WO2009027785A2

WO2009027785A2 - 1, 3-oxazole derivatives as cetp inhibitors

Info

Publication number: WO2009027785A2
Application number: PCT/IB2008/002164
Authority: WO
Inventors: George Chang; Ravi Shanker Garigipati; David Austen Perry
Original assignee: Pfizer Products Inc.
Priority date: 2007-08-30
Filing date: 2008-08-18
Publication date: 2009-03-05
Also published as: AR068064A1; TW200918509A; WO2009027785A3

Abstract

Pharmaceutical compounds according to Formula I and derivatives, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans. Formula (I) or a pharmaceutically acceptable salt of said compound; wherein Formula (II) M and J are each independently CH2 or a bond wherein at least one of M and J are CH2.

Description

PHARMACEUTICAL COMPOUNDS AND DERIVATIVES

BACKGROUND OF INVENTION

This invention relates to pharmaceutical compounds and derivatives, pharmaceutical compositions containing such compounds and their use to elevate certain plasma lipid levels, including high density lipoprotein (HDL)-cholesterol and to lower certain other plasma lipid levels, such as low density lipoprotein (LDL)-cholesterol and triglycerides and accordingly to treat diseases which are affected by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in certain mammals (i.e., those which have CETP in their plasma), including humans.

Atherosclerosis and its associated coronary artery disease (CAD) is the leading cause of mortality in the industrialized world. Despite attempts to modify secondary risk factors (smoking, obesity, lack of exercise) and treatment of dyslipidemia with dietary modification and drug therapy, coronary heart disease (CHD) remains the most common cause of death in the U.S., where cardiovascular disease accounts for 44% of all deaths, with 53% of these associated with atherosclerotic coronary heart disease.

Risk for development of this condition has been shown to be strongly correlated with certain plasma lipid levels. While elevated LDL-C may be the most recognized form of dyslipidemia, it is by no means the only significant lipid associated contributor to CHD. Low HDL-C is also a known risk factor for CHD (Gordon, D.J., et al.,: "High- density Lipoprotein Cholesterol and Cardiovascular Disease", Circulation, (1989), 79: 8- 15).

High LDL-cholesterol and triglyceride levels are positively correlated, while high levels of HDL-cholesterol are negatively correlated with the risk for developing cardiovascular diseases. Thus, dyslipidemia is not a unitary risk profile for CHD but may be comprised of one or more lipid aberrations.

Among the many factors controlling plasma levels of these disease dependent principles, cholesteryl ester transfer protein (CETP) activity affects all three. The role of this 70,000 dalton plasma glycoprotein found in a number of animal species, including humans, is to transfer cholesteryl ester and triglyceride between lipoprotein particles, including high density lipoproteins (HDL), low density lipoproteins (LDL), very low density lipoproteins (VLDL), and chylomicrons. The net result of CETP activity is a lowering of HDL cholesterol and an increase in LDL cholesterol. This effect on lipoprotein profile is believed to be pro-atherogenic, especially in subjects whose lipid profile constitutes an increased risk for CHD.

No wholly satisfactory HDL-elevating therapies are on the market today. Niacin can significantly increase HDL, but has serious toleration issues that reduce compliance. Fibrates and the HMG CoA reductase inhibitors raise HDL-C, but in some patients, the result is an increase of modest porportions (-10-12%). As a result, there is an unmet medical need for an approved therapeutic agent that elevates plasma HDL levels, thereby reversing or slowing the progression of atherosclerosis.

Thus, although there are a variety of anti-atherosclerosis therapies, there is a continuing need and a continuing search in this field of art for alternative therapies.

SUMMARY OF THE INVENTION This invention is directed to compounds according to Formula I

Formula I

1. A compound of Formula I

Formula I or a pharmaceutically acceptable salt of said compound; wherein

B iS -OR⁶Or -NR⁷R⁸;

M and J are each independently CH₂ or a bond wherein at least one of M and J are W is hydrogen or a fully saturated, partially unsaturated or fully unsaturated straight or branched chain having 1 to 6 carbon atoms wherein each carbon atom of said chain is optionally replaced by a heteroatom selected from nitrogen, oxygen or sulfur, and said carbon atom of said chain is optionally mono-, di- or tri-substituted with amino, halo, cyano, (Ci-C₆)alkyl, (Ci-C₆)alkoxy, hydroxy or oxo and said nitrogen atom of said chain is optionally mono- or disubstituted with (CrC₆)alkyl, cyano or oxo and said sulfur atom of said chain is optionally substituted with one or two oxo,

R¹, R², R³, and R⁴ are each independently hydrogen, halo, cyano, hydroxy, nitro, ((CrC₆)alkyl optionally substituted with one to nine halo, one or two hydroxyl, one or two (CrC₆)alkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy), ((C₁- Cβ)alkoxy optionally substituted with one to nine halo, one or two hydroxyl, or cyano), or ((Ci-C₆)alkylthio optionally substituted with one to nine halo, one or two hydroxyl, or cyano); or R¹ and R² or R² and R³ are optionally taken together to form a 5 to 7-membered partially unsaturated or fully unsaturated ring wherein each carbon atom of said ring is optionally replaced with an oxygen atom, wherein the oxygen atoms are not connected to each other, wherein said ring is optionally mono-, di-, tri- or tetra-substituted with halo, and optionally mono- or di-substituted with hydroxy, amino, nitro, cyano, oxo, carboxy, ((d-C₆)alkyl optionally substituted with one to nine halo, one or two hydroxyl, one or two (d-CβJalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy), or ((Ci-C₆)alkoxy optionally substituted with one to nine halo, one or two hydroxyl, or cyano);

R⁵ is hydrogen or (Ci-C₆)alkyl optionally substituted with one to nine halogen; R⁶ is -(CrC₆)alkyl-NR⁹R¹⁰, -(C₀-C₆)alkyl-CO-NR⁹R¹⁰, -(C₀-C₆)alkyl-CO-OR¹³, -(C₁- C₆)alkyl-NR¹⁰-(Co-C₆)alkyl-CO-0-R¹³, -(d-CβJalkyl-NR^Co-CeJalkyl-CO-R¹³, -(C₁- C6)alkyl-NR¹⁰-(Co-C₆)alkyl-Sθ2-R¹³, -(CrC6)alkyl-0-CO-NR⁹R¹⁰, -(C₂-C₆)alkenyl-CO-O- R¹³, -(d-C₆)alkyl-aryl, -(d-C₆)alkyl-heteroaryl, -(d-CeJalkyl-O-aryl, -(C_rC₆)alkyl-O- heteroaryl, -(C₀-C₆)alkyl-heterocycle, -(C₀-C₆)alkyl-(C₃-C₆)cycloalkyl, -(Co-C₆)alkyl-(C₃- C₆)cycloalkenyl, (C₂-C₆)alkynyl, (C₂-C₆)alkenyl, (C_rC₆)alkyl, or -CO-(d-C₆)alkyl, wherein said aryl, heteroaryl, heterocycle, cycloalkenyl, cycloalkyl, alkynyl, alkenyl, and alkyl groups are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (d-C₆)alkyl, one to three (d-CβJhaloalkyl, one to three (C₁- Cβjalkoxy, one to three (d-CeJhaloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy; R⁷ and R⁸ are each independently hydrogen, -(C_rC₆)alkyl-NR⁹R¹⁰, -(C₀-C₆)alkyl-CO- NR⁹R¹⁰, -(C₀-C6)alkyl-CO-OR¹³, -(Ci-C₆)alkyl-NR¹⁰-(Co-C₆)alkyl-CO-0-R¹³, -(Cr CeJalkyl-NR^-CCo-CeJalkyl-CO-R^. -Cd-CeJalkyl-NR^^Co-CeJalkyl-SOz-R^. -CCr C₆)alkyl-O-CO-NR⁹R¹⁰, -(C₂-C₆)alkenyl-CO-O-R¹³, -(Co-C_e)alkyl-aryl, -(C₀-C₆)alkyl- heteroaryl, -(d-CeJalkyl-O-aryl, -(Ci-C₆)alkyl-O-heteroaryl, -(C₀-C₆)alkyl-heterocycle, - (C₀-C₆)alkyl-(C₃-C₆)cycloalkyl, -(C₀-C₆)alkyl-(C₃-C₆)cycloalkenyl, (C₂-C₆)alkynyl, (C₂- C₆)alkenyl, (Ci-C₆)alkyl, cyano, or -CO-(d-C₆)alkyl, wherein said aryl, heteroaryl, heterocycle, cycloalkenyl, cycloalkyl, alkynyl, alkenyl, and alkyl substituents are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (Ci-C₆)alkyl, one to three (d-C₆)haloalkyl, one to three (C_rC₆)alkoxy, one to three (d-CβJhaloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy; or R⁷ and R⁸ are optionally taken together to form a 3 to 8-membered fully saturated or partially unsaturated mono- or bi-cyclic ring having optionally one or two heteroatoms selected from oxygen, nitrogen and sulfur, wherein the ring is optionally mono-, di- or tri- substituted with R¹⁴;

R⁹ and R¹⁰ are each independently hydrogen, aryl or ((CrC₆)alkyl optionally substituted with one to nine halo;

R¹¹ and R¹² are each independently hydrogen, a fully saturated, partially unsaturated or fully unsaturated chain having 1, 2 or 3 carbon atoms, or a fully saturated, partially unsaturated or fully unsaturated mono- or bi-cyclic ring having 3 to 10 carbon atoms, wherein said ring is optionally bicyclic, and wherein each carbon atom of said ring is optionally replaced by a heteroatom selected from nitrogen, oxygen or sulfur, and said carbon atom of said chain or ring is optionally mono-, di- or tri-substituted with R¹⁴ and said nitrogen atom of said ring is optionally substituted with R¹⁵- and wherein R¹¹ and R¹² are not attached to the carbon of Y at a heteroatom, and wherein R¹¹ and R¹² are not both hydrogen, with the proviso that when B is NR⁷R⁸ then R¹² is H; or

R¹¹ and R¹² are optionally taken together to form (C₄-C₇)cycloalkyl optionally mono-, di- or tri-substituted with R¹⁴;

R¹³ is hydrogen, aryl or ((C_rC₆)alkyl optionally substituted with one to nine halo; each R¹⁴ is independently -(Co-C₆)alkyl-NR⁹R¹⁰, -(C₀-C₆)alkyl-CO-NR⁹R¹⁰, -(C₀- C₆)alkyl-CO-OR¹⁰, -O-(d-C6)alkyl-CO-O-R¹⁰, halo, (C_rC₆)alkyl, hydroxy, (C₁- C₆)alkoxy, cyano, oxo, or -CO-(C₁ -C₆)alkyl, wherein said alkyl and alkoxy groups are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (CrC₆)alkyl, one to three (CrC₆)haloalkyl, one to three (CrC₆)alkoxy, one to three (CrCβJhaloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy; each R¹⁵ is independently -(C_rC₆)alkyl-NR⁹R¹⁰, -(C₀-C₆)alkyl-CO-NR⁹R¹⁰, -(C₀- C₆)alkyl-CO-OR¹⁰, or -CO-(CrC₆)alkyl, wherein said alkyl groups are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (Cr C₆)alkyl, one to three (CrC₆)haloalkyl, one to three (CrC₆)alkoxy, one to three (Ci- C₆)haloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy; each R¹⁶ is independently halo, nitro, cyano, hydroxyl, oxo, carboxyl, (Cr C₆)alkoxycarbonyl, ((C_rC₆)alkyl optionally substituted with one to nine halo or one or two hydroxyl), ((Ci-Ce)alkoxy optionally substituted with one to nine halo or one or two hydroxyl), or ((Ci-C₆)alkylthio optionally substituted with one to nine halo or one or two hydroxyl); and n is O, 1 , 2, 3 or 4.

In addition, the present invention provides pharmaceutical compositions which comprise a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable form of said compound and a pharmaceutically acceptable vehicle, diluent or carrier.

In addition, the present invention provides pharmaceutical compositions for the treatment of atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial- hypercholesterolemia or myocardial infarction in a mammal which comprise a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable form of said compound and a pharmaceutically acceptable vehicle, diluent or carrier.

Moreover, the present invention provides pharmaceutical combination compositions comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of the present invention, or a pharmaceutically acceptable form of said compound; a second compound, said second compound being an HMG CoA reductase inhibitor, an MTP/Apo B secretion inhibitor, a PPAR modulator, a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, an antihypertensive, a combination of niacin and lovastatin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant (preferably an HMG- CoA reductase inhibitor, a PPAR modulator, fenofibrate, gemfibrozil, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin); and a pharmaceutical vehicle, diluent or carrier. This composition may be used to treat the aforementioned diseases, including atherosclerosis.

Also, the present invention provides a kit for achieving a therapeutic effect in a mammal comprising packaged in association a first therapeutic agent comprising a therapeutically effective amount of a compound of the present invention, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier, a second therapeutic agent comprising a therapeutically effective amount of an HMG CoA reductase inhibitor, a PPAR modulator, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, a combination of niacin and lovastatin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant and a pharmaceutically acceptable carrier and directions for administration of said first and second agents to achieve the therapeutic effect.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may be understood more readily by reference to the following detailed description of exemplary embodiments of the invention and the examples included therein.

Before the present compounds, compositions and methods are disclosed and described, it is to be understood that this invention is not limited to specific synthetic methods of making that may of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the present invention. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, (i.e.. salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1 ,1'-methylene-bis-(2-hydroxy-3- naphthoate)) salts.

The invention also relates to base addition salts of the compounds of the present invention. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of the present invention that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (ej^. potassium and sodium) and alkaline earth metal cations (ejL, calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

The chemist of ordinary skill will recognize that certain compounds of this invention will contain one or more atoms which may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers. All such isomers and mixtures thereof are included in this invention. Hydrates and solvates of the compounds of this invention are also included.

Where the compounds of the present invention possess two or more stereogenic centers and the absolute or relative stereochemistry is given in the name, the designations R and S refer respectively to each stereogenic center in ascending numerical order (1 , 2, 3, etc.) according to the conventional IUPAC number schemes for each molecule. Where the compounds of the present invention possess one or more stereogenic centers and no stereochemistry is given in the name or structure, it is understood that the name or structure is intended to encompass all forms of the compound, including the racemic form. The compounds of this invention may contain olefin-like double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof. The term "cis" refers to the orientation of two substituents with reference to each other and the plane of the ring (either both "up" or both "down"). Analogously, the term "trans" refers to the orientation of two substituents with reference to each other and the plane of the ring (the substituents being on opposite sides of the ring).

Alpha and Beta refer to the orientation of a substituent with reference to the plane of the ring. Beta is above the plane of the ring and Alpha is below the plane of the ring.

This invention also includes isotopically-labeled compounds, which are identical to those described by formula I, except for the fact that one or more atoms are replaced by one or more atoms having specific atomic mass or mass numbers. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, ¹⁸F, and ³⁶CI respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or of the prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated (i.e., ³H), and carbon-14 (i.e., ¹⁴C), isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H), can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, lsotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings:

As used herein in the specification, "a" or "an" may mean one or more. As used herein in the claim(s), when used in conjunction with the word "comprising", the words "a" or "an" may mean one or more than one. As used herein "another" may mean at least a second or more.

The term "about" refers to a relative term denoting an approximation of plus or minus 10% of the nominal value it refers, in one embodiment, to plus or minus 5%, in another embodiment, to plus or minus 2%. For the field of this disclosure, this level of approximation is appropriate unless the value is specifically stated require a tighter range.

As used herein, the term mammals is meant to refer to all mammals which contain CETP in their plasma, for example, rabbits and primates such as monkeys and humans, including males and females. Certain other mammals e.g., dogs, cats, cattle, goats, sheep and horses do not contain CETP in their plasma and so are not included herein.

The term "treating", "treat" or "treatment" as used herein includes preventative (e.g., prophylactic) and palliative treatment. By "pharmaceutically acceptable" is meant the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.

"Compounds" when used herein includes any pharmaceutically acceptable derivative or variation, including conformational isomers (e.g.. cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salt forms, and prodrugs. By "tautomers" is meant chemical compounds that may exist in two or more forms of different structure (isomers) in equilibrium, the forms differing, usually, in the position of a hydrogen atom. Various types of tautomerism can occur, including keto-enol, ring-chain and ring-ring tautomerism. The expression "prodrug" refers to compounds that are drug precursors which following administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form). Exemplary prodrugs upon cleavage release the corresponding free acid, and such hydrolyzable ester- forming residues of the compounds of the present invention include but are not limited to those having a carboxyl moiety wherein the free hydrogen is replaced by (C₁- C₄)alkyl, (C₂-C₇)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1- (N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl), carbamoyl-(CrC₂)alkyl, N,N-di(Ci-C₂)alkylcarbamoyl-(Ci- C₂)alkyl and piperidino-, pyrrolidine)- or morpholino(C₂-C₃)alkyl.

By "halo" or "halogen" is meant chloro, bromo, iodo, or fluoro. By "alkyl" is meant straight chain saturated hydrocarbon or branched chain saturated hydrocarbon. Exemplary of such alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, isobutyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1- methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.

"Alkenyl" referred to herein may be linear or branched, and they may also be cyclic (e.g. cyclobutenyl, cyclopentenyl, cyclohexenyl) or bicyclic or contain cyclic groups. They contain 1-3 carbon-carbon double bonds, which can be cis or trans.

By "alkoxy" is meant straight chain saturated alkyl or branched chain saturated alkyl bonded through an oxy. Exemplary of such alkoxy groups (assuming the designated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy.

The term "aryl" means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be fused. If the rings are fused, one of the rings must be fully unsaturated and the fused ring(s) may be fully saturated, partially unsaturated or fully unsaturated. The term "fused" means that a second ring is present (ie, attached or formed) by having two adjacent atoms in common (ie, shared) with the first ring. The term "fused" is equivalent to the term "condensed". The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.

The term "heteroaryl" means a carbocyclic aromatic system containing one, two, three or four heteroatoms selected independently from oxygen, nitrogen and sulfur and having one, two or three rings wherein such rings may be fused. The term "fused" means that a second ring is present (ie, attached or formed) by having two adjacent atoms in common (ie, shared) with the first ring. The term "fused" is equivalent to the term "condensed". The term "heteroaryl" embraces aromatic radicals such as quinolinyl, benzofuranyl, benzodioxanyl, piprazinyl, pyridinyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, thiazolyl and thiadiazolyl.

The term "heterocycle" means a nonaromatic carbocyclic system containing one, two, three or four heteroatoms selected independently from oxygen, nitrogen and sulfur and having one, two or three rings wherein such rings may be fused, wherein fused is defined above. The term "heterocycle" includes but is not limited to lactones, lactams, cyclic ethers and cyclic amines, including the following exemplary ring systems: epoxide, tetrahydrofuran, tetrahydropyran, dioxane, aziridines, pyrrolidine, piperidine, and morpholine.

It is to be understood that if a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate through differing ring atoms without denoting a specific point of attachment, then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridyl" means 2-, 3- or 4-pyridyl, the term "thienyl" means 2- or 3-thienyl, and so forth.

As used herein, the expressions "reaction-inert solvent" and "inert solvent" refer to a solvent or a mixture thereof which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.

In one embodiment of the compounds of the present invention, A is

or a pharmaceutically acceptable salt of said compound. In another embodiment of the compounds of the present invention, W is CH₃ or hydrogen, or a pharmaceutically acceptable salt of said compound.

In another embodiment of the compounds of the present invention, the compounds have the formula Il

Formula Il or a pharmaceutically acceptable salt of said compound.

In another embodiment of the compounds of the present invention, M is a bond; J is CH₂; and R², R³, and R⁴ are each hydrogen, methyl, cyano, or CF_3;or a pharmaceutically acceptable salt of said compound. In another embodiment of the compounds of the present invention, B is -OR⁶; R¹¹ is a 5- or 6-membered fully saturated ring optionally having one heteroatom selected from oxygen and nitrogen and the carbon atoms of said ring are optionally mono- or di- substituted with R¹⁴ and the nitrogen atoms, if present, are optionally substituted with R¹⁵; each R¹⁴ is independently halo, (CrCβJalkyl, hydroxy, (Ci-C₆)alkoxy, cyano, oxo, or -CC-HCrCβJalkyl, wherein said alkyl and alkoxy groups are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (CrCβJalkyl, one to three (d-C₆)haloalkyl, one to three (Ci-C₆)alkoxy, one to three (Ci-C₆)haloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy; or a pharmaceutically acceptable salt of said compound.

In another embodiment of the compounds of the present invention, B is -OR⁶; and R¹¹ and R¹² are optionally taken together to form (C₅-C₇)cycloalkyl optionally mono- or di-substituted with R¹⁴; and each R¹⁴ is independently halo, (CrCβJalkyl, hydroxy, (C₁- C₆)alkoxy, cyano, oxo, or -CO-(Ci-C₆)alkyl, wherein said alkyl and alkoxy groups are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (Ci-Cβ)alkyl, one to three (Ci-C₆)haloalkyl, one to three (Ci-Cβjalkoxy, one to three (CrCβJhaloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy; or a pharmaceutically acceptable salt of said compound.

In another embodiment of the compounds of the present invention, B is -NR⁷R⁸; R⁷ and R⁸ are each independently hydrogen, -(CrC₆)alkyl-NR⁹R¹⁰, -(C₀-C₆)alkyl-CO-

NR⁹R¹⁰, -(Co-C₆)alkyl-CO-OR¹³, -(Co-C₆)alkyl-(C₃-C₆)cycloalkyl, (d-Cβ)alkyl, cyano, or - CO-(Ci -C₆)alkyl, wherein said cycloalkyl, and alkyl substituents are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (Ci- C₆)alkyl, one to three (Ci-C₆)haloalkyl, one to three (CrC₆)alkoxy, one to three (d- Cβjhaloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy; R¹¹ is hydrogen, aryl, ((C₃-C₆)cycloalkyl optionally substituted with aryl, one to three (Ci- Cβ)alkyl, one to three (C-ι-C₆)alkoxy, one to three (Ci-C₆)haloalkyl, one to three (Ci- C₆)haloalkoxy, one or two hydroxy I, or one to nine halo) or ((d-C₆)alkyl wherein said (Ci-C₆)alkyl is optionally substituted with aryl, one to three (d-C₆)alkoxy, one to three (Ci-Cβjhaloalkyl, one to three (Ci-Ce)haloalkoxy, one or two hydroxyl, or one to nine halo); and R¹² is hydrogen; or a pharmaceutically acceptable salt of said compound.

In another embodiment of the compounds of the present invention, B is -NR⁷R⁸; R⁷ and R⁸ are optionally taken together to form a 5 to 8-membered fully saturated or partially unsaturated mono- or bi-cyclic ring having optionally one heteroatoms selected from oxygen and nitrogen, wherein the ring is optionally mono- or di-substituted with R¹⁴; R¹¹ is hydrogen, aryl, ((C₃-C₆)cycloalkyl optionally substituted with aryl, one to three (Ci-C₆)alkyl, one to three (CrC₆)alkoxy, one to three (CrC₆)haloalkyl, one to three (C₁- CβJhaloalkoxy, one or two hydroxyl, or one to nine halo) or ((Ci-Cejalkyl wherein said (Ci-Cβ)alkyl is optionally substituted with aryl, one to three (Ci-Ce)alkoxy, one to three (Ci-C₆)haloalkyl, one to three (CrC₆)haloalkoxy, one or two hydroxyl, or one to nine halo); R¹² is hydrogen; and each R¹⁴ is independently halo, (CrCβ)alkyl, hydroxy, (Cr C₆)alkoxy, cyano, oxo, or -CO-(CrC₆)alkyl, wherein said alkyl and alkoxy groups are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (CrC₆)alkyl, one to three (Ci-C₆)haloalkyl, one to three (Ci-C₆)alkoxy, one to three (Ci-Cβjhaloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy; or a pharmaceutically acceptable salt of said compound.

In one embodiment of the method of the present invention, atherosclerosis is treated.

In another embodiment of the method of the present invention, peripheral vascular disease is treated. In another embodiment of the method of the present invention, dyslipidemia is treated.

In another embodiment of the method of the present invention, hyperbetalipoproteinemia is treated.

In another embodiment of the method of the present invention, hypoalphalipoproteinemia is treated.

In another embodiment of the method of the present invention, familial- hypercholesterolemia is treated.

In another embodiment of the method of the present invention, coronary artery disease is treated. In another embodiment of the method of the present invention, myocardial infarction is treated.

In one embodiment of the combination or kit of the present invention, the second compound is an HMG CoA reductase inhibitor, an MTP/Apo B secretion inhibitor, a PPAR modulator, a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, a combination of niacin and lovastatin, a combination of niacin and simvastatin, a combination of niacin and atorvastatin, a combination of amlodipine and atorvastatin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant. In another embodiment of the combination or kit of the present invention, the second compound is an HMG-CoA reductase inhibitor, a PPAR modulator or niacin.

In another embodiment of the combination or kit of the present invention, the second compound is niacin, fenofibrate, gemfibrozil, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin. In another embodiment of the combination or kit of the present invention, the second compound is fenofibrate, gemfibrozil, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin.

In another embodiment of the combination or kit of the present invention, the combination further comprising a cholesterol absorption inhibitor, wherein the cholesterol absorption inhibitor may be ezetimibe.

In general, the compounds of this invention can be made by processes which include processes analogous to those known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compounds of this invention are provided as further features of the invention and are illustrated by the following reaction schemes. Other processes may be described in the experimental section.

Analogous processes are disclosed in the following U.S. patents, which are hereby incorporated by reference herein in their entirety for all purposes: U.S. Patent 6,140,342; U.S. Patent 6,362,198; U.S. Patent 6,147,090; U.S. Patent 6, 395,751 ; U.S. Patent 6,147,089; U.S. Patent 6,310,075; U.S. Patent No. 6,197,786; U.S. Patent 6,140,343; U.S. Patent 6,489,478; WO 2006/014357; WO 2006/014413; WO 2007/079186 and International Publication No. WO 00/17164 and International Patent Application No. PCT/IB2005/003500.

The Reaction Schemes herein described are intended to provide a general description of the methodology employed in the preparation of many of the Examples given. However, it will be evident from the detailed descriptions given in the Experimental section that the modes of preparation employed extend further than the general procedures described herein. In particular, it is noted that the compounds prepared according to these Schemes may be modified further to provide new Examples within the scope of this invention. For example, an ester functionality may be reacted further using procedures well known to those skilled in the art to give another ester, an amide, a carbinol or a ketone.

Formula 6 Formula 4 Formula 5

Scheme 1

According to reaction Scheme 1 , Hal is a halogen, and R¹, R², R³, and R⁴ are as described above and P is a suitable alcohol protecting group such as described in T.W. Greene, Protective Groups in Organic Synthesis. John Wiley & Sons, New York, 1991.

For this application the preferred protecting groups are silyl ethers such as tert- butyldimethylsilyl or triisopropylsilyl.

The desired intermediate compound of Formula 5 may be prepared from compounds of Formulas 2, 3, and 4 and 6. The compounds of Formula 3 may be prepared from compounds of Formula 2 by by partial reduction, for example with an aluminum hydride reagent such as diisobutylaluminum hydride (DIBAL) in a suitable reaction inert solvent such as THF at a temperature between -78⁰C and 25⁰C.

The compounds of Formula 4 may be prepared from compounds of Formula 3 by reduction with a suitable reducing agent such as sodium borohydride for which the preferred solvent is ethanol at a temperature between 0 and 100⁰C, preferably 0-50⁰C.

An alternative reducing agent is lithium aluminium hydride (LAH) in a reaction inert solvent such as dioxan, diethyl ether or THF at a temperature between 0 and 100⁰C, preferably 0-50⁰C. The Formula 5 compounds where P is a silyl group may be prepared from compounds of Formula 4 by reaction with the appropriate trialkylsilyl halide or triflate using procedures described in T.W. Greene, Protective Groups in Organic Synthesis. John Wiley & Sons, New York, 1991. The preferred protecting group is triisopropylsilyl which may be prepared by reaction of the alcohol with triisopropylsilyl chloride in the presence of a base, preferably imidazole, in a suitable reaction inert solvent such as N.N-dimethylformamide or N,N-dimethylacetamide at a temperature between 0 and 100⁰C, preferably 0-50⁰C.

Alternatively the compounds of Formula 4 may be prepared from compounds of Formula 6 by reduction with a suitable reducing agent such as as lithium aluminium hydride (LAH), or borane-tetrahydrofuran complex in a reaction inert solvent such as dioxan, diethyl ether or THF. A preferred reducing agent for reduction of compounds of Formula 6 is borane-tetrahydrofuran complex, and the preferred solvent is THF at a temperature between -78 and 100⁰C preferably at 0-50⁰C.

The compounds of Formula 6 may be prepared from compounds of Formula 2 by hydrolysis with aqueous acid or base, for example aqueous sodium hydroxide, potassium hydroxide, hydrochloric acid or sulfuric acid, optionally in the presence of a reaction inert cosolvent such as dioxane or ethanol (when under basic conditions) at a temperature between 0 and 160⁰C preferably at 50 to 120⁰C.

Formula 12a Formula 12b

Scheme 2 According to Scheme 2 the the desired compounds of Formulas 11a and 11b where R¹, R², R³, R⁴, R⁶, R¹¹, R¹², M and W are as described above and V is a phenyl group optionally substituted with one to four R¹⁶ groups, where R^1β is as described above, may be prepared alkylation of compounds of Formula 10 by compounds of Formula 12a or 12b respectively with a suitable base such as sodium hydride, potassium-tert-butoxide or potassium hexamethyldisilazine in a suitable polar solvent such as THF, dimethylformamide, or N-methylpyrrolidinone. The preferred base is sodium hydride, and the preferred solvent is THF at a temperature between O⁰C and 67⁰C, preferably 20°C-67°C.

Some suitable preparations of intermediates of Formula 12a and 12b are described in International Patent Publication No. WO2006/ 014413, which is incorporated herein by reference.

The compounds of Formula 10 where L is a leaving group such as a mesylate, tosylate, triflate, chloride or bromide may be prepared from the corresponding compound of Formula 9 by standard procedures known to those skilled in the art. For example a bromide may be prepared by reacting compounds of Formula 9 using a suitable reagent such as phosphorus tribromide or a combination of carbon tetrabromide and triphenylphosphine in a reaction inert solvent such as methylene chloride, THF, or dioxan. The preferred reagent is a combination of carbon tetrabromide and triphenylphosphine, and the preferred solvent is methylene chloride at a temperature between -78⁰C and 100⁰C, preferably -10⁰C to 3O⁰C.

The compounds of Formula 9 may be prepared from compounds of Formula 8 where P is a suitable protecting group, using procedures described in T.W. Greene, Protective Groups in Organic Synthesis. John Wiley & Sons, New York, 1991. The preferred protecting group, triisopropylsilyl, may be removed by reaction with a solution of tetrabutylammonium fluoride (TBAF) in tetrahydrofuran at a temperature between - 2O⁰C and 5O⁰C, preferably 1O⁰C to 3O⁰C.

The Formula 8 compounds may also be prepared from the corresponding alcohol of Formula 7 by an alkylation reaction well known to those skilled in the art for example as described in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis. John Wiley and Sons, Chichester, England, 1995. In the preferred method of this invention the alcohol is treated with a base such as sodium hexamethyldisilazide, potassium hydride or sodium hydride, preferably sodium hydride, in a reaction inert solvent such as THF at a temperature between -20⁰C and 5O⁰C₁ preferably 10⁰C to 3O⁰C. and reacted with the appropriate alkylating agent R⁶L where L is a leaving group such as bromide, iodide, tosylate, triflate or tosylate to give the desired compound of Formula 8.

The desired compounds of Formula 7 may be prepared from compounds of Formula 5 by first converting the aryl halide into an aryl metal derivative where the metal may be lithium or magnesium followed by reaction with the appropriate carbonyl compound of formula R¹¹R¹²CO₁ including such carbonyl compounds in which R¹¹ and R¹² are connected in the form of a ring. Methods for accomplishing these reactions are well known to those skilled in the art and include metal exchange with a Grignard reagent such as isopropylmagnesium chloride or with an alkyllithium such as n-butyl lithium or s-butyl lithium in a suitable reaction inert solvent such as THF, diethyl ether or toluene, preferably THF, at a temperature between -78⁰C and 40⁰C, preferably -78⁰C and O⁰C followed by reaction with the carbonyl compound R¹¹R¹²CO at a temperature between -78⁰C and 50⁰C, preferably -78⁰C to 25⁰C.

