methoxy-2-methyl-4"- (trifluoromethyl) -1, 1 ': 3 \ 1" Methylphenphenyl-4-carboxylate (20 mg, 0.0276 mmol), aqueous potassium hydroxide (300 μl , 3M, 0.90 mmol) and ethanol (2 ml) were stirred at 20X for 2 hours and 20 minutes to complete the hydrolysis. The reaction mixture was acidified with acetic acid. The mixture was purified by preparative CCD on silica gel, (eluted with AcOH / EtOAc / hexanes = 5/25/70, v / v) to give acid 2"- ( { (4S, 5f?) - 5 - [3,5-bis (trifluoromethyl) phenyl] -4-methyl-2-oxo-1,3-oxazolidin-3-yl} methyl) -4'-methoxy-2-methyl-4"- (trifluoromethyl) ) -1 J ': 3'J "-terphenyl-4-carboxylic acid LC-MS cale = 711.17; found = 712.10 (M + 1) + .1H NMR signals are duplicated due to atropoisomerism. 1H NMR (CDCI3 , 500 MHz) d 7.99 (d, J = 8.0 Hz, 1 H), 7.92 (d, J = 8.5 Hz, 1 H), 7.85 (d, J = 5 Hz, 1 H), 7.72 - 7.68 (m, 1.5H), 7.67 - 7.60 (m, 2.5H), 7.47 - 7.36 (m, 2H), 7.32 (d, J = 8.0 Hz, 0.5H), 7.28 (d, J = 8.0 Hz, 0.5H), 7.15 (s, 1 H), 7.08 (d, J = 8.5, 7.0 Hz, 1 H), 5.58 (d, J = 8.0 Hz, 0.5H), 5.29 (d, J = 6.5 Hz, 0.5H), 4.97 ( d, J = 15.5 Hz, 0.5H), 4.94 (d, J = 14 Hz, 0.5H), 4J6 (d, J = 16 Hz, 0.5H), 3.96 (d, J = 15.5 Hz, 0.5H), 3.87 (s, 3H), 3.83 - 3.74 (m, 1 H), 2.38, 2.33 (s, 3H), 0.55 (d, J = 6.5 Hz, 1.5H), 0.42 (d, J = 7 Hz, 1.5H ).

EXAMPLE 31 Acid 2"- (((4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl-1,4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4'- methoxy-4"- (trifluoromethyl) -1, 1 ': 3', 1"Jerphenyl-2-carboxyl 2" - ( { (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-2-oxo-1 , 3-oxazolidin-3-yl.} Methyl) -4'-methoxy-4"- (trifluoromethyl) -1, 1 ': 3', 1" -terphenyl-2-carboxylic acid methyl ester (50 mg, 0.07 mmol ), aqueous potassium hydroxide (1.1 ml, 3M, 3.3 mmol), water (1.5 ml) and ethanol (3.6 ml) were stirred at 20X for 23 hours. The reaction mixture was acidified with HCl (aq, 1 N). The volatiles were removed under reduced pressure. The resulting mixture was treated with ethyl acetate, washed with brine. The combined organic extracts were dried over Na 2 SO, filtered and concentrated to an oil. This oil was purified by reverse phase preparative HPLC (column: Kromasil 100-5C18, 100 x 21.1 mm) eluting with a gradient mixture MeCN gradient mixture (0.1% v / v regulated in its pH with TFA) / H20 (0.1 % v / v regulated in its pH with TFA) to give acid 2"- ( { (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -4- methyl-2-oxo-1,3-oxazolidin-3-yl} methyl) -4'-methoxy-4"- (trifluoromethyl) -1, r: 3'J" -terphenyl-2-carboxylic acid. CL-EM cale. = 697.15; found = 698.16 (M + 1) +. 1 H NMR signals are duplicated due to atropoisomerism 1 H NMR (CDCI 3, 500 MHz) d 7.94 (t, J = 7.0 Hz, 1 H), 7.85 (d, J = 7.0 Hz, 1 H), 7.68 - 7.63 (m , 2.5H), 7.63 - 7.59 (m, 1.5H), 7.59 - 7.54 (m, 1 H), 7.47 - 7.35 (m, 4H), 7J4 (dd, J = 8.0, 2.0 Hz, 1 H), 7.04 (d, J = 8.5 Hz, 1 H), 5.53 (d, J = 8.0 Hz, 0.4H), 5.42 (d, J = 8.0 Hz, 0.6H), 5.02 (d, J = 15.5 Hz, 0.6H) , 4.85 (d, J = 15.5 Hz, 0.4H), 4.11 - 4.02 (m, 0.4H), 3.87 - 3.77 (m, 3.6H), 0.99 (d, J = 6.5 Hz, 0.6H), 0.93 (d , J = 7.0 Hz, 0.4H), 0.58 (d, J = 7.0 Hz, 1.2H), 0.54 (d, J = 6.5 Hz, 1.8H).

EXAMPLE 32 Acid 2"- (((4S.5ff) -5-f3.5-bis (trifluoromethyl) phenan-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4'- methoxy-4"- (trifluoromethyl) -1, 1 ': 3'.1" Jerphenyl-3-carboxylic acid The title compound of Example 15 was stirred with LiOH (3 eq) in a 2: 1 mixture of dioxane and water. Room temperature overnight The solvent was removed and the aqueous solution acidified with 1 N HCl to pH 4. The mixture was extracted with EtOAc (3 x 10 mL) The combined EtOAc layers were dried over sodium sulfate. The title compound was obtained after preparative CCD on silica gel using EtOAc: hexane / 1 J as the eluent: 1 H NMR (CDCl 3) 500 MHz): d 1: 1 mixture of atropoisomers 8.32 (s, 0.5H), 8.29 (s, 0.5H), 8.08 (m, 1 H), 7.46-7.85 (m, 10H), 5.61 (d, J = 8 Hz, 0.5H), 5.20 (d, J = 8 Hz, 0.5H), 5.04 (d, J = 16 Hz, 0.5H), 4.95 (d, J = 15.5 Hz, 0.5H), 4J7 (d, J = 16 Hz, 0.5H), 3.97 (d, J = 15.5 Hz, 0.5H ), 3.91 (s, 1.5H), 3.83 (s, 1.5H), 3.79 (m, 1 H), 0.58 (d, J = 6.5 Hz, 1.5H), 0.42 (d, J = 6) .5 Hz, 1.5H). LC-MS (M + 1): 698.18.

EXAMPLE 33 Acid 2"- (((4S, 5F?) - 5-r3,5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) metin-4'-methoxy-4"- (trifluoromethyl) -1, r.3'J" Jerfenl-4-carboxylic 2"- ( { (4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl] -4 -methyl-2-oxo-1,3-oxazolidin-3-yl.} methyl) -4'-methoxy-4"- (trifluoromethyl) -1 J ': 3'J" -terphenyl-4-carboxylic acid methyl ester (10 mg, 0.014 mmol), aqueous potassium hydroxide (150 μL, 3M, 0.45 mmol) and ethanol (1 mL) were stirred at 20X for 2 hours and 30 minutes to complete the hydrolysis.The reaction mixture was acidified with HCl (aq, 1N) and then basified with sodium bicarbonate.The volatiles were removed under reduced pressure.The resulting mixture was treated with ethyl acetate, washed with brine.The combined organic extracts were dried over Na2SO4, filtered and concentrated to an oil.This oil was purified by preparative CCD on Si02 (eluted with 50% EtOAc in hexanes) to give 2"- (. {(4S, 5R) -5- [3,5-] bis (trifluor omethyl) phenyl] -4-methyl-2-oxo-1,3-oxazolidin-3-yl} methyl) -4'-methoxy-4"- (trifluoromethyl) -1, 1 ': 3', 1" Jerphenyl-4-carboxylic acid.

CL-EM cale. = 697.15; found = 698.03 (M + 1) J The 1 H NMR signals are duplicated due to atropoisomerism 1 H NMR (CDCl 3, 500 MHz) d 8.16 - 8.11 (m, 2 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.74 - 7.69 (m, 2H), 7.69 - 7.65 (m, 2.5H), 7.65 - 7.61 (m, 1.5H), 7.57 (s, 1 H), 7.48 - 7.42 (m, 2.0H), 7.11 (dd) , J = 8.8, 2.5 Hz, 1 H), 5.57 (d, J = 8.0 Hz, 0.5H), 5J7 (d, J = 8.0 Hz, 0.5H), 4.97 (d, J = 15.5 Hz, 0.5H) , 4.93 (d, J = 15.5 Hz, 0.5H), 4.16 (d, J = 16 Hz, 0.5H), 3.95 (d, J = 16.0 Hz, 0.5H), 3.88, 3.87 (s, 3H), 3.80 - 3.72 (m, 1 H), 0.55 (d, J = 6.5 Hz, 1.5H), 0.41 (d, J = 6.5 Hz, 1.5H).

EXAMPLE 34 Acid 2"- (((4S, 5f?) - 5-r3,5-bis (trifluoromethylfenin-4-methyl-2-oxo-1,3-oxazolidin-3-yl) metin-4'-chloro-2- methylene-4"- (trifluoromethyl) -1 J ': 3M" Jerphenyl-4-carboxylic acid 2"- ( { (4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl] - 4-methyl-2-oxo-1,3-oxazolidin-3-yl.} Methyl) -4'-chloro-2-methyl-4"- (trifluoromethyl) -1, r: 3'J" Jerphenyl-4 - Methyl carboxylate (25 mg, 0.034 mmol), aqueous potassium hydroxide (300 μL, 3M, 0.90 mmol) and ethanol (2 mL) were stirred at 20X overnight. The volatiles were removed under reduced pressure. The resulting residue was treated with brine followed by extraction with ethyl acetate. The combined extracts were dried over Na2SO4 followed by filtration and concentration under vacuum to give an oil. This oil was purified by preparative CCD on SiO (eluted with 50% EtOAc in hexanes) to give a clear glass. The glass was further purified by reverse phase preparative HPLC (Kromasil 100-5C18, 100x21.1 mm) eluting with a gradient mixture of MeCN (0.1% TFA, v / v) / H20 (0.1% TFA, v / v) giving acid 2"- (. {(4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-2-oxo-1,3-oxazolidin-3-yl.] Methyl) -4'-chloro-2-methyl-4" - (trifluoromethyl) -1, 1 ': 3', 1"Jerphenyl-4-carboxylic acid LC-MS cale = 715.12; found = 716.12 (M + 1) +. The 1 H NMR signals are duplicated due to atropoisomerism. 1 H NMR (CDCl 3, 500 MHz) d 7.99 (d, J = 8.0 Hz, 1 H), 7.92 (d, J = 8.5 Hz, 1 H), 7.85 (d, J = 5 Hz, 1 H), 7.72 - 7.68 (m, 1.5H), 7.67 - 7.60 (m, 2.5H), 7.47 - 7.36 (m, 2H), 7.32 (d, J = 8.0 Hz, 0.5H), 7.28 (d, J = 8.0 Hz, 0.5 H), 7.15 (s, 1 H), 7.08 (dd, J = 8.5, 7.0 Hz, 1 H), 5.58 (d, J = 8.0 Hz, 0.5H), 5.29 (d, J = 6.5 Hz, 0.5H ), 4.97 (d, J = 15.5 Hz, 0.5H), 4.94 (d, J = 14 Hz, 0.5H), 4.16 (d, J = 16 Hz, 0.5H), 3.96 (d, J = 15.5 Hz, 0.5H), 3.87 (s, 3H), 3.83 - 3.74 (m, 1 H), 2.38, 2.33 (s, 3H), 0.55 (d, J = 6.5 Hz, 1.5H), 0.42 (d, J = 7 Hz, 1.5H).

The above compound (example 34) has also been made from its methyl ester (example 23) using the following procedure: THF (12 I) was placed in a 75 I flask equipped with overhead stirrer, thermocouple, nitrogen inlet, funnel drip and a steam container containing approx. 12 I of a methanol solution of methyl triaryloxazolidinone ester (Ex 23, 2190 g, 3 moles). Hydrogen peroxide (1800 ml of a 35% by weight solution) was added. The addition was exothermic, and the batch temperature increased from 16 ° C to 23 ° C. Then, lithium hydroxide monohydrate (378 g, 9 moles) was charged to the reaction vessel, and the reaction was heated to 60X. The reaction was monitored by CLAR and completed in 15-16 hr. The reaction mixture was cooled to 0-1 OX, and aqueous sodium bisulfite (2185 g in about 18 I of water) was slowly added over 2 hours to extinguish the hydrogen peroxide. The addition was very exothermic. The peroxide absence was confirmed using EM Quant peroxide test strips. MTBE (22 I) and GMP water (8 I) were then added, and the mixture was transferred to a 100 I extractor. The lower aqueous layer was cut, and the upper organic layer was washed with 10% by weight of brine. (2010 g of NaCI in approx. 18 I of water GMP). The lower layer was cut and the turbid organic layer was dried over anhydrous sodium sulfate. The dried organic phase was transferred through an in-line filter (1 μm) to a 100 I flask attached to a batch concentrator. The MTBE was removed and replaced with cyclohexane. The volume was adjusted to 20 I. The batch it was heated to 50-65X to completely dissolve any precipitated solids, and then cooled to ca. 60 ° C and seeded with crystals obtained from previous batches. The solution was allowed to cool to room temperature overnight, giving a white solid. The white solid was isolated by filtration, rinsed with 2 x 2 l of cyclohexane, and dried under a nitrogen bag under vacuum. The solid carboxylic acid obtained at this point is a mixture of the anhydrous product and a cyclohexane solvate (typically 3-5% by weight of cyclohexane). The solvate is converted to anhydrous material by heating in a vacuum oven at a temperature of 1 10-135X, with the exact temperature depending on the design and size of the oven that was used.

EXAMPLE 35 Acid 2"-f ((4S.5ffl-5-f3.5-bis (trifluoromethyl) phenan-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -2- chloro-4'-methoxy-4"- (trifluoromethyl) -1, 1 ': 3'.1" -terphenyl-4-carboxylic acid Step A: 2"- ( { (4S.5 /?) - 5- [3,5-bis (trifluoromethyl) phenan-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl ) -2-chloro-4'-methoxy-4"- (trifluoromethyl) -1, 1 ': 3'.1" -terphenyl-4-carboxylic acid methyl ester A mixture of intermediate 9 (OJ g), intermediate 10 (OJ g, 0.25 mmole), tetrakis (triphenylphosphine) palladium (5 mol%) and sodium carbonate (58 mg, 0.55 mmole) in 7 ml of water / EtOH / toluene (1: 2: 4) was heated to reflux for 2 hr. CCD (EtOAc: hexane / 1: 9) showed that the reaction had ended The solvents were removed Water (10 ml) was added The organic compound was extracted with methylene chloride (3x 15 ml). The combined methylene compounds were washed with brine, and dried over sodium sulfate The title compound was obtained after column chromatography using CH2Cl2: hexane / 8: 2 as the eluent.1H NMR (CDCl3, 500 MHz) d mixture 1 : 1 of atropoisomers 7.10-8.20 (m, 12H), 5.60 (d, J = 8.5 Hz, 0.5H), 5.29 (d, J = 8 Hz, 0.5H), 5.01 (d, J = 16.5 Hz, 0.5H ), 4 .97 (d, J = 16.5 Hz, 0.5H), 4.21 (d, J = 16 Hz, 0.5H), 4.00 (d, J = 16 Hz, 0.5H), 3.97 (s, 3H), 3.91 (s) , 1.5H), 3.90 (s, 1.5H), 3.78 (m, 1 H), 0.55 (d, J = 7 Hz, 1.5H), 0.43 (d, J = 6.5 Hz, 1.5H).

Step B: Acid 2"- ( { (4S.5) -5- [3,5-bis (trifluoromethyl) phen'n-4-methyl-2-OXQ-1,3-oxazolidin-3-yl) metin-2- chloro-4'-methoxy-4"- (trifluoromethyl) -1 J ': 3'.1" -terphenyl-4-carboxylic acid The title compound of Example 25 was stirred with LiOH (5 eq) in a 2: 1 mixture. of dioxane and water at room temperature overnight The solvent was removed and the aqueous solution was acidified with 1 N HCl to pH ~ 4. The organic compound was extracted with EtOAc (3 x 10 ml) .The combined EtOAc layers were dried over sodium sulfate The title compound was obtained after preparative reverse phase HPLC: 1 H NMR (CDCl 3, 500 MHz): d 1: 1 mixture of atropoisomers 8.21 (d, J = 12 Hz, 1 H), 8.04 (d, j = 8 Hz, 1 H), 7.87 (d, J = 5.5 Hz, 1 H), 7.76 (s, 0.5 H), 7.72 (s, 1 H), 7.69 (s, 0.5 H), 7.67 (d, J = 3.5 Hz, 1 H), 7.65 (s, 1 H), 7.44 - 7.58 (m, 3 H), 7.37 (d, J = 2 Hz, 0.5H), 7.35 (d, J = 0.5 Hz, 0.5H), 7J3 (d, J = 4Hz, 0.5H), 7J2 (d, J = 5Hz, 0.5H), 5.61 (d, J = 8 Hz , 0.5H), 5.30 (d, J = 12.5Hz, 0.5H), 5.01 (d, J = 12.5Hz, 0.5H), 4.98 (d, J = 13Hz, 0.5H), 4.21 (d, J = 15.5 Hz, 0.5H), 4.00 (d, J = 16Hz, 0.5H), 3.91 (s, 1.5H), 3.90 (s, 1.5H), 3.80 (m, 1H), 0.56 (d, J = 6.5Hz, 1.5H), 0.44 (d, J = 6.5Hz, 1.5H). LC-MS (M + 1): 732.1.

EXAMPLE 36 The title compound of Example 24 was stirred with LiOH (3 eq) in a 2: 1 mixture of dioxane and water at room temperature overnight. The solvent was removed and the aqueous solution was acidified with 1 N HCl to pH ~ 4. The organic compound was extracted with EtOAc (3 x 10 mL). The combined EtOAc layers were dried over sodium sulfate. The title compound was obtained after preparative CCD plate using EtOAc: hexa no / 1: 1 as the eluent. 1 H NMR (CDCl 3, 500 MHz): d a 1: 1 mixture of atropoisomers 8.02 (d, J = 7.5 Hz, 1 H), 7.95 (d, J = 7.5 Hz, 1 H), 7.87 (s, 1 H) , 7.72 (s, 1 H), 7.66 (s, 1 H), 7.49 (s, 1 H), 7.24-7.41 (m, 4H), 7.15 (s, 1 H), 7.08 (d, J = 7 Hz , 0.5H), 7.06 (d, J = 8 Hz, 0.5H), 5.62 (d, J = 8.5Hz, 0.5H), 5.35 (d, J = 8 Hz, 0.5H), 4.93 (d, J = 16 Hz, 0.5H), 4.90 (d, J = 15.5 Hz, 0.5H), 4.08 (d, J = 15.5 Hz, 0.5H), 3.88 (s, 3H), 3.85 (m, 1.5H), 2.39 ( s, 1.5H), 2.34 (s, 1.5H), 0.57 (d, J = 6.5 Hz, 1.5H), 0.44 (d, J = 6.5 Hz, 1.5H). LC-MS (M): 678.3.

EXAMPLE 37 The title compound of Example 25 was stirred with LiOH (3 eq) in a 2: 1 mixture of dioxane and water at room temperature overnight. The solvent was removed and the aqueous solution was acidified with 1 N HCl to pH ~ 4. The organic compound was extracted with EtOAc (3 x 10 ml). The combined EtOAc layers were dried over sodium sulfate. The title compound was obtained after preparative CCD plate using EtOAc: hexane / 1: 1 as the eluent. LC-MS (M + 1): 612.0.

EXAMPLE 38 Acid 2"- (f (4S.5R) -5- (3,5-dichlorophenyl) -4-methyl-2-oxo-1,3-oxazolidin-3-illmethyl) -4'-methoxy-2-methyl-4" - ( trifluoromethyl) -1 J ': 3M "-terphene-4-carboxylic 2" -. { [(4S, 5R) -5- (3,5-Dichlorophenyl) -4-methyl-2-oxo-1,3-oxazolidin-3-yl] methyl} 4'-methoxy-2-methyl-4"- (trifluoromethyl) -1, 1,: 3, J" -methyl-4-carboxylic acid methyl ester (example 26) (50 mg, 0.076 mmol), hydroxide aqueous potassium (600 μl, 3M, 1.8 mmol) and ethanol (4 ml) were stirred at 20X for 6 hours. The reaction mixture was acidified with HCl (aq, 1N) and then basified with sodium bicarbonate. The volatiles were removed under reduced pressure. The resulting mixture was treated with ethyl acetate, washed with brine. The combined organic extracts were dried over Na 2 SO 4, filtered and concentrated to give an oil. The oil was purified by preparative CCD (eluted with EtOAc / hexanes) to give 2"- { [(4S, 5f?) - 5- (3,5-dichlorophenyl) -4-methyl-2-oxo- 1,3-oxazolidin-3-yl] methyl.} -4'-methoxy-2-methyl-4"- (trifluoromethyl) -1, 1 ': 3'J" -terphenyl-4-carboxylic acid.

CL-EM cale. = 643.11; found = 644.14 (M + 1) +. 1 H NMR signals are duplicated due to atropoisomerism 1 H NMR (CDCl 3, 500 MHz) d 8.01 (d, J = 5.5 Hz, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.70 (s, 1 H), 7.65 - 7.61 (m, 1.5H), 7.44 - 7.37 (m, 3H), 7.34 -7.31 (m, 1 H), 7.29 (d, J = 8.0 Hz, 0.5H), 7.29 (d, J) = 8.0 Hz, 0.5H), 7.27 - 7.24 (m, 0.5H), 7.14 (dd, J = 7.0, 2.5 Hz, 1 H), 7.09 - 7.03 (m, 1.5H), 7.00 (dd, J = 8.25 , 2.0 Hz, 1 H), 5.42 (d, J = 8.5 Hz, 0.55H), 5.17 (d, J = 8.0 Hz, 0.45H), 4.92 (d, J = 16.0 Hz, 0.55H), 4.86 (d , J = 16.0 Hz, 0.45H), 4.18 (d, J = 15.5 Hz, 0.55H), 3.96 (d, J = 15.5 Hz, 0.45H), 3.86 (s, 3H), 3.75 - 3.66 (m, 1 H), 2.38, 2.34 (s, 3H), 0.56 (d, J = 6.5 Hz, 1.35H), 0.44 (d, J = 6.5 Hz, 1.65H).

EXAMPLE 39 - [2 '- (((4S, 5F?) - 5-f3.5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -6 acid -methoxy-4 '- (trifluoromethyl) biphenyl-3-yl-1-6-methylpyridine-2-carboxylic acid Step A - (4-Methoxyphenyl) -6-methylpyridin-2-amine (4-Methoxyphenyl) boronic acid (1 g, 6.58 mmole), 5-bromo-6-methylpyridin-2-amine (1.23 g, 6.58 mmole), adduct of 1, 1'-bis (diphenylphosphino) ferrocene-palladium dichloride-dichloromethane (537 mg, 0.658 mmol), potassium acetate (1.29 g, 13.16 mmol) and 1,4-dioxane (5 ml) were placed in a tube sealed and the mixture was subjected to microwave irradiation at 140X for 30 minutes. The resulting crude mixture was purified by flash column chromatography on Si02 (Biotage 40 + M cartridge, ethyl acetate) to give 5- (4-methoxyphenyl) -6-methylpyridin-2-amine as a purple solid. CL-EM cale. = 214.11; found = 215.17 (M + 1) +.

Step B 6-Iodo-3- (4-methoxyphenyl) -2-methylpyridine 5- (4-methoxyphenyl) -6-methylpyridin-2-amine (500 mg, 2.33 mmol) and iodine (710 mg, 2.8 mmol) were stirred in chloroform (10 ml) at room temperature for 12 minutes followed by the addition of n-amyl nitrite (545.9 mg, 4.66 mmol). The resulting mixture was heated in an oil bath at 82X for 1.5 hours to complete the transformation. The reaction was quenched by the addition of saturated aqueous NaS203 solution. The reaction mixture was extracted with dichloromethane. The combined organic extracts were dried over Na 2 SO followed by filtration and concentration. The resulting crude was purified by flash column chromatography on Si02 (Biotage 40 + M cartridge, dichloromethane / hexanes gradient) to give a yellow oil. The oil was further purified by preparative CCD on SiO2 (eluted with 80% dichloromethane in hexanes) to give 6-iodo-3- (4-methoxyphenyl) -2-methylpyridine. CL-EM cale. = 325.00; found = 326.06 (M + 1) +.

Step C - (4-Methoxyphenyl) -6-methylpyridine-2-carboxylic acid benzyl 6-iodo-3- (4-methoxyphenyl) -2-methylpyridine (100 mg, 0.308 mmol), dichloro bis (triphenylphosphine) palladium (II) ( 22 mg, 0.031 mmol), triethylamine (46.7 mg, 0.462 mmol), benzyl alcohol (1 mL, 9.66 mmol) were mixed in acetonitrile (3 mL). The resulting mixture was placed under carbon monoxide at 3J6 kg / cm2 at 60X for 18 hours. The crude of the resulting reaction was purified by preparative CCD on SiO2 (eluted with 25% ethyl acetate in hexanes then 10% triethylamine, 20% ethyl acetate in hexanes) to give 5- (4-methoxyphenyl) - Benzyl 6-methylpyridin-2-carboxylate. CL-EM cale. = 333.14; found = 334.13 (M + 1) +.

Step D - (3-Vodo-4-methoxyphenyl) -6-methylpyridine-2-carboxylic acid benzyl 5- (4-methoxyphenyl) -6-methylpyridine-2-carboxylic acid benzyl ester (150 mg, 0. 45 mmol), iodine (228 mg, 0.898 mmol), silver sulfate (402 mg, 1.29 mmol) were stirred in methanol (3 ml) at room temperature overnight. Additional iodine (57 mg, 0.22 mmol) and silver sulfate (100 mg, 0.32 mmol) were added to the reaction mixture after 25 hours. Aqueous NaHSÜ3 solution (sat, 20 ml) was added to the reaction mixture after an additional 1.5 hours to quench the reaction. The reaction mixture was extracted with ethyl acetate. The combined extracts were dried over Na 2 SO followed by filtration and concentration to give a clear oil. The crude oil was purified by preparative CCD on SiO2 (eluted with 30% ethyl acetate in hexanes) to give 5- (3-iodo-4-methoxyphenyl) -6-methylpyridine-2-carboxylic acid benzyl ester. CL-EM cale. = 459.03; found = 460.17 (M + 1) +.

Step E - [2 '- (((4S.5F?) - 5-y3,5-b? S (tpfluoromet? L) phen? N-4-met? L-2-oxo-1 .3-oxazole? D n-3-? l met? l) -6-methox? -4 '- (tr? fluoromet? l) b? phen? l -3? ll-6-met? lp? r? d? na- Benzyl 2-carboxylate (4S, 5 /?) - 5- [3,5-b? S (tr? Fluoromet? L) phen? L] -4-met? L-3- [2- (4.4 , 5,5-tetramet? L-1, 3,2-d? Oxaborolan-2? L) -5- (tr? Fluoromet? L) benc? L] -1, 3-oxazole? D? N-2 -one-methane (385 mg, 0 644 mmoles) (intermediate 9), 5- (3-iodo-4-methox? phen?) -6-met? lp? r? d? na-2-carbox? lato of benzyl (148 mg, 0.322 mmol), 1,1 '-b? s dichloride (d? phen? lfosf? no) ferrocene-palladium (71 mg, 0 097 mmol), aqueous potassium hydroxide (215 μl, 3M, 645 microl) and 1,4-d-oxano (2 ml) were loaded into a tube. The vessel was purged with nitrogen and then sealed. The reaction mixture was irradiated by microwave at 120X for 20 minutes then at 140X for 30 minutes The reaction mixture was treated with water followed by extraction with ethyl acetate. The combined extracts were dried over Na2SO4 followed by filtration and concentration under vacuum to give a dark oil. This oil was purified by Preparative CCD on S02 (eluted with 45% ethyl acetate in hexanes) to give a dark oil The resulting oil was further purified by reverse phase preparative HPLC (Kromasil 100-5C18, 100x21 1 mm) eluting with a mixture of MeCN gradient (0 1% TFA, v / v) / H20 (0 1% TFA, v / v) The appropriate fractions were pooled and evaporated in a dark oil. This oil was treated with an aqueous solution of sodium bicarbonate. sodium (sat) followed by extraction is with ethyl acetate The combined extracts were dried over NaSO4 followed by filtration and concentration under vacuum to give an oil Dark. The oil still contained some impurities in the baseline. The resulting oil was again purified by preparative CCD on SiO2 (eluted with 50% ethyl acetate in hexanes) to give 5- [2 '- ( { (4S, 5R) -5- [3,5-bis ( trifluoromethyl) phenyl] -4-methyl-2-oxo-1,3-oxazolidin-3-yl.} methyl) -6-methoxy-4 '- (trifluoromethyl) biphenyl-3-yl] -6-methylpyridine-2 -carboxylate benzyl. CL-EM cale. = 802.21; found = 803.21 (M + 1) +.

Step F: Acid 5- [2 '- (((4S.5f?) - 5-f3,5-bis (trifluoromethyl) phenin-4-methyl-2-oxo-1,3-oxazolidin-3-yl ) methyl) -6-methoxy-4 '- (trifluoromethyl) biphenyl-3-yn-6-methylpyridine-2-carboxylic acid 5- [2' - ( { (4S, 5R) -5- [3,5 Bis (trifluoromethyl) phenyl] -4-methyl-2-oxo-1,3-oxazolidin-3-yl} methyl) -6-methoxy-4 '- (trifluoromethyl) biphenyl-3-yl] -6- methylpyridine-2-carboxylic acid benzyl ester (52 mg, 0.065 mmol), palladium / activated charcoal (10%, w / w) (25 mg) were mixed in ethanol (10 ml). The resulting mixture was degassed and subjected to H2 under 3J6 kg / cm2 at room temperature on a Parr shaker for 3 hours to complete the reaction. The reaction mixture was filtered through a pad of Celite (521). The filtrate was concentrated under vacuum to give a clear brown glass. The residue was purified by preparative reverse phase HPLC (Kromasil 100-5C18, 100x21.1 mm) eluting with a gradient mixture of MeCN / H20. The appropriate fractions were combined and evaporated in an aqueous residue. The resulting residue was further lyophilized to give 5- [2 '- (. {(4S, 5 /:)) -5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-2-oxo- 1,3-oxazolidin-3-yl.} Methyl) -6-methoxy-4'- (trifluoromethyl) biphenyl-3-yl] -6-methylpyridine-2-carboxylic acid. CL-EM cale. = 712.16; found = 713.19 (M + 1) +. 1 H NMR signals are duplicated due to atropoisomerism 1 H NMR (CDCl 3, 500 MHz) d 8.07 (s, 1 H), 7.86 (s, 1 H), 7.77 (s, 1 H), 7.71 - 7.62 (m, 4H ), 7.45 - 7.36 (m, 2H), 7J9 - 7.07 (m, 2H), 5.55 (d, J = 7.0 Hz, 0.55H), 5.42 (d, j = 7 Hz, 0.45H), 4.99 (d, J = 13 Hz, 0.5H), 4.85 (d, J = 12.5 Hz, 0.5H), 4.14 (d, J = 13.5 Hz, 0.5H), 3.95 (d, J = 13.5 Hz, 0.5H), 3.92 - 3.80 (m, 4H), 2.61, 2.58 (s, 3H), 0.58 (d, J = 5.0 Hz, 1.35H), 0.49 (d, J = 5.5 Hz, 1.65H).