Formula 16a

Formula 13 Formula 15a

According to Scheme 3 the the desired compounds of Formulas 17a and 17b where R¹, R², R³, R⁴, R⁶, R¹¹, R¹², M and W are as described above and V is a phenyl group optionally substituted with one to four R¹⁶ groups, where R¹⁶ is as described above, and E is CO or SO₂ may be prepared from the corresponding compounds of Formula 15a and 15b respectively by first removing the protecting group, P, using procedures described in T.W. Greene, Protective Groups in Organic Synthesis. John Wiley & Sons, New York, 1991. For example when the protecting group is tert- butoxycarbonyl (BOC) this may be removed by treatment with trifluoroacetic acid in a solvent such as methylene chloride at a temperature between about O⁰C to 30⁰C, typically ambient, for a period of about 10 minutes to 3 hours. Alternatively the BOC group may be removed by treatment with hydrogen chloride in a reaction inert solvent such as ethyl acetate, diethyl ether or dioxane at a temperature between about -78⁰C to 25⁰C for a period of about 10 minutes to 24 hours. Alternatively, when the protecting group is benzyloxycarbonyl (Cbz) this may be removed by transfer hydrogenation in the presence of a suitable hydrogenation catalyst such as palladium on carbon or palladium hydroxide and ammonium formate in a reaction inert solvent such as ethyl acetate, methanol or ethanol at a temperature between 20⁰C to 60⁰C, for a period of about 10 minutes to 24 hours. The diamine compound thus prepared is then treated with the appropriate carbonyl or sulfonyl reagent. When E is CO suitable reagents include COCI₂ (phosgene), CI₃COCOCI (diphosgene), CI₃COCO₂CCI₃ (triphosgene), in the presence of a base such as diisopropylethylamine, or using carbonyldiimidazole (CDI) in a reaction inert solvent such as dichloromethane or THF at a temperature between O⁰C to 6O⁰C, preferably room temperature. When E is SO₂ a suitable reagent is SO₂CI₂ in the presence of a base such as diisopropylethylamine in a reaction inert solvent such as dichloromethane or THF at a temperature between -3O⁰C to 3O⁰C, preferably -10⁰C. Another suitable reagent when E is SO₂ is SO₂(NH₂)₂ in the presence of a base such as pyridine at a temperature between 20⁰C to 15O⁰C, preferably 12O⁰C as described in the patent WO2006/ 014413. Compounds of Formula 15a and 15b may be prepared by reductive amination of aldehydes of Formula 13 with amines of Formula 16a and 16b respectively and a suitable reducing agent such as sodium borohydride, sodium triacetoxyborohydride, or sodium cyanoborohydride, preferably sodium triacetoxyborohydride in a suitable solvent such as THF, methylene chloride, dioxane or toluene at a temperature between 2O⁰C and 111⁰C, preferably room temperature.

Compounds of Formula 13 may be prepared by oxidation of compounds of Formula 9 using a wide variety of oxidizing agents known to those skilled in the art, such as described in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis. John Wiley and Sons, Chichester, England, 1995. Examples of suitable reagents include manganese (IV) oxide in a suitable solvent such as diethyl ether or methylene chloride 2O⁰C and 5O⁰C, preferably room temperature, or use of the Swern reagent, typically prepared by reaction of DMSO with oxalyl chloride in a suitable solvent such as methylene chloride at a temperature between -78⁰C and -50⁰C followed by addition of the alcohol and then a suitable base such as triethylamine or diisopropylethylamine at a temperature between -78⁰C and O⁰C.

Scheme 4

According to Scheme 4 the desired compounds of Formula 21 where R¹, R², R³, R⁴, R⁶, R¹¹, R¹², and W are as described above and V is a phenyl group optionally substituted with one to four R¹⁶ groups, where R¹⁶ is as described above may be prepared from the corresponding compounds of Formula 20 by an alkylation reaction well known to those skilled in the art for example as described in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis. John Wiley and Sons, Chichester, England, 1995. In the preferred method of this invention the oxazolidinone is treated with a base such as sodium hexamethyldisilazide, potassium hydride or sodium hydride, preferably sodium hydride, in a reaction inert solvent such as DMF at a temperature between -2O⁰C and 50⁰C, preferably O⁰C to 2O⁰C and reacted with the appropriate alkylating agent VCH₂L where L is a leaving group such as bromide, iodide, tosylate, triflate or tosylate to give the desired compound of Formula 21.

The compounds of Formula 20 may be prepared from the corresponding compounds of Formula 19 by treatment with COCI₂ (phosgene), CI₃COCOCI (diphosgene), CbCOCO₂CCI₃ (triphosgene), in the presence of a base such as diisopropylethylamine, or using carbonyldiimidazole (CDI) in a reaction inert solvent such as dichloromethane or THF at a temperature between 0⁰C to 6O⁰C₁ preferably room temperature.

The compounds of Formula 19 may be prepared from the corresponding compounds of Formula 18 by reduction various hydride reagents such as sodium borohydride in the presence of a metal salt such as cobalt (II) chloride or nickel (II) chloride. Another suitable method is hydrogenation over a suitable catalyst such as Raney nickel in a suitable reaction inert solvent such as methanol or ethanol, preferably methanol, preferably in the presence of an acid such as formic acid, at a temperature between between O⁰C to 100⁰C, preferably 25⁰C to 50⁰C. The compounds of Formula 18 may be prepared from the corresponding compounds of Formula 13 by reaction with a nitroalkane of formula WCH₂NO₂ in the presence of base in a reaction inert solvent such as methanol or ethanol at a temperature between -20⁰C and 5O⁰C, preferably O⁰C to 2O⁰C. Suitable bases include aqueous sodium, potassium or tetrabutylammonium hydroxide.

Formula 5

Formula 26 Formula 25

Scheme 5

According to Scheme 5 the desired compounds of Formula 27 where R¹, R², R³, R⁴ , R⁷, R⁸, and R¹¹ are as described above may be prepared from the corresponding compounds of Formula 26 by oxidation for example with manganese (IV) oxide in a suitable solvent such as diethyl ether or methylene chloride 20⁰C and 5O⁰C, preferably room temperature, or use of the Swem reagent, typically prepared by reaction of DMSO with oxalyl chloride or trifluoroacetic anhydride in a suitable solvent such as methylene chloride at a temperature between -78⁰C and -5O⁰C followed by addition of the alcohol and then a suitable base such as triethylamine or diisopropylethylamine at a temperature between -78⁰C and O⁰C.

The compounds of Formula 26 may be prepared from the corresponding compounds of Formula 25 where P is a suitable protecting group, using procedures described in T.W. Greene, Protective Groups in Organic Synthesis. John Wiley & Sons, New York, 1991. The preferred protecting group, triisopropylsilyl, may be removed by reaction with a solution of tetrabutylammonium fluoride (TBAF) in tetrahydrofuran at a temperature between -20⁰C and 5O⁰C, preferably 1O⁰C to 3O⁰C.

The compounds of Formula 25 may be prepared from the corresponding compounds of Formula 23 by a sequence similar to that described by Katritzky, A. R.; Yannakopoulou, K.; Lue, P.; Rasala, D.; Urogdi, L. J. Chem. Soc. Perkin Trans. 1, 1989, 2, 225-233. The compound of Formula 24 where Bt is benzotriazole linked through an N atom is prepared from the aldehyde of Formula 23 by reaction with the appropriate amine HNR⁷R⁸ and benzotriazole in a polar solvent, preferably ethanol. Addition of the Grignard reagent HNR¹¹MgX where X is Cl, Br or I to the compound of Formula 24 and in a suitable reaction inert solvent such as toluene at a temperature between -10⁰C and 5O⁰C, preferably O⁰C to 2O⁰C yields compounds of Formula 25.

The compounds of Formula 23 may be prepared from the corresponding compounds of Formula 22 by partial reduction, for example with an aluminum hydride reagent such as diisobutylaluminum hydride (DIBAL) in a suitable reaction inert solvent such as THF at a temperature between -78⁰C and 25⁰C.

The compounds of Formula 22 may be prepared from the corresponding compounds of Formula 5 by reaction with an appropriate metal cyanide salt such as palladium (II) cyanide or zinc cyanide or potassium ferrocyanide in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium or palladium (II) acetate in a suitable reaction inert solvent such as N,N-dimethylformamide or N₁N- dimethylacetamide at a temperature between 20⁰C and 150⁰C, preferably 120⁰C.

Formula 27 Formula 28a

Scheme 6

According to Scheme 6 the desired compounds of Formulas 32a and 32b where R¹, R², R³, R⁴, R⁷, R⁸, R¹¹, M and W are as described above and V is a phenyl group optionally substituted with one to four R¹⁶ groups, where R¹⁶ is as described above, and E is CO or SO₂ may be prepared from the corresponding compounds of Formula 31a and 31b respectively by first removing the protecting group P using procedures described in T.W. Greene, Protective Groups in Organic Synthesis. John Wiley & Sons, New York, 1991. For example when the protecting group is tert-butoxycarbonyl (BOC) this may be removed by treatment with trifluoroacetic acid in a solvent such as methylene chloride at a temperature between about O⁰C to 3O⁰C₁ typically ambient, for a period of about 10 minutes to 3 hours. Alternatively the BOC group may be removed by treatment with hydrogen chloride in a reaction inert solvent such as ethyl acetate, diethyl ether or dioxane at a temperature between about -78⁰C to 25°C for a period of about 10 minutes to 24 hours. Alternatively, when the protecting group is benzyloxycarbonyl (Cbz) this may be removed by transfer hydrogenation in the presence of a suitable hydrogenation catalyst such as palladium on carbon or palladium hydroxide and ammonium formate in a reaction inert solvent such as ethyl acetate, methanol or ethanol at a temperature between 20⁰C to 6O⁰C, for a period of about 10 minutes to 24 hours. The diamine compound thus prepared is then treated with the appropriate carbonyl or sulfonyl reagent. When E is CO suitable reagents include COCI₂ (phosgene), CI₃COCOCI (diphosgene), CI₃COCO₂CCI₃ (triphosgene), in the presence of a base such as diisopropylethylamine, or using carbonyldiimidazole (CDI) in a reaction inert solvent such as dichloromethane or THF at a temperature between O⁰C to 6O⁰C, preferably room temperature. When E is SO₂ a suitable reagent is SO₂CI₂ in the presence of a base such as diisopropylethylamine in a reaction inert solvent such as dichloromethane or THF at a temperature between -3O⁰C to 3O⁰C, preferably -1O⁰C. Another suitable reagent when E is SO₂ is SO₂(NH₂)₂ in the presence of a base such as pyridine at a temperature between 2O⁰C to 15O⁰C, preferably 12O⁰C as described in International Patent Publication No. WO2006/ 014413.

Compounds of Formula 31a and 31b may be prepared by reductive amination of aldehydes of Formula 27 with amines of Formula 16a and 16b respectively and a suitable reducing agent such as sodium borohydride, sodium triacetoxyborohydride, or sodium cyanoborohydride, preferably sodium triacetoxyborohydride in a suitable solvent such as THF, methylene chloride, dioxane or toluene at a temperature between 2O⁰C and 111⁰C, preferably room temperature. According to Scheme 6 the desired compounds of Formulas 30a and 30b where

R¹, R², R³, R⁴, R⁷, R⁸, R¹¹, M and W are as described above and V is a phenyl group optionally substituted with one to four R¹⁶ groups, where R¹⁶ is as described above, may be prepared from the corresponding compounds of Formula 28a and 28b respectively. Suitable reagents include COCI₂ (phosgene), CI₃COCOCI (diphosgene), CI₃COCO₂CCI₃ (triphosgene), in the presence of a base such as diisopropylethylamine, or using carbonyldiimidazole (CDI) in a reaction inert solvent such as dichloromethane or THF at a temperature between O⁰C to 60⁰C, preferably room temperature.

Compounds of Formula 28a and 28b may be prepared by reductive amination of aldehydes of Formula 27 with amines of Formula 29a and 29b respectively and a suitable reducing agent such as sodium borohydride, sodium triacetoxyborohydride, or sodium cyanoborohydride, preferably sodium triacetoxyborohydride in a suitable solvent such as THF, methylene chloride, dioxane or toluene at a temperature between 20⁰C and 111⁰C, preferably room temperature. A suitable method for preparation of the intermediates of Formula 29a and 29b is described in the literature reference Jingjun Yin, Mark A. Huffman, Karen M. Conrad, and Joseph D. Armstrong, III

J. Org. Chem.; 2006; 71(2) pp 840 - 843, and references therein, and in International Patent Publication No. WO2006/ 014413. Compounds of Formula 16a and 16b may be prepared from the corresponding compounds of Formula 29a and 29b by reactions well known to those skilled in the art for example as described in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis. John Wiley and Sons, Chichester, England, 1995. For example the amino group of the compound 29a or 29b is protected with a suitable protecting group such as benzyloxycarbonyl (Cbz) or tert-butoxycarbonyl (BOC) using procedures described in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991. The hydroxyl group is then converted to the amino group using procedures familiar to those skilled in the art

Formula 27 Formula 33 Formula 34 Formula 35

Formula 36

Scheme 7

According to Scheme 7 the desired compounds of Formula 36 where R¹, R², R³, R⁴, R⁷, R⁸, R¹¹ and W are as described above and V is a phenyl group optionally substituted with one to four R¹⁶ groups, where R¹⁶ is as described above may be prepared from the corresponding compounds of Formula 35 by an alkylation reaction well known to those skilled in the art for example as described in L.A. Paquette (Ed), Encyclopedia of Reagents for Organic Synthesis. John Wiley and Sons, Chichester, England, 1995. In the preferred method of this invention the oxazolidinone is treated with a base such as sodium hexamethyldisilazide, potassium hydride or sodium hydride, preferably sodium hydride, in a reaction inert solvent such as DMF at a temperature between -2O⁰C and 5O⁰C, preferably O⁰C to 2O⁰C and reacted with the appropriate alkylating agent VCH₂L where L is a leaving group such as bromide, iodide, tosylate, triflate or tosylate to give the desired compound of Formula 36.

The compounds of Formula 35 may be prepared from the corresponding compounds of Formula 34 by treatment with COCI₂ (phosgene), CI₃COCOCI (diphosgene), CI₃COCO₂CCI₃ (triphosgene), in the presence of a base such as diisopropylethylamine, or using carbonyldiimidazole (CDI) in a reaction inert solvent such as dichloromethane or THF at a temperature between 0⁰C to 60⁰C, preferably room temperature.

The compounds of Formula 34 may be prepared from the corresponding compounds of Formula 33 by reduction using various hydride reagents such as sodium borohydride in the presence of a metal salt such as cobalt (II) chloride or nickel (II) chloride. Another suitable method is hydrogenation over a suitable catalyst such as Raney nickel in a suitable reaction inert solvent such as methanol or ethanol, preferably methanol, preferably in the presence of an acid such as formic acid, at a temperature between between O⁰C to 100⁰C, preferably 25⁰C to 5O⁰C.

The compounds of Formula 33 may be prepared from the corresponding aldehyde of Formula 27 by reaction with a nitroalkane of formula WCH₂NO₂ in the presence of base in a reaction inert solvent such as methanol or ethanol at a temperature between -2O⁰C and 5O⁰C, preferably O⁰C to 2O⁰C. Suitable bases include aqueous sodium, potassium ortetrabutylammonium hydroxide.

As an initial note, in the preparation of compounds, it is noted that some of the preparation methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in intermediates). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection/deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis. John Wiley & Sons, New York, 1991.

For example, in the reaction schemes, certain compounds contain primary amines or carboxylic acid functionalities which may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group which may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as N-t-butoxycarbonyl, benzyloxycarbonyl, and 9-fluorenylmethylenoxycarbonyl for amines and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and can typically be removed without chemically altering other functionality in the compound.

Prodrugs of the compounds of the present invention may be prepared according to methods known to those skilled in the art. Exemplary processes are described below. Prodrugs of this invention where a carboxyl group in a carboxylic acid of the compounds is replaced by an ester may be prepared by combining the carboxylic acid with the appropriate alkyl halide in the presence of a base such as potassium carbonate in an inert solvent such as dimethylformamide at a temperature of about 0 to 100⁰C for about 1 to about 24 hours. Alternatively the acid is combined with an appropriate alcohol as solvent in the presence of a catalytic amount of acid such as concentrated sulfuric acid at a temperature of about 20 to 100⁰C, preferably at a reflux, for about 1 hour to about 24 hours. Another method is the reaction of the acid with a stoichiometric amount of the alcohol in the presence of a catalytic amount of acid in an inert solvent such as toluene or tetrahydrofuran, with concomitant removal of the water being produced by physical (e.g., Dean-Stark trap) or chemical (e.g., molecular sieves) means.

Prodrugs of this invention where an alcohol function has been derivatized as an ether may be prepared by combining the alcohol with the appropriate alkyl bromide or iodide in the presence of a base such as potassium carbonate in an inert solvent such as dimethylformamide at a temperature of about 0 to 100⁰C for about 1 to about 24 hours. Alkanoylaminomethyl ethers may be obtained by reaction of the alcohol with a bis-(alkanoylamino)methane in the presence of a catalytic amount of acid in an inert solvent such as tetrahydrofuran, according to a method described in US 4,997,984. Alternatively, these compounds may be prepared by the methods described by Hoffman et al. in J. Org. Chem. 1994, 59, 3530.

Glycosides are prepared by reaction of the alcohol and a carbohydrate in an inert solvent such as toluene in the presence of acid. Typically the water formed in the reaction is removed as it is being formed as described above. An alternate procedure is the reaction of the alcohol with a suitably protected glycosyl halide in the presence of base followed by deprotection.

N-(i-hydroxyalkyl) amides, N-(1-hydroxy-1-(alkoxycarbonyl)methyl) amides may be prepared by the reaction of the parent amide with the appropriate aldehyde under neutral or basic conditions (e.g., sodium ethoxide in ethanol) at temperatures between 25 and 70⁰C. N-alkoxymethyl or N-1-(alkoxy)alkyl derivatives can be obtained by reaction of the N-unsubstituted compound with the necessary alkyl halide in the presence of a base in an inert solvent.

The compounds of this invention may also be used in conjunction with other pharmaceutical agents (e.g., LDL-cholesterol lowering agents, triglyceride lowering agents) for the treatment of the disease/conditions described herein. For example, they may be used in combination with a HMG-CoA reductase inhibitor, a cholesterol synthesis inhibitor, a cholesterol absorption inhibitor, another CETP inhibitor, a MTP/Apo B secretion inhibitor, a PPAR modulator and other cholesterol lowering agents such as a fibrate, niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor, and a bile acid sequestrant. Other pharmaceutical agents would also include the following: a bile acid reuptake inhibitor, an ileal bile acid transporter inhibitor, an ACC inhibitor, an antihypertensive (such as NORVASC®), a selective estrogen receptor modulator, a selective androgen receptor modulator, an antibiotic, an antidiabetic (such as metformin, a PPARy activator, a sulfonylurea, insulin, an aldose reductase inhibitor (ARI) and a sorbitol dehydrogenase inhibitor (SDI)), and aspirin (acetylsalicylic acid or a nitric oxide releasing asprin). As used herein, "niacin" includes all available forms such as immediate release, slow release, extended release and low- flushing niacin. Niacin may also be combined with other therapeutic agents such as prostaglandins and/or statins, i.e. lovastatin or simvastatin, which are an HMG-CoA reductase inhibitor and described further below. This combination therapy is known as ADVICOR® (Kos Pharmaceuticals Inc.) In combination therapy treatment, both the compounds of this invention and the other drug therapies are administered to mammals (e.g., humans, male or female) by conventional methods. The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase. Statins inhibit HMG-CoA reductase from catalyzing this conversion. Exemplary statins include lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin, pitavastatin, (3R,5R)-7-(4-(benzylcarbamoyl)-2-(4-fluorophenyl)-5-isopropyl-1 H-imidazol-1 -yl)-3,5- dihydroxyheptanoic acid; (3R,5R)-7-(4-((4-methylbenzyl)cart)amoyl)-2-(4-fluorophenyl)- 5-isopropyl-1H-pyrazol-1-yl)-3,5-dihydroxyheptanoic acid; and (3R,5R)-7-(4-((3- fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5- dihydroxyheptanoic acid, and pharmaceutically acceptable salts thereof. Atorvastatin calcium (i.e., atorvastatin hemicalcium), disclosed in U.S. Patent No.

5,273,995, which is incorporated herein by reference, is currently sold as Lipitor^® and has the formula

Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA. As such, atorvastatin calcium is a potent lipid lowering compound. The free carboxylic acid form of atorvastatin exists predominantly as the lactone of the formula

and is disclosed in U.S. Patent No. 4,681 ,893, which is incorporated herein by reference.

Statins include such compounds as rosuvastatin disclosed in U.S. RE37.314 E, pitivastatin disclosed in EP 304063 B1 and US 5,011 ,930, simvastatin, disclosed in U.S.

4,444,784, which is incorporated herein by reference; pravastatin, disclosed in U.S.

4,346,227 which is incorporated herein by reference; cerivastatin, disclosed in U.S.

5,502,199, which is incorporated herein by reference; mevastatin, disclosed in U.S.

3,983,140, which is incorporated herein by reference; velostatin, disclosed in U.S. 4^48,784 and U.S. 4,450,171 , both of which are incorporated herein by reference; fluvastatin, disclosed in U.S. 4,739,073, which is incorporated herein by reference; compactin, disclosed in U.S. 4,804,770, which is incorporated herein by reference; lovastatin, disclosed in U.S. 4,231 ,938, which is incorporated herein by reference; dalvastatin, disclosed in European Patent Application Publication No. 738510 A2; fluindostatin, disclosed in European Patent Application Publication No. 363934 A1; atorvastatin, disclosed in U.S. Patent No. 4,681 ,893, which is incorporated herein by reference; atorvastatin calcium (which is the hemicalcium salt of atorvastatin), disclosed in U.S. Patent No. 5,273,995, which is incorporated herein by reference; and dihydrocompactin, disclosed in U.S. 4,450,171 , which is incorporated herein by reference. Further HMG CoA reductase inhibitors are disclosed in International Publication

Nos. WO 2005/105079; and PCT/IB2005/003461 filed November 14, 2005 (the disclosures of which are hereby incorporated by reference) including (3R,5R)-7-(4- (benzylcarbamoyl)-2-(4-fluorophenyl)-5-isopropyl-1H-imidazol-1-yl)-3,5- dihydroxyheptanoic acid; (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4- fluorophenyl)-1 H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid; and (3R,5R)-7-(4-((4- methylbenzyl)carbamoyl)-2-(4-fluorophenyl)-5-isopropyl-1H-pyrazol-1-yl)-3,5- dihydroxyheptanoic acid and pharmaceutically acceptable salts of said compounds.

Any PPAR modulator may be used in the combination aspect of this invention. The term PPAR modulator refers to compounds which modulate peroxisome proliferator activator receptor (PPAR) activity in mammals, particularly humans. Such modulation is readily determined by those skilled in the art according to standard assays known in the literature. It is believed that such compounds, by modulating the PPAR receptor, regulate transcription of key genes involved in lipid and glucose metabolism such as those in fatty acid oxidation and also those involved in high density lipoprotein (HDL) assembly (for example, apolipoprotein Al gene transcription), accordingly reducing whole body fat and increasing HDL cholesterol. By virtue of their activity, these compounds also reduce plasma levels of triglycerides, VLDL cholesterol, LDL cholesterol and their associated components such as apolipoprotein B in mammals, particularly humans, as well as increasing HDL cholesterol and apolipoprotein Al. Hence, these compounds are useful for the treatment and correction of the various dyslipidemias observed to be associated with the development and incidence of atherosclerosis and cardiovascular disease, including hypoalphalipoproteinemia and hypertriglyceridemia. A variety of these compounds are described and referenced below, however, others will be known to those skilled in the art. International Publication Nos. WO 2004/048334; WO 2005/092845; and WO 2006/003495 (the disclosures of which are hereby incorporated by reference) disclose certain compounds which are PPARα activators including 3-[3-(1-Carboxy-1-methyl-ethoxy)-phenyl]- piperidine-1-carboxylic acid 3-trifluoromethyl-benzyl ester; 3-[3-(1-Carboxy-1-methyl- ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; 5-[4-(4-Ethyl- benzylsulfanyl)-phenylsulfamoyl]-2-methyl-benzoic acid; and 5-{2-[4-(3,4-Difluoro- phenoxy)-phenyl]-ethylsulfamoyl}-2-methyl-benzoic acid; and pharmaceutically acceptable salts of said compounds.

Any other PPAR modulator may be used in the combination aspect of this invention. In particular, modulators of PPARβ and/or PPARγ may be useful incombination with compounds of the present invention. Exemplary PPAR inhibitors are described in International Publication No. WO 2003/084916 as {5-Methoxy-2-methyl-4- [4-(4-trifluoromethyl-benzyloxy)-benzylsulfany]-phenoxy}-acetic acid and {5-Methoxy-2- methyM-^S-trifluoromethyl-pyridin^-ylJ-benzylsulfanyll-phenoxyl-acetic acid; and pharmaceutically acceptable salts of said compounds.

Any MTP/Apo B (microsomal triglyceride transfer protein and or apolipoprotein B) secretion inhibitor may be used in the combination aspect of this invention. The term MTP/Apo B secretion inhibitor refers to compounds which inhibit the secretion of triglycerides, cholesteryl ester, and phospholipids. Such inhibition is readily determined by those skilled in the art according to standard assays (e.g., Wetterau, J. R. 1992; Science 258:999). A variety of these compounds are described and referenced below however other MTP/Apo B secretion inhibitors will be known to those skilled in the art, including implitapide (Bayer) and additional compounds such as those disclosed in WO 96/40640 and WO 98/23593, (two exemplary publications). For example, the following MTP/Apo B secretion inhibitors are particularly useful:

4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1 H-[1 ,2,4,]triazol-3-ylmethyl)- 1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide;

4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-acetylamino-ethyl)-1 ,2,3,4- tetrahydro-isoquinolin-6-yl]-amide;

(2-{6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin- 2-yl}-ethyl)-carbamic acid methyl ester;

4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(1 H-imidazol-2-ylmethyl)-1 ,2,3,4- tetrahydro-isoquinolin-6-yl]-amide; 4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2,2-diphenyl-ethyl)-1 ,2,3,4- tetrahydro-isoquinolin-6-yl]-amide;

4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-ethoxy-ethyl)-1 ,2,3,4- tetrahydro-isoquinolin-6-yl]-amide; (S)-Λ/-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4^ (trifluoromethyl)[1 , 1 '-biphenyl]-2-carboxamido]-1 H-indole-2-carboxamide;

(S)-2-[(4'-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid (pentylcarbamoyl-phenyl-methyl)-amide; 1H-indole-2-carboxamide,1-methyl-Λ/-[(1S)-2-[methyl(phenylmethyl)amino]-2- oxo-1-phenylethyl]-5-[[[4'-(trifluoromethyl)[1 ,1 '-biphenyl]-2-yl]carbonyl]amino]; and

N-[(1 S)-2-(benzylmethylamino)-2-oxo-1 -phenylethyl]-1 -methyl-5-[[[4'- (trifIuoromethyl)biphenyl-2-yl]carbonyl]amino]-1f/-indole-2-carboxamide.

Any HMG-CoA synthase inhibitor may be used in the combination aspect of this invention. The term HMG-CoA synthase inhibitor refers to compounds which inhibit the biosynthesis of hydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A and acetoacetyl-coenzyme A, catalyzed by the enzyme HMG-CoA synthase. Such inhibition is readily determined by those skilled in the art according to standard assays (Meth Enzymol. 1975; 35:155-160: Meth. Enzymol. 1985; 110:19-26 and references cited therein). A variety of these compounds are described and referenced below, however other HMG-CoA synthase inhibitors will be known to those skilled in the art. U.S. Pat. No. 5,120,729 (the disclosure of which is hereby incorporated by reference) discloses certain beta-lactam derivatives. U.S. Pat. No. 5,064,856 (the disclosure of which is hereby incorporated by reference) discloses certain spiro-lactone derivatives prepared by culturing a microorganism (MF5253). U.S. Pat. No. 4,847,271 (the disclosure of which is hereby incorporated by reference) discloses certain oxetane compounds such as 11-(3-hydroxymethyl-4-oxo-2-oxetayl)-3,5,7-trimethyl-2,4-undeca-dienoic acid derivatives.

Any compound that decreases HMG-CoA reductase gene expression may be used in the combination aspect of this invention. These agents may be HMG-CoA reductase transcription inhibitors that block the transcription of DNA or translation inhibitors that prevent or decrease translation of mRNA coding for HMG-CoA reductase into protein. Such compounds may either affect transcription or translation directly, or may be biotransformed to compounds that have the aforementioned activities by one or more enzymes in the cholesterol biosynthetic cascade or may lead to the accumulation of an isoprene metabolite that has the aforementioned activities. Such compounds may cause this effect by decreasing levels of SREBP (sterol receptor binding protein) by inhibiting the activity of site-1 protease (S 1 P) or agonizing the oxzgenal receptor or SCAP. Such regulation is readily determined by those skilled in the art according to standard assays (Meth. Enzymol. 1985; 110:9-19). Several compounds are described and referenced below, however other inhibitors of HMG-CoA reductase gene expression will be known to those skilled in the art. U.S. Pat. No. 5,041 ,432 (the disclosure of which is incorporated by reference) discloses certain 15-substituted lanosterol derivatives. Other oxygenated sterols that suppress synthesis of HMG-CoA reductase are discussed by E.I. Mercer (Prog.Lip. Res. 1993;32:357-416).

Any additional compound having activity as a CETP inhibitor can serve as the second compound in the combination therapy aspect of the present invention. The term CETP inhibitor refers to compounds that inhibit the cholesteryl ester transfer protein (CETP) mediated transport of various cholesteryl esters and triglycerides from HDL to LDL and VLDL. Such CETP inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., U.S. Pat. No. 6,140,343). A variety of CETP inhibitors will be known to those skilled in the art, for example, those disclosed in commonly assigned U.S. Patent Number 6,140,343 and commonly assigned U.S. Patent Numbers 6,197,786 and 6,723,752. CETP inhibitors disclosed in these patents include compounds, such as (2R)-3-{[3-(4-Chloro-3-ethyl-phenoxy)-phenyl]-[[3-(1₁1,2,2- tetrafluoro-ethoxy)-phenyl]-methyl]-amino}-1 ,1 ,1-trifluoro-2-propanol Moreover, CETP inhibitors included herein are also described in WO 2006/014357; WO 2006/014413; and WO2007/079186. U.S. Patent Number 5,512,548 discloses certain polypeptide derivatives having activity as CETP inhibitors, while certain CETP-inhibitory rosenonolactone derivatives and phosphate-containing analogs of cholesteryl ester are disclosed in J. Antibiot., 49(8): 815-816 (1996), and Bioorg. Med. Chem. Lett.; 6:1951- 1954 (1996), respectively.

Exemplary CETP inhibitors include cis-(2R,4S)- 2-(4-{4-[(3,5-Bis-trifluoromethyl- benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydiO-2H- quinoline-1 -carbonyl}-cyclohexyl)-acetamide; and (2R)-3-{[3-(4-Chloro-3-ethyl- phenoxy)-phenyl]-[[3-(1 ,1 ,2,2-tetrafluoro-ethoxy)-phenyl]-methyl]-amino}-1 ,1 ,1-trifluoro- 2-propanol or a pharmaceutically acceptable salt of said compounds. JT and Merck compounds ??? Any squalene synthetase inhibitor may be used in the combination aspect of this invention. The term squalene synthetase inhibitor refers to compounds which inhibit the condensation of 2 molecules of farnesylpyrophosphate to form squalene, catalyzed by the enzyme squalene synthetase. Such inhibition is readily determined by those skilled in the art according to standard assays (Meth. Enzymol. 1969; 15: 393-454 and Meth. Enzymol. 1985; 110:359-373 and references contained therein). A variety of these compounds are described in and referenced below however other squalene synthetase inhibitors will be known to those skilled in the art. U.S. Pat. No. 5,026,554 (the disclosure of which is incorporated by reference) discloses fermentation products of the microorganism MF5465 (ATCC 74011 ) including zaragozic acid. A summary of other patented squalene synthetase inhibitors has been compiled (Curr. Op. Then Patents (1993) 861-4).

Any squalene epoxidase inhibitor may be used in the combination aspect of this invention. The term squalene epoxidase inhibitor refers to compounds which inhibit the byconversion of squalene and molecular oxygen into squalene-2,3-epoxide, catalyzed by the enzyme squalene epoxidase. Such inhibition is readily determined by those skilled in the art according to standard assays (Biochim. Biophys. Acta 1984; 794:466-471 ). A variety of these compounds are described and referenced below, however other squalene epoxidase inhibitors will be known to those skilled in the art. U.S. Pat. Nos. 5,011 ,859 and 5,064,864 (the disclosures of which are incorporated by reference) disclose certain fluoro analogs of squalene. EP publication 395,768 A (the disclosure of which is incorporated by reference) discloses certain substituted allylamine derivatives. PCT publication WO 9312069 A (the disclosure of which is hereby incorporated by reference) discloses certain amino alcohol derivatives. U.S. Pat. No. 5,051 ,534 (the disclosure of which is hereby incorporated by reference) discloses certain cyclopropyloxy-squalene derivatives.