EXAMPLE 40 Acid 2"- (((4S.5 /?) - 5-f3.5-bis (trifluoromethyl) phenyl-1-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -6" - vodo-4'-methoxy-2-methyl-4"- (trifluoromethyl) -1 J ': 3'J" -terphenyl-4-carboxylic acid Step A 2-methyl-4-trifluoromethyl aniline A mixture of 2-iodo-4-trifluoromethyl aniline (5.0 g, 17.42 mmol), trimethylboroxane (3.64 ml, 26J mmol), tetrakis (triphenylphosphine) -palladium (1.0 g, 0.87 mmol) and Potassium carbonate (4.82 g, 34.8) in DMF (10 ml) was heated at 100X for 48 hr. The reaction was quenched with water (50 ml) and extracted with EtOAc (3 x 50 ml). The combined EtOAc layers were washed with brine and dried over sodium sulfate. The title compound was obtained after column chromatography using EtOAc: hexane / 1: 9 as the eluent. 1 H NMR (CDCl 3, 500 MHz): d 7.13 (s, 1 H), 7.30 (d, J = 8 Hz, 1 H), 6.71 (d, J = 8 Hz, 1 H), 3.98 (br s, 2 H ), 2.21 (s, 3H).

Step B: 2-Methyl-4-trifluoromethylphenyl iodide To a solution of 2-methyl-4-trifluoromethyl aniline (step A) (2.2 g, 12. 6 mmoles) in chloroform (20 ml) at room temperature were added n-pentyl nitrite (2.2 g, 18.9 mmoles) and iodine (6.38 g, 25 Jmmoles). The mixture was refluxed for 1 hr. The mixture was diluted with methylene chloride (50 ml). The solution was washed with saturated aqueous sodium thiosulfate, brine and dried over sodium sulfate. The title compound was obtained after column chromatography using hexane as the eluent.

Step C: 2-Methyl-4-trifluoromethyl-6-nitro-phenyl iodide A 1: 1 mixture of H2SO4 / HN03 (20 ml) was added to 2-methyl-4-trifluoromethylphenyl iodide to OX. The mixture was stirred to OX and then warmed to room temperature overnight. The LC / MS analysis indicated that no starting material was left. The mixture was diluted with water and extracted with EtOAc (3x50 ml). The combined EtOAc layers were washed with sodium bicarbonate and brine and dried over sodium sulfate. The title compound was obtained after removal of the solvent. 1 H NMR (CDCl 3> 500 MHz): d 7.71 (s, 1 H), 7.69 (s, 1 H), 2.68 (s, 3 H).

Step D 1- (bromomethyl) -2-vodo-3-nitro-5- (trifluoromethyl) benzene A mixture of the title compound from step C (0.38 g, 1 J 5 mmole), NBS (0.24 g, 1.38 mmole) and catalytic amount of AIBN in carbon tetrachloride (5 ml) was heated to reflux for 3 days. During the period most AIBN was added daily. The mixture was cooled and concentrated. The title compound was obtained after column chromatography using hexane as the eluent. H NMR (CDCl 3, 500 MHz): d 7.91 (s, 1 H), 7.80 (s, 1 H), 4.75 (s, 2H).

Step E (4S, 5ft) -5J3,5-bis (trifluoromethyl) phenyl1-3J2-vodo-3-nitro-5- (trifluoromethyl) benzylH-methyH, 3-oxazolidin-2-one To a solution of (4S, 5f ?) - 5- [3,5-bis (trifluoromethyl) pheny] - 4-methyl-1,3-oxazolidin-2-one (0J4 g, 0.44 mmol) in THF (3 ml) at 0X, added NaH (21 mg, 0.53 mmol, 60%). The mixture was stirred at 0X for 30 min.

A solution of the title compound from step D (0.15 g, 0.37 mmol) in THF (1 mL) was added. The mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride (5 mL) and extracted with EtOAc (3x15 mL). The combined EtOAc layers were washed with brine and dried over sodium sulfate. The title compound was obtained after column chromatography using EtOAc: hexane / 15: 85 as the eluent. 1 H NMR (CDCl 3, 500 MHz) d 7.95 (s, 1 H), 7.87 (d, J = 1.5 Hz, 1 H), 7.83 (s, 2 H), 7.79 (d, J = 1.5 Hz, 1 H) , 5.83 (d, J = 8 Hz, 1 H), 4.95 (d, J = 16.5 Hz, 1 H), 4.53 (d, J = 16.5 Hz, 1 H), 4.19 (m, 1 H), 0.87 ( d, J = 6.5 Hz, 3H).

Step F 2"-amino-6" - (4S.5R) -5-f3.5-bis (trifluoromethyl) phenin-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4 '-methoxy-2-methyl-4"- (trifluoromethyl) -1 J': 3'J" Methylphenphenyl-4-carboxylate To a solution of the title compound from step E (0J7g, 0.26mmol) in EtOH ( 5 ml), tin chloride dihydrate (0.30 g, 1.32 g.) Was added. mmoles). The mixture was stirred at room temperature for 4 h. The LC-MS analysis indicated the complete consumption of the starting material. EtOH was removed. EtOAc (20 ml) was added to the residue. The mixture was washed with water, brine and dried over sodium sulfate. Removal of the solvent gave a white solid which was mixed with 4'-methoxy-2-methyl-3 '- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) biphenyl-4 methyl carboxylate (intermediate 11, excess), tetrakis (triphenylphosphine) palladium (5 mol%) and sodium carbonate (0.062 g, 0.58 mmole) in 7 ml of water / EtOH / toluene (1: 2: 4) and heated to reflux for 2 hr. CCD (EtOAc: hexane / 1: 3) showed that the reaction was over. The solvents were removed. Water (10 ml) was added. The organic compound was extracted with methylene chloride (3x 20 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after purification with preparative CCD using 20% EtOAc in hexane as the eluent. 1 H NMR (CDCl 3, 500 MHz) d a 2: 1 mixture of atropoisomers 7. 96 (m, 1 H), 7.88 (m, 2H), 7.73 (s, 0.66H), 7.66 (s, 0.33H), 7.44 (m, 1 H), 7.28 (m, 2H), 7.16 (m, 2H), 7.02-7.07 (m, 2H), 5.59 (d, J = 8 Hz, 0.66H), 5.42 (d, J = 8 Hz, 0.33H), 4.80 (d, J = 12 Hz, 0.33H) , 4.77 (d, J = 12 Hz, 0.66H), 3.95 (s, 3H), 3.94 (m, 1 H), 3.90 (s, 2H), 3.87 (s, 1 H), 3.82 (d, J = 12 Hz, 1 H), 2.38 (s, 1 H), 2.37 (s, 2 H), 0.59 (d, J = 6.5 Hz, 1 H), 0.54 (d, J = 6.5 Hz, 2 H).

Step G 2"- (((4S.5F?) - 5- [3,5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -6" -vodo-4'- methoxy-2-methyl-4"- (trifluoromethyl) -1 J ': 3'J" -terphenyl-4-carboxylic acid methyl ester To a solution of the title compound from step F (OX g, 0J 35 mmol) in chloroform ( 5 ml) at room temperature, n-pentyl nitrite (0.024 g, 0.20 mmole) and iodine (0.044 g, 0 J7 mmole) were added. The mixture was refluxed for 1 hr. The mixture was diluted with methylene chloride (10 ml). The solution was washed with saturated aqueous sodium thiosulfate, brine and dried over sodium sulfate. The residue was purified by preparative reverse phase HPLC to give the title compound. 1 H NMR (CDCl 3, 500 MHz): d 2: 1 mixture of atropoisomers 8.21 (s, 1 H), 7.97 (s, 1 H), 7.88 (s, 2 H), 7.72 (s, 1 H), 7.76 (m , 1 H), 7.44 (m, 1 H), 7.29 (m, 1 H), 7.20 (m, 1 H), 7J2 (m, 1 H), 7.00 (m, 1 H), 5.59 (d, J = 8 Hz, 0.66H), 53 (d, J = 8 Hz, OR 33H), 4 80 (d, J = 16 Hz, 1 H), 3 96 (d, J = 15 5 Hz, 1 H), 3 95 (s, 3H) , 3 90 (m, 1 H), 3 89 (s, 2H), 3 86 (s, 1 H), 2 04 (s, 1 H), 2 38 (s, 2H), O 60 (d, J = 6 5 Hz, 1 H), OR 54 (d, J = 6 5 Hz, 2H) LC-MS (M + 1) 852 1 Step H Acid 2"- ( { (4S.5 /?) - 5-f3.5-b? S (tpfluoromet? L) phen? N-4-met? L-2-oxo-1,3-oxazole? d? n-3-? l) met? l) -6"-iodo-4'-methox? -2-met? l-4" - (tr? fluoromet? l) -1.1 '3'.1"Jerfen α-4-carboxyl? To a solution of the title compound from step G (0 016 g, 0 0188 mmol) in dioxane (2 ml) at room temperature, an aqueous solution of LiOH H20 (0 007 g, 0 16 mmol) (1 ml) The mixture was stirred at room temperature for 5 hr CCD (EtOAc / hexane / 2 8) showed no starting material The solvent was removed 1N HCl (1 ml) was added The mixture was extracted with EtOAc (3x15 ml) The combined EtOAc layers were dried over sodium sulfate The title compound was obtained by preparative reversed phase HPLC H NMR (CDCI3, 500 MHz) d mixture 2 1 of atropoisomers 8 21 (s, 1 H), 8 01 (s, 1 H), 7 94 (d, J = 7 5 Hz, 1 H), 7 89 (s, 1 H), 7 72 (s, 1 H), 7 69 (s, 1 H) , 7 66 (d, J = 7 5 Hz, 1 H), 7 45 (m, 1 H), 7 37 (m, 1 H), 7 14 (m, 1 H), 7 00 (m, 1 H ), 5 60 (d, J = 8 Hz, 0 66H), 5 54 (d, J = 8 Hz, 0 33H), 4 82 (d, J = 7 5 Hz, 0 33H), 4 79 (d, J = 8 Hz, 0 66H), 3 99 (d, J = 10 Hz, 0 33H) , 3 96 (d, J = 9 5 Hz, 0 66H), 3 91 (m, 1 H), 3 90 (s, 2H), 3 86 (s, 1 H), 2 42 (s, 1 H) , 2 41 (s, 2H), 0 60 (d, J = 7 Hz, 1 H), 0 55 (d, J = 6 5 Hz, 2H) EXAMPLE 41 (4S.5?) - 5- [3,5-bis (trifluoromethyl) phenyl-3 - ([6'-hydroxy-2"-methyl-4- (trifluoromethyl) -1 J ': 3'J" -terphenyl -2-illmethyl) -4-methyl-1, 3-oxazolidin-2-one To a cold solution (-78X bath) of (4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl] -3-. { [6'-methoxy-2"-methyl-4- (trifluoromethyl) -1,1 ': 3', 1" Jerphenyl-2-yl] methyl} -4-methyl-1,3-oxazolidin-2-one (75 mg, 0.11 mmol) in dichloromethane (1 ml) was added boron tribromide (106.6 mg, 0.426 mmol). The resulting mixture was aged cold (-78X bath) for 1 hour then allowed to warm to room temperature overnight. The reaction was quenched with ice followed by extraction with dichloromethane. The combined extracts were washed with brine and then Na2SO4. The resulting mixture was filtered and concentrated. The residue was purified by preparative CCD on SiO2 (eluted with 30% ethyl acetate in hexanes) to give (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -3-. { [6'-hydroxy-2"-methyl-4- (trifluoromethyl) -1, V: 3'J" Jerphenyl-2-yl] methyl} -4-methyl-1,3-oxazolidin-2-one. CL-EM cale. = 653.16; found = 654.19 (M + 1) +.

The 1 H NMR signals are duplicated due to atropoisomerism 1 H NMR (CDCI 3, 500 MHz) d 7.87 - 7.84 (m, 1 H), 7.76 (s, 0.5 H), 7.72 - 7.65 (m, 2.5 H), 7.63 (s) , 1 H), 7.53 - 7.47 (m, 1 H), 7.33 - 7.23 (m, 3H), 7.23 - 7.16 (m, 2H), 7.12 (dd, J = 10.5, 2.5 Hz, 1 H), 7.04 ( d, J = 8.0 Hz, 0.5H), 7.02 (d, J = 8.5 Hz, 0.5H), 5.64 (d, J = 8.0 Hz, 0.5H), 5.32 (d, J = 7.5 Hz, 0.5H), 4.98, 4.92 (d, J = 16 Hz, 1 H), 4.23 (d, J = 15.5 Hz, 0.5H), 4.07 (d, J = 15.5 Hz, 0.5H), 3.89 - 3.82 (m, 0.5H) , 3.74 - 3.67 (m, 0.5H), 2.32, 2.28 (s, 3H), 0.58 (d, J = 7 Hz, 1.5H), 0.49 (d, J = 6.5 Hz, 1.5H).

EXAMPLE 42 (4S.5F?) - 5- [3,5-bis (trifluoromethyl) phenyl-4-methyl-3- (f3 '- (1 H -pyrazol-1-yl) -4- (trifluoromethyl) biphenyl-2- illmethyl) -1, 3-oxazolidin-2-one A mixture of (4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl] -3- [2-iodo-5- (trifluoromethyl) -benzyl) ] -4-Methyl-1, 3-oxazolidin-2-one (0.05 g, 0.084 mmol), 3- (1 H -pyrazol-1-yl) phenylboronic acid (0.031 g, 0.167 mmol), tetrakis (triphenylphosphine) palladium (5 mol%) and sodium carbonate (0.019 g, 0.18 mmoles) in 7 ml of water / EtOH / toluene (1: 2: 4) was heated to reflux for 4 hr. CCD (EtOAc: hexane / 1: 1) showed that the reaction was over. The solvents were removed. Water (10 ml) was added. The organic compound was extracted with methylene chloride (3x 10 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after column chromatography using EtOAc: hexane / 1: 1 as the eluent. 1 H NMR (CDCl 3, 500 MHz): d 8.02 (d, J = 2.5 Hz, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.76 (s, 1H), 7.75 (s, 2H), 7.73 (m, 1H), 7.71 (m, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.26 (m, 1H), 6.54 (t, J = 2 Hz, 1H), 5.55 (d, J = 7.5 Hz, 1H), 5.02 (d, J = 16 Hz, 1H), 4.21 (d, J = 16 Hz, 1H), 3.82 (m, 1H), 0.54 (d, J = 6.5 Hz, 3H). LC-MS (M + 1): 614.3.

EXAMPLE 43 4-f2 '- ( { (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) ) methyl) -6-methoxy-4 '- (trifluoromethyl) biphenyl-3-ip-5-methyl-1,3-thiazole-2-carboxylic acid ethyl ester 2 '- (((4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -6-methoxy- 4 '- (trifluoromethyl) biphenyl-3-carbaldehyde A mixture of (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -3- [2-iodo-5- (trifluoromethyl) -benzyl] - 4-methyl-1,3-oxazolidin-2-one (0.50 g, 0.84 mmol), 5-formyl-2-methoxyphenylboronic acid (0.22 g, 1.25 mmol), tetrakis (triphenylphosphine) palladium (48 mg, 5 mol%) and sodium carbonate (0J9 g, 1.84 mmol) in 20 ml of water / EtOH / toluene (1: 2: 4) was heated to reflux for 4 hr. CCD (CH CI2: hexane / 1: 1) showed that the reaction was over. The solvents were removed. Water (30 ml) was added. The organic compound was extracted with methylene chloride (3x 40 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after column chromatography using EtOAc: hexane / 3: 7 as the eluent. 1 H NMR (CDCl 3, 500 MHz): d 1: 1 mixture of atropoisomers 9.95 (s, 1 H), 7.62-7.98 (m, 6H), 7.42 (m, 1 H), 7.17 (m, 2H), 5.65 (d, J = 8 Hz, 0.5H), . 20 (d, J = 8 Hz, 0.5H), 4.96 (d, J = 15.5 Hz, 0.5H), 4.92 (d, J = 16.5 Hz, 0.5H), 3.85-4J 0 (m, 2H), 3.98 (s, 1.5H), 3.92 (s, 1.5H), 0.59 (d, J = 6.5 Hz, 1. 5H), 0.42 (d, J = 6 Hz, 1.5H).

Step B (4S.5) -5J3,5-bis (trifluoromethylphenyl-3- { R5 '- (1-hydroxypropyl) -2'-methoxy-4- (trifluoromethyl) biphenyl-2-ylmethyl) -4-methyl-1, 3-oxazolidin-2-one To a solution of the title compound from Step A (0.44 g, 0.73 mmol) in THF at 0X, EtMgBr (0.87 mL, 0.87 mmol, 1 M in THF) was added. ). The solution was stirred at 0X for 2 hr. The reaction was quenched with saturated ammonium chloride solution (10 ml). The organic compound was extracted with EtOAc (3x 15ml). The combined EtOAc layers were washed with brine and dried over sodium sulfate. The title compound was obtained after column chromatography using EtOAc: hexane / 1: 1 as the eluent. 1 H NMR (CDCl 3, 500 MHz): d mixture of atropoisomers and diastereomers 7.86 (s, 1 H), 7.61-7.71 (m, 4 H), 7.18-7.47 (m, 4 H), 6.99 (m, 1 H), 5.28-5.49 (m, 1 H), 4.92-5.07 (m, 1 H), 4.61 (m, 1 H), 3.92-4.14 (m, 1 H), 3.97 (m, 3 H), 3.66 -3.79 (m, 1 H), 1.80 (m, 2H), 0.98 (m, 3H), 0.50-0.60 (m, 3H).

Step C (4S, 5f?) - 5-f3.5-bis (trifluoromethyl) phenyl1-3- (r2Xmethoxy-5'-propionyl-4- (trifluoromethyl) b-phenyl-2-illmethyl) -4-methyl-1 , 3-oxazolidin-2-one To a solution of the title compound from step B (0.32 g, 0.50 mmol) in methylene chloride (10 ml) at room temperature, Dess-Martin periodinane (0.28 g, 0.65 mmol) was added. ). The mixture was stirred at room temperature for 4 h. CCD showed that the reaction was over (EtOAc: hexane / 2: 8). The mixture was filtered and the filtrate was concentrated. The title compound was obtained after column chromatography using EtOAc: hexane / 2: 8 as the eluent.

H NMR (CDCl 3, 500 MHz): d 1: 1 mixture of atropoisomers 8.06 (m, 1H), 7.86 (m, 2H), 7.62-7.75 (m, 4H), 7.40 (m, 1 H), 7.07 (m , 1 H), 5.65 (d, J = 8 Hz, 0.5H), 5.20 (d, J = 8 Hz, 0.5H), 4.97 (d, J = 15 Hz, 0.5H), 4.90 (d, J = 15.5 Hz, 0.5H), 4.09 (d, J = 15 Hz, 0.5H), 3.94 (s, 1.5H), 3.90 (s, 1.5H), 3.84 (d, J = 15.5 Hz, 0.5H), 3.70 -3.82 (m, 1 H), 3.00 (m, 2H), 1.22 (m, 3H), 0.59 (d, J = 7 Hz, 1.5H), 0.41 (d, J = 6.5 Hz, 1.5H).

Step D (4S.5R) -5-f3.5-bis (trifluoromethyl) phenyl-3- (f5X (2-bromopropanoyl) -2'-methoxy-4- (trifluoromethyl) biphenyl-2-illmethyl) -4-methyl -1, 3-oxazolidin-2-one To a solution of the title compound from step C (0.28 g, 0.44 mmol) in a 1: 1 mixture of MeOH / CH2Cl2 (5 mL) at room temperature, tetrabutylammonium tribromide was added. (0.28 g, 0.57 mmol). The mixture was stirred at room temperature for 24 hr. Water was added. The mixture was extracted with EtOAc (3 mL). The combined EtOAc layers were washed with brine and dried over sodium sulfate. The title compound is obtained after column chromatography using EtOAc: hexane / 2: 8 as the eluent. 1 H NMR (CDCb, 500 MHz): d mixture of atropoisomers and diastereomers 8.10-8.18 (m, 1 H), 7.85-7.98 (m, 2H), 7.62-7.77 (m, 4H), 7.39-7.46 (m, 1 H), 7.08-7.12 (m, 1 H), 4.88-5.65 (m, 3H), 4.06-4.12 (m, 1 H), 3.90 (m, 3H), 3.65-3.86 (m, 2H), 1.90 ( m, 3H), 0.37-0.59 (m, 3H).

Step E: 4-y2 '- (((4S.5?) - 5- [3,5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) Ethyl 6-methoxy-4 '- (trifluoromethyl) biphenyl-3-yl-1-5-methyl-l, 3-thiazole-2-carboxylate A mixture of the title compound of Example 67, Step D (0.040 g, 0.056 mmol) and ethyl thiooxamate (11 mg, 0.084 mmol) in EtOH (2 ml) was heated to reflux overnight. The reaction mixture was concentrated. The title compound was obtained after preparative CCD plate using EtOAc: hexane / 3: 7 as the eluent. LC-MS (M + 1): 747.2.

EXAMPLE 44 (4S.5f?) - 5-r3,5-bis (trifluoromethyl) phenyl-3- (2'-methoxy-5'-piperidin-1-yl-4- (trifluoromethyl) biphenyl-2-ylmethyl) -4- methyl-1,3-oxazolidin-2-one A mixture of (4S, 5) -5- [3,5-bis (trifluoromethyl) phenyl] -3- [2-iodo-5- (trifluoromethyl) -benzyl] - 4-methyl-1,3-oxazolidin-2-one (0.05 g, 0.084 mmol), 3- (piperidine) phenyl boronic acid (0.040 g, 0.167 mmol), tetrakis (triphenylphosphine) palladium (5 mol%) and sodium carbonate (0.019 g, 0.18 mmol) in 7 mL of water / EtOH / toluene (1: 2: 4) was heated to reflux for 4 hr. CCD (EtOAc: hexane / 1: 1) showed that the reaction was over. The solvents were removed. Water (10 ml) was added. The organic compound was extracted with methylene chloride (3x 10 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after column chromatography using EtOAc: hexane / 6: 4 as the eluent. LC-MS (M + 1): 631.1.

EXAMPLE 45 (4S.5f?) - 5-l, 3, 5-bis (trifluoromethyl) phenyl-1-4-methyl-3J [3'-pyrrolidin-1-yl-4- (trifluoromethyl) biphenyl-2-ipmethyl) -1, 3-oxazolidin-2-one A mixture of (4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl] -3- [2-iodo-5- (trifluoromethyl) -benzyl] -4-methyl -1, 3-oxazolidin-2-one (0.05 g, 0.084 mmol), 3- (pyrrolidine) phenyl boronic acid (0.032 g, 0.167 mmol), tetrakis (triphenylphosphine) palladium (5 mol%) and sodium carbonate ( 0.019 g, 0.18 mmol) in 7 mL of water / EtOH / toluene (1: 2: 4) was heated to reflux for 4 hr. CCD (EtOAc: hexane / 1: 1) showed that the reaction was over. The solvents were removed. Water (10 ml) was added. The organic compound was extracted with methylene chloride (3x 10 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after column chromatography using EtOAc: hexane / 6: 4 as the eluent. LC-MS (M + 1): 617.0.

EXAMPLE 46 2"- ((4R.5f?) - 3- [3,5-bis (trifluoromethyl) benzyl-4-methyl-2-oxo-1,3-oxazolidin-5-yl) -4'-methoxy-2-methyl acid -4"- (trifluoromethyl) -1, 1 ': 3M" -terphenyl-4-carboxylic acid Step A 4'-methoxy-2-methyl-2"- [(4 5R) -4-methyl-2-oxo-1,3-oxazolidin-5-ill-4" - (trifluoromethyl) -1 J ': 3'J methyl-methyl-4-carboxylate (4R, 5f?) - 5- [2-iodo-5- (trifluoromethyl) phenyl] -4-methyl-1,3-oxazolidin-2-one (intermediate 12, 100 mg, 0.269 mmole), 4'-methoxy-2-methyl-3 '- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) biphenyl-4-carboxylic acid methyl ester ( intermediary 11, 124 mg, 0.323 mmoles), adduct of 1 J '-bis (diphenylphosphino) ferrocene-palladium dichloride-dichloromethane (44 mg, 0.054 mmol), carbonate aqueous potassium (270 μl, 2M, 0.538 mmol) and 1,4-dioxane (2 ml) were sealed in a microwave vessel. The vessel was irradiated by microwave at 140X for 30 minutes. LC-MS of the aliquot indicated the complete consumption of starting iodine. The crude mixture was purified by SiO2 (preparative CCD plates, 50% ethyl acetate in hexanes) to give a glassy residue. The residue was further purified by SiO (preparative CCD plates, 10% ethyl acetate in dichloromethane) to give 4-methoxy-2-methyl-2"- [(4f?, 5ft) -4-methyl-? 2-oxo-1,3-oxazolidin-5-yl] -4"- (trifluoromethyl) -1,1 ': 3', 1" -methyl-4-carboxylic acid methyl ester LC-MS cale = 499.16; = 500.08 (M + 1).

Step B 2"-K4R, 5f?) - 3-f3,5-bis (trifluoromethyl) benzyl-1-4-methyl-2-oxo-1,3-oxazolidin-5-yl) -4'-methoxy-2-methyl-4"- (trifluoromethyl) -1 J ': 3M" Jerphenyl-4-carboxylic acid methyl ester 4-methoxy-2-methyl-2"- [(4f?, 5R) -4-methyl-2-oxo- 1, 3-oxazolidin-5-yl] -4"- (trifluoromethyl) -1, 1 ': 3'J" -methyl-4-carboxylic acid methyl ester (40 mg, 0.080 mmol) was dissolved in THF anhydrous (1 ml) and cooled in a water bath ice. Sodium hydride (60% w / w in mineral oil, 3.5 mg, 0.088 mmol) was added to the mixture. The reaction mixture was stirred cold (ice bath) for 10 min followed by the addition of 1- (bromomethyl) -3,5-bis (trifluoromethyl) benzene (22 μL, 36.8 mg, 0J20 mmol). The resulting mixture was stirred cold for 20 min then the cooling bath was removed. The aliquot in the 2.5 hour reaction time indicated approximately 50% conversion. The crude of the reaction was cooled (ice bath) and quenched with NH 4 Cl (aq, sat). The resulting biphasic mixture was treated with ethyl acetate. The combined organic extracts were dried over Na 2 SO 4, filtered and concentrated to give an oil. This oil was purified by preparative reverse phase HPLC (Kromasil 100-5C18, 100x21.1 mm) was eluted with a gradient mixture of MeCN (0.1% TFA, v / v) / H20 (0.1% TFA, v / v). The related fractions were combined and evaporated to give 2"- { (4 / =? 5f?) - 3- [3,5-bis (trifluoromethyl) benzyl] -4-methyl-2-oxo-1, 3-oxazolidin-5-yl.} - 4'-methoxy-2-methyl-4"- (trifluoromethyl) -1, 1 ': 3', 1" -terphenyl-4-carboxylic acid methyl ester. Unreacted starting material was also recovered CL-MS cale = 725.18; found = 726.19 (M + 1).

Step C Acid 2"- ((4 5R) -3-f3.5-bis (trifluoromethyl) benzyl-4-methyl-2-oxo-1,3-oxazolidin-5-yl) -4'-methoxy-2-methyl- 4"- (trifluoromethyl) -1.1 ': 3'.1" -terphenyl-4-carboxylic io 2"-. { (4R, 5F?) - 3- [3,5-bis (trifluoromethyl) benzyl] -4-methyl-2-oxo-1, 3-oxazolidin-5-yl} -4, -methoxy-2-methyl-4"- (trifluoromethyl) -1, r: 3M" Jerfenyl-4-methyl carboxylate (21 mg, 0.029 mmol), lithium hydroxide monohydrate (9 mg, 0.21 mmol), Water (0.4 ml) and 1,4-dioxane (1 ml) were stirred at 20X for 2 hours to complete the hydrolysis. The reaction mixture is acidified with HCl (aq, 1 ml). The resulting crude mixture was treated with ethyl acetate. The combined organic extracts were dried over Na 2 SO 4) filtered and concentrated to a clear oil. This oil was purified by preparative reverse phase HPLC (Kromasil 100-5C18, 100x21.1 mm) eluted with a gradient mixture of MeCN (0.1% TFA, v / v) / H20 (0.1% TFA, v / v). The related fractions were combined and evaporated to give 2"-. {(4f?, 5R) -3- [3,5-bis (trifluoromethyl) benzyl] -4-methyl-2-oxo-1, 3-acid. oxazolidin-5-yl.} - 4'-methoxy-2-methyl-4"- (trifluoromethyl) -1 J ': 3'J" -terphenyl-4-carboxylic acid LC-MS cale = 711.17; found = 712.28 (M + 1) +.

The signals of 1 H NMR are duplicated due to atropoisomepsmo 1 H NMR (CDCI 3, 500 MHz) d 8 01 (s, 0 4 H), 7 97 (s, 0 6 H), 7 95 (d, J = 7 0 Hz, 0 4 H ), 7 93 (d, J = 6 5 Hz, 0 6H), 7 81 (s, 0 4H), 7 77 (s, 0 6H), 7 75 (s, 0 4H), 7 71 (s, 0 6H), 768 (d, J = 6 5 Hz, 0 6H), 7 66 (d, J = 6 5 Hz, 0 4H), 7 62 (s, 1 H), 7 55 (s, 1 H) , 7 41 - 7 35 (m, 2H), 7 32 (d, J = 6 5 Hz, 0 4H), 7 23 (d, J = 6 5 Hz, 0 6H), 7 16 (d, J = 2 Hz, 0 4H), 7 08 (d, J = 7 5 Hz, 0 6H), 7 02 (d, J = 7 5 Hz, 0 4H), 6 98 (d, J = 2 0 Hz, 0 6H) , 5 22 (d, J = 4 Hz, 0 6H), 5 13 (d, J = 4 5 Hz, 0 4H), 4 82, 4 75 (d, J = 13 5 Hz, 1 H), 4 29 , 4 26 (d, J = 15 5 Hz, 1 H), 3 86 (s, 1 8 H), 3 59 (s, 1 2 H), 3 53 - 3 48 (m, 0 4 H), 3 30 -3 24 (m, 0 6H), 2 36, 2 22 (s, 3H), 0 89, 0 75 (d, J = 5 5 Hz, 3H) EXAMPLE 47 Step A (4 5R) -3- [3,5-b? S (tr? Fluoromet? L) benc? Ll-5- [2-iodo-5- (tr? Fluoromet? L) phen? Ll-4-met? l-l3-oxazole d-n-2-one (4 /? 5f?) - 5- [2-iodo-5- (tr? fluoromet? l) phen? l] -4-met? l- 1,3-oxazole d-n-2-one (intermediate 12, 451 g, 3,910 mmol) was dissolved in anhydrous THF (30 ml) and cooled in an ice bath. Sodium hydride (60%) was added. p / p in mineral oil, 172 mg, 4301 mmol) in the reaction mixture all at once. The reaction was stirred cold (ice bath) for 30 min followed by the addition of 1- (bromomet? L) -3,5-b? S (tr? fluoromet? l) benzene (1078 ml, 1 80 mg, 5 865 mmol) The crude mixture was cooled (ice bath) and quenched by adding NH4CI (aq, sat) when the reaction time was 5 hours The crude from the reaction was extracted with ethyl acetate. The combined organic extracts were dried over Na 2 SO 4, filtered and concentrated to an oil. The oil was purified by flash chromatography (S 1 O 2, Biotage 40 + M cartridge, EtOAc / hexanes) to give (4R, 5R) -3- [3,5-b? S (tr? Fluoromet? L) benc? L] -5- [2-iodo-5- (tr? Fluoromet? L) phen? L] -4 -met? l-1, 3-oxazole? d? n-2-one LC-MS cale = 596 98, found = 598 05 (M + 1) + 132 6 mg of unreacted starting material was also recovered Step B (4R5R-3J3.5-bis (trifluoromethyl) benzyl-5J5'-bromo-2'-methoxy-4- (trifluoromethyl) biphenyl-2-ill-4-methyl-1,3-oxazolidin-2-one (4R5f? ) -3- [3,5-bis (trifluoromethyl) benzyl] -5- [5'-bromo-2'-methoxy-4- (trifluoromethyl) biphenyl-2-yl] -4-methyl-1,3-oxazolidin -2-one (500 mg, 0.837 mmol), acid (5-bromo-2-methoxyphenyl) boronic acid (222 mg, 0.962 mmol), aqueous sodium carbonate (0.885 mL, 2M, 1.77 mmol), ethanol (300 μL) and toluene (2.5 ml) were stirred at room temperature for 0.5 hr followed by the addition of tetrakis (triphenylphosphine) palladium (0) (44 mg, 4.5 mol%) .The resulting mixture was heated in a 90X oil bath for 28.5 The reaction was then treated with water followed by extraction with ethyl acetate.The combined extracts were dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give an oil. This oil was purified by flash chromatography (Si02, cart uch Biotage 40 + M, gradient of EtOAc / hexanes) to give (4f?, 5 / :?) -3- [3,5-bis (trifluoromethyl) benzyl] -5- [5'-bromo-2'-methoxy -4- (trifluoromethyl) biphenyl-2-yl] -4-methyl-1,3-oxazolidin-2-one. CL-EM cale. = 657.04; found = 597.95 (M + 1) +.

Step C 2-amino-2"J (4R5R-3-f3,5-bis (trifluoromethyl) benzyl-4-methyl-2-oxo-1,3-oxazolidin-5-yl) -4'-methoxy-4" - ( trifluoromethyl) -1 J ': 3'J "Methylphenphenyl-4-carboxylate (4R5f?) -3- [3,5-bis (trifluoromethyl) benzyl] -5- [5, -bromo-2'-methoxy- 4- (trifluoromethyl) biphenyl-2-yl] -4-methyl-1,3-oxazolidin-2-one (358 mg, 0.545 mmol), [2-amino-4- (methoxycarbonyl) phenyl] boronic acid (214 mg , 1 J mmoles), dichloro bis (triphenylphosphine) palladium (11) (76.5 mg, 0.109 mmol), aqueous potassium carbonate (545 μl, 2M, 1.09 mmol) and ethanol (5 ml) were mixed and heated in a bath of oil at 80X The aliquot in the reaction time 2 hours and 3.5 hours indicated approximately 6% unreacted starting material More [2-amino-4- (methoxycarbonyl) phenyl] boronic acid (50 mg, 0.256) was added. mmoles) when the reaction time was 3 hours 45 minutes The aliquot did not show any additional progress The crude mixture was cooled and mixed with brine The volatile compounds were removed from the udo under reduced pressure. The resulting mixture was treated with water followed by extraction with ethyl acetate. The combined extracts were dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give a dark oil. The resulting oil was purified by flash chromatography (Si02, Biotage 40 + M cartridge, EtOAc / hexanes gradient) followed by purification by preparative CCD (Si 2, 10% ethyl acetate in dichloromethane) to give 2-amino-2. -. {(4c?, 5R) -3- [3,5-bis (trifluoromethyl) benzyl] -4-methyl-2-oxo-1,3-oxazolidin-5-yl.} -4'-methoxy -4"- (trifluoromethyl) -1, r: 3 ', 1" Jerfenyl-4-carboxylic acid methyl, LC-MS cale = 726.18, found = 727.29 (M + 1) +.

Step D 2"- { (4, 5R-3-r3,5-bis (trifluoromethyl) benzyl-1-4-methyl-2-oxo-1,3-oxazolidin-5-yl) -2-chloro-4'-methoxy -4"- (trifluoromethyl) -1 J ': 3'J" Methyl phenylphenylcarboxylate Amyl nitrite (33 μl, 29 mg, 0.248 mmole) and copper chloride (ll) (27 mg, 0.198 mmole) they were dissolved in anhydrous acetonitrile (1 ml) and sealed in a microwave vessel.The vessel was heated in an oil bath at 65. To this hot solution was added 2-amino-2"-. { (4R, 5R) -3- [3,5-bis (trifluoromethyl) benzyl] -4-methyl-2-oxo-1,3-oxazolidin-5-yl} Methyl 4'-methoxy-4"- (trifluoromethyl) -1, 1 ': 3'J" -terphenyl-4-carboxylate starting material (120 mg, 0J65 mmol, in 1 ml MeCN) in about 1 minute. The sealed container was then heated in a 65X oil bath for 1 hour. The aliquot (LC-MS) indicated that the reaction had been completed. The crude solution was filtered and purified by a preparative reverse phase HPLC (Kromasil 100-5C18, 100 x 21.1 mm) eluting with a MeCN gradient mixture (0.1% TFA, v / v) / H20 (0.1% TFA, v / v). The appropriate fractions were combined and evaporated under vacuum to give 2"- { (4R5f?) - 3- [3,5-bis (trifluoromethyl) benzyl] -4-methyl-2-oxo-1,3-oxazolidin -5-yl.) -2-chloro-4'-methoxy-4"- (trifluoromethyl) -1, 1 ': 3', 1" -terphenyl-4-carboxylic acid methyl-CL caleme = 745.13; found = 746.12 (M + 1) +.

Step E: Acid 2"J (4R5R-3- [3,5-bis (trifluoromethyl) benzyl-4-methyl-2-QXO-1,3-oxazolidin-5-yl) -2-chloro-4 ' -methoxy-4"- (trifluoromethyl) -1, 1 ': 3', 1" -terphenyl-4-carboxylic acid To a solution of 1,4-dioxane (2 ml) of 2"-. { (4R5f?) - 3- [3,5-bis (trifluoromethyl) benzyl] -4-methyl-2-oxo-1,3-oxazolidin-5-yl} Methyl-2-chloro-4'-methoxy-4"- (trifluoromethyl) -1, 1 ': 3,, 1" -terphene-4-carboxylate (65 mg, 0.087 mmol) was added a solution of lithium hydroxide monohydrate (36.5 mg, 0.87 mmol) in water (1 ml). The resulting mixture was turned into a slightly purple, cloudy mixture (of a clear yellow solution). The aliquot at the reaction time = 22 min indicated that the reaction had been completed. The crude of the reaction was acidified (1 N HCl, ac). The volatile compounds were removed from the crude mixture. The resulting mixture was purified by preparative reverse phase HPLC (Kromasil 100-5C18, 100 x 21.1 mm) eluting with a gradient mixture of MeCN (0.1% TFA, v / v) / H20 (0.1% TFA, v / v). The related fractions were combined and evaporated under vacuum to give a colorless glass. The glass was dissolved in dichloromethane and washed with water. The organic layer was separated, dried over NaSO4, filtered and concentrated under vacuum to give 2"-. {(4R5ft) -3- [3,5-bis (trifluoromethyl) benzyl] -4-methyl- acid. 2-oxo-1,3-oxazolidin-5-yl.} -2-chloro-4'-methoxy-4"- (trifluoromethyl) -1 J ': 3', 1" -terphenyl-4-carboxylic acid. -EM cale = 731.11; found = 732.08 (M + 1) + .1H NMR signals are duplicated due to atropoisomerism H-NMR (CDCI3, 500 MHz) 8.22, 8J 3 (d, J = 1.5 Hz, 1 H ), 8.05 -7.99 (m, 1 H), 7.79 (s, 1 H), 7.74 (s, 1 H), 7.70 - 7.64 (m, 1 H), 7.60 (s, 0.6H), 7.54 - 7.51 ( m, 1.8H), 7.50 - 7.44 (m, 1 H), 7.42 - 7.30 (m, 2H), 7J 3 (d, J = 2.5 Hz, 0.6H), 7.10 (d, J = 9.0 Hz, 0.6H ), 7J7 (d, J = 8.5 Hz, 0.4H), 5.22 (d, J = 4.5 Hz, 1 H), 4.82, 4.77 (d, J = 16 Hz, 1 H), 4.27, 4.22 (d, J = 16 Hz, 1 H), 3.87 (s, 1.8H), 3.59 (s, 1.2H), 3.49 - 3.43 (m, 0.4H), 3.32 - 3.25 (m, 0.6H), 0.86 (d, j = 6.0 Hz, 1.2H), 0.73 (d, J = 6.5 Hz, 1.8H).

EXAMPLE 48 Step A 3'-Amino-4'-chloro-2-methylbiphenyl-4-carboxylic acid methyl (3-amino-4-chlorophenyl) boronic acid (1.0 g, 5.834 mmol), methyl 4-bromo-3-methylbenzoate (1.337 g) , 5.834 mmoles), adduct of 1,1 '-bis (diphenylphosphino) ferrocene-palladium dichloride-dichloromethane (476 mg, 0.583 mmol), aqueous potassium carbonate (11.57 ml, 1 M, 11.57 mmol) and acetone (53 ml ) were mixed and heated in a 70X oil bath for 1.5 hours to complete the coupling. The volatile compounds were removed from the crude mixture under reduced pressure. The resulting mixture was treated with water followed by extraction with ethyl acetate. The combined extracts were dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give a dark oil. The resulting oil was purified by flash chromatography (Si02, Biotage 40 + M cartridge, 0-40% EtOAc in hexanes) to give 3'-am? no-4'-chloro-2-met? lb? phen? l-4-carboxylic acid methyl ester LC-MS cale = 275 07, found = 276 23 (M + 1 ) + Step B Methyl 3'-bromo-4'-chloro-2-meth? Lb? Phen? L-4-carboxylate 3'-am? No-4'-chloro-2-met? Lb? Phen? L-4-carboxylate of methyl (946 mg, 3 43 mmol) was dissolved in a mixture of CHBr 3 (5 ml) and dichloromethane (5 ml) To the above stirred mixture was added f-butyl nitrite (680 μl, 530 6 mg, 5 145 mmol). heated at 80 ° C for 30 minutes The aliquot (LC-MS) indicated the complete consumption of the starting material. The crude mixture was purified by flash chromatography (S? 02> Biotage cartridge 40 + S) to give 3'-bromo- Methyl 4'-chloro-2-methyl-methyl-phenyl-4-carboxylate LC-MS cale = 339 97, found = 340.98 (M + 1) + Step C 4'-Chloro-2-methyl-3 '- (4,4,5,5-tetramethyl-1,2-dioxaborolan-2-yl) biphenyl-4-carboxylic acid methyl 3'-bromo-4'-chloro-2- methyl methylbiphenyl-4-carboxylate (699 mg, 2.06 mmol), bis (pinacolato) diboro (556 mg, 2.47 mmol), adduct of 1, 1'-bis (diphenylphosphino) ferrocene-palladium dichloride-dichloromethane (226 mg, 0.277 mmol), potassium acetate (404 mg, 4J 2 mmol) and 1,4-dioxane (10 ml) were sealed in a beaker. microwave. The reaction mixture was irradiated by microwave at 140X for 45 minutes. The aliquot (LC-MS) indicated that the reaction was complete. The crude of the reaction was treated with water followed by extractions with ethyl acetate. The combined extracts were dried over Na2SO4 followed by filtration and concentration to give a dark oil as the crude mixture of 4'-chloro-2-methyl-3 '- (4,4,5,5-tetramethyl-1, 3.2 -dioxaborolan-2-yl) biphenyl-4-carboxylic acid methyl ester which was used in the next step without further purification. CL-EM cale. = 386.15; found = 387.13 (M + 1) +.

Step D 2"-f (4f?, 5R-3- [3,5-bis (trifluoromethyl) benzyl-1-4-methyl-2-oxo-1, 3-oxazolidin-5-yl) -4'-chloro-2-methyl-4"- (trifluoromethyl) -1 J ': 3M" -methylphenyl-4-carboxylic acid methyl (4R5R) -3- [3,5-bis (trifluoromethyl) benzyl] -5- [2-iodo-5- (trifluoromethyl) ) phenyl] -4-methyl-1,3-oxazolidin-2-one (103 mg, 0 J72 mmol, in 515 μl of toluene), 4'-chloro-2-methyl-3 '- (4,4,5, Methyl 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) biphenyl-4-carboxylate (100 mg, 0.259 mmol), adduct of 1,1-bis (diphenylphosphino) ferrocene-palladium dichloride-dichloromethane ( 14 mg, 10%), aqueous potassium carbonate (344 μl, 2M, 0.688 mmol), and ethanol (2 ml) were sealed in a microwave container. The reaction mixture was irradiated by microwave at 140X for 45 minutes. The LC / MS analysis indicated the complete consumption of the starting material. The crude material was purified by SiO (CCD-Prep 30% EtOAc / hex) to give a yellow residue. The residue was further purified by preparative reverse phase HPLC (Kromasil 100-5C18, 100 x 21 J mm) eluting with a gradient mixture of MeCN (0.1% TFA, v / v) / H20 (0.1% TFA, v / v) giving 2"- { (4R5F?) - 3- [3,5-bis (trifluoromethyl) benzyl] -4-methyl-2-oxo-1,3-oxazolidin-5-yl.} -4 '-chloro-2-methyl-4"- (trifluoromethyl) -1 J ': 3'J "-terphenyl-4-carboxylic acid methyl ester LC-MS cale = 729.13; found = 730.14 (M + IV * Step E Acid 2"J (4R5R-3-f3,5-bis (trifluoromethyl) benzyl-4-methyl-2-oxo-1,3-oxazolidin-5-yl) -4'-chloro-2-methyl-4" - (trifluoromethyl) ) -1 J ': 3'J "Jerphenyl-4-carboxylic To a solution in 1,4-dioxane (3 ml) of 2" -. { (4R, 5R) -3- [3,5-bis (trifluoromethyl) benzyl] -4-methyl-2-oxo-1,3-oxazolidin-5-yl} 4'-Chloro-2-methyl-4"- (trifluoromethyl) -1 J ': 3', 1" -terphenyl-4-carboxylic acid methyl ester (65 mg, 0.089 mmol) was added a solution of lithium hydroxide monohydrate (26 mg, 0.623 mmol) in water (1.2 ml). The aliquot in the 2 hour reaction time indicated that the reaction had been completed (atropoisomers present). The crude mixture was acidified with HCl (aq, 1 N, 1 ml). The cloudy precipitation was dissolved by MeCN (2 ml). The resulting solution was purified by reverse phase HPLC-preparative (Kromasil 100-5C18, 100x21.1 mm) eluting with a gradient mixture of MeCN (0.1% TFA, v / v) / H20 (0.1% TFA, v / v) giving acid 2"- { (4R5R) -3- [3,5-bis (trifluoromethyl) benzyl] -4-methyl-2-oxo-1, 3- oxazolidin-5-yl} 4'-chloro-2-methyl-4"- (trifluoromethyl) -1 J ': 3'J" -terphenyl-4-carboxylic acid. CL-EM cale. = 715.12; found = 716.20 (M + 1) +. H NMR signals are duplicated due to atropoisomerism. 1 H NMR 1 H NMR (CDCl 3, 500 MHz) 8.04 (s, 0.5H), 8.00 (s, 0.5H), 7.98 -7.93 (m, 1 H), 7.80-7.75 (m, 1.5H), 7.75 (s, 0.5H), 7.74 - 7.69 (m, 1 H), 7.63 -7.59 (m, 2H), 7.58, 7.56 (d, J = 3.5 Hz, 1 H), 7.42 (d, J = 7.5 Hz, 0.5H) , 7.40 -7.34 (m, 1.5H), 7.31 (d, J = 7.5 Hz, 0.4H), 7.28 (d, J = 2 Hz, 0.6H), 7.24 (d, J = 8.0 Hz, 0.6H), 7.09 (d, J = 2.5 Hz, 0.4H), 5.14 (d, J = 5.5 Hz, 0.4H), 5J0 (d, J = 4.5 Hz, 0.6H), 4.83 (d, J = 16 Hz, 0.6 H), 4.73 (d, J = 16 Hz, 0.4H), 4.28 (d, J = 16 Hz, 1 H), 3.57 - 3.51 (m, 0.4H), 3.42 - 3.35 (m, 0.6H), 2.35 , 2.25 (s, 3H), 0.91 (d, J = 6.5 Hz, 1.8H), 0.85 (d, J = 6 Hz, 1.2H).

EXAMPLE 49 (4S.5R) -5-f3.5-bis (trifluoromethyl) phenan-3- (f6'-chloro-4"- (hydroxymethyl) -2" -methyl-4- (trifluoromethyl) -1.1 ': 3 'J' Jerphenyl-2-illmethyl) -4-methyl-1,3-oxazolidin-2-one To a solution of the acid of example 34 (1.0 g, 1.40 mmol) in THF (15 ml) at -78X was added borane (2.79 mL, 2.79 mmol, 1 M solution in THF) The solution was stirred at -78X for 30 min and slowly warmed to room temperature for 2 hr CCD showed no more starting material (EtOAc / hexane 3: 7). Water (10 ml) was added The mixture was extracted with EtOAc (3 x 20 ml) The combined EtOAc layers were washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. the residue was purified by column chromatography on silica gel, eluting with EtOAc / hexane (30:70) to give the title compound as a colorless solid.1H NMR (CDCl3, 500 MHz): d a mixture of 1: 1 artopoisomers 7.89 (s, 1 H), 7.73 (s, 1 H), 7.72 (s, 2 H), 7.70 (m, 1 H), 7.59 (d, J = 8.0 Hz, 1 H), 7.49 (d, J = 8.5 Hz, 0.5H), 7.47 (d, J = 8.0 Hz, 0.5H), 7.39-7.36 (m, 2H), 7.32 (s, 1 H), 7.25 (m 1.5H), 7.20 (d, J = 2.0 Hz, 0.5H), 5.62 (d, J = 8.0 Hz, 1 H), 4.99 (d, J = 15.0 Hz, 0.5H), 4.83 (d, J = 16.0 Hz, 0.5H), 4.73 (s, 2H), 4.15 (s, 1 H), 4.10 (d, J = 16.0 Hz, 0.5H), 4.01 (d, J = 15.5 Hz, 0.5H), 3.96 (m, 0.5H), 3.86 (m, 0.5H), 2.34 (s, 1.5H), 2.33 (s, 1.5H), 0.61 (d, J = 6.5 Hz, 1.5H), 0.58 (d, J = 6.5 Hz, 1.5H).

EXAMPLE 50 2"- (((4S.5R-5- [3,5-b? S (tr? Fluoromet? L) phen? N-4-met? L-2-oxo-1, 3-oxazole? D? N -3-? L) met? L) -4'-chloro-2-met? L-4"- (tr? Fluoromet? L) -1 J '3M" Jerfen? L-4-carbaldehyde Peryodinan from Dess-Martin (145 mg, 0 34 mmol) was added to an alcohol solution of Example 49 (200 mg, 0 285 mmol) in methylene chloride (5 mL) at room temperature. The resulting suspension was stirred at room temperature for 1 hr. No material. The starting material was seen by CCD (EtOAc / hexane 2 8) The solid was filtered The filtrate was concentrated The residue was purified by column chromatography on silica gel, eluting with EtOAc / hexane (30-70) to give the title compound as a colorless solid 1 H NMR (CDCl 3, 500 MHz) d a mixture of 6 4 of artopoisomers 10 03 (s, 1 H), 7 90 (s, 2 / 5H), 7 89 (s, 3 / 5H), 7 83 (s, 1 H), 7 78 (d, J = 8 0 Hz, 3 / 5H), 7 75 (d, J = 8 0 Hz, 2/5 H), 7 74 (s, 1 2H), 7 73 (s, 0 8H), 7 72 (s, 2 / 5H), 7 70 (s, 3 / 5H), 7 64 (d, J = 8 0 Hz, 1 H), 7 52 (d, J = 8 0 Hz, 3 / 5H), 7 47 (d, J = 8 0 Hz, 2 / 5H), 7 46 (d, J = 8 0 Hz, 3 / 5H), 7 43 (d, J = 8 0 Hz, 2 / 5H), 7.40 (m, 1 H), 7.28 (m, 1.5H), 7.23 (d, J = 2.0 Hz, 0.5H), 5.64 (d, J = 8.0 Hz, 1 H), 5.04 (d, J = 15.5 Hz, 3 / 5H), 4.83 (d, J = 16 Hz, 2 / 5H), 4.09 (d, J = 16 Hz, 2 / 5H), 4.01 (d, J = 15.0 Hz, 3 / 5H), 4.00 (m, 2 / 5H), 3.91 (m, 3 / 5H), 2.43 (s, 1.8H), 2.41 (s, 1.2H), 0.65 (d, J = 6.5 Hz, 1.8H ), 0.61 (d, J = 7.0 Hz, 1 .2H).

EXAMPLE 51 (4S, 5R-5-f3.5-bis (trifluoromethyl) phenyl1-3-d6'-chloro-4"- (1-hydroxyethyl) -2" -methyl-4- (trifluoromethyl) -1, 1 ' : 3'.1"Jerphenyl-2-illmethyl) -4-methyl-1,3-oxazolidin-2-ojia MeMgBr (0.274 mL, 0.274 mmol, 1 M solution) was added to an aldehyde solution of Example 50 (160 mg, 0.229 mmole) in THF (3 mL) at -78X The solution was stirred at -78X for 2 h, saturated ammonium chloride solution was added, the mixture was extracted with EtOAc (3 x 10 mL). of combined EtOAc were washed with brine, and dried over sodium sulfate The residue was purified by column chromatography on silica gel, eluting with EtOAc / hexane (30:70) to give the title compound as a colorless solid. 1 H NMR (CDCb, 500 MHz): d a 1: 1 mixture of artopoisomers 7.89 (s, 1 H), 7.72 (m, 4 H), 7.58 (d, J = 8.5 Hz, 1 H), 7.48 (m, 1 H), 7.38 (m, 1 H), 7.32 -7.20 (m, 4H), 5.62 (d, J = 8.0 Hz, 1 H), 5.00 (d, J = 15.5 Hz, 0.5H), 4.93 (m , 1 H), 4.82 (d, J = 16.0 Hz, 0.5H), 4J 0 (d, J = 15.5 Hz, 0.5H), 4.01 (d, J = 15.5 Hz, 0.5H), 3.88 (m, 0.5 H), 3.87 (m, 0.5H), 2.34 (s, 1.5H), 2.33 (s, 1.5H), 1.55 (m, 3H), 0.61 (d, J = 6.5 Hz, 1.5H), 0.58 (d) , J = 6.5 Hz, 1.5H). LC / MS: M + -18: 698.16.

EXAMPLE 52 (4S.5R-3J [4"-acetyl-6'-chloro-2" -methyl-4- (trifluoromethyl) -1 J ': 3M "-terphenyl-2-illmethyl) -5- [3.5 bis (trifluoromethyl) phenin-4-methyl-1,3-oxazolidin-2-one Dess-Martin periodinane (58.3 mg, 0.J37 mmol) was added to a solution of the alcohol of Example 51 (82 mg, 0.05 mmol). mmoles) in methylene chloride (5 ml) at room temperature The resulting suspension was stirred at room temperature for 1 hr.

CCD (EtOAc / hexane 2: 8). The solid was filtered. The filtrate was concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc / hexane (20 80) to give the title compound as a colorless 1 H NMR solid (CDCl 3, 500 MHz) d a mixture of 1 1 of 7 90 artopoisomers (s) , 1 H), 7 89 (s, 1 H), 7 84 (d, J = 8 Hz, 1 H), 7 72 (m, 4 H), 7 62 (d, J = 8 5 Hz, 1 H) , 7 51 (d, J = 8 0 Hz, 0 5H), 7 46 (d, J = 8 0 Hz, 0 5H), 7 40-7 34 (m, 2H), 7 26 (d, J = 2 5 Hz, 0 5H), 7 21 (d, J = 2 5 Hz, 0 5H), 5 62 (d, J = 8 0 Hz, 1 H), 5 02 (d, J = 15 5 Hz, 0 5H ), 4 83 (d, J = 16 0 Hz, 0 5H), 4 08 (d, J = 16 0 Hz, 0 5H), 4 01 (d, J = 15 5 Hz, 0.5H), 3 99 ( m, 0 5H), 3 90 (m, 0 5H), 2 64 (s, 3H), 2 40 (s, 1 5H), 2 39 (s, 1 5H), 0 64 (d, J = 6 5 Hz, 1 5H), 0 62 (d, J = 6 5 Hz, 1 5H) LC / MS M + 714 01 EXAMPLE 53 (4S.5ffl-5- [3,5-bis (trifluoromethyl) phenyl-3- (6'-chloro-4"- (1-hydroxy-1-methylethyl) -2" -methyl-4- (trifluoromethyl) - 1, 1 ': 3'.1"-terphenyl-2-illmethyl) -4-methyl-1,3-oxazolidin-2-one MeMgBr (0.168 mL, 0.168 mmol, 1 M solution) was added to a ketone solution of Example 52 (80 mg, 0.112 mmol) in THF (3 mL) at -78X The solution was stirred at -78X for 2 h, saturated ammonium chloride solution was added, the mixture was extracted with EtOAc (3 x 10 mL). The combined EtOAc layers were washed with brine, and dried over sodium sulfate The residue was purified by column chromatography on silica gel, eluting with EtOAc / hexane (30:70) to give the title compound as a solid colorless H NMR (CDCl 3, 500 MHz): d a 1: 1 mixture of artopoisomers 7.89 (s, 2H), 7.83 (d, J = 8 Hz, 1 H), 7.72 (m, 4H), 7.63 (d , J = 8.5 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 0.5H), 7.46 (d, J = 8.0 Hz, 0.5H), 7.40-7.34 (m, 2H), 7.27 (d, J = 2.0 Hz, 0.5H), 7.21 (d, J = 2.5 Hz, 0.5H), 5.64 (d, J = 8.0 Hz, 0.5H), 5.63 (d, J = 8.0 Hz, 0.5H), 5.02 (d , J = 16.0 Hz, 0.5H), 4.83 (d, J = 16.0 Hz, 0.5H), 4 .08 (d, J = 16.0 Hz, 0.5H), 4.01 (d, J = 15.5 Hz, 0.5H), 4.00 (m, 0.5H), 3.90 (m, 0.5H), 2.41 (s, 1.5H) , 2.39 (s, 1.5H), 1.60 (m, 3H), 1.28 (m, 3H), 0.64 (d, J = 6.5 Hz, 1.5H), 0.62 (d, J = 6.5 Hz, 1.5H).

EXAMPLE 54 Acid 2"- (((4S, 5R-5- [3,5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -6'-Jouro-4'- methoxy-2-methyl-4"- (trifluoromethyl) -1, 1 ': 3'.1" -terphenyl-4-carboxylic acid Step A: Methyl 2'-fluoro-4'-methoxy-2-methyl-phenyl-4-carboxylate A mixture of 4-bromo-3-fluoroanisole (500 mg, 2.44 mmole), 4'-methoxy-2-methyl -3 '- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) biphenyl-4-carboxylic acid methyl ester (875 mg, 3.17 mmol), tetrakis (triphenylphosphine) palladium (282 mg , 5 mol%) and sodium carbonate (569 mg, 5.37 mmol) in 20 ml of water / EtOH / toluene (1.2.4) was heated at reflux for 4 h. CCD (CH2CI2 hexane / 1 1) showed that the reaction was complete The solvents were removed. Water (10 ml) was added. The organic compound was extracted with methylene chloride (3x 10 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after column chromatography using CH 2 Cl 2: hexane / 6: 4 as the eluent). 1 H NMR (CDCl 3, 500 MHz): d 7.98 (s, 1 H), 7.92 (dd, J = 8.0, 1.5 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 7.16 (t, J = 8.5 Hz, 1 H), 6.80 (dd, J = 8.5, 2.5 Hz, 1H), 6.77 (dd, J = 11.5, 2.5 Hz, 1 H), 3.95 (s, 3H), 3.88 (s, 3H) ), 2.28 (s, 3H).