Any squalene cyclase inhibitor may be used as the second component in the combination aspect of this invention. The term squalene cyclase inhibitor refers to compounds which inhibit the bioconversion of squalene-2,3-epoxide to ianosterol, catalyzed by the enzyme squalene cyclase. Such inhibition is readily determined by those skilled in the art according to standard assays (FEBS Lett. 1989;244:347-350.). In addition, the compounds described and referenced below are squalene cyclase inhibitors, however other squalene cyclase inhibitors will also be known to those skilled in the art. PCT publication WO9410150 (the disclosure of which is hereby incorporated by reference) discloses certain 1 ,2,3,5_I6,7_I8,8a-octahydro-5,5,8(beta)-trimethyl-6- isoquinolineamine derivatives, such as N-trifluoroacetyl-1 ,2,3,5,6,7,8, 8a-octahydro-2- allyl-5,5,8(beta)-trimethyl-6(beta)-isoquinolineamine. French patent publication 2697250 (the disclosure of which is hereby incorporated by reference) discloses certain beta, beta-dimethyl-4-piperidine ethanol derivatives such as 1-(1 ,5,9-trimethyldecyl)- beta,beta-dimethyl-4-piperidineethanol

Any combined squalene epoxidase/squalene cyclase inhibitor may be used as the second component in the combination aspect of this invention. The term combined squalene epoxidase/squalene cyclase inhibitor refers to compounds that inhibit the byconversion of squalene to lanosterol via a squalene-2,3-epoxide intermediate. In some assays it is not possible to distinguish between squalene epoxidase inhibitors and squalene cyclase inhibitors, however, these assays are recognized by those skilled in the art. Thus, inhibition by combined squalene epoxidase/squalene cyclase inhibitors is readily determined by those skilled in art according to the aforementioned standard assays for squalene cyclase or squalene epoxidase inhibitors. A variety of these compounds are described and referenced below, however other squalene epoxidase/squalene cyclase inhibitors will be known to those skilled in the art. U.S. Pat. Nos. 5,084,461 and 5,278,171 (the disclosures of which are incorporated by reference) disclose certain azadecalin derivatives. EP publication 468,434 (the disclosure of which is incorporated by reference) discloses certain piperidyl ether and thio-ether derivatives such as 2-(1-piperidyl)pentyl isopentyl sulfoxide and 2-(1-piperidyl)ethyl ethyl sulfide. PCT publication WO 9401404 (the disclosure of which is hereby incorporated by reference) discloses certain acyl-piperidines such as 1-(1-oxopentyl-5-phenylthio)-4-(2- hydroxy-1-methyl)-ethyl)piperidine. U.S. Pat. No. 5,102,915 (the disclosure of which is hereby incorporated by reference) discloses certain cyclopropyloxy-squalene derivatives.

The compounds of the present invention may also be administered in combination with naturally occurring compounds that act to lower plasma cholesterol levels. These naturally occurring compounds are commonly called nutraceuticals and include, for example, garlic extract and niacin. A slow-release form of niacin is available and is known as Niaspan. Niacin may also be combined with other therapeutic agents such as lovastatin, or another is an HMG-CoA reductase inhibitor. This combination therapy with lovastatin is known as ADVICOR™ (Kos Pharmaceuticals Inc.). Any cholesterol absorption inhibitor can be used as an additional in the combination aspect of the present invention. The term cholesterol absorption inhibition refers to the ability of a compound to prevent cholesterol contained within the lumen of the intestine from entering into the intestinal cells and/or passing from within the intestinal cells into the lymph system and/or into the blood stream. Such cholesterol absorption inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., J. Lipid Res. (1993) 34: 377-395). Cholesterol absorption inhibitors are known to those skilled in the art and are described, for example, in PCT WO 94/00480. An example of a recently approved cholesterol absorption inhibitor is ZETIA ™ (ezetimibe) (Schering-Plough/Merck).

Any ACAT inhibitor may be used in the combination therapy aspect of the present invention. The term ACAT inhibitor refers to compounds that inhibit the intracellular esterification of dietary cholesterol by the enzyme acyl CoA: cholesterol acyltransferase. Such inhibition may be determined readily by one of skill in the art according to standard assays, such as the method of Heider et al. described in Journal of Lipid Research., 24:1127 (1983). A variety of these compounds are known to those skilled in the art, for example, U.S. Patent No. 5,510,379 discloses certain carboxysulfonates, while WO 96/26948 and WO 96/10559 both disclose urea derivatives having ACAT inhibitory activity. Examples of ACAT inhibitors include compounds such as Avasimibe (Pfizer), CS-505 (Sankyo) and Eflucimibe (EIi Lilly and Pierre Fabre).

A lipase inhibitor may be used in the combination therapy aspect of the present invention. A lipase inhibitor is a compound that inhibits the metabolic cleavage of dietary triglycerides or plasma phospholipids into free fatty acids and the corresponding glycerides (e.g. EL, HL, etc.). Under normal physiological conditions, lipolysis occurs via a two-step process that involves acylation of an activated serine moiety of the lipase enzyme. This leads to the production of a fatty acid-lipase hemiacetal intermediate, which is then cleaved to release a diglyceride. Following further deacylation, the lipase- fatty acid intermediate is cleaved, resulting in free lipase, a glyceride and fatty acid. In the intestine, the resultant free fatty acids and monoglycerides are incorporated into bile acid-phospholipid micelles, which are subsequently absorbed at the level of the brush border of the small intestine. The micelles eventually enter the peripheral circulation as chylomicrons. Such lipase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. 286: 190- 231).

Pancreatic lipase mediates the metabolic cleavage of fatty acids from triglycerides at the 1- and 3-carbon positions. The primary site of the metabolism of ingested fats is in the duodenum and proximal jejunum by pancreatic lipase, which is usually secreted in vast excess of the amounts necessary for the breakdown of fats in the upper small intestine. Because pancreatic lipase is the primary enzyme required for the absorption of dietary triglycerides, inhibitors have utility in the treatment of obesity and the other related conditions. Such pancreatic lipase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. 286: 190-231).

Gastric lipase is an immunologically distinct lipase that is responsible for approximately 10 to 40% of the digestion of dietary fats. Gastric lipase is secreted in response to mechanical stimulation, ingestion of food, the presence of a fatty meal or by sympathetic agents. Gastric lipolysis of ingested fats is of physiological importance in the provision of fatty acids needed to trigger pancreatic lipase activity in the intestine and is also of importance for fat absorption in a variety of physiological and pathological conditions associated with pancreatic insufficiency. See, for example, CK. Abrams, et al., Gastroenterology, 92,125 (1987). Such gastric lipase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. 286: 190-231).

A variety of gastric and/or pancreatic lipase inhibitors are known to one of ordinary skill in the art. Preferred lipase inhibitors are those inhibitors that are selected from the group consisting of lipstatin, tetrahydrolipstatin (orlistat), valilactone, esterastin, ebelactone A, and ebelactone B. The compound tetrahydrolipstatin is especially preferred. The lipase inhibitor, N-3-trifluoromethylphenyl-N'-3-chloro-4'- trifluoromethylphenylurea, and the various urea derivatives related thereto, are disclosed in U.S. Patent No. 4,405,644. The lipase inhibitor, esteracin, is disclosed in U.S. Patent Nos. 4,189,438 and 4,242,453. The lipase inhibitor, cyclo-O,O'-[(1 ,6- hexanediyl)-bis-(iminocarbonyl)]dioxime, and the various bis(iminocarbonyl)dioximes related thereto may be prepared as described in Petersen et al., Liebig's Annalen, 562, 205-229 (1949).

A variety of pancreatic lipase inhibitors are described herein below. The pancreatic lipase inhibitors lipstatin, (2S, 3S, 5S, 7Z, 10Z)-5-[(S)-2-formamido-4- methyl-valeryloxy]-2-hexyl-3-hydroxy-7,10-hexadecanoic acid lactone, and tetrahydrolipstatin (orlistat), (2S, 3S, 5S)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2- hexyl-3-hydroxy-hexadecanoic 1 ,3 acid lactone, and the variously substituted N- formylleucine derivatives and stereoisomers thereof, are disclosed in U.S. Patent No. 4,598,089. For example, tetrahydrolipstatin is prepared as described in, e.g., U.S. Patent Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874. The pancreatic lipase inhibitor, FL-386, 1 -[4-(2-methylpropyl)cyclohexyl]-2-[(phenylsulfonyl)oxy]-ethanone, and the variously substituted sulfonate derivatives related thereto, are disclosed in U.S. Patent No. 4,452,813. The pancreatic lipase inhibitor, WAY-121898, 4-phenoxyphenyl- 4-methylpiperidin-1-yl-carboxylate, and the various carbamate esters and pharmaceutically acceptable salts related thereto, are disclosed in U.S. Patent Nos. 5,512,565; 5,391,571 and 5,602,151. The pancreatic lipase inhibitor, valilactone, and a process for the preparation thereof by the microbial cultivation of Actinomycetes strain MG147-CF2, are disclosed in Kitahara, et al., J. Antibiotics, 40 (11), 1647-1650 (1987). The pancreatic lipase inhibitors, ebelactone A and ebelactone B, and a process for the preparation thereof by the microbial cultivation of Actinomycetes strain MG7-G1 , are disclosed in Umezawa, et al., J. Antibiotics, 33, 1594-1596 (1980). The use of ebelactones A and B in the suppression of monoglyceride formation is disclosed in Japanese Kokai 08-143457, published June 4, 1996.

Other compounds that are marketed for hyperlipidemia, including hypercholesterolemia and which are intended to help prevent or treat atherosclerosis include bile acid sequestrants, such as Welchol^®, Colestid^®, LoCholest^® and Questran^®; and fibric acid derivatives, such as Atromid^®, Lopid^® and Tricor^®.

Diabetes can be treated by administering to a patient having diabetes (especially Type II), insulin resistance, impaired glucose tolerance, metabolic syndrome, or the like, or any of the diabetic complications such as neuropathy, nephropathy, retinopathy or cataracts, a therapeutically effective amount of a compound of the present invention in combination with other agents (e.g., insulin) that can be used to treat diabetes. This includes the classes of anti-diabetic agents (and specific agents) described herein. Any glycogen phosphorylase inhibitor can be used as the second agent in combination with a compound of the present invention. The term glycogen phosphorylase inhibitor refers to compounds that inhibit the byconversion of glycogen to glucose-1 -phosphate which is catalyzed by the enzyme glycogen phosphorylase. Such glycogen phosphorylase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., J. Med. Chem. 41 (1998) 2934-2938). A variety of glycogen phosphorylase inhibitors are known to those skilled in the art including those described in WO 96/39384 and WO 96/39385.

Any aldose reductase inhibitor can be used in combination with a compound of the present invention. The term aldose reductase inhibitor refers to compounds that inhibit the bioconversion of glucose to sorbitol, which is catalyzed by the enzyme aldose reductase. Aldose reductase inhibition is readily determined by those skilled in the art according to standard assays (e.g., J. Malone, Diabetes, 29:861-864 (1980). "Red Cell Sorbitol, an Indicator of Diabetic Control"). A variety of aldose reductase inhibitors are known to those skilled in the art, such as those described in U.S. Patent No. 6,579,879, which includes 6-(5-chloro-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one.

Any sorbitol dehydrogenase inhibitor can be used in combination with a compound of the present invention. The term sorbitol dehydrogenase inhibitor refers to compounds that inhibit the bioconversion of sorbitol to fructose which is catalyzed by the enzyme sorbitol dehydrogenase. Such sorbitol dehydrogenase inhibitor activity is readily determined by those skilled in the art according to standard assays (e.g., Analyt. Biochem (2000) 280: 329-331 ). A variety of sorbitol dehydrogenase inhibitors are known, for example, U.S. Patent Nos. 5,728,704 and 5,866,578 disclose compounds and a method for treating or preventing diabetic complications by inhibiting the enzyme sorbitol dehydrogenase. Any glucosidase inhibitor can be used in combination with a compound of the present invention. A glucosidase inhibitor inhibits the enzymatic hydrolysis of complex carbohydrates by glycoside hydrolases, for example amylase or maltase, into bioavailable simple sugars, for example, glucose. The rapid metabolic action of glucosidases, particularly following the intake of high levels of carbohydrates, results in a state of alimentary hyperglycemia which, in adipose or diabetic subjects, leads to enhanced secretion of insulin, increased fat synthesis and a reduction in fat degradation. Following such hyperglycemias, hypoglycemia frequently occurs, due to the augmented levels of insulin present. Additionally, it is known chyme remaining in the stomach promotes the production of gastric juice, which initiates or favors the development of gastritis or duodenal ulcers. Accordingly, glucosidase inhibitors are known to have utility in accelerating the passage of carbohydrates through the stomach and inhibiting the absorption of glucose from the intestine. Furthermore, the conversion of carbohydrates into lipids of the fatty tissue and the subsequent incorporation of alimentary fat into fatty tissue deposits is accordingly reduced or delayed, with the concomitant benefit of reducing or preventing the deleterious abnormalities resulting therefrom. Such glucosidase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Biochemistry (1969) 8: 4214).

A generally preferred glucosidase inhibitor includes an amylase inhibitor. An amylase inhibitor is a glucosidase inhibitor that inhibits the enzymatic degradation of starch or glycogen into maltose. Such amylase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., Methods Enzymol. (1955) 1 : 149). The inhibition of such enzymatic degradation is beneficial in reducing amounts of bioavailable sugars, including glucose and maltose, and the concomitant deleterious conditions resulting therefrom.

A variety of glucosidase inhibitors are known to one of ordinary skill in the art and examples are provided below. Preferred glucosidase inhibitors are those inhibitors that are selected from the group consisting of acarbose, adiposine, voglibose, miglitol, emiglitate, camiglibose, tendamistate, trestatin, pradimicin-Q and salbostatin. The glucosidase inhibitor, acarbose, and the various amino sugar derivatives related thereto are disclosed in U.S. Patent Nos. 4,062,950 and 4,174,439 respectively. The glucosidase inhibitor, adiposine, is disclosed in U.S. Patent No. 4,254,256. The glucosidase inhibitor, voglibose, 3,4-dideoxy-4-[[2-hydroxy-1- (hydroxymethyl)ethyl]amino]-2-C-(hydroxymethyl)-D-epi-inositol, and the various N- substituted pseudo-aminosugars related thereto, are disclosed in U.S. Patent No. 4,701,559. The glucosidase inhibitor, miglitol, (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2- (hydroxymethyl)-3 A5-piperidinetriol, and the various 3,4,5-trihydroxypiperidines related thereto, are disclosed in U.S. Patent No. 4,639,436. The glucosidase inhibitor, emiglitate, ethyl p-[2-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2- (hydroxymethyl)piperidino]ethoxy]-benzoate, the various derivatives related thereto and pharmaceutically acceptable acid addition salts thereof, are disclosed in U.S. Patent No. 5,192,772. The glucosidase inhibitor, MDL-25637, 2,6-dideoxy-7-O-β-D- glucopyrano-syl^.β-imino-D-glycero-L-gluco-heptitol, the various homodisaccharides related thereto and the pharmaceutically acceptable acid addition salts thereof, are disclosed in U.S. Patent No. 4,634,765. The glucosidase inhibitor, camiglibose, methyl 6-deoxy-6-[(2R_>3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidino]-α-D- glucopyranoside sesquihydrate, the deoxy-nojirimycin derivatives related thereto, the various pharmaceutically acceptable salts thereof and synthetic methods for the preparation thereof, are disclosed in U.S. Patent Nos. 5,157,116 and 5,504,078. The glycosidase inhibitor, salbostatin and the various pseudosaccharides related thereto, are disclosed in U.S. Patent No. 5,091 ,524.

A variety of amylase inhibitors are known to one of ordinary skill in the art. The amylase inhibitor, tendamistat and the various cyclic peptides related thereto, are disclosed in U.S. Patent No. 4,451 ,455. The amylase inhibitor AI-3688 and the various cyclic polypeptides related thereto are disclosed in U.S. Patent No. 4,623,714. The amylase inhibitor, trestatin, consisting of a mixture of trestatin A, trestatin B and trestatin C and the various trehalose-containing aminosugars related thereto are disclosed in U.S. Patent No. 4,273,765. Additional anti-diabetic compounds, which can be used as the second agent in combination with a compound of the present invention, include, for example, the following: biguanides (e.g., metformin), insulin secretagogues (e.g., sulfonylureas and glinides), glitazones, non-glitazone PPARy agonists, PPARβ agonists, inhibitors of DPP-IV, inhibitors of PDE5, inhibitors of GSK-3, glucagon antagonists, inhibitors of f- 1 ,6-BPase(Metabasis/Sankyo), GLP-1 /analogs (AC 2993, also known as exendin-4), insulin and insulin mimetics (Merck natural products). Other examples would include PKC-β inhibitors and AGE breakers.

The compounds of the present invention can be used in combination with anti- obesity agents. Any anti-obesity agent can be used as the second agent in such combinations and examples are provided herein. Such anti-obesity activity is readily determined by those skilled in the art according to standard assays known in the art.

Suitable anti-obesity agents include phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, β₃ adrenergic receptor agonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (e.g., sibutramine), sympathomimetic agents, serotoninergic agents, cannabinoid receptor (CB-1 ) antagonists (e.g., rimonabant described in U.S. Pat. No. 5,624,941 (SR- 141,716A), purine compounds, such as those described in US Patent Publication No. 2004/0092520; pyrazolo[1 ,5-a][1 ,3,5]triazine compounds, such as those described in US Non-Provisional Patent Application No.10/763105 filed on January 21 , 2004; and bicyclic pyrazolyl and imidazolyl compounds, such as those described in U.S. Provisional Application No. 60/518280 filed on November 7, 2003), dopamine agonists (e.g., bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors (e.g., tetrahydrolipstatin, i.e. orlistat), bombesin agonists, anorectic agents (e.g., a bombesin agonist), Neuropeptide-Y antagonists, thyroxine, thyromimetic agents, dehydroepiandrosterones or analogs thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors (e.g., Axokine™), human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, neuromedin U receptor agonists, and the like.

Rimonabant (SR141716A also known under the tradename Accomplia™ available from Sanofi-Synthelabo) can be prepared as described in U.S. Patent No. 5,624,941. Other suitable CB-1 antagonists include those described in U.S. Patent Nos. 5,747,524, 6,432,984 and 6,518,264; U.S. Patent Publication Nos. US2004/0092520, US2004/0157839, US2004/0214855, and US2004/0214838; U.S. Patent Application Serial No. 10/971599 filed on October 22, 2004; and PCT Patent Publication Nos. WO 02/076949, WO 03/075660, WO04/048317, WO04/013120, and WO 04/012671.

Preferred apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors for use as anti-obesity agents are gut-selective MTP inhibitors, such as dirlotapide described in U.S. Patent No. 6,720,351; 4-(4-(4-(4-((2-((4-methyl- 4H-1 ,2,4-triazol-3-ylthio)methyl)-2-(4-chlorophenyl)-1 ,3-dioxolan-4- yl)methoxy)phenyl)piperazin-1-yl)phenyl)-2-sec-butyl-2H-1,2,4-triazol-3(4H)-one (R103757) described in U.S. Patent Nos. 5,521,186 and 5,929,075; and implitapide (BAY 13-9952) described in U.S. Patent No. 6,265,431. As used herein, the term "gut- selective" means that the MTP inhibitor has a higher exposure to the gastro-intestinal tissues versus systemic exposure.

Any thyromimetic can be used as the second agent in combination with a compound of the present invention. Such thyromimetic activity is readily determined by those skilled in the art according to standard assays (e.g., Atherosclerosis (1996) 126: 53-63). A variety of thyromimetic agents are known to those skilled in the art, for example those disclosed in U.S. Patent Nos. 4,766,121 ; 4,826,876; 4,910,305;

5,061 ,798; 5,284,971 ; 5,401,772; 5,654,468; and 5,569,674. Other antiobesity agents include sibutramine which can be prepared as described in U.S. Patent No. 4,929,629. and bromocriptine which can be prepared as described in U.S. Patent Nos. 3,752,814 and 3,752,888. The compounds of the present invention can also be used in combination with other antihypertensive agents. Any anti-hypertensive agent can be used as the second agent in such combinations and examples are provided herein. Such antihypertensive activity is readily determined by those skilled in the art according to standard assays (e.g., blood pressure measurements). Examples of presently marketed products containing antihypertensive agents include calcium channel blockers, such as Cardizem^®, Adalat^®, Calan^®, Cardene^®, Covera^®, Dilacor^®, DynaCirc^®' Procardia XL^®, Sular^®, Tiazac^®, Vascor^®, Verelan^®, Isoptin^®, Nimotop^®' Norvasc^®, and Plendil^®; angiotensin converting enzyme (ACE) inhibitors, such as Accupril^®, Altace^®, Captopril^®, Lotensin^®, Mavik^®, Monopril^®, Prinivil^®, Univasc^®, Vasotec^® and Zestril^®.

Amlodipine and related dihydropyridine compounds are disclosed in U.S. Patent No. 4,572,909, which is incorporated herein by reference, as potent anti-ischemic and antihypertensive agents. U.S. Patent No.4,879,303, which is incorporated herein by reference, discloses amlodipine benzenesulfonate salt (also termed amlodipine besylate). Amlodipine and amlodipine besylate are potent and long lasting calcium channel blockers. As such, amlodipine, amlodipine besylate, amlodipine maleate and other pharmaceutically acceptable acid addition salts of amlodipine have utility as antihypertensive agents and as antiischemic agents. Amlodipine besylate is currently sold as Norvasc^®. Amlodipine has the formula

Calcium channel blockers which are within the scope of this invention include, but are not limited to: bepridil, which may be prepared as disclosed in U.S. Patent No. 3,962, 238 or U.S. Reissue No. 30,577; clentiazem, which may be prepared as disclosed in U.S. Patent No. 4,567,175; diltiazem, which may be prepared as disclosed in U.S. Patent No. 3,562, fendiline, which may be prepared as disclosed in U.S. Patent No. 3,262,977; gallopamil, which may be prepared as disclosed in U.S. Patent No. 3,261 ,859; mibefradil, which may be prepared as disclosed in U.S. Patent No. 4,808,605; prenylamine, which may be prepared as disclosed in U.S. Patent No. 3,152,173; semotiadil, which may be prepared as disclosed in U.S. Patent No. 4,786,635; terodiline, which may be prepared as disclosed in U.S. Patent No. 3,371,014; verapamil, which may be prepared as disclosed in U.S. Patent No. 3,261,859; aranipine, which may be prepared as disclosed in U.S. Patent No.

4,572,909; barnidipine, which may be prepared as disclosed in U.S. Patent No.

4,220,649; benidipine, which may be prepared as disclosed in European Patent

Application Publication No. 106,275; cilnidipine, which may be prepared as disclosed in U.S. Patent No. 4,672,068; efonidipine, which may be prepared as disclosed in U.S.

Patent No.4,885,284; elgodipine, which may be prepared as disclosed in U.S. Patent

No. 4,952,592; felodipine, which may be prepared as disclosed in U.S. Patent No.

4,264,611; isradipine, which may be prepared as disclosed in U.S. Patent No.

4,466,972; lacidipine, which may be prepared as disclosed in U.S. Patent No. 4,801 ,599; lercanidipine, which may be prepared as disclosed in U.S. Patent No.

4,705,797; manidipine, which may be prepared as disclosed in U.S. Patent No.

4,892,875; nicardipine, which may be prepared as disclosed in U.S. Patent No.

3,985,758; nifedipine, which may be prepared as disclosed in U.S. Patent No.

3,485,847; nilvadipine, which may be prepared as disclosed in U.S. Patent No. 4,338,322; nimodipine, which may be prepared as disclosed in U.S. Patent No.

3,799,934; nisoldipine, which may be prepared as disclosed in U.S. Patent No.

4,154,839; nitrendipine, which may be prepared as disclosed in U.S. Patent No.

3,799,934; cinnarizine, which may be prepared as disclosed in U.S. Patent No.

2,882,271; flunarizine, which may be prepared as disclosed in U.S. Patent No. 3,773,939; lidoflazine, which may be prepared as disclosed in U.S. Patent No.

3,267,104; lomerizine, which may be prepared as disclosed in U.S. Patent No.

4,663,325; bencyclane, which may be prepared as disclosed in Hungarian Patent No.

151,865; etafenone, which may be prepared as disclosed in German Patent No.

1,265,758; and perhexiline, which may be prepared as disclosed in British Patent No. 1 ,025,578. The disclosures of all such U.S. Patents are incorporated herein by reference.

Angiotensin Converting Enzyme Inhibitors (ACE-lnhibitors) which are within the scope of this invention include, but are not limited to: alacepril, which may be prepared as disclosed in U.S. Patent No. 4,248,883; benazepril, which may be prepared as disclosed in U.S. Patent No. 4,410,520; captopril, which may be prepared as disclosed in U.S. Patent Nos. 4,046,889 and 4,105,776; ceronapril, which may be prepared as disclosed in U.S. Patent No. 4,452,790; delapril, which may be prepared as disclosed in

U.S. Patent No. 4,385,051 ; enalapril, which may be prepared as disclosed in U.S.

Patent No. 4,374,829; fosinopril, which may be prepared as disclosed in U.S. Patent No. 4,337,201; imadapril, which may be prepared as disclosed in U.S. Patent No. 4,508,727; lisinopril, which may be prepared as disclosed in U.S. Patent No. 4,555,502; moveltopril, which may be prepared as disclosed in Belgian Patent No. 893,553; perindopril, which may be prepared as disclosed in U.S. Patent No. 4,508,729; quinapril, which may be prepared as disclosed in U.S. Patent No. 4,344,949; ramipril, which may be prepared as disclosed in U.S. Patent No. 4,587,258; spirapril, which may be prepared as disclosed in U.S. Patent No. 4,470,972; temocapril, which may be prepared as disclosed in U.S. Patent No. 4,699,905; and trandolapril, which may be prepared as disclosed in U.S. Patent No. 4,933,361. The disclosures of all such U.S. patents are incorporated herein by reference.

Angiotensin-ll receptor antagonists (A-Il antagonists) which are within the scope of this invention include, but are not limited to: candesartan, which may be prepared as disclosed in U.S. Patent No. 5,196,444; eprosartan, which may be prepared as disclosed in U.S. Patent No. 5,185,351; irbesartan, which may be prepared as disclosed in U.S. Patent No. 5,270,317; losartan, which may be prepared as disclosed in U.S. Patent No. 5,138,069; olmesartan and/or olmesartan medoxomil, which may be prepared as disclosed in U.S. Patent No. 5,616,599; and valsartan, which may be prepared as disclosed in U.S. Patent No. 5,399,578. The disclosures of all such U.S. patents are incorporated herein by reference. Phosphodiesterase type 5 inhibitors (PDE5 inhibitors) which are within the scope of this invention include, but are not limited to: sildenafil, which may be prepared as disclosed in U.S. Patent No. 5,250,534; and the PDE5 inhibitors disclosed in International Publication Numbers: WO2004096810, WO2005049616, WO2005049617, WO2006120552, WO 2007054778, and EP1348707. Factor Xa inhibitors which are within the scope of this invention include, but are not limited to: Apixaban, which may be prepared as disclosed in U.S. Patent Nos. 6,967,208 and 6,413,980; Rivaroxaban, which may be prepared as disclosed in International Publication No. WO2001047919; and LY-517717.

Beta-adrenergic receptor blockers (beta- or β-blockers) which are within the scope of this invention include, but are not limited to: acebutolol, which may be prepared as disclosed in U.S. Patent No. 3,857,952; alprenolol, which may be prepared as disclosed in Netherlands Patent Application No. 6,605,692; amosulalol, which may be prepared as disclosed in U.S. Patent No. 4,217,305; arotinolol, which may be prepared as disclosed in U.S. Patent No. 3,932,400; atenolol, which may be prepared as disclosed in U.S. Patent No. 3,663,607 or 3,836,671 ; befunolol, which may be prepared as disclosed in U.S. Patent No. 3,853,923; betaxolol, which may be prepared as disclosed in U.S. Patent No. 4,252,984; bevantolol, which may be prepared as disclosed in U.S. Patent No. 3,857,981; bisoprolol, which may be prepared as disclosed in U.S. Patent No. 4,171 ,370; bopindolol, which may be prepared as disclosed in U.S. Patent No. 4,340,541 ; bucumolol, which may be prepared as disclosed in U.S. Patent No. 3,663,570; bufetolol, which may be prepared as disclosed in U.S. Patent No. 3,723,476; bufuralol, which may be prepared as disclosed in U.S. Patent No. 3,929,836; bunitrolol, which may be prepared as disclosed in U.S. Patent Nos. 3,940,489 and 3,961 ,071 ; buprandolol, which may be prepared as disclosed in U.S. Patent No. 3,309,406; butiridine hydrochloride, which may be prepared as disclosed in French Patent No. 1 ,390,056; butofilolol, which may be prepared as disclosed in U.S. Patent No. 4,252,825; carazolol, which may be prepared as disclosed in German Patent No. 2,240,599; carteolol, which may be prepared as disclosed in U.S. Patent No. 3,910,924; carvedilol, which may be prepared as disclosed in U.S. Patent No. 4,503,067; celiprolol, which may be prepared as disclosed in U.S. Patent No. 4,034,009; cetamolol, which may be prepared as disclosed in U.S. Patent No. 4,059,622; cloranolol, which may be prepared as disclosed in German Patent No. 2,213,044; dilevalol, which may be prepared as disclosed in Clifton et al., Journal of Medicinal Chemistry, 1982, 25, 670; epanolol, which may be prepared as disclosed in European Patent Publication

Application No. 41,491; indenolol, which may be prepared as disclosed in U.S. Patent No. 4,045,482; labetalol, which may be prepared as disclosed in U.S. Patent No. 4,012,444; levobunolol, which may be prepared as disclosed in U.S. Patent No. 4,463,176; mepindolol, which may be prepared as disclosed in Seeman et al., HeIv. Chim. Acta, 1971. 54. 241 ; metipranolol, which may be prepared as disclosed in

Czechoslovakian Patent Application No. 128,471 ; metoprolol, which may be prepared as disclosed in U.S. Patent No. 3,873,600; moprolol, which may be prepared as disclosed in U.S. Patent No. 3,501 ,7691; nadolol, which may be prepared as disclosed in U.S. Patent No. 3,935, 267; nadoxolol, which may be prepared as disclosed in U.S. Patent No. 3,819,702; nebivalol, which may be prepared as disclosed in U.S. Patent No. 4,654,362; nipradilol, which may be prepared as disclosed in U.S. Patent No. 4,394,382; oxprenolol, which may be prepared as disclosed in British Patent No. 1,077,603; perbutolol, which may be prepared as disclosed in U.S. Patent No. 3,551 ,493; pindolol, which may be prepared as disclosed in Swiss Patent Nos. 469,002 and 472,404; practolol, which may be prepared as disclosed in U.S. Patent No. 3,408,387; pronethalol, which may be prepared as disclosed in British Patent No. 909,357; propranolol, which may be prepared as disclosed in U.S. Patent Nos. 3,337,628 and 3,520,919; sotalol, which may be prepared as disclosed in Uloth et al., Journal of Medicinal Chemistry, 1966. 9, 88; sufinalol, which may be prepared as disclosed in German Patent No. 2,728,641; talindol, which may be prepared as disclosed in U.S. Patent Nos. 3,935,259 and 4,038,313; tertatolol, which may be prepared as disclosed in U.S. Patent No. 3,960,891; tilisolol, which may be prepared as disclosed in U.S. Patent No. 4,129,565; timolol, which may be prepared as disclosed in U.S. Patent No. 3,655,663; toliprolol, which may be prepared as disclosed in U.S. Patent No. 3,432,545; and xibenolol, which may be prepared as disclosed in U.S. Patent No. 4,018,824. The disclosures of all such U.S. patents are incorporated herein by reference.

Alpha-adrenergic receptor blockers (alpha- or α-blockers) which are within the scope of this invention include, but are not limited to: amosulalol, which may be prepared as disclosed in U.S. Patent No. 4,217,307; arotinolol, which may be prepared as disclosed in U.S. Patent No. 3,932,400; dapiprazole, which may be prepared as disclosed in U.S. Patent No. 4,252,721; doxazosin, which may be prepared as disclosed in U.S. Patent No. 4,188,390; fenspiride, which may be prepared as disclosed in U.S. Patent No. 3,399,192; indoramin, which may be prepared as disclosed in U.S. Patent No. 3,527,761 ; labetolol; naftopidil, which may be prepared as disclosed in U.S. Patent No. 3,997,666; nicergoline, which may be prepared as disclosed in U.S. Patent No. 3,228,943; prazosin, which may be prepared as disclosed in U.S. Patent No. 3,511,836; tamsulosin, which may be prepared as disclosed in U.S. Patent No. 4,703,063; tolazoline, which may be prepared as disclosed in U.S. Patent No. 2,161 ,938; trimazosin, which may be prepared as disclosed in U.S. Patent No. 3,669,968; and yohimbine, which may be isolated from natural sources according to methods well known to those skilled in the art. The disclosures of all such U.S. patents are incorporated herein by reference. The term "vasodilator," where used herein, is meant to include cerebral vasodilators, coronary vasodilators and peripheral vasodilators. Cerebral vasodilators within the scope of this invention include, but are not limited to: bencyclane; cinnarizine; citicoline, which may be isolated from natural sources as disclosed in Kennedy et al., Journal of the American Chemical Society, 1955, 77. 250 or synthesized as disclosed in Kennedy, Journal of Biological Chemistry, 1956. 222. 185; cyclandelate, which may be prepared as disclosed in U.S. Patent No. 3,663,597; ciclonicate, which may be prepared as disclosed in German Patent No. 1 ,910,481; diisopropylamine dichloroacetate, which may be prepared as disclosed in British Patent No. 862,248; eburnamonine, which may be prepared as disclosed in Hermann et al., Journal of the American Chemical Society, 1979. 101. 1540; fasudil, which may be prepared as disclosed in U.S. Patent No. 4,678,783; fenoxedil, which may be prepared as disclosed in U.S. Patent No. 3,818,021 ; flunarizine, which may be prepared as disclosed in U.S. Patent No. 3,773,939; ibudilast, which may be prepared as disclosed in U.S. Patent No. 3,850,941; ifenprodil, which may be prepared as disclosed in U.S. Patent No. 3,509,164; lomerizine, which may be prepared as disclosed in U.S. Patent No. 4,663,325; nafronyl, which may be prepared as disclosed in U.S. Patent No. 3,334,096; nicametate, which may be prepared as disclosed in Blicke et al., Journal of the American Chemical Society, 1942. 64. 1722; nicergoline, which may be prepared as disclosed above; nimodipine, which may be prepared as disclosed in U.S. Patent No. 3,799,934; papaverine, which may be prepared as reviewed in Goldberg, Chem. Prod. Chem. News, 1954. 17, 371; pentifylline, which may be prepared as disclosed in German Patent No. 860,217; tinofedrine, which may be prepared as disclosed in U.S. Patent No. 3,563,997; vincamine, which may be prepared as disclosed in U.S. Patent No. 3,770,724; vinpocetine, which may be prepared as disclosed in U.S. Patent No. 4,035,750; and viquidil, which may be prepared as disclosed in U.S. Patent No. 2,500,444. The disclosures of all such U.S. patents are incorporated herein by reference.

Coronary vasodilators within the scope of this invention include, but are not limited to: amotriphene, which may be prepared as disclosed in U.S. Patent No.

3,010,965; bendazol, which may be prepared as disclosed in J. Chem. Soc. 1958, 2426; benfurodil hemisuccinate, which may be prepared as disclosed in U.S. Patent No. 3,355,463; benziodarone, which may be prepared as disclosed in U.S. Patent No. 3,012,042; chloracizine, which may be prepared as disclosed in British Patent No. 740,932; chromonar, which may be prepared as disclosed in U.S. Patent No. 3,282,938; clobenfural, which may be prepared as disclosed in British Patent No. 1 ,160,925; do nitrate, which may be prepared from propanediol according to methods well known to those skilled in the art, e.g., see Annalen, 1870, 155, 165; cloricromen, which may be prepared as disclosed in U.S. Patent No. 4,452,811; dilazep, which may be prepared as disclosed in U.S. Patent No. 3,532,685; dipyridamole, which may be prepared as disclosed in British Patent No. 807,826; droprenilamine, which may be prepared as disclosed in German Patent No. 2,521,113; efloxate, which may be prepared as disclosed in British Patent Nos. 803,372 and 824,547; erythrityl tetranitrate, which may be prepared by nitration of erythritol according to methods well-known to those skilled in the art; etafenone, which may be prepared as disclosed in German Patent No. 1 ,265,758; fendiline, which may be prepared as disclosed in U.S. Patent No. 3,262,977; floredil, which may be prepared as disclosed in German Patent No. 2,020,464; ganglefene, which may be prepared as disclosed in U.S.S.R. Patent No. 115,905; hexestrol, which may be prepared as disclosed in U.S. Patent No. 2,357,985; hexobendine, which may be prepared as disclosed in U.S. Patent No. 3,267,103; itramin tosylate, which may be prepared as disclosed in Swedish Patent No. 168,308; khellin, which may be prepared as disclosed in Baxter et al., Journal of the Chemical Society, 1949. S 30; lidoflazine, which may be prepared as disclosed in U.S. Patent No. 3,267,104; mannitol hexanitrate, which may be prepared by the nitration of mannitol according to methods well-known to those skilled in the art; medibazine, which may be prepared as disclosed in U.S. Patent No. 3,119,826; nitroglycerin; pentaerythritol tetranitrate, which may be prepared by the nitration of pentaerythritol according to methods well-known to those skilled in the art; pentrinitrol, which may be prepared as disclosed in German Patent No. 638,422-3; perhexilline, which may be prepared as disclosed above; pimefylline, which may be prepared as disclosed in U.S. Patent No. 3,350,400; prenylamine, which may be prepared as disclosed in U.S. Patent No. 3,152,173; propatyl nitrate, which may be prepared as disclosed in French Patent No. 1,103,113; trapidil, which may be prepared as disclosed in East German Patent No. 55,956; tricromyl, which may be prepared as disclosed in U.S. Patent No. 2,769,015; trimetazidine, which may be prepared as disclosed in U.S. Patent No. 3,262,852; trolnitrate phosphate, which may be prepared by nitration of triethanolamine followed by precipitation with phosphoric acid according to methods well-known to those skilled in the art; visnadine, which may be prepared as disclosed in U.S. Patent Nos. 2,816,118 and 2,980,699. The disclosures of all such U.S. patents are incorporated herein by reference.

Peripheral vasodilators within the scope of this invention include, but are not limited to: aluminum nicotinate, which may be prepared as disclosed in U.S. Patent No. 2,970,082; bamethan, which may be prepared as disclosed in Corrigan et al., Journal of the American Chemical Society, 1945. 67, 1894; bencyclane, which may be prepared as disclosed above; betahistine, which may be prepared as disclosed in Walter et al.; Journal of the American Chemical Society. 1941. 63, 2771 ; bradykinin, which may be prepared as disclosed in Hamburg et al., Arch. Biochem. Biophys., 1958. 76. 252; brovincamine, which may be prepared as disclosed in U.S. Patent No. 4,146,643; bufeniode, which may be prepared as disclosed in U.S. Patent No. 3,542,870; buflomedil, which may be prepared as disclosed in U.S. Patent No. 3,895,030; butalamine, which may be prepared as disclosed in U.S. Patent No. 3,338,899; cetiedil, which may be prepared as disclosed in French Patent Nos. 1 ,460,571; ciclonicate, which may be prepared as disclosed in German Patent No. 1 ,910,481 ; cinepazide, which may be prepared as disclosed in Belgian Patent No. 730,345; cinnarizine, which may be prepared as disclosed above; cyclandelate, which may be prepared as disclosed above; diisopropylamine dichloroacetate, which may be prepared as disclosed above; eledoisin, which may be prepared as disclosed in British Patent No. 984,810; fenoxedil, which may be prepared as disclosed above; flunarizine, which may be prepared as disclosed above; hepronicate, which may be prepared as disclosed in U.S. Patent No. 3,384,642; ifenprodil, which may be prepared as disclosed above; iloprost, which may be prepared as disclosed in U.S. Patent No. 4,692,464; inositol niacinate, which may be prepared as disclosed in Badgett et al., Journal of the American Chemical Society, 1947, 69, 2907; isoxsuprine, which may be prepared as disclosed in U.S. Patent No. 3,056,836; kallidin, which may be prepared as disclosed in Biochem. Biophys. Res. Commun., 1961 , 6, 210; kallikrein, which may be prepared as disclosed in German Patent No. 1 ,102,973; moxisylyte, which may be prepared as disclosed in German Patent No. 905,738; nafronyl, which may be prepared as disclosed above; nicametate, which may be prepared as disclosed above; nicergoline, which may be prepared as disclosed above; nicofuranose, which may be prepared as disclosed in Swiss Patent No. 366,523; nylidrin, which may be prepared as disclosed in U.S. Patent Nos. 2,661,372 and 2,661,373; pentifylline, which may be prepared as disclosed above; pentoxifylline, which may be prepared as disclosed in U.S. Patent No. 3,422,107; piribedil, which may be prepared as disclosed in U.S. Patent No. 3,299,067; prostaglandin E-i, which may be prepared by any of the methods referenced in the Merck Index, Twelfth Edition, Budaveri, Ed., New Jersey, 1996, p. 1353; suloctidil, which may be prepared as disclosed in German Patent No. 2,334,404; tolazoline, which may be prepared as disclosed in U.S. Patent No. 2,161,938; and xanthinol niacinate, which may be prepared as disclosed in German Patent No. 1,102,750 or Korbonits et al., Acta. Pharm. Hung., 1968. 38, 98. The disclosures of all such U.S. patents are incorporated herein by reference.

The term "diuretic," within the scope of this invention, is meant to include diuretic benzothiadiazine derivatives, diuretic organomercurials, diuretic purines, diuretic steroids, diuretic sulfonamide derivatives, diuretic uracils and other diuretics such as amanozine, which may be prepared as disclosed in Austrian Patent No. 168,063; amiloride, which may be prepared as disclosed in Belgian Patent No. 639,386; arbutin, which may be prepared as disclosed in Tschitschibabin, Annalen, 1930. 479. 303; chlorazanil, which may be prepared as disclosed in Austrian Patent No. 168,063; ethacrynic acid, which may be prepared as disclosed in U.S. Patent No. 3,255,241 ; etozolin, which may be prepared as disclosed in U.S. Patent No. 3,072,653; hydracarbazine, which may be prepared as disclosed in British Patent No. 856,409; isosorbide, which may be prepared as disclosed in U.S. Patent No. 3,160,641 ; mannitol; metochalcone, which may be prepared as disclosed in Freudenberg et al., Ber., 1957. 90. 957; muzolimine, which may be prepared as disclosed in U.S. Patent No. 4,018,890; perhexiline, which may be prepared as disclosed above; ticrynafen, which may be prepared as disclosed in U.S. Patent No. 3,758,506; triamterene which may be prepared as disclosed in U.S. Patent No. 3,081 ,230; and urea. The disclosures of all such U.S. patents are incorporated herein by reference.

Diuretic benzothiadiazine derivatives within the scope of this invention include, but are not limited to: althiazide, which may be prepared as disclosed in British Patent No. 902,658; bendroflumethiazide, which may be prepared as disclosed in U.S. Patent No. 3,265,573; benzthiazide, McManus et al., 136th Am. Soc. Meeting (Atlantic City, September 1959), Abstract of papers, pp 13-0; benzylhydrochlorothiazide, which may be prepared as disclosed in U.S. Patent No. 3,108,097; buthiazide, which may be prepared as disclosed in British Patent Nos. 861 ,367 and 885,078; chlorothiazide, which may be prepared as disclosed in U.S. Patent Nos. 2,809,194 and 2,937,169; chlorthalidone, which may be prepared as disclosed in U.S. Patent No. 3,055,904; cyclopenthiazide, which may be prepared as disclosed in Belgian Patent No. 587,225; cyclothiazide, which may be prepared as disclosed in Whitehead et al., Journal of Organic Chemistry, 1961. 26. 2814; epithiazide, which may be prepared as disclosed in U.S. Patent No. 3,009,911 ; ethiazide, which may be prepared as disclosed in British Patent No. 861 ,367; fenquizone, which may be prepared as disclosed in U.S. Patent No. 3,870,720; indapamide, which may be prepared as disclosed in U.S. Patent No. 3,565,911 ; hydrochlorothiazide, which may be prepared as disclosed in U.S. Patent No. 3,164,588; hydroflumethiazide, which may be prepared as disclosed in U.S. Patent No. 3,254,076; methyclothiazide, which may be prepared as disclosed in Close et al., Journal of the American Chemical Society, 1960. 82, 1132; meticrane, which may be prepared as disclosed in French Patent Nos. M2790 and 1,365,504; metolazone, which may be prepared as disclosed in U.S. Patent No. 3,360,518; paraflutizide, which may be prepared as disclosed in Belgian Patent No. 620,829; polythiazide, which may be prepared as disclosed in U.S. Patent No. 3,009,911; quinethazone, which may be prepared as disclosed in U.S. Patent No. 2,976,289; teclothiazide, which may be prepared as disclosed in Close et al., Journal of the American Chemical Society, 1960. 82. 1132; and trichlormethiazide, which may be prepared as dislcosed in deStevens et al., Experientia, 1960. 16. 113. The disclosures of all such U.S. patents are incorporated herein by reference. Diuretic sulfonamide derivatives within the scope of this invention include, but are not limited to: acetazolamide, which may be prepared as disclosed in U.S. Patent No. 2,980,679; ambuside, which may be prepared as disclosed in U.S. Patent No. 3,188,329; azosemide, which may be prepared as disclosed in U.S. Patent No. 3,665,002; bumetanide, which may be prepared as disclosed in U.S. Patent No. 3,634,583; butazolamide, which may be prepared as disclosed in British Patent No. 769,757; chloraminophenamide, which may be prepared as disclosed in U.S. Patent Nos. 2,809,194, 2,965,655 and 2,965,656; clofenamide, which may be prepared as disclosed in Olivier, Rec. Trav. Chim., 1918. 37. 307; clopamide, which may be prepared as disclosed in U.S. Patent No. 3,459,756; clorexolone, which may be prepared as disclosed in U.S. Patent No. 3,183,243; disulfamide, which may be prepared as disclosed in British Patent No. 851 ,287; ethoxolamide, which may be prepared as disclosed in British Patent No. 795,174; furosemide, which may be prepared as disclosed in U.S. Patent No. 3,058,882; mefruside, which may be prepared as disclosed in U.S. Patent No. 3,356,692; methazolamide, which may be prepared as disclosed in U.S. Patent No. 2,783,241; piretanide, which may be prepared as disclosed in U.S. Patent No. 4,010,273; torasemide, which may be prepared as disclosed in U.S. Patent No. 4,018,929; tripamide, which may be prepared as disclosed in Japanese Patent No. 7305,585; and xipamide, which may be prepared as disclosed in U.S. Patent No. 3,567,777. The disclosures of all such U.S. patents are incorporated herein by reference.

Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the U.S., the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually. Hip fractures are the most serious consequence of osteoporosis, with 5-20% of patients dying within one year, and over 50% of survivors being incapacitated. The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population. Worldwide fracture incidence is forecasted to increase three-fold over the next 60 years, and one study has estimated that there will be 4.5 million hip fractures worldwide in 2050.

Women are at greater risk of osteoporosis than men. Women experience a sharp acceleration of bone loss during the five years following menopause. Other factors that increase the risk include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake.

Those skilled in the art will recognize that anti-resorptive agents (for example progestins, polyphosphonates, bisphosphonate(s), estrogen agonists/antagonists, estrogen, estrogen/progestin combinations, Premarin^®, estrone, estriol or 17α- or 17β- ethynyl estradiol) may be used in conjunction with the compounds of the present invention.

Exemplary progestins are available from commercial sources and include: algestone acetophenide, altrenogest, amadinone acetate, anagestone acetate, chlormadinone acetate, cingestol, clogestone acetate, clomegestone acetate, delmadinone acetate, desogestrel, dimethisterone, dydrogesterone, ethynerone, ethynodiol diacetate, etonogestrel, flurogestone acetate, gestaclone, gestodene, gestonorone caproate, gestrinone, haloprogesterone, hydroxyprogesterone caproate, levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, melengestrol acetate, methynodiol diacetate, norethindrone, norethindrone acetate, norethynodrel, norgestimate, norgestomet, norgestrel, oxogestone phenpropionate, progesterone, quingestanol acetate, quingestrone, and tigestol.

Preferred progestins are medroxyprogestrone, norethindrone and norethynodrel. Exemplary bone resorption inhibiting polyphosphonates include polyphosphonates of the type disclosed in U.S. Patent 3,683,080, the disclosure of which is incorporated herein by reference. Preferred polyphosphonates are geminal diphosphonates (also referred to as bis-phosphonates). Tiludronate disodium is an especially preferred polyphosphonate. lbandranic acid is an especially preferred polyphosphonate.

Alendronate and resindronate are especially preferred polyphosphonates. Zoledronic acid is an especially preferred polyphosphonate. Other preferred polyphosphonates are 6- amino-1-hydiOxy-hexylidene-bisphosphonic acid and 1-hydroxy-3(methylpentylamino)- propylidene-bisphosphonic acid. The polyphosphonates may be administered in the form of the acid, or of a soluble alkali metal salt or alkaline earth metal salt. Hydrolyzable esters of the polyphosphonates are likewise included. Specific examples include ethane- 1-hydroxy 1,1-diphosphonic acid, methane diphosphonic acid, pentane-1-hydroxy-1,1- diphosphonic acid, methane dichloro diphosphonic acid, methane hydroxy diphosphonic acid, ethane-1-amino-1,1-diphosphonic acid, ethane-2-amino-1,1 -diphosphonic acid, propane-3-amino-1-hydroxy-1 ,1 -diphosphonic acid, propane-N,N-dimethyl-3-amino-1- hydroxy-1 ,1 -diphosphonic acid, propane-3,3-dimethyl-3-amino-1-hydroxy-1 ,1- diphosphonic acid, phenyl amino methane diphosphonic acid.N.N-dimethylamino methane diphosphonic acid, N(2-hydroxyethyl) amino methane diphosphonic acid, butane-4-amino-1-hydroxy-1 ,1 -diphosphonic acid, pentane-5-amino-1-hydroxy-1 ,1- diphosphonic acid, hexane-6-amino-1 -hydroxy-1 ,1 -diphosphonic acid and pharmaceutically acceptable esters and salts thereof.

In particular, the compounds of this invention may be combined with a mammalian estrogen agonist/antagonist. Any estrogen agonist/antagonist may be used in the combination aspect of this invention. The term estrogen agonist/antagonist refers to compounds which bind with the estrogen receptor, inhibit bone turnover and/or prevent bone loss. In particular, estrogen agonists are herein defined as chemical compounds capable of binding to the estrogen receptor sites in mammalian tissue, and mimicking the actions of estrogen in one or more tissue. Estrogen antagonists are herein defined as chemical compounds capable of binding to the estrogen receptor sites in mammalian tissue, and blocking the actions of estrogen in one or more tissues. Such activities are readily determined by those skilled in the art of standard assays including estrogen receptor binding assays, standard bone histomorphometric and densitometer methods, and Eriksen E.F. et al., Bone Histomorphometry, Raven Press, New York, 1994, pages 1- 74; Grier SJ. et. al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv. Radiol., 1996, 31(1):50-62; Wahner H.W. and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London 1994, pages 1-296). A variety of these compounds are described and referenced below. Another preferred estrogen agonist/antagonist is 3-(4-(1 ,2-diphenyl-buM-enyl)- phenyl)-acrylic acid, which is disclosed in Willson et al., Endocrinology, 1997, 138, 3901-3911.

Another preferred estrogen agonist/antagonist is tamoxifen: (ethanamine,2-(-4- (1 ,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl, (Z)-2-, 2-hydroxy-1 ,2,3- propanetricarboxylate(1:1)) and related compounds which are disclosed in U.S. patent 4,536,516, the disclosure of which is incorporated herein by reference.

Another related compound is 4-hydroxy tamoxifen, which is disclosed in U.S. patent 4,623,660, the disclosure of which is incorporated herein by reference.

A preferred estrogen agonist/antagonist is raloxifene: (methanone, (6-hydroxy-2- (4-hydroxyphenyl)benzo[b]thien-3-yl)(4-(2-(1 -piperidinyl)ethoxy)phenyl)-hydrochloride) which is disclosed in U.S. patent 4,418,068, the disclosure of which is incorporated herein by reference.

Another preferred estrogen agonist/antagonist is toremifene: (ethanamine, 2-(4- (4-chloro-1 ,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl-, (Z)-, 2-hydroxy-1 ,2,3- propanetricarboxylate (1 :1) which is disclosed in U.S. patent 4,996,225, the disclosure of which is incorporated herein by reference.

Another preferred estrogen agonist/antagonist is centchroman: 1-(2-((4- (-methoxy-2,2, dimethyl-3-phenyl-chroman-4-yl)-phenoxy)-ethyl)-pyrrolidine, which is disclosed in U.S. patent 3,822,287, the disclosure of which is incorporated herein by reference. Also preferred is levormeloxifene.

Another preferred estrogen agonist/antagonist is idoxifene: (E)-1-(2-(4-(1-(4-iodo- phenyl)-2-phenyl-but-1-enyl)-phenoxy)-ethyl)-pyrrolidinone, which is disclosed in U.S. patent 4,839,155, the disclosure of which is incorporated herein by reference.

Another preferred estrogen agonist/antagonist is 2-(4-methoxy-phenyl)-3-[4-(2- piperidin-1-yl-ethoxy)-phenoxy]- benzo[b]thiophen-6-ol which is disclosed in U.S. Patent No. 5,488,058, the disclosure of which is incorporated herein by reference.

Another preferred estrogen agonist/antagonist is 6-(4-hydroxy-phenyl)-5-(4-(2- piperidin-1-yl-ethoxy)-benzyl)-naphthalen-2-ol, which is disclosed in U.S. patent 5,484,795, the disclosure of which is incorporated herein by reference. Another preferred estrogen agonist/antagonist is (4-(2-(2-aza-bicyclo[2.2.1]hept- 2-yl)-ethoxy)-phenyl)-(6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl)- methanone which is disclosed, along with methods of preparation, in PCT publication no. WO 95/10513 assigned to Pfizer Inc. Other preferred estrogen agonist/antagonists include the compounds, TSE-424

(Wyeth-Ayerst Laboratories) and arazoxifene.

Other preferred estrogen agonist/antagonists include compounds as described in commonly assigned U.S. patent 5,552,412, the disclosure of which is incorporated herein by reference. Especially preferred compounds described therein are: c/s-6-(4-fluoro-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5_I6,7,8-tetrahydiO- naphthalene-2-ol;

(-J-c/s-e-phenyl-S^^-pyrrolidin-i-yl-ethoxyJ-phenylJ-S.β./.β-tetrahydiO- naphthalene-2-ol (also known as lasofoxifene); c/s-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydiO- naphthalene-2-ol; c/s-1-(6^l-pyrrolodinoethoxy-3'-pyridyl)-2-phenyl-6-hydroxy-1 , 2,3,4- tetrahydronaphthalene;

1 -<4'-pyrrolidinoethoxyphenyl)-2-(4ⁿ-fluorophenyl)-6-hydroxy-1 ,2,3,4- tetrahydroisoquinoline; c/s-6-(4-hydroxyphenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6_I7,8-tetrahydro- naphthalene-2-ol; and

1-(4'-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1 ,2,3,4-tetrahydroisoquinoline.

Other estrogen agonist/antagonists are described in U.S. patent 4,133,814 (the disclosure of which is incorporated herein by reference). U.S. patent 4,133,814 discloses derivatives of 2-phenyl-3-aroyl-benzothiophene and 2-phenyl-3- aroylbenzothiophene-1 -oxide.

Other anti-osteoporosis agents, which can be used as the second agent in combination with a compound of the present invention, include, for example, the following: parathyroid hormone (PTH) (a bone anabolic agent); parathyroid hormone (PTH) secretagogues (see, e.g., U.S. Patent No. 6,132,774), particularly calcium receptor antagonists; calcitonin; and vitamin D and vitamin D analogs.

Any selective androgen receptor modulator (SARM) can be used in combination with a compound of the present invention. A selective androgen receptor modulator (SARM) is a compound that possesses androgenic activity and which exerts tissue- selective effects. SARM compounds can function as androgen receptor agonists, partial agonists, partial antagonists or antagonists. Examples of suitable SARMs include compounds such as cyproterone acetate, chlormadinone, flutamide, hydroxyflutamide, bicalutamide, nilutamide, spironolactone, 4-(trifluoromethyl)-2(1H)- pyrrolidino[3,2-g] quinoline derivatives, 1 ,2-dihydropyridino [5,6-g]quinoline derivatives and piperidino[3,2-g]quinolinone derivatives.

Cypterone, also known as (1b,2b)-6-chloro-1,2-dihydro-17-hydroxy-3'H- cyclopropa[1,2]pregna-1 ,4,6-triene-3,20-dione is disclosed in U.S. Patent 3,234,093. Chlormadinone, also known as 17-(acetyloxy)-6-chloiOpregna-4,6-diene-3,20-dione, in its acetate form, acts as an anti-androgen and is disclosed in U.S. Patent 3,485,852. Nilutamide, also known as 5,5-dimethyl-3-[4-nito-3-(trifluoromethyl)phenyl]-2,4- imidazolidinedione and by the trade name Nilandron® is disclosed in U.S. Patent 4,097,578. Flutamide, also known as 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl] propanamide and the trade name Eulexin® is disclosed in U.S. Patent 3,847,988. Bicalutamide, also known as 4^l-cyano-a',a',a'-trifluorO-3-(4-fluorophenylsulfonyl)-2- hydroxy-2-methylpropiono-m-toluidide and the trade name Casodex® is disclosed in EP-100172. The enantiomers of biclutamide are discussed by Tucker and Chesterton, J. Med. Chem. 1988, 31, 885-887. Hydroxyflutamide, a known androgen receptor antagonist in most tissues, has been suggested to function as a SARM for effects on IL- 6 production by osteoblasts as disclosed in Hofbauer et al. J. Bone Miner. Res. 1999, 14, 1330-1337. Additional SARMs have been disclosed in U.S. Patent 6,017,924; WO 01/16108, WO 01/16133, WO 01/16139, WO 02/00617, WO 02/16310, U.S. Patent Application Publication No. US 2002/0099096, U.S. Patent Application Publication No. US 2003/0022868, WO 03/011302 and WO 03/011824. All of the above refences are hereby incorporated by reference herein.

The starting materials and reagents for the above described compounds, are also readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, many of the compounds used herein, are related to, or are derived from compounds in which there is a large scientific interest and commercial need, and accordingly many such compounds are commercially available or are reported in the literature or are easily prepared from other commonly available substances by methods which are reported in the literature.

Some of the compounds of this invention or intermediates in their synthesis have asymmetric carbon atoms and therefore are enantiomers or diastereomers. Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known fier se, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by, for example, chiral HPLC methods or converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, an enantiomeric mixture of the compounds or an intermediate in their synthesis which contain an acidic or basic moiety may be separated into their corresponding pure enantiomers by forming a diastereomic salt with an optically pure chiral base or acid (e.g., 1-phenyl-ethyl amine, dibenzyl tartrate or tartaric acid) and separating the diasteromers by fractional crystallization followed by neutralization to break the salt, thus providing the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers and mixtures thereof are considered as part of this invention for all of the compounds of the present invention, including the compounds of the present invention. Also, some of the compounds of this invention are atropisomers (e.g., substituted biaryls) and are considered as part of this invention.

More specifically, the compounds of this invention may be obtained in enantiomerically enriched form by resolving the racemate of the final compound or an intermediate in its synthesis, employing chromatography (preferably high pressure liquid chromatography [HPLC]) on an asymmetric resin (preferably Chiralcel™ AD or OD (obtained from Chiral Technologies, Exton, Pennsylvania)) with a mobile phase consisting of a hydrocarbon (preferably heptane or hexane) containing between 0 and 50% isopropanol (preferably between 2 and 20 %) and between 0 and 5% of an alkyl amine (preferably 0.1 % of diethylamine). Concentration of the product containing fractions affords the desired materials.

Some of the compounds of this invention are acidic and they form a salt with a pharmaceutically acceptable cation. Some of the compounds of this invention are basic and they form a salt with a pharmaceutically acceptable anion. All such salts are within the scope of this invention and they can be prepared by conventional methods such as combining the acidic and basic entities, usually in a stoichiometric ratio, in either an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered either by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate. The compounds can be obtained in crystalline form by dissolution in an appropriate solvent(s) such as ethanol, hexanes or water/ethanol mixtures.

In addition, when the compounds of this invention form hydrates or solvates they are also within the scope of the invention. The compounds of this invention, their prodrugs and the salts of such compounds and prodrugs are all adapted to therapeutic use as agents that inhibit cholesterol ester transfer protein activity in mammals, particularly humans. Thus, the compounds of this invention elevate plasma HDL cholesterol, its associated components, and the functions performed by them in mammals, particularly humans. By virtue of their activity, these agents also reduce plasma levels of triglycerides, VLDL cholesterol, Apo-B, LDL cholesterol and their associated components in mammals, particularly humans. Moreover, these compounds are useful in equalizing LDL cholesterol and HDL cholesterol. Hence, these compounds are useful for the treatment and correction of the various dyslipidemias observed to be associated with the development and incidence of atherosclerosis and cardiovascular disease, including coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, hypoalphalipoproteinemia, hyperbetalipoproteinemia, hypertriglyceridemia, hypercholesterolemia, familial-hypercholesterolemia, low HDL and associated components, elevated LDL and associated components, elevated Lp(a), elevated small-dense LDL, elevated VLDL and associated components and post-prandial lipemia.

Further, introduction of a functional CETP gene into an animal lacking CETP (mouse) results in reduced HDL levels (Age I Ion, L.B., et al: J. Biol. Chem. (1991) 266: 10796-10801.) and increased susceptibility to atherosclerosis. (Marotti, K.R., et al: Nature (1993) 364: 73-75.). Also, inhibition of CETP activity with an inhibitory antibody raises HDL-cholesterol in hamster (Evans, G. F., et al: J. of Lipid Research (1994) 35: 1634-1645.) and rabbit (Whitlock, M.E., et al: J. CHn. Invest. (1989) 84: 129-137). Suppression of increased plasma CETP by intravenous injection with antisense oligodeoxynucleotides against CETP mRNA reduced atherosclerosis in cholesterol-fed rabbits (Sugano, M., et al: J. of Biol. Chem. (1998) 273: 5033-5036.) Importantly, human subjects deficient in plasma CETP, due to a genetic mutation possess markedly elevated plasma HDL-cholesterol levels and apolipoprotein A-I, the major apoprotein component of HDL. In addition, most demonstrate markedly decreased plasma LDL cholesterol and apolipoprotein B (the major apolipoprotein component of LDL. (Inazu, A., Brown, M.L., Hesler, C.B., et al.: N. Engl. J. Med. (1990) 323: 1234-1238.)

Given the negative correlation between the levels of HDL cholesterol and HDL associated lipoproteins, and the positive correlation between triglycerides, LDL cholesterol, and their associated apolipoproteins in blood with the development of cardiovascular, cerebral vascular and peripheral vascular diseases, the compounds of this invention, their prodrugs and the salts of such compounds and prodrugs, by virtue of their pharmacologic action, are useful for the prevention, arrestment and/or regression of atherosclerosis and its associated disease states. These include cardiovascular disorders (e.g., angina, ischemia, cardiac ischemia and myocardial infarction), complications due to cardiovascular disease therapies (e.g., reperfusion injury and angioplastic restenosis), hypertension, elevated cardiovascular risk associated with hypertension, stroke, atherosclerosis associated with organ transplantation, cerebrovascular disease, cognitive dysfunction (including, but not limited to, dementia secondary to atherosclerosis, transient cerebral ischemic attacks, neurodegeneration, neuronal deficient, and delayed onset or procession of Alzheimer's disease), elevated levels of oxidative stress, elevated levels of C-Reactive Protein, Metabolic Syndrome and elevated levels of HbAIC.

Because of the beneficial effects widely associated with elevated HDL levels, an agent which inhibits CETP activity in humans, by virtue of its HDL increasing ability, also provides valuable avenues for therapy in a number of other disease areas as well. Thus, given the ability of the compounds of this invention, their prodrugs and the salts of such compounds and prodrugs to alter lipoprotein composition via inhibition of cholesterol ester transfer, they are of use in the treatment of vascular complications associated with diabetes, lipoprotein abnormalities associated with diabetes and sexual dysfunction associated with diabetes and vascular disease. Hyperlipidemia is present in most subjects with diabetes mellitus (Howard, B.V. 1987. J. Lipid Res. 28, 613). Even in the presence of normal lipid levels, diabetic subjects experience a greater risk of cardiovascular disease (Kannel, W. B. and McGee, D.L. 1979. Diabetes Care 2, 120). CETP-mediated cholesteryl ester transfer is known to be abnormally increased in both insulin-dependent (Bagdade, J. D., Subbaiah, P.V. and Ritter, M.C. 1991. Eur. J. Clin. Invest. 21 , 161 ) and non-insulin dependent diabetes (Bagdade. J. D., Ritter, M.C, Lane, J. and Subbaiah. 1993. Atherosclerosis 104, 69). It has been suggested that the abnormal increase in cholesterol transfer results in changes in lipoprotein composition, particularly for VLDL and LDL, that are more atherogenic (Bagdade, J.D., Wagner, J.D., Rudel, L.L., and Clarkson, T.B. 1995. J. Lipid Res. 36, 759). These changes would not necessarily be observed during routine lipid screening. Thus the present invention will be useful in reducing the risk of vascular complications as a result of the S diabetic condition.