Step B: Methyl 2'-fluoro-5'-iodo-4'-methoxy-2-methylbiphenyl-4-carboxylate A solution of the title compound from step A (1.30 g, 4.74 mmol) in MeOH / EtOAc (10: 1) (10 mL) was added to a mixture of Ag2SO4 (1.47 g, 4.74 mmol) and 12 (1.20 g, 4.74 mmol) in MeOH (20 mL) at room temperature. The mixture was stirred at room temperature for 4 h. The color of the solution changed from coffee to light yellow. The mixture was filtered. The filtrate was concentrated. The residue was purified by column chromatography, eluting with EtOAc / hexane (5:95) to give the title compound as a colorless solid). 1 H NMR (CDCl 3, 500 MHz): d 7.98 (s, 1 H), 7.92 (dd, J = 8.0, 2.0 Hz, 1 H), 7 67 (d, J = 8 5 Hz, 1 H), 7 28 (d, J = 9 OHz, 1 H), 6 69 (d, J = 11 5 Hz, 1 H), 3 96 (s, 3H), 3 95 (s, 3H), 2 27 (s, 3H) Step C 2"-q (4S, 5R-5- [3,5-b? S (tr? Fluorometinfen? 1-4-met? L-2-oxo-1,3-oxazole? D? N-3? ) methanol) -6'Jluoro-4'-methox? -2-met? l-4"- (trifluoromet? l) -1, 1'3'J" -terfen? l-4-carbox? lato methyl (4S, 5F?) - 5- [3,5-b? s (tpfluoromet? l) phen? l] -4-met? l-3- [2- (4,4,5,5-tetramet? l-1, 3,2-d-oxaborolan-2-? l) -5- (tr? fluoromet? l) benc? l] -1, 3-oxazole? d? n-2-one-methane (1 30) g, 2 18 mmol) (intermediate 9), the title compound of step B (1 30 g, 3 25 mmol), tetrak? s (tr? phen? lfosf? n) paladin (250 mg, 10 mol% ) and sodium carbonate (507 mg, 4 79 mmoles) in 50 ml of water / EtOH / toluene (1 2 4) was heated at reflux for 4 hr CCD (CH2CI2 hexane / 1 1) showed that the reaction was complete The solvents were removed Water (20 ml) was added The organic compound was extracted with methylene chloride (3x 30 ml) The combined methylene chloride layers were washed with brine, and dried over sodium sulfate The title compound was obtained after column chromatography using CH2CI2 hexane / 8 2 com or the 1 H NMR eluent (CDCl 3, 500 MHz) d a mixture of 1 1 Arthopoisomers 7.98 (d, J = 4.5 Hz, 1 H), 7.89 (s, 2H), 7.68 (m, 4H), 7.42 (t, J = 6.0 Hz, 1 H), 7.30 (d, J = 7.5 Hz, 0.5H), 7.26 (d, J = 7.5 Hz, 0.5H), 7.07 (t, J = 8.0 Hz, 1 H), 6.87 (d, J = 5.5 Hz, 0.5H), 6.85 (d, J = 6.0 Hz, 0.5H), 5.63 (d, J = 8.0 Hz, 0.5H), 5.41 (d, J = 8.0 Hz, 0.5H), 5.00 (d, J = 15.5 Hz, 0.5H), 4.92 (d, J = 16.0 Hz, 0.5H), 4.17 (d, J = 15.5 Hz, 0.5H), 3.95 (d, J = 16.0 Hz, 0.5H), 3.95 (s, 3H), 3.88 (s, 3H), 3.84 ( m, 1H), 2.32 (s, 1.5H), 2.28 (s, 1.5H), 0.64 (d, J = 7.0 Hz, 1.5H), 0.62 (d, J = 6.5 Hz, 1.5H). LC / MS M + 744.2 Step D: 2"- (((4S, 5R-5- [3,5-bis (trifluoromethyl) phenyl-4-methyl-2-QXO-1, 3-oxazolidin-3-yl) methyl) -6 'acid Fluoro-4'-methoxy-2-methyl-4"- (trifluoromethyl) -1,1 ': 3M" -terphenyl-4-carboxylic acid The title compound of step C (1.97 g, mmol) was stirred with LiOH ( 5 eq) in a 2: 1 mixture of dioxane and water at room temperature overnight The solvent was removed and the aqueous solution was acidified with 1 N HCl to pH ~ 4. The organic compound was extracted with EtOAc (3 x 30 ml) The combined EtOAc layers were washed with brine and dried over sodium sulfate The title compound was obtained after column chromatography eluting with EtOAc / hexane (1: 1). 1 H NMR (CDCl 3, 500 MHz): d a 1: 1 mixture of artopoisomers 8.03 (d, J = 4.5 Hz, 1 H), 7.95 (d, J = 8.5 Hz, 1 H), 7.89 (s, 1 H ), 7.73-7.65 (m, 4H), 7.43 (m, 1 H), 7.34 (d, J = 7.5 Hz, 0.5H), 7.29 (d, J = 7.5 Hz, 0.5H), 7.08 (t, J) = 8.5 Hz, 1 H), 6.88 (d, J = 5.5 Hz, 0.5H), 6.86 (d, J = 6.5 Hz, 0.5H), 5.63 (d, J = 8.0 Hz, 0.5H), 5.42 (d , J = 8.5 Hz, 0.5H), 5.01 (d, J = 16.0 Hz, 0.5H), 4.93 (d, J = 16.0 Hz, 0.5H), 4.17 (d, J = 16.0 Hz, 0.5H), 3.95 (d, J = 16.0 Hz, 0.5H), 3.89 (s, 3H), 3.84 (m, 1 H), 2.34 (s, 1.5H), 2.30 (s, 1.5H), 0.61 (d, J = 7.0 Hz, 1.5H), 0.50 (d, J = 6.5 Hz, 1.5H).

EXAMPLE 55 Acid 2"- (((4S.5R) -5- [3,5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -2-methyl- 4"- (trifluoromethyl) -1.r: 3M" Jerphenyl-4-carboxylic Step A: (4S.5) -5-y3.5-bis (trifluoromethyl) phenin-3 - ([3'-bromo-4- (trifluoromethyl) biphenyl-2-ipmethyl) -4-methyl-1, 3- oxazolidin-2-one A mixture of (4S, 5?) - 5- [3,5-bis (trifluoromethyl) phenyl] -3- [2-iodo-5- (trifluoromethyl) benzyl] -4-methyl-1, 3-oxazolidin-2-one (2.0 g, 3.35 mmol), 3-bromo-phenylboronic acid (0.74 g, 3.68 mmol), and sodium carbonate (0.71 g, 6.70 mmol) in 21 ml of 1: 2 mixture: 4 water: EtOH: toluene was stirred at room temperature for 30 min. A catalytic amount of tetrakis (triphenylphosphine) palladium (0.093 g, 5 mol%) was added. The mixture was stirred under reflux for 3 hr. The solvents were removed. Water (10 ml) was added. The mixture was extracted with methylene chloride (3x30 ml). The combined methylene chloride layers were washed with brine and dried over sodium sulfate. The title compound was obtained after column chromatography using CH2Cl2: hexane / 1: 1 as the eluent.

Step B: 2"-f ((4S.5ff) -5-y3.5-b1s (trifluoromethyl) phenyl1-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -2-methyl-4"- (trifluoromethyl) -1 J ': 3M" Methylphenphenyl-4-carboxylate A mixture of 4'-methoxy-2-methyl-3' - (4,4,5 , Methyl 5-tetramethyl-1,2-dioxaborolan-2-yl) biphenyl-4-carboxylate (150 mg, 0.542 mmol), compound of the title of step A (224 mg, 0.358 mmol), tetrakis (triphenylphosphine) palladium (20.66 mg, 5 mol%) and sodium carbonate (76 mg, 0.715 mmol) in 14 ml of water / EtOH / toluene (1: 2: 4) was heated to reflux for 1 hr. CCD (CH2Cl2: hexane / 1: 1) showed that the reaction was complete. The solvents were removed. Water (10 ml) was added. The organic compound was extracted with methylene chloride (3x 10 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after column chromatography using CH 2 Cl 2: hexane / 8: 2 as the eluent. 1 H NMR (CDCl 3, 500 MHz): d 7.99 (s, 1 H), 7.92 (dd, J = 7.5, 1.5 Hz, 1 H), 7.88 (s, 1 H), 7.75 (s, 1 H), 7.71 (s, 2 H), 7.67 (m, 1 H), 7.57 (t, J = 7.5 Hz, 1 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.42 (m, 1H), 7.35-7.28 (m, 3H), 5.53 (d, J = 8 0 Hz, 1 H), 4.97 (d, J = 15.5 Hz, 1 H), 4.25 (d, J = 16.0 Hz, 1 H), 3.95 (s, 3H), 3.80 (m, 1 H), 2.36 (s, 3H), 0.48 (d, J = 6.5 Hz, 3H).

Step C: Acid 2"- (((4S, 5R-5-f3,5-bis (trifluoromethylfenin-4-methyl-2-OXO-1,3-oxazolidin-3-yl) methyl) -2 -methyl-4"-arifluoromethyl) -1, r: 3'J" Jerphenyl-4-carboxylic The title compound of step B (30 mg, 0.043 mmol) is stirred with LiOH (5 eq) in a 2: 1 mixture of dioxane and water at room temperature overnight. The solvent was removed and the aqueous solution was acidified with 1 N HCl to pH ~ 4. The organic compound was extracted with EtOAc (3 x 10 ml). The combined EtOAc layers were washed with brine and dried over sodium sulfate. The title compound was obtained after reverse phase HPLC as a colorless solid. 1 H NMR (CDCl 3, 500 MHz): d 8.05 (s, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.90 (s, 1 H), 7.75 (s, 1 H), 7.72 (s) , 2H), 7.67 (m, 1 H), 7.59 (t, J = 7.5 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.44 (m, 1 H), 7.37 (m, 2H), 7.30 (m, 1 H), 5.54 (d, J = 8.0 Hz, 1 H), 4.98 (d, J = 15.5 Hz, 1 H), 4.25 (d, J = 16.0 Hz, 1 H), 3.81 (m, 1 H), 2.40 (s, 3H), 0.49 (d, J = 6.5 Hz, 3H). LC / MS (M + 1) 682.1.

EXAMPLE 56 Acid 2"- (((4S, 5R-5-f3,5-bis (trifluoromethyl) phenin-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -6'-fluoro-4"- (trifluoromethyl) -1.1 ': 3M" -terphenyl-4-carboxylic acid Step A: (4S, 5) -3- (3'-amino-4'-Jouro-4- (trifluoromethyl) biphenyl-2-illmethyl) -5-f3,5-bis (trifluoromethyl) phen-4 -methyl-113-oxazolidin-2-one A mixture of (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -3- [2-iodo-5- (trifluoromethyl) benzyl] - 4-methyl-1,3-oxazolidin-2-one (1.1 g, 1.84 mmol), 3-amino-4-fluorophenylboronic acid (0.43 g, 2.76 mmol), sodium carbonate (0.39 g, 3.68 mmol), and amount catalytic tetrakis (triphenylphosphine) palladium (0.213 g, 10 mol%) in 14 ml of 1: 2: 4 mixture of water: EtOH: toluene was stirred under reflux for 2 hr. The solvents were removed. Water (10 ml) was added. The mixture was extracted with methylene chloride (3x10 ml). The combined methylene chloride layers were washed with brine and dried over sodium sulfate. The title compound was obtained after column chromatography using CH2Cl2: hexane / 7: 3 as the eluent. 1 H NMR (CDCl 3, 500 MHz): d 7.89 (s, 1 H), 7.73 (s, 2 H), 7.70 (s, 1 H), 7.64 (d, J = 8.5 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.09 (dd, J = 11, 8.5 Hz, 1 H), 6.74 (dd, J = 8.0, 2.5 Hz, 1 H), 6.62 (m, 1 H), 5.55 (d, J = 8.5 Hz, 1 H), 4.94 (d, J = 15.5 Hz, 1 H), 4.23 (d, J = 16.0 Hz, 1 H), 3.80 (m, 1 H), 1.60 (br s, 2 H), 0.51 (d, J = 6.5 Hz, 3 H).

Step B: (4S, 5R-5- [3,5-bis (trifluoromethyl) phen-3-J'4'-Fluoro-3'-vodo-4- (trifluoromethyl) biphenyl-2-ylmethyl) -4-methyl- 1, 3-oxazolidin-2-one N-pentyl nitrite (0.42 g, 3.58 mmol) and iodine (0.68 g, 2.69 mmol) were added to a solution of the title compound from step A (1.04 g, 1.79 mmol) in chloroform (10 ml). The mixture was stirred under reflux for 1 hr. The mixture was diluted with methylene chloride (10 ml). The purple solution was washed with saturated sodium thiosulfate solution, brine, and dried over sodium sulfate. The title compound was obtained after column chromatography using EtOAc: hexane / 1: 9 as the eluent. 1 H NMR (CDCl 3, 500 MHz): d 7.90 (s, 1 H), 7.75 (s, 2 H), 7.74 (m, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.42 (d, J = 7.5 Hz, 1 H), 7.30 (m, 2H), 7.20 (t, J = 8.0, Hz, 1 H), 5.55 (d, J = 8.0 Hz, 1 H), 4.89 (d, J = 16.0 Hz, 1 H), 4J5 (d, J = 16.0 Hz, 1 H), 3.84 (m, 1 H), 0.51 (d, J = 6.5 Hz, 3H).

Step C: 2"- (4S, 5R-5- [3,5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -6'-fluoro-4" - (trifluoromethyl) -1,1 ': methyl 3-methylphenyl-4-carboxylate A mixture of the title compound from step B (60 mg, 0.087 mmol), 4-methoxycarbonylphenylboronic acid (31.2 mg, 0.174 mmol), sodium carbonate (18.4 mg, 0.74 mmoles), and a catalytic amount of tetrakis (triphenylphosphine) palladium (20 mg, 20 mol%) in 7 ml of a 1: 2: 4 mixture of water: EtOH: toluene was stirred under reflux for 2 hours. The solvents were removed, water (10 ml) was added, the mixture was extracted with methylene chloride (3x10 ml) The combined methylene chloride layers were washed with brine and dried over sodium sulfate. The title was obtained after column chromatography using CH2Cl2: hexane / 7: 3 as the eluent.1H NMR (CDCl3, 500 MHz): d 8.15 (d, J = 8.5 Hz, 2H), 7.89 (s, 1 H), 7.74 (s, 1 H), 7.72 (s, 2H), 7.67 (m, 2H), 7.49 (d, J = 8.0 Hz, 1 H), 7.43 (d, J = 7.5 Hz, 1 H ), 7.32 (d, J = 8.0 Hz, 2H), 5.57 (d, J = 8.0 Hz, 1 H), 4.97 (d, J = 16.0 Hz, 1 H), 4.23 (d, J = 16.0 Hz, 1 H), 3.97 (s, 3H), 3.85 (m, 1 H), 0.53 (d, J = 6 5 Hz, 3H) Step D: Acid 2"- (((4S, 5R-5- [3,5-b? S (tr? Fluoromet? L) phen? 1-4-met? L-2-0X0-1, 3-oxazole? d? n-3-? l) met? l) -6'Jluoro-4"- (tr? fluoromet? l) -1, r 3'J" Jerfen? l-4-carboxylic The title compound of step C (60 mg, 0 086 mmol) was stirred with LiOH (10 eq) in a 2 1 mixture of dioxane and water at room temperature overnight. The solvent was removed and the aqueous solution was acidified with 1 N HCl to pH ~ 4. organic compound was extracted with EtOAc (3 x 10 mL) The combined EtOAc layers were washed with brine and dried over sodium sulfate. The title compound was obtained after reverse phase HPLC as a colorless solid 1 H NMR (CDCl 3, 500 MHz) d 8 18 (d, J = 7 0 Hz, 2 H), 7 87 (s, 1 H), 7 72 (s, 1 H), 7 70 (s, 2 H), 7 68 (m, 2 H) , 7 47 (d, J = 6 5 Hz, 1 H), 7 42 (d, J = 5 5 Hz, 1 H), 7 32 (d, J = 6 5 Hz, 2 H), 5 55 (d, J = 6 5 Hz, 1 H), 4 96 (d, J = 13 0 Hz, 1 H), 4 21 (d, J = 13 0 Hz, 1 H), 3 85 (m, 1 H), 0 52 (d, J = 5 0 Hz, 3H) LC / MS M + 686 06 The following examples were obtained following the procedure general described in example 56.

The following examples were obtained using (4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl] -3-. { [2'-methoxy-5 '- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -4- (trifluoromethyl) biphenyl-2-yl] methyl} -4-methyl-1,3-oxazolidin-2-one) (100 mg, 0.14 mmol) of Example 21, Step A and the corresponding bromides following the general procedure described in Example 56, Step C.

EXAMPLE 61 Acid 2"- (((4S, 5F?) - 5 -3,5-bis (trifluoromethyl) phenyl-1-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4'-chloro- 6"-vodo-2-methyl-4" - (trifluoromethyl) -1 J ': 3'J "-terphenyl-4-carboxylic acid Step A: 2"-amino-6" - (4S.5R) -5- [3,5-bis (trifluoromethyl) phenin-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4 '-chloro-2-methyl-4"- (trifluoromethyl) -1 J': 3'J" -terphenyl-4-carboxylic acid methyl ester To a solution of the title compound of example 40, step E (500 mg, 0.779 mmol ) in EtOH (10 ml), tin chloride dihydrate (1.64 g, 7.27 mmol) was added. The mixture was stirred at room temperature for 2 hr. The LC-MS analysis indicated the complete consumption of the starting material. EtOH was removed. EtOAc (200 ml) was added to the residue. The mixture was washed with water, brine and dried over sodium sulfate. Removal of the solvent gave a white solid which was mixed with 4'-chloro-2-methyl-3 '- (4, 4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) biphenyl-4 methyl carboxylate (example 48, step C, 281 mg, 0.727 mmol), tetrakis (triphenylphosphine) palladium (10 mol%) and sodium carbonate (0.154 g, 1.45 mmol) in 32 ml of water / EtOH / toluene (1 : 2: 4) and heated to reflux for 48 hr. CCD (EtOAc: hexane / 2: 8) showed that the reaction was over. The solvents were removed. Water (10 ml) was added. The organic compound was extracted with methylene chloride (3x 30 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after purification with column chromatography using 20% EtOAc in hexane as the eluent. 1 H NMR (CDCl 3, 500 MHz): d 7.99 (s, 1 H), 7.91 (dd, J = 8.0, 2.0 Hz, 1 H), 7.88 (s, 1 H), 7.74 (s, 2 H), 7.67 ( d, J = 8.0 Hz, 1 H), 7.42 (dd, J = 8.5, 2.0 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.30-7.24 (m, 1 H), 7.07 (s, 1 H), 7.01 (s, 1 H), 5.70 (d, J = 8.0 Hz, 1 H), 4.83 (d, J = 15.0 Hz, 1 H), 4.01 (m, 1 H), 3.96 ( s, 3H), 3.83 (d, J = 15.0 Hz, 1 H), 3.81 (br s, 2H), 2.42 (s, 3H), 0.68 (d, J = 6.0 Hz, 3H).

Step B: 2"- (4S, 5R) -5-f3,5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4'-chloro- 6"-vodo-2-methyl-4" - (trifluoromethyl) -1 J ': methyl 3-methylphenyl-4-carboxylate To a solution of the title compound from step A (285 mg, 0.383 mmol) in chloroform ( 10 ml) at room temperature, were added n-pentyl nitrite (67.2 mg, 0.574 mmol) and iodine (126 mg, 0.497 mmol). The mixture was refluxed for 1 hr. The mixture was diluted with methylene chloride (10 ml). The solution was washed with saturated aqueous sodium thiosulfate, brine and dried over sodium sulfate. The residue was purified by preparative reverse phase HPLC to give the title compound as a colorless solid. 1 H NMR (CDCl 3, 500 MHz): d 8.24 (s, 1 H), 7.99 (s, 1 H), 7.92 (d, J = 8.0, Hz, 1 H), 7.90 (s, 1 H), 7.74 ( s, 2H), 7.66 (s, 1 H), 7.42 (dd, J = 8.5, 2.5 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.28 (m, 1 H), 7.21 -7J4 (m, 1 H), 5.71 (d, J = 8.0 Hz, 1H), 4.78 (d, J = 15.5 Hz, 1 H), 3.99 (m, 2H), 3.96 (s, 3H), 2.41 ( s, 3H), 0.65 (d, J = 6.5 Hz, 3H).

Step C: acid 2"- ( { (4S, 5F?) - 5- [3,5-bis (trifluoromethyl) phenyl-4-methyl-2-OXO-1,3-oxazolidin-3-yl) methyl ) -4'-chloro-6"-iodo-2-methyl-4" - (trifluoromethyl) -1 J ': 3'J "-terphenyl-4-carboxylic acid To a solution of the title compound from step B (30 mg , 0.035 mmole) in dioxane (2 ml) at room temperature, an aqueous solution of LÍOH.H20 (7.36 mg, 0.175 mmoles) was added. The mixture was stirred at room temperature overnight. CCD (EtOAc: hexane / 2: 8) no showed starting material The solvent was removed 1N HCl (1 ml) was added The mixture was extracted with methylene chloride (3x10 ml) The combined methylene chloride layers were dried over sodium sulfate The title compound was obtained by HPLC of preparative reverse phase as a colorless solid EXAMPLE 62 Acid 2"- ( { (4S, 5f?) - 5- [3,5-b? S (tr? Fluoromet? L) phen? Ll-4-met? L-2-oxo-1, 3- oxazole? d? n-3-? l) met? l) -4 ', 6'-d? fluoro-6"-iodo-2-met? l-4" - (tr? fluoromet? l) -1' , '1' '3 vM' "-terfen? L-4-carboxyl? Co The title compound was obtained using the title compound of example 40, step E and 4'-fluoro-2-met? L-3 ' - (4,4,5,5-tetramet? L-1, 3,2-d? Oxaborolan-2-? L) b? Phen? L-4-carboxylic acid methyl ester (intermediate 22), following the procedure described in Example 61 1 H NMR (CDCl 3, 500 MHz) d a mixture of 1 1 of artopoisomers 8 26 (s, 0 5 H), 8 24 (s, 0 5 H), 8 06 (s, 1 H), 7 98 (d, J = 8 0 Hz, 1 H), 7 91 (s, 1 H), 7 75 (s, 2H), 7 69 (s, 0 5 H), 7 65 (s, 0 5H), 7 39 (m, 1 H), 7 16-7 04 (m, 2H), 5 66 (d, J = 8 0 Hz, 0 5H), 5 64 (d, J = 8 5 Hz, 0 5H), 4 88 (d, J = 15 5 Hz, 0 5H), 4 81 (d, J = 16 0 Hz, 0 5H), 4 02 (m, 1 H), 3 91 (m, 1 H), 2 39 (s, 1 5H), 2 36 (s, 1 5H), 0 70 (d, J = 6 5 Hz, 1 5H), 0 69 (d, J = 6 5 Hz, 1 5H) LC / MS M + 1 844 04 The following examples were obtained using the title compound of example 56, step B and the corresponding boronic acids, following the general procedure described in example 56, step C EXAMPLE 65 (4S, 5F?) - 5-r3,5-bis (trifluoromethyl) phenyl1-3- (f4"-hydroxy-6'-methoxy-2", 4-bis (trifluoromethyl) -1 J ': 3'J " -terphenyl-2-illmethyl) -4-methyl-1,3-oxazolidin-2-one The title compound was obtained using the intermediate of example 1, step A and 4-hydroxy-2-trifluoromethylphenylboronic acid, following the procedure described in example 56, step C. LC / MS (M + 1) 737.98.

EXAMPLE 66 (4S, 5) -5-f3,5-bis (trifluoromethyl) phenin-3. { r6'-chloro-4"-hydroxy-2", 4-bis (trifluoromethyl) -1, 1 ': 3', 1"-terphenyl-2-illmethyl) -4-methyl-1,3-oxazolidin-2- The title compound was obtained using the intermediate of the Example 22, step B and 4-hydroxy-2-trifluoromethylphenylboronic acid, following the procedure described in example 56, step C. LC / MS (M +) 741.70 EXAMPLE 68 2"- (((4S, 5R) -5- [3,5-bis (trifluoromethyl) phenin-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4'-methoxy- 2-methyl-4"- (trifluoromethyl) -1 J ': 3M" Jerphenyl-4-sulfonamide To a solution of 4-bromo-3-methylene-benzenesulfonyl chloride (120 mg, 0.37 mmol) in dioxane (5%). ml) at room temperature, concentrated NH 4 OH (1 ml) was added.The mixture was stirred at room temperature for 4 h.A solution of the title compound of example 21, step A (100 mg, 0.14 mmol), sodium carbonate ( 30 mg, 0.28 mmole), and a catalytic amount of tetrakis (triphenylphosphine) palladium (5 mol%) in 14 ml of a 1: 2: 4 mixture of water: EtOH: toluene was stirred under reflux for 6 h. The mixture was extracted with water (10 ml). methylene chloride (3x10 ml). The combined methylene chloride layers were washed with brine and dried over sodium sulfate. The title compound was obtained after reverse phase HPLC. 1 H NMR (CDCb, 500 MHz): d a 1: 1 mixture of artopoisomers 7.89 (s, 1 H), 7.86 (d, J = 7.5 Hz, 1 H), 7.79 (d, J = 8.0 Hz, 1 H ), 7.72 (s, 2H), 7.68 (m, 2H), 7.45 (t, J = 8.0 Hz, 1 H), 7.39 (m, 2H), 7J3 (m, 2H), 5.60 (d, J = 8.5) Hz, 0.5H), 5.38 (d, J = 8.5 Hz, 0.5H), 5.00 (d, J = 16.0 Hz, 0.5H), 4.94 (d, J = 16.0 Hz, 0.5H), 4J7 (d, J = 16.0 Hz, 0.5H), 3.99 (d, J = 16.0 Hz, 0.5H), 3.90 (s, 1.5H), 3.89 (s, 1.5H), 3.84 (m, 1 H), 2.42 (s, 1.5 H), 2.37 (s, 1.5), 1.75 (br s, 2H), 0.59 (d, J = 6.5 Hz, 1.5H), 0.48 (d, J = 7.0 Hz, 1.5H). LC / MS (M + 1) 747.20.

EXAMPLE 69 -y2 '- (((4S.5?) - 5- [3,5-bis (trifluoromethyl) phenan-4-methyl-2-oxo-1,3-oxazolidin-S-iDmeti-e-chloro ^ '- DrifluorometiDbiphenyl-S-ill-I Hl ^^ - triazole-S-carboxamide Step A: 2 '- ( { (4S, 5F?) - 5- [3, 5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -6-chloro-4 '- (trifluoromethyl) biphenyl-3-carbonitrile mixture of (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -3- [2-iodo-5- (trifluoromethyl) benzyl] -4-methyl-1,3-oxazolidin-2-one (0.5 g, 0.837 mmol), 2-chloro-5-cyanophenylboronic acid (0.228 g, 1.26 mmol), sodium carbonate (0J 8 g, 1.67 mmol), and catalytic amount of tetrakis (triphenylphosphine) palladium (0.097 g, 10 % molar) in 14 ml of a 1: 2: 4 mixture of water: EtOH: toluene was stirred under reflux for 2 hr. The solvents were removed. Water (10 ml) was added. The mixture was extracted with methylene chloride (3x10 ml). The combined methylene chloride layers were washed with brine and dried over sodium sulfate. The title compound was obtained after column chromatography using CH 2 Cl 2: hexane / 8: 2 as the eluent. 1 H NMR (CDCl 3, 500 MHz): d a 1: 1 mixture of artopoisomers 7.91 (s, 1 H), 7.77-7.69 (m, 6H), 7.61 (d, J = 2.0 Hz, 0.5H), 7.58 (d , J = 2.0 Hz, 0. 5H), 7.42 (d, J = 8.0 Hz, 0.5H), 7.38 (d, J = 8.0 Hz, 0.5H), 5.68 (d, J = 8.0 Hz, 0.5H), 5.65 (d, J = 8.0 Hz , 0.5H), 4.89 (d, J = 15.5 Hz, 0.5H), 4.74 (d, J = 16.0 Hz, 0.5H), 4.03 (d, J = 16.0 Hz, 0.5H), 4.00 (m, 0.5H ), 3.91 (d, J = 16.0 Hz, 0.5H), 3.90 (m, 0.5H), 0.67 (d, J = 6.5 Hz, 1.5H), 0.65 (d, J = 6.5 Hz, 1.5H).

Step B: 2 '- (((4S.5F?) - 5-f3.5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl hydrochloride) - Ethyl 6-chloro-4 '- (trifluoromethyl) biphenyl-3-carboximidoate The title compound from step A (100 mg, 0J65 mmol) was mixed with a saturated solution of HCl in EtOH (10 ml). The solution was stirred at room temperature for 2 hr. CCD (EtOAc / hexane 2: 8) showed that no starting material remained. The solvent was removed to give a white solid. The material was used for the next step without purification.

Step C: 5-y2 '- ( { (4S, 5F?) - 5J3,5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl ) -6-chloro-4 '- (trifluoromethyl) biphenyl-3-yl-1 H-1.2.4-triazole-3-carboxamide A mixture of the title compound from step B (100 mg, 0J45 mmol), oxidic hydrazide ( 16.5 mg, 0J6 mmol) and KOAc (17J mg, 0.174 mmol) in EtOH (5 mL) was stirred under reflux for 2 hr. LC / MS showed that the reaction was complete. The solvent was removed and the title compound was obtained after purification with reverse phase HPLC. LC / MS (M + 1) + 692.38.

EXAMPLE 70 (4S, 5F?) - 5-f3,5-bis (trifluoromethyl) phenyl-3J [4"- (hydroxymethin-6'-methoxy-2'-Xmethyl-4- (trifluoromethyl) -1.1 ': 3'.1" -terphenyl-2-illmethyl) -4-methyl-1,3-oxazolidin-2-one Acid 2"- ( { (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -4 -methyl-2-oxo-1,3-oxazolidin-3-yl.} metl) -4'-methoxy-2-methyl-4"- (trifluoromethyl) -1,1 ': 3 \ 1" - Terfenyl-4-carboxylic acid (2 g, 2.81 mmol) and THF (18.74 ml) were stirred in OX (ice bath). Borane-tetrahydrofuran complex (5.90 ml, . 90 mmol) in 3 min. The resulting mixture was prepared at OX for 15 min. The ice bath was then removed. The reaction mixture was stirred at room temperature for additional 1 hr. CCD indicated that the reaction had been completed. The reaction was quenched with water (ice bath). The crude mixture was treated with aqueous sodium bicarbonate, extracted with ethyl acetate, dried over Na 2 SO 4, filtered and evaporated to give a dark mixture. The resulting dark mixture was purified by flash chromatography (Si02, Biotage 40M cartridge). The column was eluted by a mixture of EtOAc / hexanes (0% to 40%). The related fractions were pooled and evaporated to give the title compound. CL-EM (ESI) cale. = 697.19; found = 680.29 (M-OH -) +. 1 H NMR (CDCl 3, 400 MHz, 1: 1 mixture of atropoisomers): d 7.83 (d, J = 4 Hz, 1 H), 7.71 (s, 0.5 H), 7.67 (s, 1 H), 7.66-7.58 ( m, 2.5H) 7.43 (d, J = 8 Hz, 0.5H), 7.40 (d, J = 8 Hz, 0.5H), 7.38-7.32 (m, 1 H), 7.28-7.23 (m, 1 H), 7. 22-7.14 (m, 2H), 7.12 (s, 1 H), 7.05 (d, J = 5.6 Hz, 0.5H), 7.03 (d, J = 5.6 Hz, 0. 5H), 5.56 (d, J = 8.4 Hz, 0.5H), 5.23 (d, J = 8 Hz, 0.5H), 4.97 (d, J = 10.8 Hz, 0. 5H), 4.93 (d, J = 10.8 Hz, 0.5H), 4.68 (s, 2H), 4.15 (d, J = 15.6 Hz, 0.5H), 3.95 (d, J = 15.6 Hz, 0.5H), 3.85 (s, 1.5H), 3.83 (s, 1.5H), 3.80-3.66 (m, 1 H), 2.32 (s, 1.5H), 2.26 (s, 1.5H), 0.52 (d, J = 6.8 Hz, 1.5H), 0.38 (d, J = 6.8 Hz, 1.5H).