The described agents are useful in the treatment of obesity and elevated cardiovascular risk associated with obesity. In both humans (Radeau, T., Lau, P., Robb, M., McDonnell, M., Ailhaud, G. and McPherson, R., 1995. Journal of Lipid Research. 36 (12):2552-61) and nonhuman primates (Quinet, E., Tall, A., 0 Ramakrishnan, R. and Rudel, L., 1991. Journal of Clinical Investigation. 87 (5):1559- 66) mRNA for CETP is expressed at high levels in adipose tissue. The adipose message increases with fat feeding (Martin, L. J., Connelly, P. W., Nancoo, D., Wood, N., Zhang, Z. J., Maguire, G., Quinet, E., Tall, A. R., Marcel, Y. L. and McPherson, R., 1993. Journal of Lipid Research. 34 (3):437-46), and is translated into functional5 transfer protein and through secretion contributes significantly to plasma CETP levels. In human adipocytes the bulk of cholesterol is provided by plasma LDL and HDL (Fong, B. S., and Angel, A., 1989. Biochimica etBiophysica Acta. 1004 (1):53-60). The uptake of HDL cholesteryl ester is dependent in large part on CETP (Benoist, F., Lau, P., McDonnell, M., Doelle, H., Milne, R. and McPherson, R., 1997. Journal of Biological0 Chemistry. 272 (38):23572-7). This ability of CETP to stimulate HDL cholesteryl uptake, coupled with the enhanced binding of HDL to adipocytes in obese subjects (Jimenez, J. G., Fong, B., Julien, P., Despres, J. P., Rotstein, L., and Angel, A., 1989. International Journal of Obesity. 13 (5):699-709), suggests a role for CETP, not only in generating the low HDL phenotype for these subjects, but in the development of obesity itself by5 promoting cholesterol accumulation. Inhibitors of CETP activity that block this process therefore serve as useful adjuvants to dietary therapy in causing weight reduction.

CETP inhibitors are useful in the treatment of inflammation due to Gram- negative sepsis and septic shock. For example, the systemic toxicity of Gram-negative sepsis is in large part due to endotoxin, a lipopolysaccharide (LPS) released from the0 outer surface of the bacteria, which causes an extensive inflammatory response. Lipopolysaccharide can form complexes with lipoproteins (Ulevitch, R.J., Johnston, A.R., and Weinstein, D.B., 1981. J. Clin. Invest. 67, 827-37). In vitro studies have demonstrated that binding of LPS to HDL substantially reduces the production and release of mediators of inflammation (Ulevitch, R.J., Johhston, A.R., 1978. J. Clin. Invest. 62, 1313-24). In vivo studies show that transgenic mice expressing human apo- Al and elevated HDL levels are protected from septic shock (Levine, D.M., Parker, T.S., Donnelly, T.M., Walsh, A.M., and Rubin, A.L. 1993. Proc. Natl. Acad. Sci. 90, 12040- 44). Importantly, administration of reconstituted HDL to humans challenged with endotoxin resulted in a decreased inflammatory response (Pajkrt, D., Doran, J. E., Koster, F., Lerch, P.G., Arnet, B., van der Poll, T., ten Cate, J.W., and van Deventer, S.J.H. 1996. J. Exp. Med. 184, 1601-08). The CETP inhibitors, by virtue of the fact that they raise HDL levels, attenuate the development of inflammation and septic shock. These compounds would also be useful in the treatment of endotoxemia, autoimmune diseases and other systemic disease indications, organ or tissue transplant rejection and cancer.

The utility of the compounds of the invention, their prodrugs and the salts of such compounds and prodrugs as medical agents in the treatment of the above described disease/conditions in mammals (e.g. humans, male or female) is demonstrated by the activity of the compounds of this invention in conventional assays and the in vitro assay described below. The in vivo assay (with appropriate modifications within the skill in the art) may be used to determine the activity of other lipid or triglyceride controlling agents as well as the compounds of this invention. Such assays also provide a means whereby the activities of the compounds of this invention, their prodrugs and the salts of such compounds and prodrugs (or the other agents described herein) can be compared to each other and with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.

The following protocols can of course be varied by those skilled in the art. The hyperalphacholesterolemic activity of the compounds can be determined by assessing the effect of these compounds on the action of cholesteryl ester transfer protein by measuring the relative transfer ratio of radiolabeled lipids between lipoprotein fractions, essentially as previously described by Morton in J. Biol. Chem. 256, 11992, 1981 and by Dias in Clin. Chem. 34, 2322, 1988. CETP IN VITRO ASSAY

The following is a brief description of assays of cholesteryl ester transfer in 97% (whole) or diluted human plasma (in vitro) and animal plasma (ex vivo): CETP activity in the presence or absence of drug is assayed by determining the transfer of ³H-labeled cholesteryl oleate (CO) from exogenous tracer HDL or LDL to the nonHDL or HDL lipoprotein fraction in human plasma, respectively, or from ³H-labeled LDL to the HDL fraction in animal plasma. Labeled human lipoprotein substrates are prepared similarly to the method described by Morton in which the endogenous CETP activity in plasma is employed to transfer ³H-CO from phospholipid liposomes to all the lipoprotein fractions in plasma. ³H-labeled LDL and HDL are subsequently isolated by sequential ultracentrifugation at the density cuts of 1.019-1.063 and 1.10-1.21 g/ml, respectively.

For the 97% or whole plasma activity assay, ³H-labeled HDL is added to plasma at 10-25 nmoles CO/ml and the samples incubated at 37° C for 2.5-3 hrs. Non-HDL lipoproteins are then precipitated by the addition of an equal volume of 20% (wt/vol) polyethylene glycol 8000 (Dias). The samples are centrifuged 750 g x 20 minutes and the radioactivity contained in the HDL-containing supernatant determined by liquid scintillation counting. Introducing varying quantities of the compounds of this invention as a solution in dimethylsulfoxide into human plasma, before addition of the radiolabeled cholesteryl oleate, and comparing the amounts of radiolabel transferred compared to incubations containing no inhibitor compounds allows the cholesteryl ester transfer inhibitory activities to be determined.

Using the above described protocol for the 97% or whole plasma activity assay, the exemplified compounds demonstrated the following results (results noted as a range when number of test runs (n) is more than 1 ):

When a more sensitive assay is desirable, an in vitro assay using diluted human plasma is utilized. For this assay, ³H-labeled LDL is added to plasma at 50 nmoles CO/ml and the samples incubated at 37° C for 7 hrs. Non-HDL lipoproteins are then precipitated by the addition of potassium phosphate to 100 mM final concentration followed by manganese chloride to 20 mM final concentration. After vortexing, the samples are centrifuged 750 g x 20 minutes and the radioactivity contained in the HDL- containing supernatant determined by liquid scintillation counting. Introducing varying quantities of the compounds of this invention as a solution in dimethylsulfoxide into diluted human plasma, before addition of the radiolabeled cholesteryl oleate, and comparing the amounts of radiolabel transferred compared to incubations containing no inhibitor compounds allows the cholesteryl ester transfer inhibitory activities to be determined. This assay has been adapted to run in microtiter plate format with liquid scintillation counting accomplished using a Wallac plate reader.

Alternatively, the CETP inhibitory activity of compounds can be determined using microtiter plate-based fluorescent transfer assays where the CETP-dependent transfer of a self-quenching cholesteryl ester analog (Bodipy-CE) from human ApoAI-containing emulsion particles to the endogenous lipoproteins in plasma is monitored.

Fluorescent Bodipy-CE donors are prepared by drying down 14 mg of PC, 1.6 mg triolein and 3.5 mg of BODIPY-CE at 60⁰C in a vacuum oven and then hydrating the lipids at 80⁰C in 12 ml of PBS by probe sonication (at 25% of full power setting) for 2 min under a stream of N2. The lipid mixture is then cooled to 45⁰C and 5 mg (0.125 ?M) of human apolipoprotein Al (from Biodesign, Saco ME) is added, and again sonicated (at 25% of full power) for 20 min at 45⁰C , pausing after each minute to allow the probe to cool. The resulting emulsion is spun for 30 min at 3000 x g to remove metal probe fragments and then adjusted to 1.12 gm/ml with sodium bromide and layered below a solution of NaBr 1.10 g/ml (16 ml) and subjected to density gradient ultracentrifugation for 24 hours at 50,000-x g to remove unincorporated apolipoprotein Al and small dense particles that remain at the bottom of the gradient. The more buoyant emulsion particles are collected from the top of the gradient and dialyzed in 6 liters (2 changes) of PBS/0.02% azide, and diluted to the appropriate concentrations prior to use. The CETP-dependent transfer of fluorescent CE analog is monitored in incubations containing the fluorescent human-apolipoprotein Al-containing donor particles, and a source of CETP and acceptor lipoproteins which in these cases are present in diluted human plasma. Bodipy CE fluorescence in the donor particles in the unincubated donor particles is quenched, and the CETP-dependent transfer of Bodipy CE to acceptor particles results in an increase in fluorescence.

When a high sensitivity assay is desired, compounds in 100% dimethyl sulfoxide are tested in a 2.5% plasma 384-well microtiter plate assay. One microliter of compound in 100% dimethyl sulfoxide is added to wells containing 20 ul of 3.75% human plasma (diluted with PBS) using a clonemaster solution transfer device. Transfer is initiated via the addition of 10 ul of 7.5% donors (also diluted with PBS). Following mixing, each plate is taped or placed in a Matripress plate stacker to avoid evaporation and incubated overnight at room temp. (16- 20 hrs). Fluorescence is determined on a fluorescent plate reader, 485/530 nm filters, 505 nm dichroic filter. Note that depending upon liquid handling capabilities the intermediate dilutions of plasma and fluorescent donors and the aliquot size of those dilutions can be adjusted as necessary.

When a lower sensitivity assay is desired compounds are tested in a 20% plasma assay that is conceptually similar to the 2.5% assay. Two microliters of compound are added to dry, 96-well, half-area microtiter plates followed by 48 ul of 40% human plasma (diluted in PBS) and 50 ul of 40% donor solution. The fluorescent intensity is monitored after 3 hr incubation at room temperature. In the case of either the 2.5% or the 20% assay, the percent inhibition of CE transfer by compound is calculated by comparing to wells containing fluorescent donors and plasma but no compound. CETP IN VIVO ASSAY

Activity of these compounds in vivo can be determined by the amount of agent required to be administered, relative to control, to inhibit cholesteryl ester transfer activity by 50% at various time points ex vivo or to elevate HDL cholesterol by a given percentage in a CETP-containing animal species. Transgenic mice expressing both human CETP and human apolipoprotein Al (Charles River, Boston, MA) may be used to assess compounds in vivo. The compounds to be examined are administered by oral gavage in an emulsion vehicle containing 20% (v:v) olive oil and 80% sodium taurocholate (0.5%). Blood is taken from mice retroorbitally before dosing, if a predose blood sample is desirable. At various times after dosing, ranging from 4h to 24h, the animals are sacrificed, blood obtained by heart puncture, and lipid parameters measured, including total cholesterol, HDL and LDL cholesterol, and triglycerides. CETP activity is determined by a method similar to that described above except that ³H-cholesteryl oleate-containing LDL is used as the donor source as opposed to HDL. The values obtained for lipids and transfer activity are compared to those obtained prior to dosing and/or to those from mice receiving vehicle alone.

PLASMA LIPIDS ASSAY The activity of these compounds may also be demonstrated by determining the amount of agent required to alter plasma lipid levels, for example HDL cholesterol levels, LDL cholesterol levels, VLDL cholesterol levels or triglycerides, in the plasma of certain mammals, for example marmosets that possess CETP activity and a plasma lipoprotein profile similar to that of humans (Crook et al. Arteriosclerosis 10, 625, 1990). Adult marmosets are assigned to treatment groups so that each group has a similar mean ±SD for total, HDL, and/or LDL plasma cholesterol concentrations. After group assignment, marmosets are dosed daily with compound as a dietary admix or by intragastric intubation for from one to eight days. Control marmosets receive only the dosing vehicle. Plasma total, LDL VLDL and HDL cholesterol values can be determined at any point during the study by obtaining blood from an antecubital vein and separating plasma lipoproteins into their individual subclasses by density gradient centrifugation, and by measuring cholesterol concentration as previously described (Crook et al. Arteriosclerosis 10, 625, 1990).

IN VIVO ATHEROSCLEROSIS ASSAY Anti-atherosclerotic effects of the compounds can be determined by the amount of compound required to reduce the lipid deposition in rabbit aorta. Male New Zealand White rabbits are fed a diet containing 0.2% cholesterol and 10% coconut oil for 4 days (meal-fed once per day). Rabbits are bled from the marginal ear vein and total plasma cholesterol values are determined from these samples. The rabbits are then assigned to treatment groups so that each group has a similar mean ±SD for total plasma cholesterol concentration, HDL cholesterol concentration, triglyceride concentration and/or cholesteryl ester transfer protein activity. After group assignment, rabbits are dosed daily with compound given as a dietary admix or on a small piece of gelatin based confection. Control rabbits receive only the dosing vehicle, be it the food or the gelatin confection. The cholesterol/coconut oil diet is continued along with the compound administration throughout the study. Plasma cholesterol values and cholesteryl ester transfer protein activity can be determined at any point during the study by obtaining blood from the marginal ear vein. After 3-5 months, the rabbits are sacrificed and the aortae are removed from the thoracic arch to the branch of the iliac arteries. The aortae are cleaned of adventitia, opened longitudinally and then analyzed unstained or stained with Sudan IV as described by Holman et. al. (Lab. Invest. 1958, 7, 42-47). The percent of the lesioned surface area is quantitated by densitometry using an Optimas Image Analyzing System (Image Processing Systems). Reduced lipid deposition is indicated by a reduction in the percent of lesioned surface area in the compound-receiving group in comparison with the control rabbits.

ANTIOBESITY PROTOCOL

The ability of CETP inhibitors to cause weight loss can be assessed in obese human subjects with body mass index (BMI) > 30 kg/m². Doses of inhibitor are administered sufficient to result in an increase of > 25% in HDL cholesterol levels. BMI and body fat distribution, defined as waist (W) to hip (H) ratio (WHR), are monitored during the course of the 3-6 month studies, and the results for treatment groups compared to those receiving placebo.

IN VIVO SEPSIS ASSAY

In vivo studies show that transgenic mice expressing human apo-AI and elevated HDL levels are protected from septic shock. Thus the ability of CETP inhibitors to protect from septic shock can be demonstrated in transgenic mice expressing both human apo-AI and human CETP transgenes (Levine, D. M., Parker, T.S., Donnelly, T. M., Walsh, A. M. and Rubin, A.L., 1993. Proc. Natl. Acad. Sci. 90, 12040-44). LPS derived from E. coli is administered at 30mg/kg by i.p. injection to animals which have been administered a CETP inhibitor at an appropriate dose to result in elevation of HDL. The number of surviving mice is determined at times up to 48h after LPS injection and compared to those mice administered vehicle (minus CETP inhibitor) only.

IN VIVO BLOOD PRESSURE ASSAY In vivo rabbit model

Methods: New Zealand White male rabbits (3-4 kg) are anesthetized with sodium pentobarbital (30 mg/kg, i.v.) and a surgical plane of anesthesia is maintained by a continuous infusion of sodium pentobarbital (16 mg/kg/hr) via an ear vein catheter. A tracheotomy is performed through a ventral midline cervical incision and the rabbits are ventilated with 100% oxygen using a positive pressure ventilator. Body temperature is maintained at 38.5°C using a heating pad connected to a YSI temperature controller model 72 (Yellow Springs Instruments, Yellow Springs, MD). Fluid-filled catheters are placed in the right jugular vein (for intravenous drug administration) and in the right carotid artery for arterial pressure monitoring and for blood gas analysis using a model 248 blood gas analyzer (Bayer Diagnostics, Norwood, MA). The ventilator is adjusted as needed to maintain blood pH and pCO₂ within normal physiological ranges for rabbits. Arterial pressure is measured using a strain gauge transducer (Spectromed, Oxnard, CA), previously calibrated using a mercury manometer, positioned at the level of the heart and connected to the arterial catheter. Arterial pressure signals are digitized at 500 Hz and analyzed using a Po-Ne-Mah Data Acquisition System (Gould Instrument Systems, Valley View, OH) to obtain mean arterial pressure and heart rate values. Baseline values are collected when mean arterial pressure and heart rate have stabilized. The test compound is then administered either as a subcutaneous (SC) bolus or as an intravenous (IV) infusion. For subcutaneous (SC) dosing the test compound can be dissolved in an appropriate vehicle such as 5% ethanol in water (5% EtOH : 95% H₂O), while for intravenous dosing the test compound can be dissolved in an appropriate vehicle such as 0.9% normal saline. Arterial pressure and heart rate are monitored continuously for 4 hours following dosing of the test compound or for the duration of a continuous 4 hour infusion of the test compound. Blood is sampled after dosing or during the infusion of the test compound to determine plasma concentrations of the test compounds. In vivo primate model Methods: Adult M. fascicularis primates (6-8 kg) that have been previously instrumented with subcutaneous vascular access ports in the descending thoracic aorta and conditioned to sit quietly in specially designed primate-restraining chairs are used. All primates are fasted for 12-18 hours prior to the experiment. On the day of the experiment, with the primates restrained in the chairs, a strain gauge pressure transducer (Spectromed, Oxnard, CA), previously calibrated using a mercury manometer, is positioned at the level of the heart and connected to the vascular access port to measure arterial pressure. The primates are allowed to acclimate to the chair for at least one hour. Arterial pressure signals are digitized at 500 Hz and continuously recorded throughout the experiment and analyzed using a Po-Ne-Mah Data Acquisition System (Gould Instrument Systems, Valley View, OH) to obtain the measurements of mean arterial pressure and heart rate. Baseline values are collected when the primates are sitting calmly and when mean arterial pressure and heart rate have stabilized. The test compound is then administered as a subcutaneous (SC) bolus of a solution of the test compound in an appropriate vehicle such as 5% ethanol in water (5% EtOH : 95% H₂O). The solution of test compound or vehicle is filtered through a 0.22 micron filter prior to injection and a typical dosing volume is 0.2 ml/kg. Arterial pressure and heart rate are monitored continuously for 4 hours following dosing of the test compound and are recorded at selected time intervals for data comparison (vehicle vs test compound). Blood samples (1.5 ml) are withdrawn to determine plasma concentrations of the test compound and withdrawn blood is immediately replaced with 0.9% sterile saline to maintain blood volume.

Administration of the compounds of this invention can be via any method which delivers a compound of this invention systemically and/or locally. These methods include oral routes, parenteral, intraduodenal routes, etc. Generally, the compounds of this invention are administered orally, but parenteral administration (e.g., intravenous, intramuscular, subcutaneous or intramedullary) may be utilized, for example, where oral administration is inappropriate for the target or where the patient is unable to ingest the drug. In general an amount of a compound of this invention is used that is sufficient to achieve the therapeutic effect desired (e.g., HDL elevation).

In general an effective dosage for the compounds of this invention is about 0.001 to 100 mg/kg/day of the compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug. An especially preferred dosage is about 0.01 to 10 mg/kg/day of the compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.

A dosage of the combination pharmaceutical agents to be used in conjuction with the CETP inhibitors is used that is effective for the indication being treated. For example, typically an effective dosage for HMG-CoA reductase inhibitors is in the range of 0.01 to 100 mg/kg/day. In general an effect dosage for a PPAR modulator is in the range of 0.01 to 100 mg/kg/day.

The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds of this invention together with a pharmaceutically acceptable vehicle, diluent or carrier as described below. Thus, the compounds of this invention can be administered individually or together in any conventional oral, parenteral, rectal or transdermal dosage form.

For oral administration a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. A preferred formulation is a solution or suspension in an oil, for example, a vegetable oil, such as olive oil; triglycerides such as those marketed under the name, Miglyol™; or mono- or diglycerides such as those marketed under the name, Capmul™, for example, in a soft gelatin capsule. Antioxidants may be added to prevent long-term degradation as appropriate. When aqueous suspensions and/or elixirs are desired for oral administration, the compounds of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

Pharmaceutical compositions comprising a solid amorphous dispersion of a cholesteryl ester transfer protein (CETP) inhibitor and a concentration-enhancing polymer are described in International Publication Nos. WO 02/11710 and WO 03/000238, which are hereby incorporated by reference herein. Self-emulsifying formulations of cholesteryl ester transfer protein (CETP) inhibitors are described in International Publication No. WO 03/000295, which is hereby incorporated by reference herein. Methods for depositing small drug crystals on excipients are set forth in the literature, such as in J. Pharm. Pharmacol. 1987, 39:769-773, which is hereby incorporated by reference herein.

For purposes of parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this connection, the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.

For purposes of transdermal (e.g., topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, are prepared.

Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

Pharmaceutical compositions according to the invention may contain 0.1%-95% of the compound(s) of this invention, preferably 1 %-70%. In any event, the composition or formulation to be administered will contain a quantity of a compound(s) according to the invention in an amount effective to treat the disease/condition of the subject being treated, e.g., atherosclerosis.

Since the present invention has an aspect that relates to the treatment of the disease/conditions described herein with a combination of active ingredients which may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of the present invention, a prodrug thereof or a salt of such compound or prodrug and a second compound as described above. The kit comprises means for containing the_separate compositions such as a container, a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, ...etc.... Second Week, Monday, Tuesday,..." etc. Other variations of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of compounds of the present invention can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.

In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.

The compounds of this invention either alone or in combination with each other or other compounds generally will be administered in a convenient formulation. The following formulation examples only are illustrative and are not intended to limit the scope of the present invention.

In the formulations which follow, "active ingredient" means a compound of this invention. Formulation 1 : Gelatin Capsules

Hard gelatin capsules are prepared using the following: Ingredient Quantity

(mg/capsule)

Active ingredient 0.25-100

Starch, NF 0-650

Starch flowable powder 0-50

Silicone fluid 350 centistokes 0-15 A tablet formulation is prepared using the ingredients below:

Formulation 2: Tablets

Ingredient Quantity (mg/tablet)

Active ingredient 0.25-100

Cellulose, microcrystalline 200-650

Silicon dioxide, fumed 10-650

Stearate acid 5-15

The components are blended and compressed to form tablets. Alternatively, tablets each containing 0.25-100 mg of active ingredients are made up as follows: Formulation 3: Tablets

Ingredient Quantity (mg/tablet)

Active ingredient 0.25-100

Starch 45

Cellulose, microcrystalline 35

Polyvinylpyrrolidone (as 10% solution in 4 water)

Sodium carboxymethyl cellulose 4.5

Magnesium stearate 0.5

Talc 1

The active ingredients, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50° - 60⁰C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.

Suspensions each containing 0.25-100 mg of active ingredient per 5 ml dose are made as follows:

Formulation 4: Suspensions

Ingredient Quantity (mg/5 ml)

Active ingredient 0.25-100 mg

Sodium carboxymethyl cellulose 50 mg

Syrup 1.25 mg

Benzoic acid solution 0.1O mL

Flavor q.v.

Color q.v.

Purified Water to 5 ml_

The active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form smooth paste. The benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.

An aerosol solution is prepared containing the following ingredients: Formulation 5: Aerosol

Ingredient Quantity (% by weight)

Active ingredient 0.25

Ethanol 25.75

Propellant 22 (Chlorodifluoromethane) 70.00

The active ingredient is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to 30⁰C, and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remaining propellant. The valve units are then fitted to the container.

Suppositories are prepared as follows: Formulation 6: Suppositories

Ingredient Quantity

(mg/suppository)

Active ingredient 250

Saturated fatty acid glycerides 2,000

The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimal necessary heat. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.

An intravenous formulation is prepared as follows: Formulation 7: Intravenous Solution

Ingredient Quantity

Active ingredient dissolved in ethanol 1% 20 mg

Intralipid™ emulsion 1 ,000 ml_

The solution of the above ingredients is intravenously administered to a patient at a rate of about 1 ml_ per minute.

Soft gelatin capsules are prepared using the following: Formulation 8: Soft Gelatin Capsule with Oil Formulation

Ingredient Quantity (mg/capsule)

Active ingredient 10-500

Olive Oil or Miglyol ™ Oil 500-1000 The active ingredient above may also_be a combination of agents.

GENERAL EXPERIMENTAL PROCEDURES

The following examples are put forth so as to provide those of ordinary skill in the art with a disclosure and description of how the compounds, compositions, and methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Unless indicated otherwise, percent is percent by weight given the component and the total weight of the composition, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. Commercial reagents were utilized without further purification. Room or ambient temperature refers to 20-25 ⁰C. All non-aqueous reactions were run under a nitrogen atmosphere for convenience and to maximize yields. Concentration in vacuo means that a rotary evaporator was used. The names for the compounds of the invention were created by the Autonom 2.0 PC- batch version from Beilstein lnformationssysteme GmbH (ISBN 3-89536-976-4) or by Chemdraw® Ultra, CambridgeSoft Corporation, Cambridge MA. The chemical structures depicted may be only exemplary of the general structure or of limited isomers, and not include specific stereochemistry as recited in the chemical name. Some of the examples are prepared in a racemic form and a procedure for resolving the racemate into individual enantiomers is described. In certain cases the absolute stereochemistry of these enantiomers is not determined however both are within the scope of this invention. In these cases the order of presentation of the enantiomeric structures does not imply any relationship to their chromatographic order of separation. NMR spectra were recorded on a Varian Unity 400 (Varian Co., Palo Alto, CA) NMR spectrometer at ambient temperature. Chemical shifts are expressed in parts per million (δ) relative to an external standard (tetramethylsilane). The peak shapes are denoted as follows: s, singlet; d, doublet, t, triplet, q, quartet, m, multiplet with the prefix br indicating a broadened signal. The coupling constant (J) data given have a maximum error of ±0.41 Hz due to the digitization of the spectra that are acquired. Mass spectra were obtained by (1 ) atmospheric pressure chemical ionization (APCI) in alternating positive and negative ion mode using a Fisons Platform Il Spectrometer or a Micromass MZD Spectrometer (Micromass, Manchester, UK) or (2) electrospray ionization in alternating positive and negative ion mode using a Micromass MZD Spectrometer (Micromass, Manchester, UK) with a Gilson LC-MS interface (Gilson Instruments, Middleton, Wl), (3) a QP-8000 mass spectrometer (Shimadzu Corporation, Kyoto, Japan) operating in positive or negative single ion monitoring mode, utilizing electrospray ionization or atmospheric pressure chemical ionization or (4) a Hewlett Packard HP6890 gas chromatograph (Agilent Technologies Inc., Santa Clara, CA) coupled to a Hewlett Packard HP5973 electron impact quadrupole mass spectrometer. Where the intensity of chlorine- or bromine-containing ions are described, the expected intensity ratio was observed (approximately 3:1 for ³⁵CI/³⁷CI- containing ions and 1:1 for ⁷⁹Br/⁸¹ Br-containing ions) and the position of only the lower mass ion is given unless stated otherwise. Column chromatography was performed with either Baker Silica Gel (40 μm)

(JT. Baker, Phillipsburg, N.J.) or Silica Gel 60 (40-63 μm)(EM Sciences, Gibbstown, N. J.). Flash chromatography was performed using a Flash 12 or Flash 40 column (Biotage, Oyar Corp., Chaiiottesville, VA) or a CombiFlash Companion system using RediSep silica columns (Teledyne Isco, Teledyne Technologies Company, Lincoln, NE). Radial chromatography was performed using a chromatotron Model 7924T (Harrison Research, Palo Alto, CA). Preparative HPLC purification was performed on a Shimadzu 10A preparative HPLC system (Shimadzu Corporation, Kyoto, Japan) using a model SIL-10A autosampler and model 8A HPLC pumps.

Preparative HPLC purification was performed on a Waters Fractionlynx LC/MS/UV system (Waters Corporation; Milford, MA, USA) equipped with model 2767 injector/collector, model 2525 high flow binary pump modified by a model 515 low flow pump, a model 515 low flow pump for makeup flow, model GS splitter, model ZQ single quad mass spectrometer on the low flow side, model 996 photodiode array UV detector on the high flow side in pre-collector configuration, and a model 2487 dual UV detector on the high flow side in post-collector configuration. Fraction trigger is performed by the ZQ detector in electrospray positive (ESI+) ionization mode operating on single mass triggering. Chromatography methods are either 0.05% trifluoroacetic acid or 0.1% ammonia modified acetonitrile-water gradients. In the case of acid modified gradients Waters Symmetry C8 or C18(19 x 50mm; 5um) are typically used and in basic conditions Waters Xterra MS C8 or MS C18(19 x 50mm; 5um).

Microwave-assisted reactions were conducted in an Emrys Optimizer from Personal Chemistry (Uppsala, Sweden) or a Biotage Initiator from Biotage (Uppsala, Sweden). Optical rotations were determined using a Jasco P-1020 Polarimeter (Jascq Inc., Easton, MD)

Dimethylformamide ("DMF"), tetrahydrofuran ("THF"), toluene and dichloromethane ("DCM") were the anhydrous grade supplied by Aldrich Chemical Company (Milwaukee, Wl). Unless otherwise specified, reagents were used as obtained from commercial sources. The terms "concentrated" and "evaporated" refer to removal of solvent at 1-200 mm of mercury pressure on a rotary evaporator with a bath temperature of less than 45°C. The abbreviation "min" stands for "minutes" and "h" or "hr" stands for "hours." The abbreviation "gm" or "g" stands for grams. The abbreviation "μl" or "μl_" stands for microliters.

Preparation 1 : 2-Bromo-5-(trifluoromethyl)benzoic acid

To a solution of π-BuLi (26.7 mL of 2.5M solution in tetrahydrofuran (THF), 66.7 mmol) in THF (130 mL) at -78°C was added 2,2,6,6-tetramethylpiperidine (22.5 mL, 133.4 mmol). The mixture was stirred at -78°C for 30 minutes and then carefully lowered to -100⁰C using liquid nitrogen. Neat 1-bromo-4-(trifluoromethyl)benzene (15 g, 66. 7 mmol) was added. The mixture was kept at -100⁰C for 6 hours and poured onto freshly crushed dry ice. The resulting mixture was stirred at room temperature for 16 hours. The residue solvent was removed by evaporation. Water (150 mL) was added and the mixture was extracted with diethyl ether (3 x 50 mL). The aqueous layer was acidified using concentrated hydrochloric acid (HCI), extracted with methylene chloride (3 x 50 mL). The combined organic layers were washed with saturated sodium chloride (NaCI) (75ml), dried with magnesium sulfate (MgSO₄), filtered and concentrated to yield the title compound as a white solid (5.41 g).

¹H NMR (400 MHz, CDCI₃) δ 7.7 (dd, J=8.4, 2.3 Hz₁ 1 H) 7.9 (d, J=8.4 Hz, 1 H) 8.3 (d,

J=2.0 Hz, 1 H).

MS (ES+) CaIc: 267.93, Found: 266.7 (M-1). Preparation 2a: (2-Bromo-5-(trifluoromethvπphenvπmethanol

To an ice-cooled solution of 2-bromo-5-(trifIuoromethyl)benzoic acid (5.16 g, 19 mmol) in THF (50 ml_) was added borane-tetrahydrofuran complex (70 mL of 1 M solution in THF, 70 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with methanol. Solvent was removed. The residue was partitioned between ethyl acetate (3 x 40 mL) and 1 M sodium bicarbonate (50 mL). The combined organic layers were washed with saturated NaCI (50 mL), dried (MgSO₄) and concentrated to yield the title compound as an oil (4.85 g). ¹H NMR (400 MHz, CDCI₃) δ 4.8 (s, 2 H) 7.5 (m, 1 H) 7.7 (d, J=8.2 Hz, 1 H) 7.8 (d, J=1.6 Hz, 1 H).