EXAMPLE 71 Acid 2"- ( { (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -2,6 ' -difluoro-4'-methoxy-4"- (trifluoromethyl) -1, 1 ': 3'.1" -terphenyl-4-carboxylic acid Step A: 2J2-fluoro-4-methoxyphenyl) -4,4,5,5-tetramethyl-1, 3,2-dioxaborolane 1-bromo-2-fluoro-4-methoxybenzene (750 mg, 3.658 mmol), potassium (718 mg, 7.32 mmol), adduct of I J'-bis (diphenylphosphino) ferrocene-palladium dichloride, chloromethane (300 mg, 0 367 mmol), b? s (p? nacholate) d? boron (984 mg, 4 39 mmol) and 1,4-d? oxane (10 ml) were sealed and subjected to microwave irradiation at 140X for a total of 50 minutes (40 min + 10 min) LC-MS of the aliquot indicated complete consumption of the starting material. The crude of the reaction was filtered through a pad of Ce te (521) The filtrate was treated with brine, extracted with ethyl acetate, dried over Na 2 SO 4, filtered and evaporated to give a dark oil as the crude mixture of the title compound. It was used as such for the next step. LC-MS (ESI) cale = 252 13, found = 253 09 (M + 1) + Step B 2,2'-d? Fluoro-4'-methox? B? Phen? L-4-carboxylic acid methyl 2- (2-fluoro-4-methox? Phen? L) -4,4,5 , 5-tetramethyl-l, 3,2-d-oxaborolane (600 mg, 2 38 mmol), methyl 4-bromo-3-fluorobenzoate (665 mg, 2 856 mmol), adduct 1, 1'- b? s (d? phen? lfosf? no) ferrocene-palladium dichloride-dichloromethane (292 mg, 0 358 mmoles), potassium carbonate (2 38 ml, ac, 2M, 4 76 mmoles) and 1, 4-d Oxano (10 ml) was sealed and subjected to microwave irradiation at 145X for 15 min. The aliquot indicated the formation of the desired CCD comp (20% EtOAc / hex) indicated a bright purple spot @ Rf = 0 4 The crude mixture dried / Na2SO4 then purified by instant chromatography (Si02, Biotage 40 + M cartridge). The column was eluted with a mixture of 0% to 20% EtOAc / hexanes. The related fractions were combined and concentrated in vacuo to give the title compound. CL-EM (ESI) cale. = 278.08; found = 279.09 (M + 1) +.

Step C: methyl 2,2'-difluoro-5'-iodo-4'-methoxybiphenyl-4-carboxylate 2,2'-difluoro-4'-methoxybiphenyl-4-carboxylic acid methyl ester (585 mg, 2J0 mmol), methanol (10 ml), iodide (534 mg, 2J0 mmole), silver sulfate (655 mg, 2J0 mmole) were stirred at room temperature. LCMS indicated the formation of the desired compound. The crude of the reaction was treated with Na2HS0 (aq, sat). All volatile compounds were removed from the resulting mixture. The residue in the vessel was treated with Na 2 SO 4 / EtOAc / filtration / concentration to give a light brown solid. The crude solid was purified by flash chromatography (Si02, Biotage 40 + M cartridge). The column was eluted with a mixture of 0% to 20% EtOAc / hexanes. The 5 main fractions were spilled by accident. The remaining related fractions were combined and concentrated under vacuum to give the title compound.

CL-EM (ESI) cale. = 403.97; found = 404.92 (M + 1V * Step D: 2"-f ((4S.5 /?) - 5-f3.5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -2 , 6'-difluoro-4'-methoxy-4"- (trifluoromethyl) -1.r: 3M" -terphenyl-4-carboxylic acid methyl 2,2'-difluoro-5'-iodo-4'-methoxybiphenyl-4 methyl carboxylate (100 mg, 0.247 mmol), (4S, 5F?) - 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 (intermediate 9, 179.2 mg, 0.30 mmol), sodium carbonate (247 μl , ac, 2M, 0.494 mmoles), adduct of 1,1-bis (diphenylphosphino) ferrocene-palladium dichloride-dichloromethane (40 mg, 0.049 mmol) and 1,4-dioxane (2 J ml) were heated in a water bath. 80X oil for 8 hours The aliquot indicated the formation of the desired product The crude mixture was concentrated under reduced pressure The residue of the product was treated with H20 / EtOAc / Na2SO4 / filtration followed by concentration to give a dark oil. was purified by reverse phase CLAR-prep (Waters SunFi re PrepC18 OBD 5μ, 30x100 mm) eluting with a mixture of gradients of MeCN (0.05% TFA, v / v) / H20 (0.05% TFA, v / v) (10 to 100% in 12 min, contained 100% for 3 min). The related fractions were combined and evaporated under vacuum to give a dark oil. The oil was further purified by SiO2 (CCD-Prep 30% EtOAc / hex) to give the title compound. CL-EM (ESI) cale. = 747.15; found = 748.20 (M + 1) +.

Step E: Acid 2"- (((4S, 5f?) - 5-f3.5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-113-oxazolidin-3-yl) methyl) -2.6 '-difluoro-4'-methoxy-4"- (trifluoromethyl) -1 J': 3'J" -terphenyl-4-carboxylic acid 2"- ( { (4S, 5f?) - 5- [3,5 bis (trifluoromethyl) phenyl] -4-methyl-2-oxo-1,3-oxazolidin-3-yl} methyl) -2,6'-difluoro-4'-methoxy-4"- (trifluoromethyl) ) -1, 1 ': 3', 1"Je? Jenyl-4-carboxylic acid methyl ester (50 mg, 0.067 mmol), lithium hydroxide monohydrate (28 mg, 0.67 mmol), water (1 ml) and 1.4 Dioxane (2 ml) was stirred at room temperature for 2.5 hours. CL-MS of the aliquot indicated the formation of the desired product and the complete consumption of the starting material. The crude mixture was acidified (1 N HCl, ac). The volatiles were removed under reduced pressure. The residue from the vessel was dissolved in MeCN and purified by a reverse phase HPLC-prep (Kromasil 100-5C18, 100x21.1 mm) eluting with MeCN (0.1% TFA, v / v) / H20 (0.1% of TFA, v / v). The corresponding fractions were combined and evaporated under vacuum to give a mixture. The resulting mixture was extracted with EtOAc. The separated organic phases were washed again with water, separated, dried / NaSO4, filtered and evaporated to give the title compound. CL-EM (ESI) cale. = 733.13; found = 734.14 (M + 1) +. 1 H NMR (CDCl 3, 500 MHz, 1: 1 mixture of atropoisomers): d 7.95 (t, J = 6 Hz, 1 H), 7.89-7.83 (m, 2 H), 7.73 (s, 0.5 H), 7.71 (s) , 1 H), 7.68-7.64 (m, 2H), 7.62 (s, 0.5H) 7.58 (t, J = 7 Hz, 0.5H), 7.53 (t, J = 7.5 Hz, 0.5H), 7.42 (d , J = 8 Hz, 0.5H), 7.39 (d, J = 8 Hz, 0.5H), 7.31-7.23 (m, 1 H), 6.89 (d, J = 4 Hz, 0.5H), 6.87 (d, J = 3.5Hz, 0.5H), 5.61 (d, J = 8 Hz, 0.5H), 5.29 (d, J = 8 Hz, 0.5H), 5.05 (d, J = 16 Hz, 0.5H), 4.93 ( d, J = 16 Hz, 0.5H), 4.16 (d, J = 16.5 Hz, 0.5H), 3.94 (d, J = 16 Hz, 0.5H), 3.89 (s, 1.5H), 3.87 (s, 1.5 H), 3.85-3.72 (m, 1 H), 0.59 (d, J = 7 Hz, 1.5H), 0.43 (d, J = 6 Hz, 1.5H).

EXAMPLE 72 2"- ((((4S.5f?) - 5-f3.5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -2-chloro-6 'acid -f luoro-4'-methoxy-4"- (trifluoromethyl) -1 J ': 3'J" -terphenyl-4-carboxylic acid Step A: Methyl 2-amino-2'-fluoro-4'-methoxybiphenyl-4-carboxylate 1-bromo-2-fluoro-4-methoxybenzene (750 mg, 3.66 mmol), [2-amino-4- ( methoxycarbonyl) phenyl] boronic acid (856 mg, 4.39 mmol), potassium acetate (3.66 ml, 2M aq, 7.32 mmol), adduct of I J'-bis (diphenylphosphino) ferrocene-palladium dichloride-dichloromethane (299 mg, 10% molar) and ethanol (30 ml) were heated in an 80X oil bath for 3 hours. The crude from the reaction was treated with brine, extracted with ethyl acetate, dried over Na 2 SO, filtered and evaporated to give a dark oil. This oil was purified by S02 (Biotage Horizon Flash system, cartridge 40 + M, 0-25% of EtOAc / hexanes, v / v) to give the title compound. CL-EM (ESI) cale. = 275.10; found = 276.09 (M + 1) +.

Step B Methyl 2-chloro-2'-fluoro-4'-methox? B? Phen? L-4-carboxylate Amyl nitrite (420 μl, 3 19 mmol) and copper chloride (ll) (343 mg , 2 55 mmol) were suspended in acetonitplo (5 ml) and heated in a 65X oil bath with magnetic stirring. To this hot mixture was added 2-amino-2'-fluoro-4'-methox? B? methyl phenol-4-carboxylate (585 mg, 2 13 mmol, in 5 ml MeCN) in about 1 minute. The resulting mixture was heated in a 65X oil bath for 2 hours. The crude of the reaction was purified by S02 (Biotage Horizon Flash system, 40 + M cartridge, 0-20% EtOAc / hexanes, v / v) to give the title compound CL-MS (ESI) cale = 294 05, found = 295 03 (M + 1) + Step C 2-Chloro-2'-fluoro-5'-vodo-4'-methoxy-benzophenol-4-carboxylic acid 2-chloro-2'-fluoro-4'-methox? B? Phen? Methyl l-4-carboxylate (550 mg, 1.87 mmol), methanol (8 ml), iodide (474 mg, 1.87 mmol) and silver sulfate (583 mg, 1.87 mmol) were stirred at room temperature for 2 hours. hours The crude of the reaction was treated with NaHS0 (aq). The volatiles were removed under reduced pressure. The residue of the product was treated with brine, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated to give a light brown solid This solid was purified by S? 02 (Biotage Hopzon Flash system, cartridge 40 + M, 0-20% EtOAc / hexanes, v / v) to give the title compound CL-MS (ESI) cale = 419 94, found = 420 86 (M + 1) + Step D 2"- ( { (4S.5R) -5-f3.5-b? S (tr? Fluoromet? L) fen? Ll-4-met? L-2-oxo-1, 3-oxazole ? d? n-3-? l) met? l) -2-chloro-6'-fluoro-4'-methox? -4"- (tr? fluoromet? Q-1 J '3'J" -terfen methyl l-4-carboxylate methyl 2-chloro-2'-fluoro-5'-iodo-4'-methox? b? phen? l-4-carboxylate (177 mg, 0 42 mmol) (4S, 5R) -5- [3,5-b? S (tr? Fluoromet? L) phen? L] -4-met? L-3- [2- (4,4,5,5-tetramet L-1, 3,2-d-oxaborolan-2-? l) -5- (tr? fluoromet? l) benc? l] -1, 3-oxazol? d? n-2-one (intermediate 9, 250 mg, 0 42 mmol), potassium carbonate (0 42 ml, ac, 2M, 0 84 mmol), adduct of IJ '-b? S (d? Phen? Lfosf? No) ferrocene-palladium dichloride-dichloromethane ( 51 mg, 06.0 mmol) and 1,4-dioxane (2 ml) were sealed and subjected to microwave irradiation at 140X for 15 min. The aliquot indicated (LC-MS) the complete consumption of the starting material and the formation of the desired product This crude was treated with H2? / EtOAc / Na2SO0 / ph? ltrac? on / concentrate to give a dark oil This oil was purified by S? 02 (CCD-Prep, 5% EtOAc / 5% hex / 9 0% of DCM) to give a dark oil as a mixture of the product and impurities. The oil was further purified by reverse phase HPLC-prep (Kromasil 100-5C18, 100x21.1 mm) eluting with a gradient mixture of MeCN (0.1% TFA, v / v) / H20 (0.1% TFA, v / v). The corresponding fractions were combined and evaporated under vacuum to give 205 mg of dark green glass. CCD (30% EtOAc / hex) indicated a dark spot on the baseline and traces of impurities above and below the compound spot. The green glass was further purified by Si02 (CCD-Prep, 100% DCM) to give the title compound. CL-EM (ESI) cale. = 763.12; found = 764.09 (M + 1) +.

Step E: 2"- (((4S, 5?) - 5-y3.5-bis (trifluoromethyl) phenyl-4-methyl-2-QXQ-1, 3-oxazolidin-3-yl) methyl) -2 acid -chloro-6'-fluoro-4'-methoxy-4"- (trifluoromethyl) -1, 1 '.3', 1" Jerphenyl-4-carboxylic acid 2"- ( { (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-2-oxo-1,3-oxazolidin-3-yl} methyl) -2-chloro-6'-halo-4'-methoxy-4" - (trifluoromethyl) -1, r: 3'J "-methylphenyl-4-carboxylic acid methyl ester (84.5 mg, 0J 1 mmol), lithium hydroxide monohydrate (46.2 mg, 1 J mmol), water (1 ml) and 1 , 4-dioxane (2 ml) is agitated at room temperature LC-MS of the aliquot at 2 hr reaction time indicated completion of the reaction. Volatile compounds were removed under reduced pressure. The crude mixture was dissolved in MeCN and acidified by HCl (1 N, ac) to give a clear solution This solution was purified by a reverse phase HPLC-prep (Kromasil 100-5C18, 100x21 1 mm) eluting with a gradient mixture of MeCN (0 1% TFA, v / v) / H20 (0 1 % TFA, v / v) The corresponding fractions were combined and evaporated under vacuum to give a colorless glass. This glass was dissolved in DCM and washed with water. The organic extracts were combined, dried / Na2SO4, filtered and evaporated to give the title compound LC-MS (ESI) cale = 749 10, found = 750 06 (M + 1) + 1 H NMR (CDCl 3, 500 MHz, mixture 1 1 of atropoisomers) d 8 21 (dd, J = 10 , 2 Hz, 1 H), 8 03 (dd, J = 8, 2 Hz, 1 H), 7 86 (s, 1 H), 7 73-7 68 (m, 1 5 H), 7 68-7 62 (m, 2 5H), 7 48 (t, J = 7 5 Hz, 1 H), 7 41 (dd, J = 11, 8 Hz, 1 H), 7 17 (dd, J = 8 5, 2 Hz, 1 H), 6 86 (dd, J = 11, 3 5 Hz, 1 H), 6 60 (d, J = 8 Hz, 0 5H), 5 40 (d, J = 8 Hz, 0 5H), 4 94 (t, J = 15 Hz, 1 H), 4 18 (d, J = 16 Hz, 0 5H), 3 95 (d, J = 16 Hz, 0 5H), 3 87 (s, 3H), 3 85-3 74 (m, 1 H), 0 56 (d, J = 6 5 Hz , 1 5H), 0 46 (d, J = 6 5 Hz, 1 5H) EXAMPLE 73 Acid 2"- (4S.5ffl-5- [3,5-bis (trifluoromethyl) phenan-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4'.6'-difluoro-2 -methyl-4"- (trifluoromethyl) -1.1 ': 3'.1" -terphenyl-4-carboxylic acid Step A To 5'-amino-2 ', 4'-difluoro-2-methylbiphenyl-4-carboxylic acid methyl 5-bromo-2,4-difluoroaniline (500 mg, 2.40 mmol), 3-methyl-4- (4, Methyl 4,5,5-tetramethyl-1,2-dioxaborolan-2-yl) benzoate (intermediate 16, 797 mg, 2.88 mmol), sodium carbonate (2.40 ml, ac, 2M, 2.88 mmol), adduct of 1, 1'-bis (diphenylphosphino) ferrocene-palladium dichloride-dichloromethane (196 mg, 0.24 mmol) and ethanol (15 ml) were heated in an 80X oil bath for 3 hours, then allowed to cool to room temperature overnight. The volatile compounds were removed under reduced pressure. The residue of the product was treated with DCM / brine / Na 2 SO / filtration / concentration to give a dark oil. The resulting oil was purified by flash chromatography (Si02, Biotage 40 + M cartridge). The column was eluted by a gradient mixture from 0% to 40% EtOAc / hexanes. The related fractions were combined and concentrated under vacuum to give the title compound. CL-EM (ESI) cale. = 277.09; found = 278.03 (M + 1) +.

Step B: methyl 2 ', 4'-d-fluoro-5'-iodo-2-methylbiphenyl-4-carboxylate 5'-amino-2', 4'-difluoro-2-methylbiphenyl-4-carboxylic acid methyl ester ( 500 mg, 1.80 mmol), 3-methylbutyl nitrite (317 mg, 2.71 mmol), iodine (549 mg, 2.16 mmol) and chloroform (15 ml) were refluxed in an oil bath for 5 hours then allowed to cool at room temperature overnight. The crude of the reaction was purified by flash chromatography (SIO2, Biotage 40 + M cartridge) was eluted with a gradient mixture of EtOAc / hexanes. The related fractions were combined and concentrated in vacuo to give the title compound. CL-EM (ESI) cale. = 387.98; found = 388.92 (M + 1) +.

Step C: 2"- (((4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4 ', 6'-difluoro-2-methyl-4"- (trifluoromethyl) -1 J ': 3'J" -terphenyl-4-carboxylic acid methyl 2', 4'-difluoro-5'-iodo-2-methylbiphenyl-4 methyl carboxylate (100 mg, 0.26 mmol, dissolved in 1 ml of ethanol), (4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-3- [2- (4,4,5,5Jetramethyl-1, 3,2-dioxaborolan-2-yl) -5- (trifluoromethyl) benzyl] -1,3-oxazolidin-2-one (intermediate 9, 185 mg, 0.31 mmol, dissolved in 2.2 ml 1,4-dioxane), sodium carbonate (258 μl, ac, 2M, 0.516 mmol) and adduct of 1,1-bis (diphenylphosphino) ferrocene-palladium dichloride-dichloromethane (42 mg, 0.05 mmol ) were heated in an oil bath at 80X for 2 hours, traces of LC-MS from the reaction aliquot indicated that the reaction was complete, the crude of the reaction was dried / Na2SO4 and then deposited on 2 CCD plates. -Prep (SIO2) .The plates were developed by a mixture of 20% EtOAc / hexanes p to give a clear glass. The glass was further purified by reverse phase HPLC-prep (Kromasil 100-5C18, 100x21.1 mm) eluting with a gradient mixture of MeCN (0.1% TFA, v / v) / H20 (0.1% TFA, v / v). The fractions The corresponding particles were combined and evaporated under vacuum to give a colorless glass. This glass was dissolved in DCM and washed with water. The organic extracts were combined, dried / Na2SO4, filtered and evaporated to give the title compound. CL-EM (ESI) cale. = 731.15; found = 732.06 (M + 1) +.

Step D: acid 2"- (((4S.5 /:)) - 5- [3,5-bis (trifluoromethylphenyl) -4-methyl-2-OXO-1,3-oxazolidin-3-yl) methyl) -4 ', 6'-difluoro-2-methyl-4"- (trifluoromethyl) -1 J': 3M" -terphenyl-4-carboxylic acid 2"- ( { (4S, 5F?) - 5- [3,5 bis (trifluoromethyl) phenyl] -4-methyl-2-oxo-1,3-oxazolidin-3-yl.} methyl) -4 ', 6'-difluoro-2-methyl-4"- (trifluoromethyl) - 1, 1 ': 3', 1"Jerfenyl-4-carboxylic acid methyl ester (73.5 mg, EYO mmole), lithium hydroxide monohydrate (42 mg, 1 mmol), water (1 ml) and 1,4-dioxane (2) ml) were stirred at room temperature for 2 hr. The volatiles were removed under reduced pressure. The residue from the vessel was dissolved in a mixture of MeCN / 1 N HCl (aq) and purified by reverse phase HPLC-prep (Kromasil 100-5C18, 100x21.1 mm) eluting with a gradient MeCN mixture (0.1 % TFA, v / v) / H20 (0 1% TFA, v / v). The corresponding fractions are they combined and evaporated under vacuum to give the title compound. CL-EM (ESI) cale. = 717.14; found = 718.17 (M + 1) +. 1 H NMR (CDCl 3, 500 MHz): d 8.04 (s, 1 H), 7.97 (d, J = 8 Hz, 1 H), 7.88 (s, 1 H), 7.74-7.67 (m, 4 H), 7.51- 7.45 (m, 1 H), 7.34 (d, J = 8 Hz, 1 H), 7.19 (br s, 1 H), 7.09 (t, J = 9 Hz, 1 H), 5.59 (d, J = 8) Hz, 1H), 5.08-4.80 (m, 1H), 4.20-3.78 (m, 2H), 2.32 (s, 3H), 0.62 (s, 3H).

EXAMPLE 74 Acid 2"- (((4S, 5R) -5-y3,5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -6'-Jouro- 4'-methoxy-3-methyl-4"- (trifluoromethyl-1.r: 3M" -terphenyl-4-carboxylic acid Step A: 2'-Fluoro-4'-methoxy-3-methylbiphenyl-4-amine Acid (2-fluoro-4-methoxyphenyl) boronic acid (356.7 mg, 2.1 mmol), 4- bromo-2-methylaniline (391 mg, 2.1 mmol), potassium carbonate (3J 5 mL, 2M aq, 6.3 mmol), adduct of IJ '-bis (diphenylphosphino) ferrocene-palladium dichloride-dichloromethane (257 mg, 0.31% molar) and ethanol (12 ml) were heated in an 80X oil bath. The reaction was completed in 1 hour by CCD (40% EtOAc / hexanes) and LC-MS. The volatiles were removed under reduced pressure. The crude residue was treated with DCM / brine / Na 2 SO / filtration / concentration to give a dark oil. This oil was purified by flash chromatography (Si02, Bíotage 40 + M cartridge). The column was eluted by a mixture of 0% to 40% EtOAc / hexanes. The related fractions were combined and concentrated under vacuum to give the title compound. CL-EM (ESI) cale. = 231.11; found = 232.09 (M + 1) +.

Step B: 2-fluoro-4'-vodo-3'-methylbiphenyl-4-ylmethyl 2'-fluoro-4'-methoxy-3-methylbiphenyl-4-amine ether (190 mg, 0.822 mmol), 3- nitrite methylbutyl (144.4 mg, 1.233 mmol), iodine (251 mg, 0.986 mmol) and chloroform (7 ml) were refluxed in an oil bath for 3.5 hours, then allowed to cool to room temperature overnight. The crude of the reaction was purified by flash chromatography (Si02, Biotage 40 + M cartridge) was eluted with a gradient mixture of EtOAc / hexanes The related fractions were combined and concentrated in vacuo to give the title compound LC-MS was showing that the solid was approximately 70A% pure LC-MS (ESI) cale = LC-MS (ESI) cale. = 341 99, found = 341 94 (M) + Step C: Methyl 2'-fluoro-4'-methox? -3-met? Lb? Phen? L-4-carboxylate Ether 2-fluoro-4'-iodo-3'-methyl? Phen? L- 4-? Lmethyl (289 mg, 0 845 mmol), trans-b? S (tr? Phenylphosphine) palladium (ll) chloride (59.3 mg, 0.08 mmol), triethylamine (177? L, 1.27 mmol) and methanol (5 ml. ) were stirred under carbon monoxide (3.51 kg / cm2) at 60X for 17 hours. The aliquot indicated the complete consumption of the starting material and a peak m / e 275 (highest peak). The crude mixture was purified by S02 (CCD-Prep, 20% EtOAc / hexanes) to give the title compound. LC-MS (ESI) cale = 274 10, found = 275.09 (M + 1) +.

Step D 2'-Fluoro-5'-iodo-4'-methox? -3-met? Lb? Phen? L-4-carboxylic acid methyl 2'-fluoro-4'-methox? -3-met? methyl lb-phenol-4-carboxylate (100 mg, 365 mmol), methanol (3 ml), iodide (93 mg, 0 366 mmol) and silver sulfate (114 mg, 0 366 mmol) were added. stirred at room temperature for 15 hours. The crude of the reaction was quenched by Na 2 SO 3 (sat, ac). Volatile compounds were removed from the grayish-gray mixture. The residue of the recipent was treated with H 2 O / EtOAc / Na 2 SO 4 / ph ltrac? η / concentration to give the title compound CL-MS (ESI) cale = 400 00, found = 400 96 (M + 1) + Step E 2"- ( { (4S, 5f?) - 5- [3,5-b? S (tr? Fluoromet? L) fen? Ll-4-met? L-2-oxo-1, 3 -oxazole? d? n-3-? l) met? l) -6'-fluoro-4'-methox? -3-met? l-4"- (tr? fluoromet? l) -1 J '3' .1"-methyl-4-carboxylic acid methyl 2'-fluoro-5'-iodo-4'-methox? -3-met? Lb? Phen? L-4-carboxylate methyl (135 mg, 0 337 mmol), (4S, 5R) -5- [3,5-b? S (tr? Fluoromet? L) phen? L] -4-met? L-3- [2- (4 , 4,5,5-tetramethyl-l, 3,2-d-oxaborolan-2-? L) -5- (tr? Fluoromet? L) benc? L] -1, 3-oxazole? D? N -2-one (intermediate 9, 403 mg, 0 675 mmol, was dissolved in 4 75 ml of 1,4-d-oxano), sodium carbonate (337 μl, ac, 2M, 0 674 mmol) and adduct of IJ '-b? s (d? phen? lfosf? no) ferrocene-palladium dichloride- dichloromethane (55 mg, 07.0 mmol) was heated in an 80X oil bath for 2 hours, then allowed to cool to room temperature overnight. (4S, 5f?) - 5- [3,5-b? s (tr? fluoromet? l) phen? l] -4-met? l-3- [2- (4,4,5,5Jetramet? l-1, 3,2-d? oxaborolan-2-? l) -5- (tr? Fluoromet? L) benc? L] -1, 3-oxazol? D? N-2-one additional (intermediate 9, 200 mg, 0 335 mmol, was dissolved in 2 35 ml of 1, 4 dioxane) and the heating was resumed for a further 2 hours. The reaction aliquot indicated the presence of M + 23 (LC-MS). The crude mixture was cooled, dried / Na 2 SO 4 and deposited on CCD-Prep plates (S? 02) The plates were developed in a mixture of 30% DCM / hex to give a green oil of 350 mg. The green oil was further purified by CCD-Prep (S? 02, 30% CM / hexanes) to give a glass green The oil / green glass was further purified Nally by CCD-Prep (S? 02, 20% EtOAc / hexanes) to give the title compound LC-MS (ESI) cale = 743 17, found = 744 (M + 1) + Step F acid 2"- ( { (4S, 5ff) -5- [3,5-b? S (tr? Fluoromet? L) phen? N-4-met? L-2-QXO-1, 3 -oxazole? d? n-3-? l) met? l) -6'-fluoro-4'-methox? -3-methyl-4"- (tpfluoromet? l) -1 J '3'.1" - terfen? l-4-carboxyl? co 2"- ( { (4S, 5R) -5- [3,5-b? s (tr? fluoromet? l) phen? l] -4-met? l- 2-oxo-1,3-oxazole? D? N-3-? L.] Met? L) -6'J? Uoro-4'-methox? -3-met? L-4"- (tpfluoromet? L) -1, 1 '3', 1"-terphene-4-carboxylic acid methyl ester (55 mg, O 074 mmol), lithium hydroxide monohydrate (31 mg, 0 74 mmol), water (1 ml) and 1, 4-d-oxane (2 ml) was stirred at room temperature overnight Traces of LC-MS from the reaction aliquot indicated that the reaction had been completed The crude mixture was acidified with HCl (ac 1 N) Compounds The volatiles were removed under reduced pressure. The residue from the vessel was dissolved in a water / MeCN mixture and purified by reverse phase HPLC-prep (Kromasil 100-5C18, 100x21 1 mm) eluting with a gradient mixture of MeCN (0 1% TFA, v / v) / H20 (0 1% TFA, v / v) The corresponding fractions were combined and evaporated under vacuum to give a light yellow glass. This residue was dissolved in EtOAc and washed with Water (10 ml x 2), separated, dried / Na 2 SO 4, filtered and concentrated to give the title compound LC-MS (ESI) cale = 729 16, found = 730 15 (M + 1) + 1 H NMR (CDCl 3, 500 MHz, mixture 1 1 of atropoisomers) d 8 10 (t, J = 7 8 Hz, 1 H), 7 85 (d, J = 5 Hz, 1 H), 7 70 (s, 1 5 H) , 7 66 (d, J = 8 Hz, 1 H), 7 62 (s, 1 5H), 7 47-7 38 (m, 3H), 7 30-7 25 (m, 1 H), 6 85 (dd, J = 12 5, 3 Hz, 1 H), 5 61 (d, J = 8 Hz, 0 5H), 5 31 (d, J = 8 Hz, 0 5H), 4 94 (d, J = 4 5 Hz, 0 5H), 4 91 (d, J = 4 Hz, 0 5H), 4 15 (d, J = 16 5 Hz, 0 5H), 3 93 (d, J = 16 Hz, O 5 H), 3 86 (s, 3 H), 3 86-3 76 (m, 1 H), 2 68 (s, 3 H), O 57 (d, J = 6 5 Hz, 1 5 H), 0 46 (d, J = 6 5 Hz 1 5H) EXAMPLE 75 2"- (((4S, 5R) -5-f3,5-b? S (tr? Fluoromet? L) phen? N-4-met? L-2-oxo-1, 3-oxazole? D? N -3-? L) met? L) -4'-methox? -NN2Jr? Met? L-4"- (tr? Fluoromet? L) -1, r 3'.1" -terfen? L-4- carboxamide Acid 2"- ( { (4S, 5R) -5- [3,5-b? s (tr? fluoromet? l) phen? l] -4-met? l-2-oxo-1 , 3-oxazole? D? N-3-? L.) Met? L) -4'-methox? -2-met? L-4"- (tpfluoromet? L) -1, 1 '3', 1"Jerfen? L-4-carboxy co (example 30, 300 mg, 0 42 mmol), N-methylmethanamine hydrochloride (41 mg, 0 50 mmol), N- [3- (d? Met? Lam? N hydrochloride propylene] -N'-et? lcarbod ?? m? da (121 mg, 0 63 mmol), hydrate of 1 H-1, 2,3-benzotr? azol-1-ol (86 mg, 0 56 mmoles) and triethylamine (146 μl, 1 05 mmoles) were stirred in DCM (5 ml) at room temperature for 15 hrs LC-MS of the aliquot at this time indicated the formation of the desired product and the complete consumption of the starting material The crude mixture was diluted with MeCN and purified by preparative reverse phase HPLC (Kromasil 100-5C18, 100x21.1 mm) eluting with (acetonitrile + 0.1% v / v TFA) / (water + 0.1% v / v TFA) (10% to 100% organic in 10 min, maintained at 100% during 2 min, 20 ml / min) to give a solid foam. This solid foam was dissolved in EtOAc and washed with NaHCO 3 (sat., Aq.) And then with water. The aqueous layers were separated from the extracts. The combined aqueous phases were extracted again with EtOAc. The combined extracts were dried over Na 2 SO 4, filtered and then concentrated under vacuum to give the title compound. CL-EM (ESI) cale. = 738.21; found = 739.41 (M + 1) +. 1 H NMR (CDCl 3, 500 MHz, 1: 1 mixture of atropoisomers): d 7. 85 (s, 0.5H), 7.71 (s, 0.5H), 7.69 (s, 1 H), 7.67-7.62 (m, 2.5H), 7.44 (d, J = 8 Hz, 0.5H), 7.41 (d , J = 8.5 Hz, 0.5H), 7.36 (t, J = 7.5 Hz, 1 H), 7.32 (d, J = 8 Hz, 1 H), 7.25 (s, 0.5H), 7.23 (s, 1 H) ), 7J 9 (d, J = 8 Hz, 0.5H), 7J 2 (t, J = 2 Hz, 1 H), 7.07 (d, J = 7 Hz, 0.5H), 7.05 (d, J = 7 Hz, 0.5H), 5.58 (d, J = 8 Hz, 0.5H), 5.30 (d, J = 8 Hz, 0.5H), 4.96 (d, J = 16 Hz, 1 H), 4J6 (d, J = 16 Hz, 0.5H), 3.97 (d, J = 15.5 Hz, 0.5H), 3.86 (s, 3H), 3.81-3.73 (m, 1 H), 3.1 1 (s, 3H), 3.02 (s, 3H), 2.33 (s, 1.5H), 2.27 (s, 1.5H), 0.54 (d, J = 6.5Hz, 1.5H), 0.41 (d, J = 6.5 Hz, 1.5H). The following compounds were prepared following the general procedure delineated in Example 21.

The following compounds were prepared following the general procedure outlined in Example 1.

EXAMPLE 83 (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl-3Jf4, -fluoro-5 '- (1-glvcoloylpiperidin-4-yl) -2'-methoxy-4- (trifluoromethyl) biphenyl -2-ylmethyl) -4-methyl-1,3-oxazolidin-2-one Step A: Ethyl 2- [4- (2-fluoro-5-iodo-4-methoxyphenyl) piperidin-1-yl-2-oxoacetate A stirred solution of 4- (2-fluoro-5-iodo-4-methoxyphenyl) ) piperidine (50 mg, 0.149 mmol) in DMF (1.2 ml) under N2 was treated with N, N-diisopropylethylamine (26 μl, 0.149 mmol), followed by acetoxyacetyl chloride (16 μl, 0.149 mmol). The resulting solution was stirred at room temperature for 5 hr. The reaction was partitioned between EtOAc (25 mL) and saturated NaHCO 3 (25 mL). The aqueous layer was extracted with EtOAc (3 x 25 mL) and the combined organic fractions were washed with water and brine (25 mL each), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with EtOAc / hexanes, to give ethyl 2- [4- (2-fluoro-5-iodo-4-methoxyphenyl) piperidin-1-yl] -2-oxoacetate as a colorless oil. LC-MS = 435.8 (M + 1) +. 1 H NMR (CDCl 3, 500 MHz) d 7.52 (d, J = 8.2 Hz, 1 H), 6.56 (d, J = 12.2 Hz, 1 H), 4.76 (s, 2 H), 4.76-4.70 (m, 1 H), 3.85 (s, 3 H), 3.76 (br d, J = 13 Hz, 1 H), 3.17 (t, J = 12.6 Hz, 1 H), 2.98 (tt, J = 12.1, 3.4 Hz, 1 H), 2.68 (t, J = 12.4 Hz, 1 H), 2.20 (s, 3 H), 1.90-1.82 (m, 2 H), 1.70-1.62 (m, 2 H).

Step B: 2J4- [2 '- ( { (4S, 5) -5- [3,5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4-fluoro-6-methoxy-4 '- (trifluoromethyl) biphenyl-3-yl-piperidin-1-yl) -2-oxoacetate ethyl A mixture of 2- [4- (2-fluoro-5-iodo- Ethyl 4-methoxyphenyl) piperidin-1-yl] -2-oxoacetate (step A, 33 mg, 0.076 mmol) and (4S, 5f?) - 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 (intermediate) 9; 68 mg, 0.114 mmol) was treated with 1,1'-bis (dl-f-butylphosphino) ferrocene palladium dichloride (-5 mg) as described above. The product was purified by chiral HPLC (ChiralPak IA column, 15% IPA / Heptane) to give 2-. { 4- [2 '- ( { (4S, 5tf) -5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-2-oxo-1,3-oxazolidin-3-yl}. methyl) -4-fluoro-6-methoxy-4 '- (trifluoromethyl) biphenyl-3-yl] piperidin-1-yl} Ethyl -2-oxoacetate as a colorless glass. LC-MS = 779.0 (M + 1) +. 1 H NMR (CDCl 3, 500 MHz, mixture of atropoisomers) d 7.86 (s, 1 H), 7.69 (s, 2 H), 7.68-7.60 (m, 2 H), 7.32 (d, J = 7.8 Hz, 1 H), 6.96-6.91 (m, 1 H), 6.72 (dd, J = 11.9, 2.1 Hz, 1 H), 5.59-5.54 (m, 1 H), 4.90 (d, J = 15.6 Hz, 1 H), 4.80-4.65 (m, 3 H), 4J 3-4.04 (m, 1 H), 3.88-3.72 (m, 2 H), 3.78 (s, 3 H), 3.21-3.04 (m, 2 H), 2.72-2.67 (m, 1 H), 2J7 (s, 3 H), 1.96-1.83 (m, 2 H), 1.70-1.59 (, 2 H), 0.42-0.39 (m, 3 H) Step C (4S.5f?) - 5-r3.5-b? S (tr? Fluoromet? L) phen? Ll-3 - ([4'-fluoro-5 '- (1-qlycolo? Lp? Per? d? n-4-? l) -2'-methox? -4- (tr? fluoromet? l) b? phen? l-2? nmet? l) -4-meth? -1,3-oxazole D-n-2-one To a stirred solution of 2- 4- [2 '- ( { (4S, 5R) -5- [3,5-b? s (tpfluoromet? l) phen? l] -4-methyl-2-oxo-1,3-oxazole? D? N-3-? L.) Met? L) -4-fluoro-6-methox? -4 '- (tr? Fluoromet? l) b? fen? l-3-? l] p? per? d? n-1-? l} Ethyl -2-oxoacetate (24 mg, 0 031 mmol) in MeOH (1 mL) under N2 was added sodium methoxide (66.6 mg, 0 031 mmol) The resulting mixture was stirred at room temperature for 15 min. Water (10 ml) was added and the mixture was extracted with EtOAc (3 x 10 ml) The combined organic fractions were washed with brine (10 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% EtOAc / hexanes) to give (4S, 5f?) - 5- [3,5-b] ? s (tr? fluoromet? l) phen? l] -3-. { [4'-Fluoro-5 '- (1-gl? Colo? Lp? Pepd? N-4-? L) -2'-methox? -4- (tr? Fluoromet? L) b? Phen? 2- ?] l? } -4-methyl-1, 3-oxazole? D-n-2-one as a yellow gum LC-MS = 737 1 (M + 1) + 1 H NMR (CDCl 3, 500 MHz, mixture of atropoisomers) d 7 87 (s, 1 H), 7 69 (s, 2 H), 7 68-7 60 (m, 2 H), 7 34-7 30 (m, 1 H), 6 96-6 91 (m, 1 H), 6 72 (d, J = 11 9 Hz, 1 H), 5 44 (d, J = 7 8 Hz, 1 H), 4 90 (d, J = 15 8 Hz, 1 H), 4 78-4 70 ( m, 1 H), 4 18-4 13 (m, 2 H), 3 78 (s, 3 H), 3 62-3 54 (m, 1 H), 3 15-3 05 (m, 2 H) , 2 82-2 73 (m, 1 H), 1 96-1 84 (m, 2 H), 1 70-1 52 (m, 4 H), 0 43-0 39 (m, 3 H) The following compounds were prepared by analogous methods to those described in example 83.

EXAMPLE 94 4- [2 '- ( { (4S, 5R) -5- [3,5-bis (trifluoromethylphenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4- 6-Fluoro-6-methoxy-4 '- (trifluoromethyl) biphenyl-3-yl-piperidine-1-carboxylic acid ester A mixture of 4- (2-fluoro-5-iodo-4-methoxyphenyl) piperidine-1-carboxylate from / er-butyl (58 mg, 0.133 mmol) and (4S, 5F?) - 5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-3- [2- (4,4,5,5Jetramethyl- 1, 3,2-dioxaborolan-2-yl) -5- (trifluoromethyl) benzyl] -1,3-oxazolidin-2-one (111 mg, 0.187 mmol) was treated with 1,1-bis (di-dichloride). -t-butylphosphino) ferrocene palladium (-10 mg) as described above. The product was purified by chiral HPLC (ChiralPak OD column, 10% IPA / Heptane) to give 4- [2 '- ( { (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] - 4-Methyl-2-oxo-1,3-oxazolidin-3-yl.} Methyl) -4-fluoro-6-methoxy-4 '- (trifluoromethyl) b-phenyl-3-yl] piperidin-1 - tert-butyl carboxylate as a colorless glass. LC-MS = 678.8 (M + 1-100) +. 1 H NMR (CDCl 3, 500 MHz, mixture of atropoisomers) d 7.86 (s, 1 H), 7.69 (s, 2 H), 7.64-7.61 (m, 2 H), 7.32 (d, J = 8 Hz, 1 H ), 6.96 (d, J = 8.4 Hz, 1 H), 6.70 (d, J = 11.9 Hz, 1 H), 5.57 (d, J = 8 Hz, 1 H), 4.88 (d, J = 15.8) Hz, 1 H), 4.26-4J7 (m, 2 H), 3.86 (d, J = 15.8 Hz, 1 H), 3.83-3.78 (m, 1 H), 3.77 (s, 3 H), 3.01-2.93 (m, 1 H), 2.84-2.75 (m, 2 H), 1.84-1.69 (m, 2 H), 1.64-1.50 (m, 2 H), 1.45 (s, 9 H), 0.38 (d, J) = 6.7 Hz, 3 H).

EXAMPLE 95 2"-ff (4S, 5F?) - 5- (3Jluorophen-4-methyl-2-oxo-1,3-oxazolidin-3-inmethyl) -4'-methoxy-2-methyl-4" - (trifluoromethyl) -1 J ': 3'J "-methyl-methyl-4-carboxylate To a solution at 0 ° C of (4S, 5f?) - 5- (3-fluorophenyl) -4-methyl-1,3-oxazolidin- 2-one (16.2 mg, 0.0830 mmol) in DMA (1 mL) was added with NaHMDS (83 μL, 0.083 mmol), followed by a solution of 2"- (bromomethyl) -4'-methoxy-2-methyl-4". - (trifluoromethyl) -1 J ': 3'J "-terphenyl-4-carboxylic acid methyl ester (49 mg, 0.0996 mmol) in DMA (1 ml) was added by cannula. After 5 minutes, the reaction was quenched with saturated NH CI solution (10 mL) and diluted with EtOAc (20 mL). The aqueous layer was extracted with EtOAc (20 ml), and the combined organic extracts were washed with brine (10 ml), dried over Na 2 SO 4, filtered and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 25% EtOAc / hexanes) gave 2"- { [(4S, 5R) -5- (3-Jouro-phenyl) -4-methyl-2-oxo-1,3-oxazolidin-3-yl] methyl.} -4'-methoxy-2-methyl -4"- (trifluoromethyl) -1 J ': 3', 1" -terphenyl-4-carboxylic acid methyl ester LC-MS = 608.2 (M + 1) +. 1 H NMR (CDCl 3, 500 MHz, rotamers present) d 7.94 (d, J = 5.9 Hz, 1 H), 7.87 (d, J = 7.8 Hz, 1 H), 7.71-7.61 (m, 2H), 7.41-7.36 (m, 2H), 7.33-7.24 (m, 2H), 7J4-7J2 (m, 1H), 7.07-7.05 (m, 1 H), 7.02-6.90 (m, 3H), 5.46 (d, J = 8.2 Hz), 5.24 (d, J = 8.2 Hz) , 4.90 (d, J = 15.8 Hz), 4.82 (d, J = 15.8 Hz), 4.20 (d, J = 15.8 Hz), 3.97 (d, J = 15.8 Hz), 3.92 (s, 3H), 3.95 ( s, 3H), 3.75-3.69 (m, 1 H), 2.36 (s), 2.31 (s), 0.53 (d, J = 6.6 Hz), 0.43 (d, J = 6.6 Hz).

EXAMPLE 96 2"J [(4S, 5S) -5- (5-chloro-2Jhienyl) -4-methyl-2-oxo-1,3-oxazolidin-3-methane) -4'-methoxy- 2-methyl-4"- (trifluoromethyl) -1 J ': methyl 3-methyl-3-phenyl carboxylate To a solution of (4S, 5S) -5- (5-chloro-2-thienyl) -4 methyl-1, 3-oxazolidin-2-one (39.9 mg, 0J 84 mmol) in DMF (1.8 ml) was added f-BuOK (21 J mg, 0J 83 mmol) The reaction was stirred for 15 minutes, then a solution of 2"- (bromomethyl) -4'-methoxy-2-methyl-4" - (trifluoromethyl) -1 J ': 3'J "- Methyl terfenyl-4-carboxylate (90 mg, 184-4 mmol) in DMF (2 ml) was added by cannula. The reaction was stirred at room temperature for 1 hour, and then quenched with saturated NH 4 Cl solution ( 10 ml), diluted with EtOAc (20 ml), washed with brine (10 ml), dried over Na 2 SO 4, filtered and concentrated. The residue was purified by reverse phase chromatography (C-18, 10 to 95% of MeCN / water with 0 1% TFA) to give 2"- { [(4S, 5S) -5- (5-chloro-2Jh? in? l) -4-met? l-2-oxo- 1,3-oxazole? D? N-3-? L] met? L.}. 4'-methox? -2-met? L-4"- (tr? Fluoromet? L) -1,1 '3 'J' -Methyl-1-methyl-4-carboxylic acid ester Rf-0 43 (50% EtOAc / hexanes) LC-MS = 629 7 (M + 1) + 1 H NMR (CDCl 3, 500 MHz, rotamers present) d 7 88-7 71 (m, 3H), 7 67-748 (m, 2H), 7 28-7 12 (m, 2H), 7 00-6 92 (m, 2H), 6 66- 6 55 (m, 2H), 5 42 (d, J = 8 0 Hz), 5 21 (d, J = 8 0 Hz), 4 70 (d, J = 16 0 Hz), 4 58 (d, J = 16 0 Hz), 4 14 (d, J = 16 0 Hz), 3 88 (d, J = 16 0 Hz), 3 79 (m, 3H), 3 72-3 71 (m, 3H), 3 58-3 55 (m, 1 H), 2 23 (s), 2 20 (s), 0 59 (d, J = 6 4 Hz), 0 51 (d, J = 6 4 Hz) In a similar way, we synthesized the next compound EXAMPLE 98 4'-methoxy-2"J [(4S, 5f?) - 5- (3-methoxyphenyl) -4-methyl-2-oxo-1,3-oxazolidin-3-illmethyl) -2-methyl-4" - (trifluoromethyl) -1 J ': 3'J "Methylphenphenyl-4-carboxylate To a solution at 0 ° C of [(1 S, 2R) -2-hydroxy-2- (3-methoxyphenyl) -1-methylethylcarbamate of benzyl (40 mg, 0.126 mmol) in DMA (1.5 ml) was added NaHMDS (0.246 ml of a 1 M solution in THF, 0.246 mmol) After 5 minutes, a solution of 2"- (bromomethyl) -4 ' methyl-methoxy-2-methyl-4"- (trifluoromethyl) -1, 1 ': 3', 1" -terphenyl-4-carboxylate (68 mg, 0J38 mmol) in DMA (2.5 ml) was added by cannula. After 5 minutes, the reaction was quenched with saturated NH 4 Cl solution (10 ml), was diluted with EtOAc (20 ml), washed with brine (10 ml), dried over Na 2 SO 4, filtered and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 25% acetone / hexanes), followed by reverse phase chromatography (C-18, 10 to 95% MeCN / water with 0.1% TFA) gave 4 ' -methoxy-2"- { [(4S, 5f?) - 5- (3-methoxyphenyl) -4-methyl-2-oxo-1,3-oxazolidin-3-yl] methyl.} -2- methyl-4"- (trifluoromethyl) -1 J ': 3'J" -terphenyl-4-carboxylic acid methyl ester LC-MS = 644.0 (M + 1) +. 1 H NMR (CDCl 3, 500 MHz, rotamers present) d 7 94-7 86 (m, H), 7 71-7 62 (m, 2 H), 7 43-7 36 (m, 2 H), 7 31-7 22 (m, 2H), 7 3 (m, 1 H), 08-7 05 (m, 1 H), 6 85-6 83 (m, 1 H), 6 75-6 68 (m, 2H), 5 45 (d, J = 8 0 Hz), 23 (d, J = 8 0 Hz), 4 89 (d, J = 16 0 Hz), 4 82 (d, J = 16 0 Hz), 4 20 (d , J = 5 8 Hz), 3 96 (d, J = 15 8 Hz), 3 91 (s, 3H), 3 85 (s, 3H), 3 77-3 75 (m, 3H), 72-3 69 (m, 1 H), 2 31 (s), 2 08 (s), 0 54 (d, J = 6 4 Hz), 0 44 (d, J = 6 4 Hz) In a similar way, it was synthesized the next compound EXAMPLE 100 4'-methox? -2-met? L-2"J [(4S, 5f?) -4-met? L-2-oxo-5- (3,4,5-tpfluorophen? L) -1, 3- acid oxazole? d? n-3-? nmet? l) -4"- (tr? fluoromet? l) -1 J '3'J" Jerfen? l-4-carboxylic To a solution of 4'-methox? -2 -met? l-2"-. { [(4S, 5f?) - 4-met? L-2-oxo-5- (3,4,5Jr? Fluorophen? L) -1, 3-oxazole? D? N -3? L] meth? } -4"- (tr? Fluoromet? L) -1, 1 '3'J" -terfen? L-4-carboxylic acid methyl ester (23 mg, 0 0358 mmol) in MeOH (1 ml) was added 4M KOH (0 5 mL) The reaction was stirred at room temperature for 3 hours, then quenched with 1 N HCl (5 mL) and diluted with EtOAc (15 mL). The aqueous layer was extracted with EtOAc (10 mL). , and the combined organic extracts were washed with brine (10 ml), dried over Na 2 SO 4, filtered and concentrated. The residue was purified by reverse phase chromatography (C-18, 10 to 95% MeCN / water with 0 1 % TFA) to give 4'-methox? -2-met? l-2"- { [(4S, 5) -4-met? l-2-oxo-5- (3,4,5 -tpfluorophen? -1) -1, 3-oxazole? d? n -3? l] met? l.}. 4"- (tr? fluoromet? l) -1, 1 '3', 1" -terfen ? l-4-carboxylic LC-MS = 629 9 (M + 1) + H NMR (CDCl 3, 500 MHz, rotamers present) d 8 01-7 93 (m, 2H), 7 70-7 62 (m, 2H ), 7 43-7 38 (m, 2H), 7 33-7 30 (m, 1 H), 7 14-7 12 (m, 1 H), 7 09-7 06 (m, 1 H), 6 88-6 80 (m, 2H), 5 39 (d, J = 8.0 Hz), 5 15 (d, J = 8 0 Hz), 4 92 (d, J = 15 6 Hz), 4 86 (d, J = 15 6 Hz), 4 16 (d, J = 15 8 Hz), 3 95 (d, j = 15 8 Hz), 3 86 (m, 3H), 3 72-3 69 (m, 1 H), 2 38 (s), 2 34 (s), 0 57 (d, J = 6 6 Hz), 0 46 (d, J = 6 6 Hz) In a similar way, the following were synthesized compounds: EXAMPLE 105 Acid 2"J [(4S) -4-benzyl-2-oxo-1,3-oxazolidin-3-illmethyl) -4'-methoxy-2-methyl-4" - (trifluoromethyl) -1 J ': 3M " Jerphenyl-4-carboxylic acid To a solution of (4S) -4-benzyl-1,3-oxazolidin-2-one (29.8 mg, 0J68 mmoles) in DMF (1.5 ml) was added f-BuOK (17.5 mg, 0J52 mmoles). After 10 minutes, a solution of 2"- (bromomethyl) -4'-methoxy-2-methyl-4" - (trifluoromethyl) -1 J ': 3'J "-terphenyl-4-carboxylic acid methyl ester (75 mg 0.152 mmole) in DMF (1.5 ml) was added by cannula, the reaction was stirred for 30 minutes, and then quenched with saturated NH4CI solution (10 ml), diluted with EtOAc (15 ml), washed with brine. (10 ml), dried over Na 2 SO 4, filtered and concentrated The residue was dissolved with MeOH (2 ml) and 4M KOH solution (0.5 ml) was added.The reaction was stirred at room temperature. environment for 2 hours, then stored in the freezer for 16 hours. The reaction was warmed to room temperature, and stirred for 2 hours. The reaction was quenched with 1 N HCl solution (5 ml), diluted with EtOAc (15 ml ), washed with brine (5 ml), dried over Na 2 SO 4, filtered and concentrated The residue was purified by reverse phase chromatography (C-18, 10 to 95% MeCN / water with 0 1% TFA) , followed by lyophilization to give 2"- { [(4S) -4-benzyl-l-2-oxo-1,3-oxazole? d? n-3-? l] met? l.}. -4'-methox? -2-met? L-4"- (tr? Fluoromet? L) -IJ '3', 1" -terfen? L-4-carboxyl? Co LC-MS = 576 0 (M + 1) + 1 H NMR (CDCl 3, 500 MHz, rotamers present) d 8 01-7 86 (m, 2 H), 7 67-7 50 (m, 2 H), 7 44-7 32 (m, 3 H), 7 23 -7 07 (m, 5H), 6 91 -6 85 (m, 2H), 4 92-4 58 (m, 2H), 4 27 (d, J = 15 6 Hz), 4 1 1 (d, J = 15 6 Hz), 4 06-3 82 (m, 5H), 3 64-3 51 (m, 1 H), 2 86-2 71 (m, 1 H), 2 47-2 28 (m, 4H ) In a similar manner, the following compound was synthesized EXAMPLE 107 Acid 2"J [(4S, 5F?) - 5- (3-chloro-4-chloro-phenyl) -4-methyl-2-oxo-1,3-oxazolidin-3-illmethyl) -4'-methoxy-2-methyl-4" - (trifluoromethyl) -1, 1 ': 3'.1"-terphenyl-4-carboxylic acid To a solution at 0 ° C of [(1 S, 2R) -2- (3-chloro-4-fluorophenyl) -2-hydroxy-1-methyl-ethyl] carbamic acid (51.4 mg, 0.152 mmol) in DMA (-1.5 mL) was added with NaHMDS (0.296 mL of a 1 M solution in THF, 0.296 mmol). After 5 minutes, a solution of 2"- (bromomethyl) -4'-methoxy-2-methyl-4" - (trifluoromethyl) -1, r: 3 ', 1"-methyl-4-carboxylic acid methyl ester (75 mg, 0.152 mmol) in DMA (2.5 ml) was added by cannula After 5 minutes, saturated aqueous NaOH solution (3 ml) was added and the mixture was allowed to warm to room temperature. The mixture was acidified with 6N HCl and concentrated.The residue was purified by reverse phase chromatography (C-18, 10 to 95% MeCN / water with 0.1% TFA) to give 2"- acid. { [(4S, 5f?) - 5- (3-chloro-4-fluorophenyl) -4-methyl-2-oxo-1,3-oxazolidin-3-yl] methyl} 4'-methoxy-2-methyl-4"- (trifluoromethyl) -1, 1 ': 3'J" -terphenyl-4-carboxylic acid. LC-MS = 627.9 (M + 1) +. 1 H NMR (CDCl 3, 500 MHz, rotamers present) d 7.95-7.62 (m, 2H), 7.69-7.52 (m, 2H), 7.43-7.37 (m, 2H), 7.30-7.24 (m, 1 H), 7.18-7.1 1 (m, 2H), 7.08-6.86 (m, 3H), 5.44 (d, J = 8.0 Hz), 5.18 (d, J = 8.0 Hz), 4.92-4.85 (m, 1 H), 4.18 (d, J = 15.5), 3.96 (d, J = 15.5), 3.93- 3.85 (m, 3H), 3.73-3.66 (m, 1 H), 2.36 (s), 2.32 (s), 0.55 (d, J = 6.6 Hz), 0.44 (d, J = 6.6 Hz).

EXAMPLE 108 Acid 2"- ((5-f3.5-bis (trifluoromethyl) phenin-4,4-dimethyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4'-methoxy-2-methyl-4" - (trifluoromethyl) -1 J ': 3'J "Jerphenyl-4-carboxylic acid To a solution of benzyl (2- {3,5-bis (trifluoromethyl) phenyl] -2-hydroxy-1 J-dimethylethylcarbamate ( 65 mg, 0J49 mmoles) in THF (1.5 ml) was added NaH (13 mg, 0.542 mmol) and 2"- (bromomethyl) -4'-methoxy-2-methyl-4" - (trifluoromethyl) -1, 1 ' : 3 ', 1"Jerfenyl-4-carboxylic acid methyl ester (91.1 mg, 0.185 mmol). The reaction was stirred for 72 hours, and then additional NaH (36.2 mg, 1.51 mmol) was added. After a further 6 hours at room temperature, the reaction was quenched with saturated NH 4 Cl solution (10 mL) and diluted with EtOAc (20 mL). The aqueous layer was extracted with EtOAc (20 ml), and the combined organic extracts were washed with brine (10 ml), dried over Na2SO4, filtered and concentrated. Purification of the residue by reverse phase chromatography (C-18, 10 to 95% MeCN / water with 0.1% TFA) gave 2"- (. {5- [3,5-bis (trifluoromethyl) phenyl]] 4,4-dimethyl-2-oxo-1,3-oxazolidin-3-yl.} Methyl) -4'-methoxy-2-methyl-4"- (trifluoromethyl) -1, r: 3 ', 1"-terphenyl-4-carboxylic acid LC-MS = 726.0 (M + 1) +. 1 H NMR (CDCl 3, 500 MHz, rotamers present) d 8.03-8.02 (m, 1 H), 7.80-7.96 (m, 1 H), 7.89 (s, 1 H), 7.79-7.76 (m, 2H), 7.62-7.59 (m, 1 H), 7. 42-7.31 (m, 3H), 7.22-7.08 (m, 3H), 5.26-5.28 (m, 1 H), 4.81 (d, J = 16.6 Hz), 4.44-4.42 (m, 1 H), 4.02 ( d, J = 16.6 Hz), 3.85 (s, 3H), 2.37-2.35 (m, 3H), 1.24 (s), 1.06 (s), 0.56-0.54 (m, 3H).

EXAMPLE 109 4J2-r2 acid [(((4S, 5) -5- [3,5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) - 4- (trifluoromethyl) phen-1, 3-thiazol-4-yl) -3-methylbenzopic Step 1: (4S, 5) -5- [3,5-bis (trifluoromethyl) phenyl-3-f2- (4-bromo-1,3-thiazol-2-yl) -5- (trifluoromethyl) benzip -4-methyl-1, 3-oxazolidin-2-one In a tube were placed (4S, 5f?) - 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 (59 mg, 0.099 mmol), 2, 4-dibromothiazole (60 mg, 0.247 mmol), DME (420 μl), EtOH (140 μl), and 1 M Na 2 CO 3 (296 μl, 0.296 mmol).

The mixture was degassed with N2 and then Pd (PPh3) 4 (5.7 mg, 4.94 x 10-3 mmol) was added. The mixture was degassed with N2 again, and then the tube was sealed, and the reaction was heated at 100 ° C for 90 minutes. The reaction was cooled to room temperature and diluted with EtOAc (30 mL). The organic layer was washed with water and brine (10 ml) each, dried over Na2SO, filtered and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 25% EtOAc / hexanes) gave (4S, 5) -5- [3,5-bis (trifluoromethyl) phenyl] -3- [2- (4- bromine-1, 3-Jiazol-2-yl) -5- (trifluoromethyl) benzyl] -4-methyl-1,3-oxazolidin-2-one. R, = 0.33 (25% EtOAc / hexanes). LC-MS = 635.0 (M + 1) +. 1 H NMR (CDCl 3, 500 MHz) d 7.89 (bs, 2 H), 7.78 (s, 2 H), 7.75 (d, J = 8.3 Hz, 1 H), 7.68 (dd, J = 8.1, 1.0 Hz, 1 H) , 7.41 (s, 1H), 5.66 (d, J = 8.0 Hz, 1 H), 5.02 (d, J = 15.8 Hz, 1 H), 4.84 (d, J = 15.8 Hz, 1 H), 4.20 (m , 1 H), 0.78 (d, J = 6.7 Hz, 3H).

Step 2: 4J2- [2 - (((4S, 5f?) - 5- [315-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4 - (Methyl trifluoromethyl) phenyl-1, 3-thiazol-4-yl) -3-methylbenzoate In one tube were placed (4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl) ] -3- [2- (4-Bromo-1,3-thiazol-2-yl) -5- (trifluoromethyl) benzyl] -4-methyl-1,3-oxazolidin-2-one (46.0 mg, 0.073 mmol) ), Methyl 3-methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) benzoate (30 mg, 0.11 mmol), 1 J'-bis dichloride ( di-r-butylphosphino) ferrocene palladium (5 mg, 7.3 x 10-3 mmol), THF (1 ml) and 1 M K2CO3 (1 ml, 1 mmol). The mixture was degassed with N2, the tube was sealed, and the reaction was heated at 90 ° C for 90 minutes. The reaction was cooled to room temperature and diluted with EtOAc (30 mL). The organic layer was washed with water and brine (10 ml) each, dried over Na 2 SO 4, filtered and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 40% EtOAc / hexanes) gave 4-. { 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-thiazol-4-yl} Methyl-3-methylbenzoate. Rf = 0.29 (25% EtOAc / hexanes). LC-MS = 702.9 (M + 1) +. 1 H NMR (CDCl 3, 600 MHz) d 7.97 (s, 1 H), 7.92 (dd, J = 8.0, 1.4 Hz, 1 H), 7.85-7.86 (m, 3 H), 7.69-7.72 (m, 4 H), 7.53 (s, 1H), 5.66 (d, J = 8.0 Hz, 1 H), 5.11 (d, J = 16.2 Hz, 1 H), 4.95 (d, J = 16.2 Hz, 1 H), 4.11 (m, 1 H), 3.93 (s, 3H), 2.54 (s, 3H), 0.60 (d, J = 6.6 Hz, 3H).