Preparation 2b: Alternative preparation of [2-BrOmo-5-(trifluoromethyl)phenvnmethanol To a solution of 2-bromo-5-(trifluoromethyl)benzenecarbonitrile (493 g, 1.1 mol, 1 eq) in dichloromethane (4930 mL) contained in a 12L 3-neck round bottom flask equipped with a mechanical stirrer cooled to 0-10⁰C was added dropwise a solution of diisobutylaluminum hydride (1M in toluene, 2169 mL, 2.17 mol, 1.1 eq) over about 45 minutes maintaining the internal temperature at 0-10⁰C. The reaction progress was monitored by TLC (9:1 Hexane:THF), preparing sample by quenching in dilute HCI and extracting with dichloromethane, spotting the organic layer. Restarting material): 0.5; Rf(product): 0.52-0.55. When the reaction was complete the yellow mixture was very carefully transferred via cannula into a 12L flask containing aqueous HCI (2M, 2.7 L) cooled to -1O⁰C (ice/methanol bath) with vigorous mechanical stirring and maintaining the reaction temperature below 1O⁰C. The mixture was allowed to warm to room temperature and stirred for 16hr. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 1 L). The combined organic layer was washed with water (2 x 1 L). The combined aqueous layers were extracted with dichloromethane (2 L). This organic layer was washed with water (1 L). All organic layers were combined, dried over anhydrous magnesium sulfate and the solvent was carefully removed under reduced pressure to give an orange-red oi (49Og). This crude aldehyde was dissolved in methanol (1.3L) in a 5L 3-neck round bottom flask and with mechanical stirring solid sodium borohydride (30 g, 0.788 mol, 0.4 eq) was added portion wise at a rate to maintain temperature <15°C (approximately 1 hour). The reaction was monitored by TLC (9:1 Hexane:THF), preparing the sample by quenching with water and extracting with ethyl acetate, spotting the organic layer. Restarting aldehyde): 0.55; Rf(product): 0.25. When no starting aldehyde remained (60 minutes) the yellow solution was diluted with water (2.7 L) and the resulting suspension was stirred for 1 hour at 10-15⁰C. The solids were collected by filtration onto a polypropylene filter pad and partially dried in a current of air. The slightly wet solid was dissolved in ethyl acetate (550 mL) and dried over anhydrous magnesium sulfate. The filtrate was diluted with hexane (917mL) and the solution was loaded onto a plug of silica gel (400 g, d=18 cm, h=5 cm). The silica gel plug was eluted with 1:1 ethyl acetate:hexane (1:1) until no more product was observed in the fractions by TLC (9:1 hexane:THF). The fractions containing product were combined and concentrated under reduced pressure to give the crude product as a yellow oil (519g). This was dissolved in hexane (519 mL), cooled to -10⁰C and stirred for 2 hours at -1O⁰C. The solid was collected by filtration onto a polypropylene filter pad, washed with cold (-1O⁰C) hexane (2 x 100 mL) and dried under vaccum to give the title compound as a white solid. A second fraction was obtained from the combined mother liquor by evaporation under reduced pressure followed by crystallization from hexane (1 mL /g crude) as described above. By this method the total yield was 401 gm (80%). Elemental analysis: calc: C 37.68%, H 2.37%, Br 31.33%; found: C 37.73%, H 2.29%, Br 31.12%

Preparation 3: 1 -Bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene

To a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (4.7 g, 18 mmol) in methylene chloride (50 mL) at -1O⁰C was added carbon tetrabromide (CBr₄) (7.17 g, 21.6 mmol). The resulting mixture was stirred at -1O⁰C for 15 minutes. Triphenylphosphine (5.61 g, 21.4 mmol) was then slowly added portion-wise. This mixture was stirred at room temperature for 16 hours. The mixture was partitioned between saturated ammonium chloride (NH₄CI) (50ml) and methylene chloride (2 x 50 mL). The combined organic layers were washed with saturated NaCI (50 mL), dried (MgSO₄) and concentrated. The residue was purified by flash chromatography (silica gel) (eluted with 3:1 hexanes-ethyl acetate) to yield the title compound as a white solid (4.01 g). ¹H NMR (400 MHz, CDCI₃) δ 4.6 (s, 2 H) 7.5 (dd, J=8.3, 1.6 Hz₁ 1 H) 7.8 (m, 2 H). Preparation 4: (2-Bromo-5-trifluoromethvl-benzvloxv)-tert-butvl-dimethvl-silane

To a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (from Preparation 2a, 1O g, 39 mmol) in DMF (20 mL) was added imidazole (5.87 g, 86.3 mmol) followed by t- butyldimethylsilyl chloride (7.11 g, 47.2 mmol) and the reaction was stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+M Biotage silica column (eluted with 0-20% ethyl acetate in heptane) (5CV), 20% (1CV) to afford a colorless oil (14g, 97%) of the title compound. ¹H NMR (400 MHz, CDCI₃) δ ppm 0.15 (s, 6 H) 0.98 (s, 9 H) 4.75 (S, 2 H) 7.36 (m, 1 H) 7.60 (d, J =8.3 Hz, 1 H) 7.84 (s, 1 H)). GCMS : 311 (M-57,t-bu).

Preparation 5: f2-(tert-butyl-dimethyl-silanyloxymethyl)-4-trifluoromethyl-phenyl1- cvclohexyl-methaπone

To a solution of (2-bromo-5-trifluoromethyl-benzyloxy)-tert-butyl-dimethyl-silane (3.69 g, 10 mmol) in THF (35 mL) at room temperature was added i-PrMgCI/LiCI (21 ml_,1.5M, 30.5 mmol) in THF. The mixture was stirred at room temperature for 3 h. Transmetallation was followed by GC-MS. The reaction mixture was cooled to -78⁰C and CuCN.2LiCI (10 ml, 1M, 10.0 mmol) was added and stirred for 30 min. Cyclohexanecarbonyl chloride (2.93 g, 20.0 mmol) in 3 ml THF was added to reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 30 min. Reaction was quenched by pouring onto sat. aq. NH₄CI in NH₄OH solution and extracted with ethyl acetate. Combined organic layers (200 mL) were washed with brine, dried over sodium sulfate and concentrated in vacuo The crude product was purified on Biotage column (40+M), eluting with ethyl acetate in heptane, starting with 0-20% (1 OCV), 20% (2CV) to yield the title compound (4.5 g, 41.5%) as colorless oil.

¹H NMR (400 MHz₁ CDCI₃) δ ppm 0.09 (s, 6 H) 0.9 (s, 9 H) 1.2 (m, 4 H) 1.7 (m, 4 H) 2.4 (m, 2 H) 3.1 (m, 1 H) 4.8 (s, 2 H) 7.5 (d, J=7.9 Hz, 1 H) 7.7 (d, J=8.3 Hz, 1 H) 8.0 (s, 1 H

).

GCMS : CaIc: 400, Found: 343 (M-57,t-bu).

Preparation 6: (SH2-(tert-butyl-dimethyl-silanyloxymethyl)-4-trifluoromethyl-phenyll- cvclohexyl-methanol

A mixture of [lrHCI₂(COD)]₂ (33 mg, 0.044 mmol) and (1R,2/?)-Λ/, Λ/'-bis[2- (diphenylphosphino)benzyl]cyclohexane-1 ,2-diamine (29 mg, 0.044 mmol) in isopropanol (37 ml) was stirred at room temperature for 30 min. A solution of [2-(tert- butyl-dimethyl-silanyloxymethylH-trifluoromethyl-phenyfl-cyclohexyl-methanone (1.6 g, 4 mmol) in isopropanol (5 ml) was added to mixture followed by potassium hydroxide (28 mg, 0.5 mmol) and stirred for 16 h. Isopropanol was removed in vacuo and the residue was purified by chromatography over 25+M Biotage silica column eluted with ethyl acetate in heptanes 0% (1CV), 2-20% (10CV), 20% (2CV) to yield the title compound (1.4 g, 87%) as colorless oil. ¹H NMR (400 MHz, CDCI₃) δ ppm 0.09 (s, 6 H) 0.9 (s, 9 H) 1.2 (m, 3 H) 1.6 (d, J=7.4 Hz, 1 H) 1.7 (m, 4 H) 2.0 (m, 1 H) 2.2 (m, 1 H) 2.4 (m, 1 H) 4.5 (m, 1 H) 4.7 (d, J = 13.7 Hz, 1 H) 4.8 (d, J = 13.7 Hz, 1 H ) 7.5 (d, J = 1.2 Hz, 2 H) 7.6 (s, 1 H ). Chiral SFC, Retention time t = 1.93 min. indicates product is 95.0% ee. [a]²° = - 12.99 deg (c = 9.5 mg/mL, acetone)

Preparation 7: (S)-tert-butyl-r2-(cvclohexyl-methoxy-methyl)-5-triflυoromethyl-benzyloxy1- dimethyl-silane

To a solution of (S)-[2-(tert-butyl-dimethyl-silanyloxymethyl)-4-trifluoromethyl-phenyl]- cyclohexyl-methanol (1.4 g, 3.5 mmol) in THF (3 mL) at O⁰C under nitrogen was added sodium hydride (278 mg, 7.0 mmol, 60% dispersion in mineral oil). The reaction was stirred for 30 min., allowing it to warm to room temperature. The reaction mixture was then treated in a dropwise manner with methyl iodide (1.5 g, 650 μl_, 10.4 mmol) at O⁰C. The ice bath was removed after the addition and the reaction was stirred at room temperature overnight. Ethyl ether was added and the reaction was washed with brine, dried (MgSO₄) and concentrated in vacuo. The residue was purified by chromatography on Biotage column 25+S, eluting with ethyl acetate in heptane 2-30% (10CV) and 30% (3CV) to yield the title compound (1.0 g, 88%) as colorless oil. ¹H NMR (400 MHz, CDCI₃) δ ppm 0.08 (s, 6 H) 0.9 (s, 9 H) 1.2 (m, 3 H) 1.6 (m, 2 H) 1.7 (m, 4 H) 2.0 (d, J = 12.8, 1 H) 2.2 (m, 1 H) 3.1 (s, 3 H) 4.0 (d, J = 7.5, 1 H) 4.0 (d, J = 13.7, 1 H) 4.7 (d, J = 13.7 Hz, 1 H ) 7.4 (d, J = 7.9 Hz, 1 H) 7.5 (d, J = 7.9 Hz, 1 H) 7.7 (s, 1 H).

Preparation 8: (Sl-β-fcvclohexyl-methoxy-methviyS-trifluoromethyl-phenyll-methanol

To a solution of (S)-tert-butyl-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl- benzyloxy]-dimethyl-silane (1.13 g, 2.4 mmol) in THF (5ml) was added a solution of tetrabutyl ammonium fluoride (4.8 ml, 1 M, 4.8 mmol) at room temperature and stirred for overnight. The reaction mixture was concentrated in vacuo and purified on Biotage column 25+M, eluting with 0-30% ethyl acetate in heptane (10 CV), 30% (2 CV) to yield the title compound (0.6 g, 73%) as colorless oil. ¹H NMR (400 MHz, CDCI₃) δ ppm 0.8 m (m, 2 H) 1.1 (m, 4 H) 1.3 (m, 1 H) 1.5 (m, 2 H) 1.6 (m, 1 H) 2.0 (d, J = 12.9, 1 H) 2.3 (m, 1 H) 3.1 (S, 3 H) 4.0 (d, J = 7.9, 1 H) 4.7 (dd, J = 13.7 & 7.5 Hz, 2 H ) 7.3 (d, J = 8.3 Hz, 1 H) 7.4 (d, J = 7.8 Hz, 1 H) 7.7 (s, 1 H).

Preparation 9: (S)-2-bromomethyl-1 -(cvclohexyl-methoxy-methvD-Φtrifluoromethyl- benzene

To a solution of (S)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-phenyl]-methanol (340 mg, 1.2 mmol) in methylene chloride (10 ml_) at O⁰C was added carbon tetrabromide (485 mg, 1.46 mmol) and stirred for 10 min followed by addition of triphenylphosphine (383 mg, 1.46 mmol). Reaction was stirred at O⁰C for 1 hour and allowed to warm to room temperature and stirred for 16 hours. Reaction was concentrated in vacuo and purified on 25+S Biotage column eluting with 0-20% ethyl acetate in heptane (10 CV), 20% (2CV), to yield the title compound (270 mg, 66%) as a colorless oil. This oil solidified upon standing and was recrystalized from hexane to yield crystals (mp = 43 - 45⁰C)₁ which was submitted to X-ray crystallography to establish absolute configuration. ¹H NMR (400 MHz, CDCI₃) δ ppm 1.1 (m, 4 H) 1.3 (m, 2 H) 1.6 (m, 3 H) 1.7 (m, 1 H) 2.0 (d, J = 12.6, 1 H) 3.2 (s, 3 H) 4.2 (d, J = 7.9, 1 H) 4.5 (d, J = 10.3 Hz, 1 H ) 4.6 (d, J = 10.3 Hz, 1 H ) 7.4 (d, J = 8.3 Hz₁ 1 H) 7.5 (d, J = 8.3 Hz, 1 H) 7.6 (s, 1 H). [αf = - 50 deg (c = 11.5 mg/mL, acetone)

Preparation 10: (2-bromo-5-(trifluoromethv0benzyloxy)triisopropylsilane

To a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (10 g; 39 mmol) in N₁N- dimethylformamide (100 ml_) was added imidazole (6.82g; 100.1 mmol) and triisopropylsilyl chloride (9.6 ml_; 55.2 mmol) under N₂. The reaction was stirred at room temperature for 48 hours. The reaction was diluted with ethyl acetate and washed with water (4X) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by 8Og RediSep column (eluted with 5-10% ethyl acetate in heptane) to yield the title compound (16.47g, 100%) as a colorless oil. MS (GC) CaIc: 410.0, Found: 391 (M-F). ¹H NMR (CDCI₃) δ ppm 7.94 (s, 1H), 7.62 (d, J=8.30Hz, 1H), 7.39 (d, J=8.30Hz, 1H), 4.84 (s, 2H), 1.25 (m, 3H), 1.12(d, 18H).

Preparation 11: 1-(4-ftrifluoromethyl)-2- (ftriisopropylsilyloxy)methyl)phenyl)cvcloheptanol

To a solution of (2-bromo-5-(trifluoromethyl)benzyloxy)triisopropylsilane (604 mg; 1.47 mmoll) in tetrahydrofuran (4 ml_) under N₂ at -78⁰C was added n-butyllithium (0.9 mL; 2.25 mmol; 2.5M in hexanes) dropwise over 10 minutes. Reaction was stirred for 5 minutes. A solution of cycloheptanone (0.21 mL; 1.78 mmol) in hexanes (1.0 mL) was added dropwise over 6 minutes. After stirring for 1 hour at -78⁰C, the bath was removed and stirred for 1 hour. The reaction mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed twice with water and then with brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over a 12g RediSep column (eluted with 5-10% ethyl acetate in heptane) to yield 387 mg (59.3%) of the title compound as a colorless oil. MS - GC (El): CaIc: 444.6, Found: 426 (M-H₂O). ¹H NMR (CDCI₃) δ ppm 7.62 (s, 1H), 7.49 (dd, J=8.30, 7.88Hz, 1H), 7.44 (d, J=8.30Hz, 1 H), 5.11 (s, 2H), 4.03 (s, 1 H)₁ 2.07-1.98 (m, 4H), 1.94-1.82 (m, 2H), 1.79-1.69 (m, 2H), 1.67-1.5 (m, 4H), 1.19 (m, 3H)₁ 1.08 (s, 18H).

Preparation 12: (2-(1-methoxycvcloheptyl)-5- (trifluoromethyl)benzyloxy)triisopropylsilane

To a solution of i-^trifluoiOmethyO^-fttriisopropylsilyloxy^ethyOphenyOcycloheptanol (284 mg; 0.639 mmol) in tetrahydrofuran (3.5 mL) at room temperature was added sodium hydride (40 mg; 1 mmol; 60% dispersion in mineral oil). After stirring at room temperature for 15 minutes methyl iodide (80 uL; 1.28 mmol) was added. Reaction stirred for 16 hours. More sodium hydride (20 mg; 0.5 mmol;60% dispersion in mineral oil) was added. After 5 minutes methyl iodide (0.1 mL; 1.6 mmol) was added. The reaction was stirred for 16 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water (2x) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over a 12g RediSep column (eluted with 5-15% ethyl acetate in heptanes) to yield 279 mg (95.2%) of the title compound as a colorless oil. MS - GC (El): CaIc: 458.6 Found: 439 (M-F). ¹H NMR (400 MHz₁ CDCI₃): δ ppm 8.22 (d, J=1.24Hz, 1H), 7.44 (dd, J=8.30, 1.24Hz, 1H), 7.34 (d, J=8.30Hz, 1H), 5.11 (s, 2H), 2.95 (s, 3H), 2.16 (m, 2H), 2.01 (m, 2H), 2.0 (dd, J=14.94, 14.52Hz, 1H), 1.97 (dd, J=14.94, 14.52Hz, 1H), 1.83-1.58 (m, 6H), 1.3-1.16 (m, 2H), 1.13 (s, 12H), 1.11 (s, 6H).

Preparation 13: (2-(1-methoxycvcloheptyl)-5-(trifluoromethyl)phenyl)methanol

To a solution of (2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyloxy)triisopropylsilane (276 mg; 0.602 mmol) in tetrahydrofuran (3.5 mL) was added tetrabutylammonium fluoride (0.62 mL; 0.62 mmol;1.0M solution in tetrahydrofuran). Reaction was stirred at room temperature for 1.5 hours. Solvent was evaporated under reduced pressure. The residue was purified by 12g RediSep column (eluted with 10-30% ethyl acetate in heptane) to yield 169 mg (92.9%) of the title compound as a colorless gum. MS^C (El): CaIc: 302.3, Found: 302 (M). ¹H NMR (400 MHz, CDCI₃): δ ppm 7.89 (s, 1H), 7.49 (dd, J=8.30Hz, 1H), 7.40 (d, J=8.30Hz, 1H), 5.03 (s, 2H), 3.00 (s, 3H), 2.54 (bs, 1H), 2.23 (m, 2H), 2.04 (m, 2H), 1.88-1.55 (m, 8H).

Preparation 14: 2-(1 -methoxycvcloheptvD-δ-ftrifluoromethvDbenzaldehvde

To a solution of (2-(1-methoxycycloheptyl)-5-(trifluoiOmethyl)phenyl)methanol (167 mg; 0.552 mmol) in methylene chloride (3.0 mL) was added Dess-Martin reagent (290 mg; 0.683 mmol). Reaction was stirred at room temperature for 5 hours. The reaction was diluted with ethyl acetate and quenched with aqueous 1 N sodium hydroxide. After partitioning off the aqueous layer, the organic layer was washed with water and brine. It was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over a Bakerbond 1g silica cartridge (Mallinkrodt Baker Inc. Phillipsburg, NJ) (eluted with 0-5% heptane) to yield 167 mg of a cloudy oil. ¹H NMR (400 MHz, CDCI₃): δ ppm 10.91 (s, 1 H), 8.11 (d, J=2.07Hz, 1H), 7.73 (dd, J=8.71, 8.30Hz, 1H)₁ 7.48 (d, J=7.88Hz, 1H), 2.96 (s, 3H), 2.25 (m, 2H), 2.09 (m, 2H), 1.94-1.57 (m, 8H).

Preparation 15: (4S.5R)-5-r3.5-bis(trifluoromethyl)phenyl1-4-methyl-1.3-oxazolidin-2- one

This compound was prepared from CBZ-L-alanine by the method described in patent application WO2006/014357

Preparation 16: (4R.5SV5-r3.5-bis(trifluoromethyl)phenyl1-4-methyl-1.3-oxazolidin-2- one

This compound was prepared from CBZ-D-alanine by the method described in patent application WO2006/014357

Preparation 17: (4R.5RV5-[3.5-bis(trifluoromethyl)phenvn-4-methyl-1.3-oxazolidin-2- one This compound was prepared by the method described in patent application WO2006/014413

Preparation 18: (4S.5S)-5-[3.5-bis(trifluoromethyl)phenyll-4-methyl-1.3-oxazolidin-2- one

This compound was prepared by the method described in patent application WO2006/014413

Example 1: (4S.5R)-5-r3.5-BisrtrifluorDmethyl)phenvn-3-{2-r(S)- cvclohexyirmethoxy)methvn-5-(tιifluorDmethyl)benzvD-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 (Preparation 15, 152 mg, 0,17 mmol) in THF (0.4 ml) at room temperature was added sodium hydride (14 mg, 0.34 mmol). The mixture was stirred at room temperature for 1 hour. (S)-2-Bromomethyl-1-(cyclohexyl-methoxy-methyl)-4-trifluoromethyl-benzene (50mg, 0.14 mmol) in THF was added. The mixture was stirred a room temperature for 16 hours. Reaction was diluted with ethyl acetate, washed with water, dried over MgSO₄ and concentrated in vacuo. The residue was purified on Biotage column 12+S, eluting with 2-30% of ethyl acetate in heptane (10CV), 30% (2CV) to afford 58 mg (71%) of the product as an oil. ¹H NMR (400 MHz, CDCI₃) δ 7.9 (s), 7.80 (s), 7.62 (s), 7.60 (S)₁ 5.72 (d, J=7.9Hz), 4.95 (d, J=16.2Hz), 4.35 (d, J=16Hz), 4.18 (d, J=7.1 Hz), 3.18 (s), 0.78 (d, J=6.6Hz).MS (ES⁺) CaIc: 597.2, Found: 572 (M - 25 (-CO)).

Preparation 19: (R)-f2-(tert-butyl-dimethyl-silanyloxymethyl)-4-trifluoromethyl-phenyll- cvclohexyl-methanol

The desired alcohol was prepared according to the procedure described in Preparation 6 with the exception that (1S,2S)-Λ/, Λ/-bis[2-(diphenylphosphino)benzyl] cyclohexane- 1 ,2-diamine was used for the chiral reduction. Optical rotation of final alcohol: [af° = + 13 deg (c = 0.0102, acetone)

Preparation 20: (R)-2-bromomethyl-1 -(cvclohexyl-methoxy-methyl)-4-trifluoromethyl- benzene

The desired benzyl bromide was prepared from Preparation 19 and using analogous procedures to those described in Preparations 8 and 9. ¹H NMR (400 MHz, CDCI₃) δ ppm 1.1 (m. 4 H) 1.3 (m, 2 H) 1.6 (m. 3 H) 1.7 (m. 1 H) 2.0 (d, J = 12.6, 1 H) 3.2 (s, 3 H) 4.2 (d, J = 7.9, 1 H) 4.5 (d, J = 10.3 Hz, 1 H ) 4.6 (d, J = 10.3 Hz, 1 H ) 7.4 (d, J = 8.3 Hz, 1 H) 7.5 (d, J = 8.3 Hz, 1 H) 7.6 (s, 1 H).

Example 2: (4S.5RV5-r3.5-Bis(trifluoromethyl)phenyl1-3-{2-r(R)- cvclohexyl(methoxy)methyll-5-(trifluoromethvπbenzyl)-4-methyl-1.3-oxazolidin-2-one

The title compound was prepared according to the procedure described in Example 1 using (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1 ,3-oxazolidin-2-one (Preparation 15) and (R)-2-bromomethyl-1-(cyclohexyl-methoxy-methyl)-4- trifluoromethyl-benzene (Preparation 20). ¹H NMR (400 MHz, CDCI₃) δ 7.9 (s), 7.79 (s), 7.60 (S)₁ 7.53 (S), 5.68 (d, J=7,9Hz), 4.99 (d, J=15.8Hz), 4.35 (d, J=15.6Hz), 3.20 (s), 0.81 (d, J=6.4Hz). MS (ES⁺) CaIc: 597.2, Found: 572 (M - 25 (-CO)).

Example 3: (4R.5S)-5-r3.5-Bis(trifluoromethyl)Dhenvn-3-(2-r(S)- cvclohexyl(methoxy)methvn-5-(trifluoromethyl)benzyl)-4-methyl-1.3-oxazolidin-2-one

The title compound was prepared according to the procedure described for Example 1 using (4R,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1 ,3-oxazolidin-2-one (Preparation 16) and (S)-2-bromomethyl-1-(cyclohexyl-methoxy-methyl)-4- trifluoromethyl-benzene (Preparation 9). ¹H NMR (400 MHz, CDCI₃) δ 7.9 (s), 7.79 (s), 7.60 (s), 7.53 (s), 5.68 (d, J=7.9Hz), 4.99 (d, J=15.8Hz), 4.35 (d, J=15.6Hz), 3.20 (s), 0.81 (d, J=6.4Hz). MS (ES⁺) CaIc: 597.2, Found: 642 (M -1 + formic acid (+ 46)).

Example 4: (4R.5SV5-f3.5-BisftrifluorOmethyl)phenyll-3-(2-f(R)- cvclohexyl(methoxy)methvn-5-(trifluoromethyl)benzyl)-4-methyl-1.3-oxazolidin-2-one

The title compound was prepared according to the procedure described in Example 1 using (4R,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (Preparation 16) and (R)-2-bromomethyl-1-(cyclohexyl-methoxy-methyl)-4- trifluoromethyl-benzene (Preparation 20). ¹H NMR (400 MHz, CDCI₃) δ 7.9 (s), 7.80 (s), 7.62 (s), 7.60 (s), 5.72 (d, J=7.9Hz), 4.95 (d, J=16.2Hz), 4.35 (d, J=16Hz), 4.18 (d, J=7.1Hz), 3.18 (s), 0.78 (d, J=6.6Hz). MS (ES⁺) CaIc: 597.2, Found: 572 (M - 25 (- CO)).

Example 5: (4R.5R)-5-f3.5-Bis(trifluoromethyl)phenvn-3-J2-r(S)- cvclohexyl(methoxy)methvn-5-(trifluoromethvπbenzyl>-4-methyl-1.3-oxazolidin-2-one

The title compound was prepared according to the procedure described in Example 1 and using (4R,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1 ,3-oxazolidin-2-one (Preparation 17) and (S)-2-bromomethyl-1-(cyclohexyl-methoxy-methyl)-4- trifluoromethyl-benzene (Preparation 9). ¹H NMR (400 MHz, CDCI₃) δ 7.92 (s), 7.83 (s), 7.35 (S), 5.18 (d, J=7.1Hz), 4.75 (d, J=16.4Hz), 4.60 (d, J=16.4Hz), 4.13 (d, J=7.5Hz), 3.18 (s), 1.36 (d, J=6.2Hz). MS (ES⁺) CaIc: 597.2, Found: 642 (M -1 + formic acid (+ 46)).

Example 6: (4R.5R)-5-r3.5-Bis(trifluoiOmethyl)phenvn-3-l2-r(R)- cyclohexyl(methoxy)methvn-5-(trifluoromethyl)benzyl)-4-methyl-1.3-oxazolidin-2-one

The title compound was prepared according to the procedure described in Example 1 and using (4R,5R)-5-[3_!5-bis(trifluoromethyl)phenyl]-4-methyl-1 ,3-oxazolidin-2-one (Preparation 17)and (R)-2-bromomethyl-1 -(cyclohexyl-methoxy-methyl)-4- trifluoromethyl-benzene (Preparation 20). ¹H NMR (400 MHz, CDCI₃) δ 7.9 (s), 7.79 (s), 7.33 (s), 5.18 (d, J=6.2Hz), 4.82 (d, J=16.1Hz), 4.60 (d, J=16.1Hz), 4.11 (d, J=7.9Hz), 3.11 (S)₁ 1.42 (d, J=6.2Hz). MS (ES⁺) CaIc: 597.2

Example 7; (4S.5SV5-r3.5-Bis(trifluoromethyl)phenyll-3-(2-KS)- cvclohexyl(methoxy)methvn-5-(trifluoromethyl)benzyl)-4-methyl-1_l3-oxazolidin-2-one

The title compound was prepared according to the procedure described in Example 1 using (4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (Preparation 18) and (S)-2-bromomethyl-1-(cyclohexyl-methoxy-methyl)-4- trifluoromethyl-benzene (Preparation 9). ¹H NMR (400 MHz₁ CDCI₃) δ 7.9 (s), 7.79 (s), 7.33 (S), 5.18 (d, J=6.2Hz), 4.82 (d, J=16.1Hz), 4.60 (d, J=16.1Hz), 4.11 (d, J=7.9Hz), 3.11 (S), 1.42 (d, J=6.2Hz). MS (ES⁺) CaIc: 597.2, Found: 572 (M - 25 (-CO)). Example 8: f4S.5SV5-f3.5-Bisftrifluoromethyl)phenvn-3-(2-f(RV cvclohexvl(methoxv)methvi1-5-(trifluoromethvl)benzvl)-4-methvl-1.3-oxazolidin-2-one

The title compound was prepared according to the procedure described in Example 1 using (4S,5S)-5-[3_l5-bis(trifluoromethyl)phenyl]-4-methyl-1 ,3-oxazolidin-2-one (Preparation 18) and (R)-2-bromomethyl-1-(cyclohexyl-methoxy-methyl)-4- trifluoromethyl-benzene (Preparation 20). ¹H NMR (400 MHz₁ CDCI₃) δ 7.92 (s), 7.83 (S), 7.35 (S), 5.18 (d, J=7.1Hz), 4.75 (d, J=16.4Hz), 4.60 (d, J=16.4Hz), 4.13 (d, J=7.5Hz), 3.18 (s), 1.36 (d, J=6.2Hz). MS (ES⁺) CaIc: 597.2, Found: 598.4 (M -1 + formic acid (+ 46)).

Example 9: (4S.5R)-5-r3.5-Bis(trifluoromethyl)phenvn-3-(2-r(S)- cvclohexyl(methoxy)methvn-5-(trifluoromethyl)benzyl)-4-methyl-1.3-oxazolidin-2-one and (4S.5RV5-r3.5-Bisftrifluoromethyl)phenvn-3-{2-r(R)-cvclohexyl(methoxy)methvn-5- (trifluoromethyl)benzylM-methyl-1.3-oxazolidin-2-one

STEP A: Preparation of [2-(tert-butyl-dirπethyl-silanyloxymethyl)-4-trifluoromethyl- phenyl]-cyclohexyl-methanol

To a solution of (2-brorπo-5-trifluoromethyl-benzyloxy)-tert-butyl-dimethyl-silane (58 mg 0.16 mmol) in THF (0.4 ml) at O⁰C was added i-PrMgCI/LiCI (0.3 ml of 1.3M solution, 0.39 mmol). The mixture was stirred at O⁰C for 3 hours and cyclohexanecarboxaldehyde (60 mg, 0.5 mmol) was added. The mixture was stirred at O⁰C and warmed to room temperature over a 2 hour period. The reaction was diluted with ethyl acetate and quenched with aqueous NH₄CI. The organic layer was filtered through a short pad of Na₂SO₄, and concentrated in vacuo. The residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-20% ethyl acetate in heptane) to afford the alcohol as a colorless oil (70.2 mg). MS (ES⁺) CaIc: 402, Found: 385 (M + 1 - 18 (-OH)).

STEP B: Preparation of 2-bromomethyl-1-(cyclohexyl-methoxy-methyl)-4-trifluoromethyl- benzene

Using the procedures described in Example 1 , the alcohol from Example 9, Step A was converted to the desired title compound. ¹H NMR (400 MHz, CDCI₃) δ ppm 1.1 (m, 4 H) 1.3 (m, 2 H) 1.6 (m, 3 H) 1.7 (m, 1 H) 2.0 (d, J = 12.6, 1 H) 3.2 (s, 3 H) 4.2 (d, J = 7.9, 1 H) 4.5 (d, J = 10.3 Hz, 1 H ) 4.6 (d, J = 10.3 Hz, 1 H ) 7.4 (d, J = 8.3 Hz, 1 H) 7.5 (d, J = 8.3 Hz, 1 H) 7.6 (s, 1 H). STEP C: Preparation of (4S.5R)-5-r3.5-Bis(trifluoromethyl)phenvn-3-(2-rf SV cvclohexyl(methoxy)methyl1-5-(trifluoromethyl)benzyl)-4-methyl-1.3-oxazolidin-2-one and (4S.5RV5-r3.5-Bis(trifluoromethyl)phenyll-3-(2-f(R)-cvclohexyl(methoxy)metrivn-5- (trifluoromethyl)benzyl)-4-methyl-1.3-oxazolidin-2-one

The title compound was prepared according to the procedure described in Example 1 and using the oxazolidinone from (Preparation 15) and the bromide from Example 9, Step B. ¹H NMR (400 MHz, CDCI₃) δ 7.91 (s), 7.83 (s), 7.80 (s), 7.66 (s), 5.72 (d, J=8.1 Hz), 5.68 (d, J=7.9Hz), 4.21 (d, J=7.1 Hz), 4.18 (d, J=7.3Hz), 3.20 (s), 3.16 (s), 0.89 (d, J=6.6Hz), 0.86 (d, J=6.6Hz), 0.81 (d, J=6.6Hz), 0.78 (d, J=6.6Hz). MS (ES⁺) CaIc: 597.2, Found: 572 (M - 25 (-CO)).

According to the procedure described in Example 9, and using corresponding aldehyde and alkylating reagents, Examples 10 to 23 were made (wherein the arrow depicts the point of attachment):

According to the procedure described in Example 9, and using the oxazolidinone from Preparation 16 and the corresponding aldehyde and alkylating reagents, Examples 24 to 25 were made (wherein the arrow depicts the point of attachment):

Example 26: Methyl 44f2-(((4S.5R)-5-r3.5-bis(trifluoromethyl)phenvn-4-methyl-2-oxo-

1.3-oxazolidin-3-yl>methyl)-4-(trifluoromethyl)phenyll(methoxy)methyl)piperidine-1- carboxylate

STEP A: Preparation of tert-butyl 4-{[2-({(4S,5R>-5-[3,5-bis(trifluoromethyl)phenyl]-4- methyl-2-oxo-1 ,3-oxazolidin-3-yl}methyl)-4-

(trifluoiOmethyl)phenyl](methoxy)methyl}piperidine-1-carboxylate

The title compound was prepared according to the procedure described in Example 9, and using {[2-bromo-5-(trifluoromethyl)benzyl]oxy}(triisopropyl)silane and tert-butyl 4- formylpiperidine-1-carboxylate and the oxazolidinone (Preparation 15). MS (ES⁺) CaIc: 698.2, Found: 699.5 (M + 1).

STEP B: Preparation of (4S,5R)-5-[3,5-bis(trifluoromethyl) 2-[methoxy(piperidin-4- yl)methyl]-5-(trifluoromethyl)benzyl}-4-methyl-1,3-oxazolidin-2-one

To a solution of tert-butyl 4-{[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2- oxo-1 ,3-oxazolidin-3-yl}methyl)-4-(trifluoiOmethyl)phenyl](methoxy)methyl}piperidine-1- carboxylate (Example 26, Step A, 103 mg, 0.15 mmol) in methylene chloride (0.2 ml) at room temperature was added trifluoroacetic acid (0.2 ml). The mixture was stirred at room temperature for 1.5 hours. Solvent and TFA were removed in vacuo. The residue was dissolve in methanol and filtered through an ion exchange SCX cartridge. The product was released with ammonia in methanol (6 ml_) to afford a colorless oil (81 mg, 92%) MS (ES⁺) CaIc: 598.2 Found: 599.4 (M + 1).

STEP C: Preparation of methyl 4-{[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4- methyl-2-oxo-1 ,3-oxazolidin-3-yl}methyl)-4-

(trifluoromethyl)phenyl](methoxy)methyl}piperidine-1-carboxylate

To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl) 2-[methoxy(piperidin-4-yl)methyl]-5- (trifluoromethyl) benzyl}-4-methyl-1 ,3-oxazolidin-2-one (16 mg, 0.027 mmol) in methylene chloride (0.4 ml) at room temperature was added diisopropylethylamine (7.4 mg, 0.057 mmol) followed by methyl chloroformate (6 mg, 0.06 mmol). The mixture was stirred at room temperature for 3 hours. The reaction was diluted with ethyl acetate and washed with 1 N HCI, water, and brine, dried over Na₂SO₄ and concentrated in vacuo to yield a colorless oil (16 mg). The residue was purified by chromatography over 12+S Biotage silica column (eluted with 20-100% ethyl acetate in heptane) to afford a colorless oil (13.1 mg, 75%) ¹H NMR (400 MHz, CDCI₃) δ 7.91 (s), 7.79 (s), 7.65 (s), 7.63 (s), 5.74 (d, J=8.1Hz), 5.66 (d, J=7.7Hz), 4.99 (d, J=15.6Hz), 4.90 (d, J=16.0Hz), 3.68 (s), 3.67 (s), 3.21 (s), 3.19 (s), 0.83 (d, J=6.6Hz), 0.77 (d, J=6.6Hz). MS (ES⁺) CaIc: 656.2, Found: 657.4 (M + 1 ).

According to the procedure described in Example 26, Step C, and using corresponding acylating or alkylating reagents, Examples 27 to 30 were prepared (wherein the arrow depicts the point of attachment):

Example 31 : (4S.5R)-5-r3.5-bis(trifluoromethvnphenvn-3-F2-(1-cvclohexyl-1- methoxyethyl)-5-(trifluoromethvπbenzyll-4-methyl-1.3-oxazolidin-2-one

STEP A: Preparation of 1-(2-((tert-butyldimethylsilyloxy)methyl)-4- (trifluoromethyl)phenyl)-1-cyclohexylethanol

To a solution of [2-(tert-butyl-dimethyl-silanyloxymethylM-tπ?luoromethyl-phenyl]- cyclohexyl-methanone (300 mg, 0.75 mmol) in THF (3 ml) at O⁰C was added methylmagnesium bromide (0.5 ml of 3M solution, 1.5 mmol) in ether. The mixture was stirred at room temperature for 3 hours and then quenched with aqueous NH₄CI solution and extracted with ethyl acetate. Combined organic layers (200 ml_) were washed with brine, dried over MgSO₄ and concentrated in vacuo. The crude product was purified on Biotage column (40+M), eluting with ethyl acetate-heptane, starting with 0-20% (10CV), 20% (2CV) to afford 250 mg of the desired product as an oil. ¹H NMR (400 MHz, CDCI₃) δ 7.69 (brs, 1H), 7.54 (m, 2H), 4.86 (d, J=13.1Hz, 1 H), 4.76 (d, J=13.1 Hz, 1 H), 1.58 (S, 3H), 0.95 (s, 9H), 0.14 (s, 6H).

STEP B: Preparation of 1-[2-(bromomethyl)-4-(trifluoromethyl)phenyl]-1-cyclohexylethyl methyl ether

Using the procedures described in Example 1 , the alcohol from Example 31 , Step A was converted to the desired title compound. 50% yield. ¹H NMR (400 MHz, CDCI₃) δ 7.76 (m ,1H), 7.44 (m, 1H), 7.24 (d, J=8.5Hz), 5.26 (d, J=IOHz), 4.97 (d, J=IOHz), 3.03 (s, 3H), 2.12 (m, 1 H), 1.99 (m, 1 H), 1.80 (m, 1 H), 1.68-1.56 (m, 2H), 1.54 (s, 3H), 1.26 (m, 2H), 1.19-1.02 (m, 3H).

STEP C: Preparation of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1-cyclohexyl-1- methoxyethylJ-δ-ttrifluoromethylJbenzyll^-methyl-I .S-oxazolidin^-one

The title compound was prepared according to the procedure described in Example 1 and using the oxazolidinone (Preparation 15) and the bromide from Example 31, Step B. ¹H NMR (400 MHz, CDCI₃) δ 7.91 (s), 7.83 (s), 7.80 (s), 7.63 (s), 5.80 (d, J=7.9Hz), 5.68 (d, J=7.9Hz), 5.08 (d, J=16.8Hz), 5.05 (d, J=17.8Hz), 3.08 (s), 3.05 (s), 1.57 (s), 1.56 (s), 0.80 (d, J=6.9Hz), 0.75 (d, J=6.6Hz). MS (ES^") CaIc: 611.2, Found: 656.2 (M 1 + formic acid (+ 46)).

Example 32: (4R.5SV4-r3.5-bisαrifluoromethyl)phenyll-1-(2-f(S)- cvclohexyKmetho^methvn-δ^trifluoromethvDbenzvD-δ-methylimidazolidin^-one

STEP A: Preparation of benzyl {(1S,2R)-2-amino-2-[3,5-bis(trifluoromethyl)phenyl]-1- methylethyljcarbamate

To a solution of benzyl {(1S,2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1- methylethyljcarbamate (102 mg, 0.24 mmol) in methylene chloride (1 ml) at O⁰C was added triethylamine (50 mg, 0.5 mmol) followed by methanesulfonyl chloride (53 mg, 0.47 mmol). The mixture was stirred at O⁰C for 24 hours. Additional methanesulfonyl chloride (0.035 ml) and triethylamine (0.07 ml) were added and the mixture was stirred at O⁰C for 4 hours. Solvent was removed and the residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-40% ethyl acetate in heptane) to afford (1 S,2S)-1 -(3,5-bis(trifluoromethyl)phenyl)-2-(benzyloxycarbonyl)piOpyl methanesulfonate as a colorless oil (48 mg, 40%) MS (ES⁺) CaIc: 499.1 , Found: 500.2 (M +1 ).

A mixture of (1S,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-(benzyloxycarbonyl)propyl methane sulfonate (48 mg, 0.096 mmol) and sodium azide (18.7 mg, 0.29 mmol) in DMF (0.5 ml) was stirred at 6O⁰C overnight. Water was added and the mixture was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in heptane) to afford benzyl (1 R,2S)-1 -(3,5-bis(trifluoromethyl)phenyl)-1 -azidopropan-2-ylcarbamate as a white solid (23.7mg, 55%) MS (ESO CaIc: 446.12, Found: 445.3 (M -1).

To a solution of benzyl (1R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-1-azidopropan-2- ylcarbamate (325 mg, 0.728 mmol) in THF (0.5 ml) at room temperature was added triphenylphosphine (229 mg, 0.874 mmol). The mixture was stirred at room temperature for 15 min and water was added. The mixture was stirred at 6O⁰C for overnight. Solvent was removed and the residue was dissolved in methanol, divided into three portions and each portion was loaded on an ion exchange SCX cartridge and washed with methanol. The amine was released with 2M NH₃ in methanol to yield the title compound as a colorless oil which solidified on standing (313 mg, 100%). MS (ES⁺) CaIc: 420.1 , Found: 421.3 (M +1).

STEP B: Preparation of tert-butyl {(1 R,2S)-2-amino-1-[3,5- bis(trifluoromethyl)phenyl]propyl}carbamate

To a solution of benzyl {(1S,2R)-2-amino-2-[3,5-bis(trifluoromethyl)phenyl]-1- methylethyl}carbamate (117 mg, 0.28 mmol) in dichloromethane (2ml) at room temperature was added triethylamine (60 mg, 0.6 mmol) and di-tert-butyldicarbonate (87 mg, 0.4 mmol). The mixture was stirred at room temperature for overnight. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated in vacuo to yield benzyl tert-butyl {(1R,2S)-1-[3,5-bis(trifluoromethyl)phenyQpropane-1,2-diyl}biscarbamate as a white solid which is not readily soluble in methanol, ethyl acetate or dichloromethane (181 mg). (ES⁺) CaIc: 520.2, Found: 421.3 (M +1 - BOC (-100)).

The benzyl tert-butyl {(1 R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]propane-1 ,2- diyl}biscarbamate (155 mg, 0.30 mmol) in methanol (30 ml) was hydrogenated with Pd/C (30 mg) under 50 psi at room temperature for 12h. The reaction was filtered through Celite. The filtrate was concentrated in vacuo and purified by chromatography over 12+S Biotage silica column (eluted with 1-10% methanol in methylene chloride) to yield the title compound as a white solid (78 mg, 67%). (ES⁺) CaIc: 386.1 , Found: 387.3 (M +1).

STEP C: Preparation of tert-butyl [(1 R,2S)-1 -[3,5-bis(trifluoromethyl)phenyl]-2-({2-[(S)- cyclohexyl(methoxy)methyl]-5-(trifluoromethyl)benzyl}amino)propyl]carbamate

A mixture of 2-[(S)-cyclohexyl(methoxy)methyl]-5-(trifluoromethyl)benzalclehyde (35 mg, 0.12 mmol) and tert-butyl {(1R,2S)-2-amino-1-[3,5- bis(trifluoromethyl)phenyl]propyl}carbamate (43 mg, 0.11 mmol) in ethanol was stirred at room temperature overnight. Sodium borohydride (25 mg, 0.66 mmol) was added and the mixture was stirred at room temperature for 2h. Solvent was removed and the residue was purified by chromatography over 12+S Biotage silica column (eluted with 0- 30% ethyl acetate in heptane) to afford a colorless oil (34.3 mg, 46%). (ES⁺) CaIc: 670.3, Found: 671.5 (M +1 ).

STEP D: Preparation of (1 R,2S)-1 -[3,5-bis(trifluoromethyl)phenyl]-N~2~-{2-[(S)- cyclohexyl(methoxy)methyl]-5-(trifluoromethyl)benzyl}propane-1,2-diamine

To a solution of tert-butyl [(1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-({2-[(S)- cyclohexyl(methoxy)methyl]-5-(trifluoromethyl)benzyl}amino)piOpyl]carbamate (40 mg, 0.06 mmol) in methylene chloride (0.2 ml) at room temperature was added TFA (0.1 ml). The mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was dissolved in methanol and filtered through SCX cartridge, washed with methanol (2x1 CV) and released with ammonia in methanol (5 ml.) to yield a pale yellow oil (46 mg). (ES⁺) CaIc: 570.2, Found: 571.4 (M +1).

STEP E: Preparation of (4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{2-[(S)- cyclohexyKmethoxyJmethylJ-S^trifluorOmethyObenzylJ-δ-methylimidazolidin^-one

To a solution of (1R,2S)-1-[3,5-bis(tiifluoromethyl)phenyl]-N~2~-{2-[(S)- cyclohexyl(methoxy)-methyl]-5-(trifluoromethyl)benzyl}propane-1 ,2-diamine (22 mg, 0.039 mmol) in methylene chloride (0.3 ml) at O⁰C was added N,N-diisopropylethylamine (0.04 ml, 0.2 mmol) followed by triphosgene (13 mg, 0.043 mmol). The mixture was stirred at O⁰C for 30 min and then diluted with ethyl acetate. The mixture was washed with NaHCO₃ and brine, filtered through a short pad of Na₂SO₄. The filtrate was concentrated in vacuo. The residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in heptane) to afford a colorless oil (14.3 mg, 61%). ¹H NMR (400 MHz, CDCI₃) δ 7.87 (s), 7.80 (s), 5.34 (brs), 5.05 (d, J=8.7Hz), 4.82 (d, J=16.2Hz), 4.30 (d, J=16.2Hz), 4.20 (d, J=7.1Hz), 3.17 (s), 0.70 (d, J=6.6Hz). (ES⁺) CaIc: 596.2, Found: 597.3 (M +1).

Preparation 21 : i-^^bromomethylM-ftrifluoromethvDphenvD-i-methoxycvcloheptane

To a stirred solution of 2-(1-methoxycycloheptyl)-5-(trifluoromethyl)phenyl)methanol (2.03 g, 6.71 mmol) in methylene chloride (20 mL) was added carbon tetrabromide (3.34 g, 10.1 mmol). A solution of triphenylphosphine (3.54 g) in methylene chloride (15 mL) was added. The mixture was stirred at room temperature for 1.5 hours then absorbed onto a silica gel cartridge (10gm). The product was purified by chromatography on silica gel eluting with The product was purified by chromatography on silica gel (Redipak 80 g silica column) eluting with an ethyl acetate/heptane gradient (2-10%) to yield the desired compound as a colorless oil (2.52 gm). 1H NMR (400 MHz, CDCI₃): δ ppm: 7.81 (m, 1H), 7.47 (m, 1H), 7.37 (d, J=8.5Hz, 1H), 5.11 (s, 2H), 3.02 (s, 3H), 2.24 (m, 2H), 2.04 (m, 2H), 1.84 (m, 2H), 1.74-1.52 (m, 6H).

Example 33: (4S.5R)-3-<2-( 1 -methoxycvcloheptyl V5-(trifluoromethvnbenzvn-5-r3.5- bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one

To a stirred solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3- oxazolidin-2-one (Preparation 15, 81 mg, 0.26mmol) in DMF (1 mL) was added sodium hydride (60% dispersion in mineral oil, 13 mg). The mixture was stirred at room temperature for 20 minutes before adding a solution of 1-(2-(bromomethyl)-4- (trifluoromethyOphenyO-i-methoxycycloheptane (79 mg. 0.22mmol) in DMF (0.9 mL). After stirring at room temperature for 16 hours, water was added and the mixture was extracted with ethyl acetate /heptane (1 :1). The organic layer was washed with 2N HCI₁ water (2x), and brine, dried over anhydrous sodium sulfate and concentrated to dryness under vacuum. The product was purified by chromatography on silica eluting with an ethyl acetate/heptane gradient (5-50%) to yield the desired compound as a colorless gum (83mg). LC-MS (ES⁺) CaIc: 597.19, Found: 642.4 (M+HCO₂ ) and 566.3 (M- OCH₃). ¹H NMR (400 MHz, CDCI₃) δ ppm: 7.90 (1H₁ s), 7.83 (2H, s), 7.63 (1H, s), 7.51 (d, J=8.3Hz, 1H)₁ 7.44 (d, J=8.3Hz, 1H), 5.81 (d, J=7.9Hz, 1H), 5.04(d, J=17.2Hz, 1H), 4.97 (d, J=17.2Hz, 1H), 4.12 (m, 1H), 3.00 (s, 3H), 2.24 (m, 1H), 2.17 (m, 1H), 2.05 (m, 1 H), 2.02 (m, 1 H)₁ 1.81 (m, 2H)₁ 1.75-1.50 (m, 6H), 0.77 (d, J=6.4Hz, 3H).

Example 34: (4R.5S)-3-(2-(1 -methoxycvcloheptvO-δ-ftrifluoromethvObenzvO-δ-re.δ- bis(trifluoromethv0phenyl)-4-methyloxazolidin-2-one

This compound was prepared in a manner exactly analogous to that described for example 33 using (4R,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-4-rnethyl-1 ,3-oxazolidin-2- one. LC-MS (ES^") CaIc: 597.19, Found: 642.2 (M+HCO₂ ). ¹H NMR (400 MHz, CDCI₃) δ ppm: 7.90 (1H₁ s), 7.83 (2H₁ s), 7.63 (1H₁ s), 7.51 (d, J=8.3Hz, 1H), 7.44 (d, J=8.3Hz, 1H), 5.81 (d, J=7.9Hz, 1H)₁ 5.04(d, J=17.2Hz, 1H), 4.97 (d, J=17.2Hz, 1H), 4.12 (m, 1H), 3.00 (s, 3H), 2.24 (m, 1H), 2.17 (m, 1H)₁ 2.05 (m, 1H), 2.02 (m, 1H), 1.81 (m, 2H), 1.75-1.50 (m, 6H), 0.77 (d, J=6.4Hz, 3H).

Example 35: (4R5ffl-3-(2-(1 -methoxycvcloheptvn-δ-rtrifluoromethvDbenzylVδ-O.δ- bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one

This compound was prepared in a manner analogous to that described in example 33 using (4R,5f?)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1 ,3-oxazolidin-2-one. LC-MS (ES⁺) CaIc: 597.19, Found: 642.2 (M+HCO₂ ^") and 607.3 (M+OCH₃). ¹H NMR (400 MHz, CDCI₃) δ ppm: 7.92 (1 H₁ s), 7.86 (s, 2H)₁ 7.44 (m, 1 H), 7.40 (d, J=8.3Hz, 1 H), 7.32 (brs, 1H), 5.22 (d, J=6.2Hz, 1H), 5.05 (d, J=17.4Hz, 1H), 4.91 (d, J=17.4Hz, 1H), 3.67 (m, 1H), 3.01 (S₁ 3H), 2.21 (m, 1H), 2.18 (m, 1H), 2.07-1.97 (m, 2H), 1.88-1.74 (m, 2H), 1.74-1.51 (m, 6H).

Example 36: (R)-3-(2-(1-methoxycvcloheptyl)-5-ftrifluoromethyl)benzyl)-4- beπzyloxazolidin-2-one

To a stirred solution of (R)-4-benzyloxazolidin-2-one (74mg) under nitrogen in DMF (1.6 ml_) was added sodium hydride (60% dispersion in oil, 25 mg). The mixture was stirred at room temperature for 20 minutes before adding a solution of 1-(2-(bromomethyl)-4-

(trifluoromethyl)phenyl)-1-methoxycycloheptane (117 mg) in DMF (0.9 ml_). After 72 hours, water (5 drops) was added and the mixture was extracted with ethyl acetate

/heptane (1 :1). The organic layer was washed with water (3x) and brine, dried over anhydrous sodium sulfate and concentrated to dryness under vacuum. The product was purified by chromatography on silica (Redipak 4gm column) eluting with an ethyl acetate/heptane gradient (5-35%) to yield the desired compound as a colorless gum (44mg).

LC-MS (ES⁺) CaIc: 461.52, Found: 923.6 (M₂ + H⁺) ¹H NMR (400 MHz, CDCI₃) δ ppm: 7.61 (1H₁ s), 7.51 (m, 1H), 7.44 (d, J=8.5Hz, 1H), 7.33-7.22 (m, 5H), 7.06 (m, 2H), 5.10 (d, J=17.2Hz, 1H), 4.97 (d, J=17.2Hz, 1H), 4.26 (m, 1H), 4.16 (dd, J=9.0, 4.8Hz, 1H), 3.95 (m, 1 H), 3.04 (s, 3H), 3.03 (m, 1H), 2.64 (dd, J=13.5, 9.9Hz, 1H), 2.27 (m, 1H), 2.22 (m, 1 H)₁ 2.11-2.00 (m, 2H), 1.90-1.77 (m, 2H), 1.77-1.53 (m, 4H).

Example 37: (S)-3-(2-(1 -methoxycvcloheptvD-S-ftrifluoromethvDbenzylM- benzyloxazolidin-2-one

To a stirred solution of (S)-4-benzyloxazolidin-2-one (75mg) under nitrogen in DMF (1.6 mL) was added sodium hydride (60% dispersion in oil, 26 mg). The mixture was stirred at room temperature for 20 minutes before adding a solution of 1-(2-(bromomethyl)-4- (trifluoromethyl)phenyl)-1-methoxycycloheptane (118 mg) in DMF (0.9 mL). After 16 hours water (5 drops) was added and the mixture was extracted with ethyl acetate/heptane (1 :1 ). The organic layer was washed with water (3x) and brine, dried over anhydrous sodium sulfate and concentrated to dryness under vacuum. The product was purified by chromatography on silica (Redipak 4gm column) eluting with an ethyl acetate/heptane gradient (5-35%) to yield the desired compound as a colorless gum (44mg).

LC-MS (ES⁺) CaIc: 461.52, Found: 923.8 (M₂ + H⁺) ¹H NMR (400 MHz, CDCI₃) δ ppm: 7.61 (1 H, s), 7.51 (m, 1H), 7.44 (d, J=8.5Hz, 1 H), 7.33-7.22 (m, 5H), 7.06 (m, 2H), 5.10 (d, J=17.2Hz, 1H), 4.97 (d, J=17.2Hz, 1H), 4.26 (m, 1H), 4.16 (dd, J=9.0, 4.8Hz, 1H), 3.95 (m, 1H), 3.04 (s, 3H), 3.03 (m, 1 H), 2.64 (dd, J=13.5, 9.9Hz, 1 H), 2.27 (m, 1H), 2.22 (m, 1 H), 2.11 -2.00 (m, 2H), 1.90-1.77 (m, 2H)₁ 1.77-1.53 (m. 4H).

Preparation 22: 5-(3.5-bis(trifluoromethyl)phenyl)oxazolidin-2-one This compound was prepared by a method closely similar to that described in patent application WO2006/014357.

STEP A: Preparation of 1-(3.5-bis(trifluoromethyl)phenyl)-2-nitroethanol 3,5-Bistrifluoromethylbenzaldehyde (4 g, 16.5 mmol) was dissolved in ethanol (24OmL) and nitromethane (56 mL, 97.90 mmol) was added. After cooling to O⁰C 10 % aqueous NaOH solution (17.3mmol, 6.9mL) was added. The reaction mixture was stirring for 1 hour at O⁰C. Aqueous acetic acid (2%, 105 mL) was added and the mixture stirred for 1 hour at room temperature. The mixture was partitioned between water and ethyl acetate and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with water followed by brine. It was dried over sodium sulfate and the solvent was distilled off under reduced pressure to give the desired material (4.5 g, 90%). 1H NMR (400 MHz₁ CDCI₃): δ 7.9 (m, 3H), 5.6 (m, 1H), 4.55 (m, 2H), 3.44 (s, 1H).

STEP B: Preparation of 1-(3.5-bis(trifluoromethyl)phenyl)-2-aminoethanol

A stirred solution of 1-(3,5-bis(trifluoromethyl)phenyl)-2-nitroethanol (5 g, 16.5 mmol) in methanol (60 mL) and 40% formic acid (30 mL) was sparged for 30 min with argon then Raney-nickel (3.0 g) was added. The reaction mixture was stirred for 16 hours at room temperature under a hydrogen atmosphere using a balloon. The catalyst was removed by filtration through celite and and the solvent removed under vacuum. The gummy residue was treated with 28% aqueous ammonia to a pH of 9-10 and then diluted with water. The mixture was extracted with ethyl acetate and the organic part was washed with water followed by brine. The combined organics was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The crude solid material was washed with hexane to give the title compound (3.2 g, 71 %). ¹H NMR (400 MHz, CDCI₃): δ 7.63 (m, 2H), 7.78 (m, 1 H), 4.71 (m, 1 H)₁ 3.13 (m, 1 H)

STEP C: Preparation of 5-(3.5-bis(trifluoromethyl)phenyl)oxazolidin-2-one To a stirred suspension of triphosgene (1.7 g, 5.8 mmol) in 40 ml dichloromethane was added 1-(3,5-bis(trifluoromethyl)phenyl)-2-aminoethanol (3.2 g, 11.7 mmol) in dichloromethane (40 ml) at O⁰C slowly followed by diisopropylethylamine (12.5 ml, 70 mmol) at 0⁰C. The reaction mixture was stiired for 1 h at O⁰C and diluted with water. The mixture was extracted with dichloromethane and the organic part was washed with water followed by brine. The combined organics was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The crude reaction mixture was purified over silica gel using 20-30 % ethyl acetate-hexane to obtain the title compound (2.61 g, 75 %). ¹H NMR (400 MHz, DMSO-d6): δ 7.89 (m, 1H), 7.83 (m, 2H), 5.74 (t, J=8.0 Hz, 1H), 5.45 (s, 1H), 4.10 (t, J=8.4 Hz, 1 H), 3.51 (m, 1H).

Example 38: (f?SV-3-(2-(1-methoxycvcloheptyl)-5-(trifluoromethyl)benzvn-5-(3.5- bis(trifluoromethyl)phenyl)oxazolidin-2-one

To a stirred solution of 5-(3,5-bis(trifluoromethyl)phenyl)oxazolidin-2-one (79 mg) under nitrogen in DMF (1.5 ml.) was added sodium hydride (60% dispersion in mineral oil, 25 mg). After stirring at room temperature for 20 minutes a solution of 1-(2-(bromomethyl)- 4-(trifluoromethyl)phenyl)-1-methoxycycloheptane (112 mg) in DMF (0.9 mL) was added. After stirring for 16 hours water (5 drops) was added and the mixture was diluted with ethyl acetate/heptane (1 :1). The organic layer was washed with brine, dried over sodium sulfate and evaporate to dryness under vacuum. The product was purified by chromatography on silica (Redipak 4gm column) eluting with an ethyl acetate/heptane gradient (5-35%) to yield the desired compound as a colorless gum (73mg). LC/MS ES- CaIc 583.18, Found: 628.4 (M+HCOO ). ¹H NMR (400 MHz, CDCI₃): δ ppm: 7.91 (s, 1 H), 7.85 (s, 2H), 7.48 (d, J=8.3Hz, 1H), 7.46 (s, 1H), 7.42 (d, J=8.3Hz, 1 H), 5.71 (m, 1H), 5.06 (d, J=16.6Hz, 1H), 5.01 (d, J=16.6Hz, 1 H), 3.96 (m, 1 H), 3.34 (m, 1 H), 2.97 (s, 3H), 2.22-2.12 (m, 2H), 2.04-1.95 (m, 2H), 1.87-1.75 (m, 2H), 1.74-1.64 (m, 2H), 1.64-1.50 (m, 4H). Examples 39: Trans-3-(3.5-bisttrifluorOmethvnbenzyl)-5-(2-((S)- cvclohexyl(methoxy)methyl)-5-(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one

STEP A: Preparation of (S)-2-(cyclohexyl(methoxy)methyl)-5- (trifluoromethyl)benzaldehyde

To a solution of (S)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-phenyl]-methanol (390mg, 1.29mmol) in dichloromethane (1OmL) was added the Dess-Martin periodinane (711 mg, 1.68mmol). After stirring at room temperature for 45 minutes aqueous sodium hydroxide (1 M₁ 10 ml_) was added. The mixture was extracted with ethyl acetate (3 x 20 ml) and the combined organics dried with sodium sulfate and concentrated under reduced pressure to give 400 mg of a pale yellow oil. The product was purified by chromatography on silica (Redipak 4gm column) eluting with an ethyl acetate/heptane gradient (0-15%) to yield the desired compound as a colorless oil (343mg). ¹H NMR (400 MHz, CDCI₃): δ ppm: 10.42 (s, 1H), 8.16 (m, 1H), 7.82 (m, 1H), 7.68 (d, J=8.1Hz, 1 H), 4.74 (d, J=6.4Hz, 1 H), 3.23 (s, 3H), 1.87 (m, 1 H), 1.74 (m, 1 H), 1.71-1.55 (m, 3H), 1.38 (m, 1H), 1.20-1.06 (m, 5H).

STEP B: Preparation of 1-(2-((S)-cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)phenyl)- 2-nitropropan-1-ol

To a solution of the product from Step A (290mg, 0.966mmol) in ethanol (3 ml_) was added nitroethane (341 mg, 4.54mmol) followed by sodium hydroxide solution (2.5M, 0.464mL, 1.16mmol). The solution stirred at room temperature for 16 hours then the solvent was removed under reduced pressure. Water (1 OmL) was added followed by 2N HCI (1mL). The mixture was extracted with of ethyl acetate (3 x 25 ml), the organics combined and dried with sodium sulfate. Solution was concentrated under reduced pressure to give 330 mg of a clear oil. The product was purified by chromatography on silica (Redipak 12gm column) eluting with an ethyl acetate/heptane gradient (0-40%) to yield the desired nitro compound as a clear gum (60mg).

STEP C: Preparation of 2-amino-1-(2-((S)-cyclohexyl(methoxy)methyl)-5- (trifluoromethyl)phenyl)propan-1-ol

1 -(2-((S)-cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)phenyl)-2-nitropropan-1 -ol (158mg, 0.42mmol) was dissolved in a mixture of 10 ml of methanol (1OmL) and formic acid (0.5mL). The solution was pumped through a Raney nickel catalyst cartridge at 5O⁰C using an H-cube® apparatus (ThalesNano Nanotechnology Inc., Monmouth JCT, NJ 08852). This operation was repeated to complete the reaction as judged by tic. The solvent was removed under reduced pressure to give the desired material as a formate salt (122mg). LC/MS+ CaIc 345.4, found 346 (M+H⁺).

STEP D: Preparation of (4S,5S)-5-(2-((S)-cyclohexyl(methoxy)methyl)-5- (trifluoromethyl)phenyl)-4-methyloxazolidin-2-one and (4R,5R)-5-(2-((S)- cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one

The product obtained from Step C (122mg, 0.312mmol) was dissolved in dichloromethane (1OmL) and diisopropylethylamine (65mg) was added followed by triphosgene (121 mg, 0.406mmol). The solution was stirred at room temperature for 1.5 hours. A saturated solution of sodium hydrogen carbonate (10 ml_) was added and the mixture was extracted with of ethyl acetate (3 x 25 ml_). The combined organics was dried with sodium sulfate and concentrated under reduced pressure to give a yellow gum (153 mg). The product was purified by chromatography on silica (Redipak 12gm column) eluting with an ethyl acetate/heptane gradient (0-60%) to yield the desired product as a mixture of diastereoisomers (27mg). LC/MS- CaIc 371.39, found 370 (M-H⁺).