Step 3: Acid 4- (2- [2í (((4S.5 /?) - 5- [3,5-bisftrifluoromethyl) phen'n-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4- (trifluoromethyl) phenin-1,3-thiazol-4-yl) -3-methylbenzoic acid To a solution of 4-. { 2- [2- ( { (4S, 5ft) -5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-2-oxo-1,3-oxazolidin-3-yl} methyl. ) -4- (trifluoromethyl) phenyl] -1,3-thiazol-4-yl} Methyl-3-methylbenzoate (35.2 mg, 0.05 mmol) in THF (2 ml) was added water (800 μl), 4N KOH (75 μl, 0.3 mmol), and EtOH (200 μl). The reaction was stirred at room temperature for 24 hours and then acidified with 1 N HCl and extracted with EtOAc (30 mL). The organic layer was washed with water and brine (10 ml each), dried over Na 2 SO, filtered and concentrated. Purification of the residue by flash chromatography on silica gel (10 to 100% EtOAc / hexanes) gave 4-acid. { 2- [2 [( { (4S, 5?) - 5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-2-oxo-1,3-oxazolidin-3-yl}. methyl) -4- (trifluoromethyl) phenyl] -1,3-thiazol-4-yl} -3-methylbenzoic acid. LC-MS = 688.8 (M + 1) +. 1 H NMR (CDCl 3, 500 MHz) d 8.04 (s, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.84-7.87 (m, 3 H), 7.70-7.75 (m, 4 H), 7.56 ( s, 1 H), 5.67 (d, J = 8.1 Hz, 1 H), 5.14 (d, J = 16.2 Hz, 1 H), 4.96 (d, J = 16.2 Hz, 1 H), 4.10 (m, 1 H), 2.56 (s, 3H), 0.62 (d, J = 6.6 Hz, 3H).

EXAMPLE 110 2"-d (4S, 5F?) - 5- (2-chloropyridin-4-yl) -4-methyl-2-oxo-1,3-oxazolidin-3-methy1) -4'-methoxy-2-methyl -4"- (trifluoromethyl) -1 J ': 3M" Methylphenphenyl-4-carboxylate To a solution of 4'-methoxy-2-methyl-2"-. { [(4S, 5R) -4-methyl-2-oxo-5-pyridin-4-yl-1, 3-oxazolidin-3-yl] methyl} -4"- (trifluoromethyl) -1, r: 3'J" Methylphenphenyl-4-carboxylate (175 mg, 0.296 mmole) in CH2Cl2 (15 ml) at 0 ° C under N2, 3-chloroperbenzoic acid ( 146 mg, 0.593 mmol) as a powder. The mixture was stirred at 0 ° C for 15 min. Then, it was allowed to warm to room temperature and was stirred for 2 hr. The reaction mixture was diluted with CH 2 Cl 2 and washed with saturated NaSO 3 (1 x) followed by saturated K 2 CO 3 (2 x). The organic layer was dried (Na 2 SO), filtered and the solvent was evaporated under vacuum. The residue obtained was dissolved in POCI3 (10 ml). The resulting solution was heated at 110 ° C under N2 for 2 hr. Then, it was allowed to warm to room temperature and was stirred for 2 hr. The reaction was concentrated under vacuum. The residue was diluted with EtOAc (50 ml) and water (10 ml) and washed with saturated NaHCO 3 (20 ml). The aqueous layer was extracted with EtOAc (2 x 40 ml). The combined organic layers were dried (Na2SO4), filtered and the solvent evaporated under vacuum. The residue was purified by flash chromatography on silica gel to give 2"- { [(4S, 5f?) - 5- (2-chloropyridin-4-yl) -4-methyl-2-oxo-1, 3 -oxazolidin-3-yl] methyl.} - 4'-methoxy-2-methyl-4"- (trifluoromethyl) -1, 1 ': 3', 1" -terphenyl-4-carboxylic acid methyl ester. cale = 625.2; found = 625.0 (M + 1) +. 1H NMR (500 MHz, CDCI3, 1: 1 mixture of atropoisomers) d 8.40 (s, 0.5 H), 8.39 (s, 0.5 H), 7.97 (s) , 1 H), 7.90 (t, J = 5.8 Hz, 1 H), 7.72 (s, 0.5 H), 7.69-7.63 (m, 1.5 H), 7.48 (d, J = 11.8 Hz, 0.5 H), 7.44 (s, 0.5 H), 7.43-7.37 (m, 1 H), 7.32-7.26 (m, 1 H), 7.24 (s, 0.5 H), 7.20 (s, 0.5 H), 7.16 (d, J = 2.2 Hz, 0.5 H), 7.14 (d, J = 2.2 Hz, 0.5 H), 7.12-7.06 (m, 1.5 H), 7.05 (d, J = 5.1 Hz, 0.5 H), 5.42 (d, J = 8.1 Hz , 0.5 H), 5.18 (d, J = 8.1 Hz, 0.5 H), 4.92 (dd, J = 15.9, 18.5 Hz, 1 H), 4.19 (d, J = 15.8 Hz, 0.5 H), 3.99 (d, J = 15.8 Hz, 0.5 H), 3.95 (s, 3 H), 3.88 (s, 3 H), 3.81-3.75 (m, 1 H), 2.39 (s, 1.5 H), 2.35 (s, 1.5 H) 0.60 (d, J = 6.5 Hz, 1.5 H), 0.49 (d, J = 6.5 Hz, 1.5 H).

EXAMPLE 111 4'-methoxy-2-methyl-2"JÍ (4S, 5F?) - 4-methyl-5- (2-methylpyridin-4-yl) -2-oxo-1,3-oxazolidin-3-illmethyl) - 4"- (trifluoromethyl) -1 J ': 3'J" -methylphenyl-4-carboxylate methyl To a solution of 2"-. { [(4S, 5 /?) - 5- (2-chloropyridin-4-yl) -4-methyl-2-oxo-1,3-oxazolidin-3-yl] methyl} 4'-methoxy-2-methyl-4"- (trifluoromethyl) -1, 1 ': 3', 1" -terphenyl-4-carboxylic acid methyl ester (48 mg, 0.077 mmol) in THF (1 ml) and K2C03 (1 N) (1 ml) was added trimethylboroxin (0J 07 ml, 0.768 mmol) and 1 J-bis (di-te? -butylphosphino) ferrocene palladium dichloride (7J mg, 0.011 mmole). The mixture was sealed and heated at 80 ° C overnight. The mixture was diluted with water and EtOAc and filtered through Celite. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x). The combined organic layers were washed with brine (1 x), dried (Na 2 SO 4), filtered and the solvent was evaporated under vacuum. The residue was purified by flash chromatography on silica gel to give 4'-methoxy-2-methyl-2"- { [(4S, 5f?) - 4-methyl-5- (2-methylpyridin-4-yl) ) -2-oxo-1, 3-oxazolidin-3-yl] methyl.} -4"- (trifluoromethyl) -1, 1 ': 3, J" Methylphenphenyl-4-carboxylate, CL-MS cale. = 605.2; found = 605.0 (M + 1) +. 1 H NMR (500 MHz, CDCl 3, 1: 1 mixture of atropoisomers) d 8.49 (t, J = 4.3 Hz, 1 H); 7.98 (t, J = 6.6 Hz, 1 H); 7.91 (t, J = 10.0 Hz, 1 H); 7.73 (s, 0.5 H); 7.67 (s, 0.5 H); 7.65 (s, 1 H); 7.47-7.39 (m, 2 H); 7.33-7.26 (m, 1 H); 7J 5 (dd, J = 2.2, 5.7 Hz, 1 H); 7.09 (dd, J = 6.8, 8.4 Hz, 1 H); 7.06 (s, 0.5 H); 7.00 (s, 0.5 H); 6.95 (d, J = 4.8 Hz, 0.5 H); 6.90 (d, J = 4.7 Hz, 0.5 H); 5.43 (d, j = 8.2 Hz, 0.5 H); 5J8 (d, J = 8.1 Hz, 0.5 H); 4.92 (d, J = 15.8 Hz, 0.5 H); 4.87 (d, J = 15.8 Hz, 0.5 H); 4.22 (d, J = 15.8 Hz, 0.5 H); 4.00 (d, J = 15.8 Hz, 0.5 H); 3.95 (s, 3 H); 3.89 (s, 1.5 H); 3.88 (s, 1.5 H); 3.81-3.73 (m, 1 H); 2.57 (s, 1.5 H); 2.56 (s, 1.5 H); 2.39 (s, 1.5 H); 2.34 (s, 1.5 H); 0.57 (d, J = 6.6 Hz, 1.5 H); 0.47 (d, J = 6.6 Hz, 1.5 H).

EXAMPLE 112 4'-methoxy-2-methyl-2"- { [(4S, 5F?) - 4-methyl-5- (2-methylpyridin-4-in-2-OXO-1, 3-oxazolidin-3 -inmethyl) -4"- (trifluoromethyl) -1.1 ': 3'.1" -terphenyl-4-carboxylic acid To a solution of 4'-methoxy-2-methyl-2"- { [(4S, 5F?) - 4-methyl-5- (2-methylpyridin-4-yl) -2-oxo-1, 3 -oxazolidin-3-yl] methyl.} -4"- (trifluoromethyl) -1, 1 ': 3', 1" -terphenyl-4-carboxylic acid methyl ester (30.1 mg, 0.050 mmol) in 1,4-dioxane (1.5 ml) and water (1.5 ml) was added 1M aqueous LiOH (0.498 ml, 0.498 mmol) The mixture was stirred at room temperature for 4 hr.The mixture was acidified with 1N HCl. The aqueous layer was extracted with EtOAc (3 x) The combined organic layers were dried (Na2SO4), filtered and the solvent was evaporated under vacuum.The crude material was purified by preparative reverse phase CLAR (C-18), eluting with MeCN / water. The fractions were collected and lyophilized to give 4'-methoxy-2-methyl-2"- acid. { [(4S, 5F?) - 4-methyl-5- (2-methylpyridin-4-yl) -2-oxo- 1,3-oxazolidin-3-yl] methyl} -4"- (trifluoromethyl) -1, 1 ': 3'J" -terphenyl-4-carboxylic acid. CL-EM cale. = 591.2; found = 591.1 (M + 1) +. 1 H NMR (500 MHz, CDCl 3, 1: 1 mixture of atropoisomers) d 8.83 (s, 1 H); 8.02 (s, 1 H); 7.94 (t, J = 10.0 Hz, 1 H); 7.72 (s, 0.5 H); 7.69 (t, J = 6.0 Hz, 1 H); 7.64 (s, 0.5 H); 7.49-7.43 (m, 3 H); 7.40 (d, J = 5.2 Hz, 0.5 H); 7.35 (d, J = 5.4 Hz, 0.5 H); 7.31 (m, 1 H); 7.16 (dd, J = 2.1, 6.0 Hz, 1 H); 7.12 (t, J = 8.8 Hz, 1 H); 5.56 (d, J = 8.1 Hz, 0.5 H); 5.26 (d, J = 8.2 Hz, 0.5 H); 4.94 (dd, J = 8.7, 15.7 Hz, 1 H); 4.77 (br s, 1 H); 4.20 (d, J = 15.8 Hz, 0.5 H); 4.00 (d, J = 15.7 Hz, 0.5 H); 3.90 (s, 1.5 H); 3.89 (s, 1.5 H); 3.89-3.81 (m, 1 H); 2.82 (s, 1.5H); 2.81 (s, 1.5 H); 2.41 (s, 1.5 H); 2.36 (s, 1.5 H); 0.62 (d, J = 6.5 Hz, 1.5 H); 0.49 (d, J = 6.5 Hz, 1.5 H).

EXAMPLE 113 4'-Methoxy-2-methyl-2"- (r (4S, 5f?) - 4-methyl-5- (2-methylpyridin-4-yn-2-oxo-1,3-oxazolidin-3-inmethyl) ) -4"- (trifluoromethyl) -1 J ': 3'J" -terphenyl-4-carboxamide To a solution of 4'-methoxy-2-methyl-2"- { [(4S, 5f?) Acid -4-methyl-5- (2-methylpyridin-4-yl) -2-oxo-1,3-oxazolidin-3-yl] methyl.} -4"- (trifluoromethyl) -1, 1 ': 3 ', 1"-terphenyl-4-carboxylic acid (15 mg, 0.025 mmol) in CH2Cl2 (2 mL), 2M oxalyl chloride in CH2Cl2 (0.038 mL, 0.076 mmol) and 2 drops of DMF were added.

The mixture was stirred at room temperature under N2 for 30 min. The reaction mixture was concentrated under vacuum. The residue was re-dissolved in THF (2 ml), then ammonium hydroxide (0.035 ml, 0.254 mmol) and diisopropylethylamine (0.013 ml, 0.076 mmol) were added. The resulting mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under vacuum and the residue was purified by reverse phase preparative HPLC (C-18), eluting with MeCN / water. The fractions were collected and lyophilized to give 4'-methoxy-2-methyl-2"- { [(4S, 5R) -4-methyl-5- (2-methylpyridin-4-yl) -2-oxo- 1,3-oxazolidin-3-yl] methyl.} -4"- (trifluoromethyl) -1 J ': 3'J" -terphenyl-4-carboxamide as a white powder, LC-MS cale = 590.2; = 590.0 (M + 1) +. 1 H NMR (500 MHz, CDCl 3, 1: 1 mixture of atropoisomers) d 8.49 (t, J = 4.3 Hz, 1 H), 7.77 (br s, 1 H), 7.72 (s) , 0.5 H), 7.66 (br s, 1.5 H), 7.46-7.38 (m, 3 H), 7.33-7.29 (m, 1 H), 7J4 (dd, J = 2.2, 7.7 Hz, 1 H), 7.09 (dd, J = 6.2, 8.5 Hz, 1 H), 7.06 (s, 0.5 H), 7.01 (s, 0.5 H), 6.95 (d, J = 4.3 Hz, 0.5 H), 6.90 (d, J = 4.4 Hz, 0.5 H), 6.17 (br s, 1 H), 5.79 (br s, 1 H), 5.43 (d, J = 8.1 Hz, 0.5 H), 5.20 (d, J = 8.0 Hz, 0.5 H); 4.92 (d, J = 15.9 Hz, 0.5 H), 4.86 (d, J = 15.8 Hz, 0.5 H), 4.22 (d, J = 15.8 Hz, 0.5 H), 4.00 (d, J = 15.8 Hz, 0.5 H) ), 3.88 (s, 1.5 H), 3.87 (s, 1.5 H), 3.80-3.75 (m, 1 H), 2.57 (s, 1.5 H), 2.56 (s, 1.5 H), 2.39 (s, 1. 5 H), 2.35 (s, 1.5 H), 0.58 (d, J = 6.5 Hz, 1.5 H), 0.47 (d, J = 6.5 Hz, 1.5 H). The following Examples 1-14-123 were prepared according to the procedures described above.

EXAMPLE 124 4- (4-f2- (f (4S.5?) - 5-f3.5-bis (trifluoromethyl) phenin-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) -4 - (Methyl trifluoromethyl) phenin-5-ethyl-l, 3-thiazol-2-yl) -3-methylbenzoate A solution of (4S, 5ft) -5- [3,5-bis (trifluoromethyl) phenyl] -3 - [2- (2-bromobutanoyl) -5- (trifluoromethyl) benzyl] -4-methyl-1,3-oxazolidin-2-one (25 mg, 0.040 mmol) and methyl 4- (aminocarbonothioyl) -3-methylbenzoate (16.87 mg, 0.081 mmol) in EtOH (450 μl) was heated at 70 ° C overnight. The reaction was concentrated under vacuum and the residue was purified by preparative CCD (Si, 1000 micras, Hex / EtOAc (80:20)) to give 4-. { 4- [2- ( { (4S, 5F?) - 5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-2-oxo-1,3-oxazolidin-3-yl}. methyl) -4- (trifluoromethyl) -phenyl] -5-ethyl-1,3-thiazol-2-yl} Methyl-3-methylbenzoate, as a colorless oil. CL-EM cale. = 731.2; found = 731.0 (M + 1) +. 1 H NMR (500 MHz, CDCl 3) d 7.99 (s, 1 H); 7.92 (d, J = 8.1 Hz, 1 H); 7.86 (d, J = 8.0 Hz, 2 H); 7.79 (s, 1 H); 7.72 (d, J = 7.9 Hz, 1 H); 7.69 (s, 1 H); 7 55 (d, J = 7.9 Hz, 1 H); 7 29 (s, 1 H); 5.59 (d, J = 8.0 Hz, 1 H); 4.91 (d, J = 15.7 Hz, 1 H); 4.27 (d, J = 15.7 Hz, 1 H); 4.04-3.99 (m, 1 H); 3.95 (s, 3 H); 2.88-276 (m, 2 H); 2.68 (s, 3 H); 1.36 (t, J = 7.5 Hz, 3 H); 0.57 (d, J = 6.5 Hz, 3 H).

EXAMPLE 125 4- (4- [2-q (4S, 5F?) - 5-y3,5-bis (trifluoromethyl) phenyl-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) - acid 4- (trifluoromethyl) phen.p-5-ethyl-1,3-thiazol-2-yl) -3-methylbenzoic acid To a solution of 4-. { 4- [2- ( { (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-2-oxo-1,3-oxazolidin-3-yl} methyl. ) -4- (trifluoromethyl) phenyl] -5-ethyl-1,3-thiazol-2-yl} Methyl-3-methylbenzoate (11 mg, 0.015 mmol) in 1,4-dioxane (0.4 ml) and water (0.4 ml), 1 N LiOH (0.151 ml, 0.151 mmol) was added. The mixture was stirred at room temperature for 2 hr. The mixture was acidified with 1 N HCl. The aqueous layer was extracted with EtOAc (3 x). The combined organic layers were dried (Na2SO4), filtered and the solvent evaporated under vacuum. The residue was purified by reverse phase preparative HPLC (C-18), eluting with MeCN / water containing 0.1% TFA. The fractions were collected and lyophilized to give 4- acid. { 4- [2- ( { (4S, 5f?) - 5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-2-oxo-1,3-oxazolidin-3-yl}. methyl) -4- (trifluoromethyl) phenyl] -5-ethyl-1,3-thiazol-2-yl} -3-methylbenzoic acid.

CL-EM cale. = 717.1; found = 717.0 (M + 1) +. 1 H NMR (500 MHz, CDCl 3) d 8.05 (s, 1 H); 7.99 (d, J = 8.1 Hz, 1 H); 7.89 (d, J = 8.1 Hz, 1 H); 7.87 (s, 1 H); 7.78 (s, 1 H); 7.74 (d, J = 8.0 Hz, 1 H); 7.71 (s, 2 H); 7.57 (d, J = 7.9 Hz, 1 H); 5.61 (d, J = 8.0 Hz, 1 H); 4.94 (d, J = 15.7 Hz, 1 H); 4.25 (d, J = 15.7 Hz, 1 H); 4.04-3.98 (m, 1 H); 2.89-2.76 (m, 2 H); 2.69 (s, 3 H); 1.37 (t, J = 7.5 Hz, 3 H); 0.60 (d, J = 6.5 Hz, 3 H). The following compounds were synthesized according to the procedure described in Example 124 from intermediate 20 and the corresponding thioamides.

EXAMPLE 136 (4S, 5?) - 5- [3,5-Bis (trifluoromethyl) phenin-3- [2- (4-ethyl-1-Jahenyl-1 Hp -razol-3-yl) -5- (trifluoromethyl) benzip) -4-methyl-1, 3-oxazolidin-2-one A solution of (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -3- [2-butyryl-5- (trifluoromethyl) benzyl] ] -4-Methyl-1,3-oxazolidin-2-one (300 mg, 0.554 mmol) (46.3 mg, 0.086 mmol) in dimethyl acetal of NN-dimethylformamide (0.5 mL, 3.78 mmol) was heated at 110 ° C during the night. The reaction was concentrated under vacuum to give the crude enaminone. The enaminone obtained was dissolved in EtOH (200 μl) and phenylhydrazine (16.97 μl, 0.J71 mmol) was added. The mixture was heated at 80 ° C for 3 hr. The reaction mixture was concentrated under vacuum and the residue was purified by reverse phase preparative HPLC (C-18), eluting with MeCN / water. Fractions to elute from the second peak were collected and lyophilized to give a mixture of diastereomers of the title compound. The diastereoisomers were separated by preparative CCD (Si, 1000 micras, Hex / EtOAc (70:30)), to give (4S, 5R) -5- [3,5-bis (trifluoromethyl) phenyl] -3- [2- (4-ethyl-1-phenyl-1 H -pyrazol-3-yl) -5- (trifluoromethyl) benzyl] -4-methyl-1,3-oxazolidin-2-one. CL-EM cale. = 642.2; found = 641.9 (M + 1) +. 1 H NMR (500 MHz, CDCl 3) d 7.89 (s, 1 H); 7.87 (s, 1 H); 7.84 (s, 1 H); 7.74-7.65 (m, 5 H); 7.57 (d, J = 7.9 Hz, 1 H); 7.46 (t, J = 7.9 Hz, 2 H); 7.31 (d, j = 7.9 Hz, 1 H); 5.59 (d, J = 8.0 Hz, 1 H); 4.97 (d, J = 15.5 Hz, 1 H); 4.36 (d, J = 15.5 Hz, 1 H); 4.05-4.00 (m, 1 H); 2.50 (q, J = 7.5 Hz, 2 H); 1.22 (t, J = 7.5 Hz, 3 H); 0.53 (d, J = 6.5 Hz, 3 H).

EXAMPLE 137 This was done by the method of example 75.

LC / MS 725.2 EXAMPLE 138 2"- ( { (4S.5F?) - 5- [3,5-bis (trifluoromethyl) phenan-4-methyl-2-oxo-1,3-oxazolidin-3-yl) methyl) - 4'-methoxy-2-methyl-4"- (trifluoromethyl) -1.1 ': 3'.1" -terphenyl-4-carboxylic acid 2-methoxy-2-oxoethyl Acid 2"- ( { (4S, 5R ) -5- [3,5-bis (trifluoromethyl) phenyl] -4-methyl-2-oxo-1,3-oxazolidin-3-yl.} Methyl) -4'-methoxy-2-methyl-4" - (trifluoromethyl) -1, 1 ': 3', 1"Jerphenyl-4-carboxylic acid (example 30, 200 mg, 0.281 mmol), methyl hydroxyacetate (0.022 ml, 0.281 mmol), N- [3- ( dimethylamino) propyl] -? / '- ethylcarbodiimide (81 mg, 0.422 mmol) and triethylamine (0.059 ml, 0.422 mmol) were stirred in DCM (2811 ml) at room temperature overnight. CL-MS of the aliquot indicated the formation of the desired product and the complete consumption of the starting material. The volatiles were evaporated from the reaction crude. The residue of the product was purified by HPLC prep to give a light yellow solid as the title compound.

CL-EM (ESI) cale. = 783.19; found = 784.0 (M + 1) +. 1 H NMR (CDCl 3, 400 MHz, 1: 1 mixture of atropoisomers): d 7.99 (d, J = 6.8 Hz, 1 H), 7.92 (d, J = 8 Hz, 1 H), 7.85 (s, 1 H) , 7.72-7.68 (m, 1.5H), 7.67-7.61 (m, 2.5H), 7.45-7.36 (m, 2H), 7.32-7.26 (m, 1 H), 7.13 (s, 1 H), 7.08 ( d, J = 5.6 Hz, 0.5H), 7.06 (d, J = 5.6 Hz, 0.5H), 5.59 (d, J = 8 Hz, 0.5H), 5.30 (d, J = 8 Hz, 0.5H), 4.97 (d, J = 14 Hz, 0.5H), 4.93 (d, J = 14 Hz, 0.5H), 4.87 (s, 2H), 4.16 (d, J = 15.6 Hz, 0.5H), 3.95 (d, J = 16 Hz, 0.5H), 3.86 (s, 3H), 3.80 (s, 3H), 3.80-3.75 (m, 1 H), 2.37 (s, 1.5H), 2.32 (s, 1.5H), 0.54 (d, J = 6.8 Hz, 1.5 H), 0.42 (d, J = 6.8 Hz, 1.5H). The following compounds were made using the method of example 138.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound having the formula I, or a pharmaceutically acceptable salt thereof, wherein B I I Y is selected from the group consisting of -C (= 0) - and - (CRR) -; X is selected from the group consisting of -O-, -NH-, -N (C1-C5 alkyl) -, and - (CRR) -; Z is selected from the group consisting of -C (= 0) -, -S (0) 2-, and -C (= NR) -, in g where R is selected from the group consisting of H, -CN, and C C5 alkyl optionally substituted with 1-11 halogens; Each R is independently selected from the group consisting of H, C 1 -C 5 alkyl, and halogen, wherein C 1 -C 5 alkyl is optionally substituted with 1-11 halogens; B is selected from the group consisting of A1 and A2, where A1 has the structure: R1 and R6 are each selected from the group consisting of H, -alkyl of d- C5, halogen, and - (C (R) 2) nA2, wherein -alkyl of C ^ Cs is optionally substituted with 1-11 halogens; R2 is selected from the group consisting of H, -C1-C5 alkyl, halogen, A1, and - (C (R) 2) nA2, wherein-C1-C5 alkyl is optionally substituted with 1-11 halogens; Where one of B and R2 is A1; and one of B, R1, R2, and R is A2 or - (C (R) 2) nA2; so that the compound of the formula I includes a group A1 and a group A2; A3 is selected from the group consisting of: (a) an aromatic ring selected from phenyl and naphthyl; (b) a phenyl ring fused to a non-aromatic 5-7 membered cycloalkyl ring, optionally comprising 1-2 double bonds; (c) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group, where the point of attachment of A3 to the phenyl ring to which A3 is attached is a carbon atom; and (d) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and -S (0) x- and optionally 1-2 doubles bonds, wherein the point of attachment of A3 to the phenyl ring to which A3 is attached is a carbon atom; wherein A3 is substituted with an A4 group and is optionally substituted with 1-4 Ra groups; A2 is selected from the group consisting of: (a) an aromatic ring selected from phenyl and naphthyl; (b) a phenyl ring fused to a non-aromatic 5-7 membered cycloalkyl ring, optionally comprising 1-2 double bonds; (c) a 5-6 member heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group; (d) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S and optionally 1-2 double bonds; and (e) a C3-C8-cycloalkyl ring optionally having 1-3 double bonds; wherein A2 is optionally substituted with 1-5 substituent groups independently selected from Ra; A4 is selected from the group consisting of: (a) an aromatic ring selected from phenyl and naphthyl; (b) a phenyl ring fused to a non-aromatic 5-7 membered cycloalkyl ring, optionally comprising 1-2 double bonds; (c) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group; and (d) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and -S (0) x- and optionally 1-2 doubles links; wherein when A4 is (a) an aromatic ring selected from phenyl and naphthyl; (b) a phenyl ring fused to a non-aromatic 5-7 membered cycloalkyl ring, optionally comprising 1-2 double bonds; (c) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group, wherein the point of attachment of the heterocyclic ring to A3 is an N atom of A4; or (d) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and -S (0) x- and optionally 1-2 doubles links; then A4 is optionally substituted with 1-5 Ra groups; and when A4 is a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group, wherein the point of attachment of the heterocyclic ring to A3 is a carbon atom of A4, then A4 is substituted with a group Re and is also optionally substituted with 1-4 groups independently selected from Ra; Each Ra is independently selected from the group consisting of-CrCß alkyl, -C2-C6 alkenyl, -C2-C6alkynyl, -C3-C8cycloalkyl optionally having 1-3 double bonds, -O-Alkenyl-O-alkyl C2-C6, -C2-C6alkynyl, -3C8 cycloalkyl optionally having 1-3 double bonds, -C (= 0) C6-C6 alkyl (= 0) C3-C8 cycloalkyl, -C ( = 0) H, -C02H, -C02alkyl of d-C6, -C (= 0) C6 alkyl, -OH, -NR3R4, -C (= 0) NR3R4, -N R3C (= 0) O-alkyl of C C6, -NR3C (= 0) NR3R4, -S (0) xalkyl of C C6, -S (0) and NR3R4, -NR3S (0) and NR3R4, halogen, -CN, -N02, and a heterocyclic ring of 5-6 members having 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally also comprises a carbonyl group and optionally also comprises 1-3 double bonds, wherein the point of The binding of said heterocyclic ring to the ring to which Ra is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen, -C C3 alkyl, and -C1-C3 alkyl , wherein-C1-C3 alkyl and -O CrC3 alkyl are optionally substituted with 1-7 halogens; wherein for compounds in which Ra is selected from the group consisting of - CrC6 alkyl, - C2-C6 alkenyl, - C2-C6alkynyl, - C3-C8 cycloalkyl optionally having 1-3 double bonds, - O-alkyl CrCß, -O-C2-C6alkenyl, -C2-C6alkynyl, -3C8 -cycloalkyl optionally having 1-3 double bonds, -C (= 0) CrC6 alkyl, -C (= 0) cycloalkyl of C3-C8, -C02alkyl of C? -C6, -C (= O) C6-C6-alkyl, -NR3C (= 0) C6-C6alkyl, and -S (0) CrCßalkyl, Ra is optionally substituted with 1-15 halogens and is optionally substituted with 1-3 substituent groups independently selected from (a) -OH, (b) -CN, (c) -NR3R4, (d) -C3-C8 cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (e) -C4 C4alkyl optionally substituted with 1-9 halogens and optionally substituted with 1-2 substituent groups independently selected from -O-C2 alkyl and phenyl, (f) - C3-C8 Occloalkyl having optionally 1-3 double bonds and optionally substituted with 1-15 halogens, (g) -C02H, (h) -C (= 0) CH3, (i) -C02alkyl of C C4 which is optionally substituted with 1-9 halogens, and (j) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3, -CF3, -OCH3, and -OCF3; Each Re is selected independently of A group consisting of -C2-C6alkenyl, -C2-C6alkynyl, -C3-C8cycloalkyl optionally having 1-3 double bonds, -C2-C6Oalkenyl, -C2-C6alkynyl, -O-cycloalkyl C3-C8 having optionally 1-3 double bonds, -C (= 0) C alquilo-C6 alkyl, -C (= 0) C3-C8 cycloalkyl, -C (= 0) H, -C02H, -C02alkyl of C C6, -C (= 0) C6-C6, -OH, -NR3R4, -C (= 0) NR3R4, -NR3C (= 0) O-C6-C6, -NR3C (= 0) NR3R4, - S (0) xalkyl of C Ce, -S (0) and NR3R4, -NR3S (0) and NR3R4, -CN, -N02, and a heterocyclic ring of 5-6 members having 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally also comprising 1-3 double bonds, wherein the point of attachment of said heterocyclic ring to the ring to which Re is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen, -D3 alkyl, and CrC3 -Oalkyl, wherein CrC3 alkyl and C1-C3 alkyl are optionally substituted with 1 -7 halogens; wherein for compounds in which Re is selected from the group consisting of-C2-C6 alkenyl, -C2-C6alkynyl, -C3-C8cycloalkyl optionally having 1-3 double bonds, -C2-C6alkenyl , -C2-C6alkynyl, -CS-Cs-cycloalkyl optionally having 1-3 double bonds, -C (= 0) CrCe alkyl, -C (= 0) C3-C8 cycloalkyl, -C02C6alkyl , -C (= 0) C6 C, NR3C (= 0) C6 C6, and -S (0) C6 alkyl xalkyl, Re is optionally substituted with 1-15 halogens and is optionally substituted with 1-3 groups substituents independently selected from (a) -OH, (b) -CN, (c) -NR3R4, (d) -C3-C8 cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (e) ) -C4 C4 alkyl optionally substituted with 1-9 halogens and also optionally substituted with 1-2 substituent groups independently selected from -O C2 alkyl and phenyl, (f) -C3-C8 cycloalkyl optionally having 1-3 doubles bonds and optionally substituted with 1-15 halogens, (g) -C02H, (h) -C (= 0) CH3, (i) -C02alkyl of C C4 which is optionally substituted with 1-9 halogens, and (j) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3, -CF3, -OCH3, and -OCF3; n is 0 or 1; p is an integer of 0-4; x is 0, 1 or 2; and it is 1 or 2; R3 and R4 are each independently selected from H, - CrC5 alkyl, -C (= 0) C1-C5 alkyl and -S (0) and C1-C5 alkyl, wherein -C1-C5 alkyl at all cases is optionally substituted with 1-11 halogens; and R5 is selected from the group consisting of H, -OH, -C1-C5 alkyl, and halogen, wherein -C1-C5 alkyl is optionally substituted with 1-11 halogens.

2. The compound according to claim 1, further characterized in that it is selected from the group consisting of compounds having the formula la, Ib, and Id, or a pharmaceutically acceptable salt thereof: (C (R) 2) n? 2 the A2 . Y (R) 2 ^ N ^ ZA A2 (C (R) 2) n-C-C-R5 R R Id

3. - The compound according to claim 1, or a pharmaceutically acceptable salt thereof, further characterized in that: Y is - (CRR1) -; R and R6 are each independently selected from the group which consists of H and -alkyl of CrCs, wherein -CrC5 alkyl is optionally substituted with 1-11 halogens; R1 is selected from the group that consists of H, -C1-C5 alkyl, and - (C (R) 2) nA2, wherein - CrC alkyl is optionally substituted with 1-11 halogens, wherein one of B and R2 is A1; and one of B, R1, and R2 is A2 or - (C (R) 2) nA2; whereby the compound of formula I includes a group A1 and a group A2; A3 is selected from the group consisting of: (a) an aromatic ring selected from phenyl and naphthyl; (b) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group, where the point of attachment of A3 to the phenyl ring to which A3 is attached is a carbon atom; and (c) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and -S (0) x- and optionally 1-2 doubles bonds, wherein the point of attachment of A3 to the phenyl ring to which A3 is attached is a carbon atom; wherein A3 is substituted with an A4 group and is optionally substituted with 1-4 Ra groups; A2 is selected from the group consisting of: (a) an aromatic ring selected from phenyl and naphthyl; (b) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group; (c) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S and optionally 1-2 double bonds; and (d) a C3-C8-cycloalkyl ring which optionally has 1-3 double bonds; wherein A2 is optionally substituted with 1-5 substituent groups independently selected from Ra; Each Ra is independently selected from the group consisting of - CrCß alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl optionally having 1-3 double bonds, - CrCe O-alkyl, -C (= 0) alkyl CrC6, -C (= 0) H, -C02H, -C02alkyl of C? -C6, -OH, -NR3R4, -NR3C (= 0) Oalkyl of C C6, -S (0) xalkyl of CrCe, halogen, -CN, -N02, and a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected fN, S, and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally also comprising 1 -3 double bonds, wherein the point of attachment of said heterocyclic ring to the ring to which Ra is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected fhalogen, -alkyl C C3, and -O-C3 alkyl, wherein-C3 alkyl and -C3 C3Oalkyl are optionally substituted with 1-7 halogens; wherein for compounds in which Ra is selected from the group consisting of -CrCß alkyl, -C2-C6 alkenyl, -C3-C8 cycloalkyl optionally having 1-3 double bonds, -O CrCe alkyl, -C ( = 0) CrCß alkyl, CrCe-2alkyl, -NR3C (= 0) CrC6alkyl, and -S (0) CrC6alkyl, Ra is optionally substituted with 1-15 halogens and is optionally substituted with a group substituent selected from (a) -OH, (b) -NR3R4, (c) -C04alkyl optionally substituted with 1-9 halogens and optionally substituted with 1- 2 substituent groups independently selected from -O-alkyl of CrC2 and phenyl, and (d) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3 > -CF3, -OCH3, and -OCF3; Each Re is independently selected from the group consisting of -C2-C6alkenyl, -C3-C8cycloalkyl optionally having 1-3 double bonds, -C (= 0) C6-C6alkyl (= 0) H, -C02H, -C02alkyl of C C6, -OH, -NR3R4, -NR3C (= 0) O-alkyl of C C6, -S (0) xalkyl of C C6, -CN, -N02, and a heterocyclic ring of 5 -6 members having 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally also comprising 1-3 double bonds, wherein the point of attachment of said heterocyclic ring to the ring to which Re is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen, -CrC3 alkyl, and -C1-C3Oalkyl, wherein -alkyl is C1-C3 and -Oalkyl of CrC3 are optionally substituted with 1-7 halogens; wherein for compounds in which Re is selected from the group consisting of-C2-C6 alkenyl, -C3-C8 cycloalkyl optionally having 1-3 double bonds, -C (= 0) CrC6 alkyl, -C02 alkyl CrC6, -NR3C (= 0) O-alkyl of C C6, and -S (0) xalkyl of CrC6, Re is optionally substituted with 1-15 halogens and is optionally substituted with a substituent group selected from (a) -OH, (b ) -NR3R4, (c) -O C4 alkyl alkyl optionally substituted with 1-9 halogens and also optionally substituted with 1-2 substituent groups independently selected from -O-C2 alkyl and phenyl, and (d) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3, -CF3, -OCH3, and -OCF3; p is an integer of 0-2; R3 and R4 are each independently selected from H and -C1-C5 alkyl, wherein-C5alkyl in all cases is optionally substituted with 1-11 halogens; R5 is selected from the group consisting of H, -OH, and -alkyl of CrCs, wherein-C1-C5alkyl is optionally substituted with 1-11 halogens. 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, further characterized in that: Y is - (CRR1) -; Z is selected from the group consisting of -C (= 0) -, -S (0) 2-, and -C (= N-R9) -, wherein R9 is selected from the group consisting of H, -CN, and CH3; Each R is independently selected from the group consisting of H and C C2 alkyl; R6 is selected from the group consisting of H and-C3 alkyl, wherein CrC3 alkyl is optionally substituted with 1-5 halogens; R1 is selected from the group consisting of H, -alkyl of CrC3, and - (C (R) 2) nA2, wherein - CrC3 alkyl is optionally substituted with 1-5 halogens; R2 is selected from the group consisting of H, -alkyl of C C3, A1, and - (C (R) 2) nA2, wherein-C3 alkyl is optionally substituted with 1-5 halogens, wherein one of B and R2 is A1; and one of B, R1, and R2 is A2 or - (C (R) 2) nA2; whereby the compound of formula I includes a group A1 and a group A2; A3 is selected from the group consisting of: (a) phenyl; (b) a 5-6 membered aromatic heterocyclic ring having 1-2 heteroatoms independently selected from N, S, O, and -N (O) -, wherein the point of attachment of A3 to the phenyl ring to which A3 is attached is a carbon atom; and (c) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-membered aromatic heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and -S (0) x, wherein the point of attachment of A3 to the phenyl ring to which A3 is attached is a carbon atom; wherein A3 is substituted with an A4 group and is optionally substituted with 1-4 Ra groups; A2 is selected from the group consisting of: (a) phenyl; (b) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds; (c) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S; and (d) a C5-C6 cycloalkyl ring; wherein A2 is optionally substituted with 1-5 substituent groups independently selected from Ra; Each Ra is independently selected from the group consisting of -CrC alkyl, -C2-C4 alkenyl, cyclopropyl, -C0-C alkyl, -C (= 0) C2 alkyl, -C (= 0) H , -C02H, -C02alkyl of C C4, -OH, -NR3R4, -NR3C (= 0) O-alkyl of C C4, -S (0) xalkyl of C C2, halogen, -CN, -N02, and a heterocyclic ring of 5-6 members having 1-2 heteroatoms independently selected from N, S, and O, wherein the point of attachment of said heterocyclic ring to the ring to which Ra is attached to the ring is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen; wherein for compounds in which Ra is selected from the group consisting of -C1-C4alkyl, -C2-Calkenyl, -C02alkyl, -C (= 0) C2alkyl, -C02Calkyl C4, -NR3C (= 0) O-alkyl of CrC4, and -S (0) xalkyl of CrC2, the alkyl group of Ra is optionally substituted with 1-5 halogens and is optionally substituted with a substituent group selected from (a) -OH , (b) -NR3R4, (c) -OCH3 optionally substituted with 1-3 fluorine atoms and also optionally substituted with a phenyl group, and (d) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, - CH3I -CF3, -OCH3, and -OCF3; Each Re is independently selected from the group consisting of-C2-C4 alkenyl, cyclopropyl, -C (= 0) C2 alkyl, -C (= 0) H, -C02H, -C02C4 alkyl, -OH, -NR3R4, -NR3C (= 0) O-alkyl of C C4, -S (0) xalkyl of CrC2, -CN, -N02, and a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from N, S , and O, wherein the point of attachment of said heterocyclic ring to the ring to which Re is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen; wherein for compounds in which Re is selected from the group consisting of-C2-C4 alkenyl, -C (= 0) d-C2 alkyl, -C02alkyl of dd, -NR3C (= 0) Oalkyl of dd, and -S (0) xalkyl of d-C2, the alkyl group of Re is optionally substituted with 1-5 halogens and is also optionally substituted with a substituent group selected from (a) -OH, (b) -NR3R4, (c) -OCH3 optionally substituted with 1-3 fluorine atoms and optionally substituted with a phenyl group, and (d) phenyl which is optionally substituted with 1-3 independently selected groups of halogen, -CH3, -CF3, -OCH3, and -OCF3; p is an integer of 0-2; R3, R4 and R5 are each independently selected from H and-C3 alkyl. 5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, further characterized in that X is -O-; Z is -C (= 0) -; Y is -CHR1, wherein R1 is selected from H and C2C2alkyl; R and R5 are H; R2 and B are selected from A1 and A2, wherein one of R2 and B is A1 and the other of R2 and B is A2; A2 is selected from the group consisting of phenyl, pyridyl, pyrazolyl, thienyl, 1,4-triazolyl and imidazolyl; A3 is selected from the group consisting of phenyl, thiazolyl and pyrazolyl; A4 is selected from the group consisting of phenyl, pyridyl, thiazolyl, pyrazolyl, 1,4-triazolyl, pyrimidinyl, piperidinyl, pyrrolidinyl and azetidinyl; A2 is optionally substituted with 1-3 substituents independently selected from halogen, -OCH3, -OCF3, and d-C3 alkyl optionally substituted with 1-3 halogens; A3 is substituted with a group A4 and is optionally substituted with 1-2 substituents independently selected from halogen, -OH, -OCH3, -OCF3, and d-C3 alkyl optionally substituted with 1-3 halogens; A4 is optionally substituted with 1-3 substituents independently selected from the group consisting of (a) -alkyl of CrCs optionally substituted with 1-3 halogens and optionally substituted with -OH, (b) -C2-C4 alkenyl optionally substituted with 1 -3 halogens, (c)

-C (= 0) d-C2 alkyl optionally substituted with 1-3 halogens and optionally substituted with a group selected from -OH, -C02CH3, -C (= 0) CH3, -NR3R4, and -O-C2-O-Alkyl C C2, (d) -C (= 0) H, (e) -C02H, (f) -C? 2alkyl of d-C4 optionally substituted with a group selected from -C (= 0) alkyl of dd, -OH , -C02CH3, -C02H, -NR3R4, and -D-denoOalkyl of CrC2, (g) -OH, (h) -S (0) xalkyl of d-C2, (i) halogen, (j) -CN , (k) -N02, (I) -C (= 0) NR3R4, (m) -C-C2-OoalkylO-alkyl of d-C2, (n) -O-C3-alkyl of optionally substituted with 1-3 halogens, (o) -C (= 0) C 1 -C 2 alkyl optionally substituted with 1-3 halogens and optionally substituted with a group selected from -OH, -CO 2 CH 3, -NR R 4, and -O-alkyl d-C 2 eneOalkyl of d-C 2, (p )

-NR3C (= 0) C2 alkyl, (q) -NR3R4, and (r) -S (0) x NR3R4; provided that if A4 is a heterocyclic group connected to A3 through a ring carbon atom of A4, then at least one A4 solvent must be selected from Re, where Re is selected from the group consisting of (a) -C1-C5 alkyl substituted with -OH and optionally substituted with 1-3 halogens, (b) -C2-C4 alkenyl optionally substituted with 1-3 halogens, (c) -C (= 0) C2 alkyl optionally substituted with 1-3 halogens and optionally substituted with a group selected from -OH, -C02CH3, -C (= 0) CH3, -NR3R4, and -O-C2-alkylCalkyl of dd, (d) -C (= 0) H , (e) -C02H, (f) -C02alkyl of dd optionally substituted with a group selected from -C (= 0) C2alkyl, -OH, -C02CH3, -C02H, -NR3R4, and -O-C2OalkylOalkyl of C C2, (g) -OH, (h) -S (0) xalkyl of d-C2, (i) -CN, (j) -N02, (k) -C (= 0) NR3R4, (I) -O-alkyl of d-C2enoOalkyl of d-C2, (m) -C (= 0) O-alkyl of d- C2 optionally substituted with 1-3 halogens and optionally substituted with a group selected from -OH, -C02CH3, -NR3R4, and -O-alkyl of d-C2oenoalkyl of C C2, (n) -NR3C (= 0) C1-C2 alkyl , (o) -NR3R4; and (p) -S (0) xNR3R4; Ra is selected from halogen, -CH3, -CF3, -OCH3 and -OCF3; R3 and R4 are each independently selected from H and CH3; and x is 0, 1 or 2.

6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, further characterized in that B is A1 and R2 is A2.

7. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, further characterized in that B is A2 and R2 is A1.

8. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, further characterized in that A2, A3 and A4 are phenyl; and each Ra is selected from the group consisting of (a) -alkyl of d-d which is optionally substituted with 1-5 fluorine atoms and is optionally substituted with a group selected from -OH, -OCH3, and -NR3R4; (b) -O-alkyl of d-d, which is optionally substituted with 1-3 fluorine atoms; (c) -C2-C alkenyl; (d) - d-d-O-alkyl d-C2-phenyl alkyl; (e) cyclopropyl; (f) -C (= 0) H; (g) -C02H; (h) -C02alkyl of d-d; (i) -OH; (j) -NR3R4; (k) -S (0) xalkyl of C C2; (I) halogen; (m) -CN; (n) -N02; and (o) a 5-6 membered heterocyclic ring comprising 1-2 oxygen atoms which is optionally substituted with d-C2 alkyl.

9. The compound according to claim 1, further characterized in that it has the formula le, or a pharmaceutically acceptable salt thereof, wherein you where one of B1 and B2 is and the other of B1 and B2 is Ar1 (Rc) u; Ar1 is selected from the group consisting of: (a) an aromatic ring selected from phenyl and naphthyl; (b) a phenyl ring fused to a non-aromatic 5-7 membered cycloalkyl ring, optionally comprising 1-2 double bonds; (c) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group; (d) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6 membered heterocyclic ring has 1-2 heteroatoms independently selected from O, N, and S and optionally 1-2 double bonds; and (e) a C3-C8 cycloalkyl ring having optionally 1-3 double bonds; Ar2 is selected from the group consisting of: (a) an aromatic ring selected from phenyl and naphthyl; (b) a phenyl ring fused to a non-aromatic 5-7 membered cycloalkyl ring, optionally comprising 1-2 double bonds; (c) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S and optionally 1-2 double bonds; and (d) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group; R1 is selected from the group consisting of H, -C1-C5 alkyl, and halogen, wherein -alkyl of d-d is optionally substituted with 1-11 halogens; R3 and R4 are each independently selected from H, -alkyl of dd, -C (= 0) alkyl of dd and -S (0) and alkyl of dd, wherein -alkyl of CrCs in all cases is optionally substituted with 1; -11 halogens; Each Ra, Rb, Rc and Rd is independently selected from the group consisting of - dd alkyl, C2-Ce alkenyl, dd-alkynyl, C3-C8 cycloalkyl optionally having 1-3 double bonds, - O-alkyl of dd, -C2-C6alkenyl, -C2-C6alkynyl, -3C8 cycloalkyl optionally having 1-3 double bonds, -C (= 0) dd alkyl, -C (= 0) cycloalkyl C3-C8, -C (= 0) H, -C02H, -C02alkyl of dd, -C (= 0) Salicyl of d-C6, -OH, -NR3R4, -C (= 0) NR3R4, -NR3C (= 0) O-alkyl of C? -C6, -NR3C (= 0) NR3R4, -S ( 0) xalkyl of d-C6, -S (0) and NR3R4, -NR3S (0) and NR3R4, halogen, -CN, -N02, and a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S and O, said optionally heterocyclic ring also comprising a carbonyl group and optionally also comprising 1-3 double bonds, wherein the point of attachment of said heterocyclic ring to the ring to which Ra, Rb, Rc or Rd is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen, dd alkyl, and dd -Oalkyl, wherein dd alkyl and dd -Oalkyl are optionally -7 halogens; wherein when Ra, Rb, Rc and Rd are selected from the group consisting of -d6 -alkyl, dd-alkenyl, dd-alkynyl, d-C8-cycloalkyl optionally having 1-3 double bonds, - O-alkyl of dd, -C 2 -C 6 -alkenyl-C 2 -C 6 -alkynyl, -O-cycloalkyl of d-C 8 having optionally 1-3 double bonds, -C (= 0) alkyl of dd, -C (= 0) cycloalkyl of C3-C8, -C02alkyl of dd, -C (= 0) C6-C6-alkyl, -NR3C (= 0) C6-C6alkyl, and -S (0) C6-C6alkyl, then Ra, R, Rc and Rd they are optionally substituted with 1-15 halogens and are optionally substituted with 1-3 substituent groups independently selected from (a) -OH, (b) -CN, (c) -NR3R4, (d) -C3-C8 cycloalkyl having optionally 1-3 double bonds and optionally substituted with 1-15 halogens, (e) -Dalkyl of dd optionally substituted with 1-9 halogens and optionally substituted with 1-2 substituent groups independently selected from -O-alkyl of dd and phenyl, (f) -C3-C8-cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (g) -C02H, (h) -C (= 0) CH3, (i) -C0 alkyl of dd which is optionally substituted with 1-9 halogens, and (j) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3, -CF3, -OCH, and -OCF3; Re is selected from the group consisting of-C2-d alkenyl, dd-alkynyl, C3-C8-cycloalkyl optionally having 1-3 double bonds, -C2-C6-O-alkenyl, -C2-d-O-alkynyl, - C3-C8cycloalkyl optionally having 1-3 double bonds, -C (= O) alkyl of dd, -C (= 0) cycloalkyl of dd, -C (= 0) H, -C02H, -C02alkyl of CrC6, -C (= 0) Salkyl of dd, -OH, -NR3R4, -C (= 0) NR3R4, -NR3C (= 0) Oalkyl of dd, -NR3C (= 0) NR3R4, -S (0) xalkyl of dd, -S (0) and NR3R4, -NR3S (0) and NR3R4, -CN, -N02, and a heterocyclic ring of 5-6 members having 1- 4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally also comprising 1-3 double bonds, wherein the point of attachment of said heterocyclic ring to the ring to which Re is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen, -alkyl of dd, and -O-C3 alkyl, wherein -alkyl of dd and -Oalkyl of C d are optionally substituted with 1-7 halogens; in wherein when Re is selected from the group consisting of-C2-C6 alkenyl, -C2-C6alkynyl, -C3-C8cycloalkyl optionally having 1-3 double bonds, -C2-C6alkenyl, -C2 -alkynyl -C6, -C3-C8cycloalkyl optionally having 1-3 double bonds, -C (= 0) alkyl of dd, -C (= 0) cycloalkyl of C3-C8, -C02alkyl of C C6, -C (= 0) CrC6 salt, -NR3C (= 0) C6 alkyl O-alkyl, and -S (0) x d alkyl, then Re is optionally substituted with 1-15 halogens and is optionally substituted with 1-3 substituent groups independently selected from (a) -OH, (b) -CN, (c) -NR3R4, (d) -d-C8 cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (e) -Dalkyl optionally substituted with 1-9 halogens and optionally substituted with 1-2 substituent groups independently selected from -Dalkyl of dd and phenyl, (f) -O-cycloalkyl of d-C8 optionally having 1-3 doubles bonds and optionally substituted with 1-15 halogens, (g) -C02H, (h) -C (= 0) CH3, (i) -C02alkyl of Cd which is optionally substituted with 1-9 halogens, and (j) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3; p is an integer of 0-4; q is an integer of 0-4; u is an integer of 0-5; x is 0, 1 or 2; and y is 1 or 2; wherein when Ar2 is selected from the group consisting of: (a) an aromatic ring selected from phenyl and naphthyl; (b) a phenyl ring fused to a non-aromatic 5-7 membered cycloalkyl ring, optionally comprising 1-2 double bonds; (c) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S and optionally 1-2 double bonds; and (d) a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group, wherein the point of attachment of the heterocyclic ring to the phenyl group to which the heterocyclic ring is attached is a heteroatom of the heterocyclic ring; then t is an integer of 0-5, and w is 0; and when Ar2 is a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O and -N (O) -, and optionally also comprising 1-3 double bonds and a carbonyl group, where the point of attachment of the heterocyclic ring to the phenyl group to which the heterocyclic ring is attached is a carbon atom of the heterocyclic ring, then t is an integer of 0-4, and w is 1.

10. The compound in accordance with claim 9, further characterized in that it has the formula le, or a pharmaceutically acceptable salt thereof:

11. - The compound according to claim 9, further characterized in that it has the formula If, or a pharmaceutically acceptable salt thereof:

12. - The compound according to claim 10, further characterized in that it has the formula Ig, or a pharmaceutically acceptable salt thereof, wherein each Rd is independently selected from the group consisting of -alkyl of dd, -C2-C4alkenyl, cyclopropyl, -Oalkyl of dd, -C (= 0) alkyl of dd, -C (= 0) H, -C02H- C02alkyl of dd, -OH, -NR3R4, -NR3C (= 0) Oalkyl of dd, -S (0) xalkyl of d-C2, halogen, -CN, -N02, and a heterocyclic ring of 5-6 members having 1-2 heteroatoms independently selected from N, S, and O, where the point of attachment of said heterocyclic ring to the ring to which Rd is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen; wherein when Rd is selected from the group consisting of - dd alkyl, -C2-C4 alkenyl, cyclopropyl, -Dalkyl of dd, -C (= 0) dd alkyl, -C02alkyl of d-C4, -NR3C ( = 0) O-alkyl of C C4, and -S (0) xalkyl of dd, then the alkyl, alkenyl and cyclopropyl group of Rd is optionally substituted with 1-5 halogens and is optionally substituted with a substituent group selected from (a) - OH, (b) -NR3R4, (c) -OCH3 optionally substituted with 1-3 fluorine atoms and optionally substituted with a phenyl group, and (d) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, - CH3, -CF3, -OCH3, and -OCF3 and t is an integer of 0-5.

13. The compound according to claim 12, further characterized in that it has the formula Ih, or a pharmaceutically acceptable salt thereof: lh

14. - The compound in accordance with any of the claims 9-13, or a pharmaceutically acceptable salt thereof: further characterized in that R1 is selected from the group consisting of H, and -alkyl of d-d, wherein -alkyl of d-d is optionally substituted with 1-11 halogens; R3 and R4 are each independently selected from H and -alkyl of d-d, wherein -alkyl of d-d in all cases is optionally substituted with 1-11 halogens; Each Ra, Rb and Rc is independently selected from the group consisting of - dd alkyl, dd-alkenyl, C3-C8 cycloalkyl optionally having 1-3 double bonds, - D-C6Oalkyl, -C (= 0) alkyl of dd, -C (= 0) H, -C02H, -C02alkyl of CrC6, -OH, -NR3R4, -NR3C (= 0) Oalkyl of dd, -S (0) xalkyl of dd, halogen, - CN, -N02, and a 5-6 membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally also comprising 1-3 double bonds, wherein the point of attachment of said heterocyclic ring to the ring to which Ra is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen, - dd alkyl, and -Oalkyl of CrC3, wherein -alkyl of dd and -Oalkyl of dd are optionally substituted with 1-7 halogens; wherein when Ra, Rb and Rc are selected from the group consisting of - dd alkyl, - C2-C6 alkenyl, - C3-C8 cycloalkyl optionally having 1-3 double bonds, - O-alkyl from dd, -C ( = 0) dd alkyl, -C02alkyl of d-C6, -NR3C (= 0) Oalkyl of d-C6, and -S (0) xalkyl of dd, then Ra, R and Rd they are optionally substituted with 1-15 halogens and are optionally substituted with a substituent group selected from (a) -OH, (b) -NR3R4, (c) -Dalkyl of dd optionally substituted by 1-9 halogens and optionally substituted by 1- 2 groups independently selected from -O-alkyl of d-C2 and phenyl, and (d) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3; Each Rd is independently selected from the group consisting of -CC alkyl, -C2-C4 alkenyl, -Dalkyl, -C (= 0) d-C2 alkyl, -C (= 0) H, -C02H- C02alkyl of dd, -OH, -NR3R4, -NR3C (= 0) Oalkyl of d-C4, -S (0) xalkyl of dd, halogen, -CN, -N02 and a heterocyclic ring of 5-6 members having 1 -2 heteroatoms independently selected from N, S, and O, wherein the point of attachment of said heterocyclic ring to the ring to which Ra is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen; wherein when Rd is selected from the group consisting of - dd alkyl, C2-C4 alkenyl, -O-alkyl of d-C2, -C (= 0) dd alkyl, -C02alkyl of dd, -NR3C (= 0 ) CCalkyl, and -S (0) xalkyl of C C2, then the alkyl or alkenyl group of Rd is optionally substituted with 1-5 halogens and is optionally substituted with a group selected from (a) -OH, (b) -NR3R4, (c) -OCH3 optionally substituted with 1-3 fluorine atoms and optionally substituted with a phenyl group, and (d) phenyl which is optionally substituted with 1-3 independently selected groups of halogen, -CH3, -CF3, -OCH3, and -OCF3; p is an integer of 0-2; q is an integer of 0-2; t is an integer of 0-3; u is an integer of 0-2; x is 0, 1 or 2; and y is 1 or 2.

15. The compound according to any of claims 9-13, or a pharmaceutically acceptable salt thereof, further characterized in that: R1 is selected from H and -alkyl from d-d; R3 and R4 are each independently selected from H and -alkyl of d-d; Each R a, R b and R c is independently selected from the group consisting of -alkyl of C d, -alkenyl of C2-C4, -Oalkyl of d-C2, -C (= 0) alkyl of C C2, -C (= 0 ) H, -C02H, -C02alkyl of dd, -OH, -NR3R4, -NR3C (= 0) Oalkyl of dd, -S (0) xalkyl of CrC2, halogen, -CN, and -N02; wherein when Ra, Rb and Rc are selected from -CC alkyl, -C2-C4 alkenyl, -Dalkyl of dd, -C (= 0) dd alkyl, -C02Calkyl, -NR3C (= 0) Oalkyl of Crd, and -S (0) xalkyl of dd, then the alkyl and alkenyl groups of Ra, Rb and Rc are optionally substituted with 1-5 halogens and are optionally substituted with a group selected from (a) -OH, (b ) -NR3R4, (c) -OCH3 optionally substituted with 1-3 fluorine atoms and optionally substituted with a phenyl group, and (d) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, -CH3, -CF3 , -OCH3 and -OCF3; Rd is selected from the group consisting of -alkyl of d-C4, -alkenyl of C2-C4, -NR3R4, -C (= 0) H, -C02H, -C02alkyl of dd, -OH, halogen, -CN, and -N02, wherein -alkyl of dd and -alkenyl of C2-C4 in all uses are optionally substituted with 1-5 fluorine atoms; p is a whole of 1-2; q is an integer of 1-2; t is an integer of 0-3; u is an integer of 1-2; x is 0, 1 or 2.

16. The compound according to any of claims 9-13, or a pharmaceutically acceptable salt thereof, further characterized in that R1, R3 and R4 are each independently selected from H and CH3; Ra, Rb, and Rc are each independently selected from the group consisting of-C3 alkyl, -Dalkyl, halogen, and -OH, wherein d3 alkyl and -Dalkyl are optionally substituted with 1-3 F; Rd is selected from the group consisting of -alkyl of dd, -NR3R4, -C02H, -C02alkyl of d-C3, halogen, and -CN, wherein -alkyl of dd and -C? 2alkyl of dd are optionally substituted with -3 F; p is an integer of 1-2; q is an integer of 1-2; t is an integer of 0-3; u is an integer of 1-2.

17. The compound according to any of claims 9-11, or a pharmaceutically acceptable salt thereof, further characterized in that Ar2 is selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, pyrrolyl, oxazolyl, isoxazolyl , thiazolyl, isothiazolyl, thienyl, furyl, benzothiophenyl, benzoxazolyl, benzisoxazolyl and benzofuryl.

18. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. The compound according to claim 1, further characterized in that it is selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof:

20. The compound according to claim 1, further characterized in that it is selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof: wherein R1 is selected from the group consisting of: It is selected from the group consisting of: where R is selected from the group consisting of: where R is selected from the group consisting of: where R is selected from the group consisting of: 15 wherein R is selected from the group consisting of: 4 isomers racemic 20 where R and R 'are defined as follows: where R is selected from the group consisting of: where R? It is selected from the group consisting of: 5? ° ^ N-

21. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for raising HDL-C in a patient.

22. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for reducing LDL-C in a patient.

23. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful for the treatment of atherosclerosis in a patient.

24. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt of the same, a pharmaceutically acceptable carrier, and one or more active ingredients selected from the group consisting of: (i) HMG-CoA reductase inhibitors; (ii) bile acid sequestrants; (iii) niacin and related compounds; (iv) PPARa agonists; (v) cholesterol absorption inhibitors; (vi) acyl CoA or cholesterol acyltransferase (ACAT) inhibitors; (vii) phenolic anti-oxidants; (viii) inhibitors of microsomal triglyceride transfer secretion (MTP) / ApoB; (ix) anti-oxidant vitamins; (x) thyromimetics; (xi) LDL receptor inducers (low density lipoprotein); (xii) platelet aggregation inhibitors; (xiii) vitamin B12 (also known as cyanocobalamin); (xiv) folic acid or a pharmaceutically acceptable salt or ester thereof; (xv) ligands FXR and LXR; (xvi) agents that increase the expression of ABCA1 genes; and (xvii) ileal bile acid transporters.