STEP E: Preparation of (4S,5S)-3-(3₁5-bis(trifluoromethyl)benzyl)-5-(2-((S)- cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one and (4R,5R)-3-(3_I5-bis(trifluoromethyl)benzyl)-5-(2-((S)-cyclohexyl(methoxy)methyl)-5- (tιifluoromethyl)phenyl)-4-methyloxazolidin-2-one

The product from Step D (27mg, 0.073mmol) was dissolved in 3 ml of dry DMF (3 ml_), cooled to O⁰C and sodium hydride (60% dispersion in mineral oil, 3.78mg, 0.0945mmol) was added. To the yellow solution was added 3,5-bistrifluoromethylbenzyl bromide (24.6mg, O.Oδmmol). After 5 minutes the mixture was allowed to warm to room temperature. After stirring for 16 hours water (1OmL) was added and the mixture was extracted with of ethyl acetate (3 x20 mL). The combined organics were dried with sodium sulfate and concentrated under pressure to give a yellow oil (53 mg). The product was purified by chromatography on silica (Redipak 4gm column) eluting with an ethyl acetate/heptane gradient (0-40%) to yiejd the desired product as an approximately 1 :3 mixture of diastereoisomers (24mg). LC/MS+ CaIc 597, found 598 ( M+H⁺) ¹H NMR (400 MHz, CDCI₃): δ ppm: Major diastereoisomer: 7.84 (s, 1H), 7.76 (s, 2H), 7.62 (m, 1H), 7.55 (brs, 1H), 7.47 (d, J=8.1Hz, 1H)₁ 5.56 (d, J=6.9Hz, 1H), 4.84 (d, J=16.0Hz, 1H), 4.47 (d, J=16.0Hz, 1H), 4.07 (d, J=7.5Hz, 1H), 3.63 (m, 1H), 3.13 (s, 3H), 2.00 (m, 1H), 1.81-1.73 (m, 1H), 1.71-1.61 (m, 2H), 1.57-1.46 (m, 1H), 1.35 (d, J=6.2Hz, 3H)₁ 1.32- 1.19 (m, 2H), 1.19-0.99 (m, 4H). Minor diastereoisomer: 7.81 (s, 1H), 7.78 (s, 2H), 7.57 (m, 1H), 7.49 (brs, 1H), 7.33 (d, J=7.9Hz, 1H), 5.69 (d, J=5.8Hz, 1H), 4.91 (d, J=15.8Hz, 1H), 4.41 (d, J=15.8Hz, 1H), 3.91 (d, J=8.5Hz, 1H), 3.63 (m, 1H), 3.13 (s, 3H), 2.14 (m, 1H), 1.81-1.73 (m, 1H), 1.71-1.61 (m, 2H), 1.57-1.46 (m, 1H), 1.33 (d, J=6.2Hz, 3H), 1.32-1.19 (m, 2H), 1.19-0.99 (m, 4H).

Preparation 23: 2-bromo-4,5-dimethylbenzoic acid

Oxalyl chloride (25 g) and 4-bromo-1 ,2-dimethylbenzene (30 g) in carbon disulfide (100 ml.) were slowly added to aluminum chloride (50 g) in carbon disulfide (100 ml.) at O⁰C. The mixture was stirred for 2 hours and kept at O⁰C for 16 hours. The reaction mixture was then quenched with crushed ice and extracted with ethyl acetate. The organic layer was washed with water and brine. It was dried over Na₂SO₄ and concentrated. The residue was purified over silica gel using ethyl acetate-hexane to obtain 16 g (43 %) of the title compound. ¹H NMR (400 MHz, DMSO-d6): δ ppm 13.1 (s, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 2.24 (s, 3H), 2.20 (s, 3H).

Preparation 24: (2-bromo-4.5-dimethylphenvπmethanol

To a solution of 2-bromo-4,5-dimethylbenzoic acid (15 g, 229 mmol) in dry THF (200 ml) at 0⁰C was added borane-dimethylsulfide complex (9.3 ml, 75.95 m mol) and the mixture was stirred at 23°C for 16 hours. Methanol was added to quench the reaction mixture and it was then concentrated. The residue was purified over silica gel using ethyl acetate-hexane to obtain 12.1 g (85 %) of the title compound. ¹H NMR (400 MHz, DMSO-d6): δ 7.32 (s, 1H), 7.27 (s, 1H), 5.31 (t, J=5.6 Hz, 1H), 4.42(d, J=5.6 Hz, 2H), 2.18 (s, 6H).

Example 40: S-^-CcvclohexyKmethoxylmethylM.δ-dimethylbenzvD-S-O.δ- bis(trifluoromethyl)phenyl)oxazolidin-2-one

STEP A: Preparation of Cyclohexyl(4,5-dimethyl-2- ((triisopropylsilyloxy)methyl)phenyl)methanol

To a solution of (2-bromo-4,5-dimethylphenyl)methanol (2gm, 9.3mmol) in dry DMF

(25mL) was added triisopropylsilyl chloride (1.97gm) followed by imidazole (1.58gm).

The solution was stirred at room temperature for 16 hours then water (2 mL) was added.

The mixture was extracted with of ethyl acetate (3 x 50 ml). The combined organics were dried with sodium sulfate and concentrated under reduced pressure. The crude product was purified by chromatography on silica (Redipak 80gm column) eluting with an ethyl acetate/heptane gradient (0-10%) to yield (2-bromo-4,5- dimethylbenzyloxy)triisopropylsilane as a clear oil (3.25gm).

A portion of this material (313mg, 0.843mmol) was dissolved in dry THF (1OmL), cooled to -78⁰C and n-BuLi (2.5M in hexanes, 0.438mL) was added with stirring. After 2 minutes, cyclohexanecarboxaldehyde (123mg) was added to the cloudy solution and the mixture was stirred for 45 minutes at -78⁰C. The mixture was then allowed to warm to room temperature. After 1.5 hours water (1 OmL) was added and the mixture was extracted with ethyl acetate (3 x 20 ml_). The combined organics were dried with sodium sulfate and concentrated under reduced pressure to give a clear oil (329 mg). The crude product was purified by chromatography on silica (Redipak 12gm column) eluting with an ethyl acetate/heptane gradient (0-60%) to yield cyclohexyl(4,5-dimethyl-2- ((triisopropylsilyloxy)methyl)phenyl)methanol as a clear oil (275 mg).

STEP B: Preparation of (2-(cyclohexyl(methoxy)methyl)-4,5- dimethylbenzyloxy)triisopropylsilane

To a solution of cyclohexyl(4,5-dimethyl-2-((triisopropylsilyloxy)methyl)phenyl)methanol

(201 mg, 0.497mmol) in 5 ml of dry THF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 99.3mg) to give a dark yellow solution, lodomethane (0.155mL, 352mg) was added and the mixture was stirred at room temperature for 16 hours before adding water (5 mL) and extracting with ethyl acetate (3 x 15 mL). The combined organics were dried with sodium sulfate and concentrated to dryness to give an oil (220 mg). The crude product was purified by chromatography on silica (Redipak 12gm column) eluting with an ethyl acetate/heptane gradient (0-40%) to yield the title compound.

STEP C: Preparation of (2-(cyclohexyl(methoxy)methyl)-4,5-dimethylphenyl)methanol

To a solution of (2-(cyclohexyl(methoxy)methyl)-4,5-dimethylbenzyloxy)triisopropylsilane (950mg, 2.27mmol) in dry THF (25mL) was added tetrabutylammonium fluoride (1 M in THF, 2.95mL, 2.95mmol). The solution was stirred at room temperature for 16 hours then the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica (Redipak 40gm column) eluting with an ethyl acetate/heptane gradient (0-60%) to yield the title compound as a clear oil (411 mg).

STEP D: Preparation of 3-(2-(cyclohexyl(methoxy)methyl)-4,5-dimethylbenzyl)-5-(3,5- bis(trifluoromethyl)phenyl)oxazolidin-2-one

To a solution of the product from Step C (50mg, 0.19mmol) in dichloromethane (3 mL) was added carbon tetrabromide (75.8mg) followed by triphenylphosphine (65mg). The mixture was stirred at room temperature for 1.5 hours then concentrated under reduced pressure to give a reddish gum (62mg). This material was dissolved in dry DMF (3 mL) and added to the yellow solution obtained by the addition of sodium hydride (60% dispersion in mineral oil, 6.86mg) to a solution of 5-(3,5- bis(trifluoromethyl)phenyl)oxazolidin-2-one (74.1 mg) in DMF (2 mL) and stirring for 30 minutes. The resulting red solution was stirred at room temperature for 16 hours then water(10 ml) was added. The mixture was extracted with of ethyl acetate (3 x 10 ml) and the combined organics were dried with sodium sulfate and concentrated under reduced pressure to give a brown oil. The crude product was purified by chromatography on silica (Redipak 4gm column) eluting with an ethyl acetate/heptane gradient (0-70%) to yield the title compound as a 1 :1 mixture of diastereoisomers which was not further separated (45mg, clear glass). LC/MS+ CaIc 543.54, found 512.3 (M-OCH₃)⁺. ¹H NMR (400 MHz, CDCI₃): δ ppm (two overlapping spectra for the two isomers): 7.88 (s, 1 H), 7.87 (s, 1 H), 7.80 (s, 2H), 7.78 (s, 2H), 7.10 (s, 1H), 7.09 (s, 1H), 6.95 (s, 1H), 6.95 (s, 1H), 5.60 (d, J=8.3Hz, 1H), 5.56 (d, J=8.3Hz, 1H), 4.70 (d, J=14.9Hz, 1H), 4.58 (d, J=14.7Hz, 1H), 4.53 (d, J=14.7Hz, 1 H), 4.41 (d, J=14.9Hz, 1 H), 4.03 (m, 2H), 3.85 (m, 2H), 3.26 (m, 2H), 3.15 (s, 3H), 3.08 (s, 3H), 2.26 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H), 2.21 (s, 3H), 2.10 (m,

2H), 1.75 (m, 2H), 1.68-1.48 (m, 6H), 1.36-0.97 (m, 14H). Example 41 : (4R.5SV3-(2-( 1-(4-fhvdroxymethyl)piperidin-1-vπ-2-methylDropyl)-5- (trifluoromethvπbenzyl)-5-(3.5-bis(trifluorOmethyl)phenyl)-4-methyloxazolidin-2-one:

To a solution of (2-bromo-5-(trifluoromethyl)benzyloxy)triisopropylsilane (Preparation 10, 1.48g., 3.6OmMoI.) in dimethylacetamide (6mL) was added palladium (II) acetate (0.08g., 0.36mmol.) and potassium ferrocyanide (0.334g., 3.96mMol.). The solution which turned black gradually was stirred at 12O⁰C for 4 hours. The solution was cooled to room temperature and diluted with ethyl acetate (25ml_). This resulting mixture was washed with water (2XIOmL), dried, filtered, concentrated and purified by flash chromatography on silica to yield 4-(trifluoromethyl)-2-((triisopropylsilyloxy)methyl) benzonitrile (1.2g, 93%). ¹H NMR (400 MHz, CDCI₃) δ 8.05 (2, 1H), 7.75 (d, 1H), 7.60 (d, 1H), 5.05 (S, 2H), 1.20 (m, 3H), 1.10 (s, 18h).

To a solution of 4-(trifluoromethyl)-2-((triisopropylsilyloxy)methyl)beπzonitrile (1.21g., 3.38mmol.) in CH₂CI₂ (2OmL) at O⁰C was added DIBAL (2.93mL. of 1M solution in THF) and the solution was stirred at O⁰C for 1 hour and was carefully quenched with 1 N HCI. The resulting solution was warmed to room temperature for 4hours, and extracted with CHCI₃ (3X25mL). The organic extract was dried, filtered, concentrated and purified on flash chromatography to afford 4-(trifluoromethyl)-2-

((triisopropylsilyloxy)methyl)benzaldehyde (1.11g. 91%). ¹H NMR (400 MHz, CDCI₃) δ 10.05 (s, 1H), 8.20 (2, 1H), 7.95 (d, 1H), 7.70 (d, 1H), 5.25 (s, 2H), 1.22 (m, 3H), 1.10 (s, 18h).

A solution of 4-(trifluoromethyl)-2-((triisopropylsilyloxy)methyl)benzaldehyde (1.11g, 3.1 mmol), benzotriazole (0.44g., 3.69 mmol) and 4-hydroxymethylpiperidine (0.426g., 3.69 mmol in ethanol (1OmL) was stirred overnight. The resulting mixture was concentrated and azeotroped with toluene (2*30ml_) and the residue was dissolved in toluene (2OmL) and was cooled to O⁰C. A solution of isopropymagnesium chloride (1.4M, 6.16mL) was added to this solution and theresulting mixture was stirred at O⁰C for 2hours. The reaction mixture was quenched with saturated NH₄CI solution (1OmL) and was stirred at room temperature for 30 minutes. The resulting mixture was extracted with CHCI₃ (3*25mL) and was concentrated. The residue was dissolved in toluene (5OmL) and was washed with 10% Na₂CO₃ solution (3* 2OmL). The organic layer was separated dried, filtered, concentrated and purified by flash chromatography on silica to yield (1-(2- methyl-1 -(4-(trifluoromethyl)-2-((triisopropylsilyloxy)methyl)phenyl) propyl)piperidin-4- yl)methanol (1.08g., 70%). ¹H NMR (400 MHz, CDCI₃) δ 7.95 (d, 1H), 7.40 (dd, 2H), 4.90 (q, 2H), 3.44 (br, 2H), 3.3 (d, 1 H), 2.83 (dd, 2H)₁ 2.22 (m, 1H), 1.90 (m, 3H), 2.63 (brdd, 2H), 1.50 (no, 1H), 1.30 (m, 3H), 1.20 (m, 4H), 1.10 (d, 6H), 0.95 (d, 3H), 0.7 (d, 3H). MS (ES⁺) CaIc 501.32, Found 502.5 (M+1)

To a solution of (1 -(2-methyl-1 -(4-(trifluoromethyl)-2-((triisopropylsilyloxy)methyl)phenyl) propyl)piperidin-4-yl)methanol (1.08g., 2.15 mMol) and diisopropylethylamine (0.56mL,3.23 mMol)in THF (3OmL) at O⁰C was added acetyl chloride (0.18mL, 2.6 mMol). The resulting solution was stirred at O⁰C for 30 minutes, and the solution was quenched with 10% Na₂CO₃. This mixture was extracted with ethyl acetate (2X30mL). The combined organic extracts were dried, filtered, concentrated and purified by flash chromatography on silica to yield 940 mgs of (1-(2-methyl-1-(4-(trifluoromethyl)-2- ((triisopropylsilyloxy)methyl)phenyl)propyl) piperidin-4-yl)methyl acetate (80%). ¹H NMR (400 MHz₁ CDCI₃) δ 7.95 (d, 1H), 7.40 (dd, 2H), 4.90 (q, 2H), 3.90 (d, 2H), 3.3 (d, 1H), 2.83 (dd, 2H), 2.22 (m, 1H), 2.05 (s, 3H), 1.90 (m, 3H), 2.63 (brdd, 2H), 1.50 (m, 1H), 1.30 (m, 3H), 1.20 (m, 4H), 1.10 (d, 6H), 0.95 (d, 3H), 0.7 (d, 3H). MS (ES⁺) CaIc 543.78, Found 544.5 (M+1)

To solution of (1-(2-methyl-1-(4-(trifluoromethyl)-2-

((triisopropylsilyloxy)methyl)phenyl)propyl) piperidin-4-yl)methyl acetate (0.94mg, 1.73mMol.) in THF (2OmL), was added a solution of TBAF in THF (1 M, 2.07mL) and the solution was stirred at room temperature for 2 hours. The solution was concentrated and purified by flash chromatography on silica gel to afford 260 mg of (1-(1-(2- (hydroxymethyl)-4-(trifluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)methyl acetate

(39%). ¹H NMR (400 MHz, CDCI₃) δ 7.70 (d, 1H), 7.40 (dd, 2H), 4.80 (s, 2H)₁ 3.90 (d, 2H), 3.42 (d, 1 H), 2.93 (dd, 2H), 2.40 (m, 1H), 2.10 (m, 2H), 2.0 (s, 3H)₁ 1.60 (m, 4H), 1.2(m, 3H), 1.07 (d, 3H), 0.7 (d, 3H) MS (ES⁺) CaIc 387.44, Found 388.3 (M+1 )

Dimethyl Sulfoxide (0.12 ml_, 1.69mMol.) was added to solution of oxalyl chloride (74uL, 0.84mMol.) in dichloromethane (5ml_) at -78⁰C and the solution was stirred for 10 minutes. A solution of (1-(1-(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)-2- methylpropyl)piperidin-4-yl)methyl acetate in dichloromethane (5mL) was added over 1 minute and the resulting mixture was stirred for 15minutes at -78⁰C. Diisopropylethyl amine was added to this cloudy solution and it was stirred at -78⁰C for 1 hour. The mixture was warmed to room temperature slowly and then was poured into water and was extracted with CH2CI2 (3X15mL) and the combined organic extracts were dried, filtered, concentrated and purified by flash chromatography on silica to yield 157mg of (1 -(1 -(2-formyl-4-(trifluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)methyl acetate (60%). ¹H NMR (400 MHz, CDCI₃) δ 10.2 (s, 1 H),8.10 (s, 1H), 7.60 (dd, 2H), 4.20 (d, 1 H), 3.85 (d, 2H), 2.90 (brdd, 2H), 2.40 (m, 1 H), 2.0 (d, 3H), 1.80 (dq, 2H), 1.60 (brdd, 2H), 0.95 (d, 3H), 0.70 (d, 3H)

A solution of (1-(1-(2-formyl-4-(trifluoromethyl)phenyl)-2-methylpropyl)piperidin-4- yl)methyl acetate (157mg, 0.4mMol.) and (1R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2- aminopropan-1-ol (0.105mg., 0.367mMol.) in CH₂CI₂ was stirred for 2 hours, and sodium triacetoxyborohydride (0.26mg., 3.OmMoI.) was added in portion. The solution was stirred for 2 hours, and was quenched with 10%Na₂CO₃. The resulting mixture was extracted with CHCI₃ (3*15ml_) and the extract was dried, filtered, concentrated and purified by flash chromatography on silica to afford 219mg of (1-(1-(2-(2-((1 R,2S)-1- (3,5-bis(trifluoromethyl)phenyl)-1-hydroxypropan-2-ylamino)ethyl)-4- (trifluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)methyl acetate (82%). ¹H NMR (400 MHz, CDCI₃) δ 7.8 (m, 3H), 7.6 (s, 1H), 7.50 )d, 1H), 7.25 (d, 1H), 7.20 (d, 1H), 5.0 (dd, 1 H), 4.10 (m, 1H), 4.0 (m, 2H), 3.7 (d, 1H), 3.50 (dd, 1H), 3.10 (m, 1 H), 2.95 (brdd, 1 H), 2.82 (brdd, 1 H)2.30 (m, 1 H), 2.0 (d, 3H), 1.95 (qq, 1 H), 1.83 (q, 1 H), 1.60 (brm, 5H), 1.05 (d, 1 H), 0.95 (d, 1H), 0.90 (m, 1H), 0.8 (d, 3H), 0.70 (s, 3H). MS (ES⁺) CaIc 656.64, Found 657.5 (M+1 )

A solution of (1-(1-(2-(2-((1 R,2S)-1-(3,5-bis(trifluoromethyl)phenyl)-1-hydroxypropan-2- ylamino)ethyl)-4-(trifluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)methyl acetate (119mg., 0.32mMol) and CDI (51 mg. 0.3ImMoI) in CH₂CI₂ (2mL) was stirred at room temperature for 5 hours, and the solution was concentrated and purified by flash chromatography on silica to yield 210mg of (1-(1-(2-(((4S,5R)-5-(3,5- bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl)-4- (trifluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)methyl acetate (100%). MS (ES⁺) CaIc 682.63, Found 683.6 (M+1 )

A solution of (1-(H2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2- oxooxazolidin-3-yl)methyl)-4-(trifluoromethyl)phenyl)-2-methylpropyl)piperidin-4- yl)methyl acetate (219mg, 0.321mMol.) and LiOH (8mg., 0.321mMol.) in 1:1/H₂O:MeOH (4mL) was stirred for 2 hours. The resulting mixture was concentrated and purified by flash chromatography on silica to afford 142mg of (4R,5S)-3-(2-(1-(4- (hydroxymethyl)piperidin-1-yl)-2-methylpropyl)-5-(trifluoromethyl)benzyl)-5-(3,5- bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one (69%). ¹H NMR (400 MHz, CDCI₃) δ 7.9 (m, 1H), 7.78 (m, 2H), 7.6 (m, 1 H), 7.45 (m, 2H), 5.60 (dd, 1H), 5.10 (dd, 1H), 4.20 (dd, 1 H), 3.90 (dq, 1 H), 3.60 (dd, 1 H), 3.45 (m, 2H), 305 (dd, 1 H), 2.80 (dd, 1 H), 2.30 (m, 1H)₁ 1.95 (brt, 1 H), 1.80 (br, 1H), 1.65 (br, 2H), 1.20 (br, 4H), 1.15 (d, 1H), 0.95 (d, 1H), 0.7 (m, 6H). MS (ES⁺) CaIc 640.58, Found 641.4 (M+1)

Example 42: 1-(1-(2-f((4S.5R)-5-(3.5-bisαrifluoromethylbhenyl)-4-methyl-2- oxooxazolidin-3-yl)methyl)-4-(trifluoromethyl)phenv<)-2-methylpropyl)piperidine-4- carboxylic acid

Dimethyl Sulfoxide (47uL, 0.665mMol.) was added to solution of oxalyl chloride (29uL, 0.333mMol.) in dichloromethane (5mL) at -78⁰C and the solution was stirred for 10 minutes. A solution of (4R,5S)-3-(2-(1 -(4-(hydroxymethyl)piperidin-1 -yl)-2-methylpropyl)- 5-(trifluoromethyl)benzyl)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one (0.142 mg, 0.22mMol.) in dichloromethane (5mL) was added over 1 minute and the resulting mixture was stirred for 15 minutes at -78⁰C. Diisopropylethyl amine (0.232mL, 1.33mMol) was added to this cloudy solution and it was stirred at -78⁰C for 1 hour. The S mixture was warmed to room temperature slowly and then was poured into water and was extracted with CH₂CI₂ (3X15mL) and the combined organic extracts were dried, filtered, concentrated and purified by flash chromatography on silica to yield 86mg of (1- (1-(2-formyl-4-(trifluoromethyl)phenyl)-2-methylpropyl)piperidin-4-yl)methyl acetate (60%). ¹H NMR (400 MHz, CDCI₃) δ 9.6 (d, 1 H), 7.9 (d, 1H), 7.8 (dd, 2H), 7.50 (m, 3H),0 5.62 (dd, 1 H), 5.10 (dd, 1 H), 4.20 (dd, 1 H), 3.95 (q, 1 H), 3.83 (q, 1 H), 3.60 (dd, 1 H), 2.90 (dd, 1H), 2.78 (dd, 1H), 2.30 (m, 1H), 2.10 (m, 2H), 1.95 (m, 1H), 1.85 (m, 2H), 1.70 (m, 1H), 1.55 (m, 1h), 1.3 (m, 3H), 1.10 (d, 1H), 0.95 (d, 1H), 0.83 (t, 1H), 0.75(t, 3H), 0.7 (d, 1H). MS (ES⁺) CaIc 638.58, Found 639.4 (M+1)

5 To a solution of the aldehyde from the last step (86mg 0.13mMol) in DMF (1mL) was added Oxone and the solution was stirred for 4 hours. The solution was diluted with ethyl acetate and water and the organic layer was separated. The organic extract was washed with water, saturated NaHCO₃, saturated NH₄CI and dried, filtered, concentrated and purified by flash chromatography on silicagel to afford 76mg of 1-(1-0 (2-(((4S,5R)-5-(3,5-bis(trifluo^iOmethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl)-4- (trifluoromethyl)phenyl)-2-methylpropyl)piperidine-4-carboxylic acid (86%). ¹H NMR

(400 MHz, CDCI₃) δ 8.0 (m, 3H), 7.8 (m, 3H)₁ 5.85 (dd, 1H)₁ 5.10 (d, 1H), 4.83 (d, 1H), 4.55 (d, 1H), 4.35 (d, 1H), 4.23 (quintet, 1 H)₁ 4.10 (quintet, 1H), 3.80 (dd, 2H), 3.3 (m, 2H)₁ 3.10 (d, 1H), 2.9 (dd, 1H), 2.40 (m, 1 H)₁ 2.10 (, m, 3H), 1.90 (m, 2H), 2.78 (m, 1H)₁5 2.68 (m, 1H), 1.10 (d, 1H)₁ 1.00 (d, 1H), 0.83 (t, 1H), 0.75(t, 3H), 0.7 (d, 1H). MS (ES⁺) CaIc 654.58, Found 655.4 (M+1)

Examples 43 and 44 f4S.5R)-3-((SV2-f(S)-1-(4-fluoropiperidin-1-yl)-2-methylpropyl)-5- (trifluoromethyl)benzyl)-5-(3.5-bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-oneand0 (4S.5R)-3-((R)-2-((R)-1-(4-fluoropiperidin-1-yl)-2-methylpropyn-5-

(trifluoromethyl)benzvπ-5-(3.5-bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one:

1-(2-methyl-1-(4-(trifluoromethyl)-2-((triisopropylsilyloxy)methyl)phenyl)propyl)piperidin- 4-ol was prepared from 4-(trifluoromethyl)-2-((triisopropylsilyloxy)methyl)benzaldehyde, 4-hydroxy piperidine and isopropylmagnesium chloride using a procedure analogous to that described for example 42. ¹H NMR (400 MHz, CDCI₃) ■ 7.9 (s, 1 H), 7.4 (dd, 2H), 4.9 (dd, 2H), 4.15 (dd, 1 H), 3.5 (br, 1 H), 3.3 (d, 1 H), 2.7 (m, 2H), 2.2 (m, 1 H), 2.07 (m, 2H), 1.8, (m, 2H), 1.50 (m, 2H), 1.3 (t, 1 H), 1.2 (m, 1 H), 1.1 (d, 18H), 0.95 (d, 3H), 0.7 (d, 3H). MS (ES⁺) CaIc 487.31, Found 488.4 (M+1).

To a solution of the alcohol (1.59g, 3.25mmol.) from previous step in CH₂CI₂ (2OmL) at O⁰C was added DeoxoFluor (Aid rich, 0.8g., 3.5mmol) and the solution was stirred for 1 hour. The resulting mixture was concentrated and the residue was purified to afford 4- fluoro-1 -(2-methyl-1 -(4-{trifluoiOmethyl)-2- ((triisopropylsilyloxy)methyl)phenyl)propyl)piperidine (620mg, 38%), which was subjected to chiral chromatography and the separated enantiomers were used in the next step. ¹H NMR (400 MHz, CDCI₃) δ 7.9 (s, 1 H), 7.4 (dd, 2H), 4.9 (dd, 2H), 4.50 (br, 1 H), 3.3 (d, 1H), 2.6 (m, 2H), 2.25 (m, 3H), 1.8, (m, 4H), 1.20 (m, 4H), 1.1 (d, 18H), 0.95 (d, 3H), 0.7 (d, 3H). MS (ES⁺) CaIc 489.31 , Found 490.4 (M+1).

The fluoropiperidines from the previous step was converted to (4S,5R)-5-(3_>5-bis- trifluoromethyl- phenyl)-3-{2-[1-(4-fluoro-piperidin-1-yl)-2-methyl-propyl]-5-trifluoiOmethyl-benzyl}-4- methyl-oxazolidin-2-one, using the procedure described above in Example 42. ¹H NMR (400 MHz, CDCI₃) δ 7.9 (m, 1H), 7.78 (m, 2H), 7.58 (m, 2H), 7.50 (s, 1H), 5.7 (d, 1H), 5.0 (d, 1 H), 4.58 (brd, 1 H), 4.3 (d, 1 H), 3.95 (quintet, 1 H), 3.58 (d, 1 H), 2.6 (br, 2H), 2.3 (br, 3H), 1.8 (br, 4H), 0.8 (d, 3H), 0.7 (m, 6H). MS (ES⁺) CaIc 628.21 , Found 629.42 (M+1).

Examples 45 and 46: (4S.5R)-3-(fS)-2-f(S)-1-f4-(ethoxymethyl)-4-fluoroDiperidin-1-vn-2- methylpiOPyl)-5-(trifluoromethyl)benzvπ-5-(3.5-bis(trifluoromethyl)phenvπ-4- methyloxazolidin-2-one and (4S.5R)-3-((R)-2-((RV1 -(4-(ethoxymethyl)-4-fluoropiperidin- 1-yl)-2-methylpropyl)-5-(trifluoroπnethyl)benzyl)-5-(3.5-bis(trifluoromethyl)phenylV4- methyloxazolidin-2-one:

4-Ethoxymethyl-1-[2-methyl-1-(4-trifluoromethyl-2-triisopropylsilanyloxymethyl-phenyl)- propyl]-piperidin-4-ol was prepared from 4-(trifluoromethyl)-2- ((triisopropylsilyloxy)methyl)benzaldehyde, 4-(ethoxymethyl)piperidin-4-ol and isopropylmagnesium chloride using a procedure analogous to that described for example 42.¹H NMR (400 MHz, CDCI₃) δ 7.9 (s, 1H), 7.57 (m, 1H), 7.40 (dd, 2H), 4.90 (dd, 2H)₁ 3.50 (q, 2H), 3.3 (d, 1 H), 3.20 (dd, 2H), 2.6 (m, 1H), 2.45 (m, 1 H), 2.30 (m, 4H), 1.60 (m, 2H), 1.50 (m, 2H), 1.30 (m, 2H), 1.20 (m, 3H), 1.10 (d, 18H), 0.9 (d, 3H)₁ 0.85 (t, 3H), 0.7 (d, 3H). MS (ES⁺) CaIc 545.35, Found 546.40(M+1).

The alcohol from the previous step was converted to 4-Ethoxymethyl-4-fluoro-1-[2- methyl-1-(4-trifluoromethyl-2-triisopropylsilanyloxymethyl-phenyl)-propyl]-piperidine using DeoxoFluor (Aldrich) using a procedure analogous to that described above for examples 44 and 45. ¹H NMR (400 MHz, CDCI₃) δ 7.9 (s, 1H), 7.60 (dd, 2H), 4.90 (dd, 2H)₁ 3.50 (q, 2H), 2.70 (m, 1 H), 2.50 (m, 1H), 2.30 (m, 2H).1.80 (m, 2H), 1.60 (m, 1H), 1.23 (m, 1 H), 1.20 (t, 3H), 1.10 (d, 18H), 0.9 (t, 3H), 0.7 (t, 3H). MS (ES⁺) CaIc 547.35, Found 548.40(M+1). The fluoropiperidines from the previous step was converted to (4S,5R)-5-(3,5-Bis- trifluoromethyl-phenyl)-3-{2-[1-(4-ethoxymethyl-4-fluoro-piperidin-1-yl)-2-methyl-propyl]- 5-trifluoromethyl-benzyl}-4-methyl-oxazolidin-2-one using a procedure analogous to that described for example 42. ¹H NMR (400 MHz, CDCI₃) δ 7.9 (s, 1H)₁ 776 (s, 2H), 7.60 (d, 2H)₁ 7.50 (d, 1H)₁ 5.60 (d, 1H)₁ 5.17 (d, 1H), 4.10 (d, 1H)₁ 3.83 (quintet, 1H), 3.65 (d, 1H), 3.50 (q, 2H)₁ 3.38 (d, 2H), 2.85 (brd, 1H), 2.6 (brd, 1H), 2.30 (m, 2H), 2.10 (t, 1H), 1.80 (m, 2H), 1.70 (m, 1 H), 1.60 (m, 1 H), 1.20 (t, 3H), 1.07 (d, 3H), 0.8 (d, 3H), 0.7 (d, 3H). MS (ES⁺) CaIc 686.26, Found 687.30(M+1).

Example 47: (4S.5R)-5-(3.5-Bis-trifluoromethyl-phenyl)-3-f2-f1-f3-fluorO-azetidin-1 -yl)-2- methyl-piOpyn-5-trifluoromethyl-benzyl>-4-methyl-oxazolidin-2-one

1-[2-Methyl-1-(4-trifluoromethyl-2-triisopropylsilanyloxymethyl-phenyl)-propyl]-azetidin- 3-ol was prepared from 4-(trifluoromethyl)-2-((triisopiOpylsilyloxy)methyl)benzaldehyde₁ 2-hydroxyazetidine and isopropylmagnesium chloride using a procedure analogous to that described for example 42. ¹H NMR (400 MHz₁ CDCI₃) δ 7.9 (s, 1H), 7.5 ( dd, 2H), 5.0 (d, 1H), 4.82 (brd, 1H), 4.40 (brm, 1 H), 3.7 (t, 1 H), 3.3 (brm, 2H), 2.90 (t, 1H), 2.65 (t, 1H), 2.9 (m, 1 H)₁ 2.83 (br, 1 H), 1.8 (m, 3H), 1.1 (d, 18H), 0.8 (t, 6H) MS (ES⁺) CaIc 459.67, Found 460.30(M+1).

The alcohol from the previous step was converted to 3-fluoro-1-[2-methyl-1-(4-trifluoro methyl-2-triisopropylsilanyloxymethyl-phenyl)-propyl]-azetidine using DeoxoFluor (Aid rich) using a procedure analogous to that described for examples 44 and 45. MS (ES⁺) CaIc 461.27, Found 462.40(M+1 ). The fluoroazetidines from the previous step was converted to (4S,5R)-5-(3,5-Bis- trifIuoromethyl-phenyl)-3-{2-[1-(3-fluoro-azetidin-1-yl)-2-methyl-propyl]-5-trifluoromethyl- benzyl}-4-methyl-oxazolidin-2-one using a procedure analogous to the one described in example 42. ¹H NMR (400 MHz, CDCI₃) δ 7.9 (s, 1H), 7.8 (s, 2H), 7.65 (br, 1H), 7.55 (m, 3H), 5.70 (d, 1 H), 5.10 (d of quintet, 1 H), 4.90 (brd, 1 H), 4.40 (brd, 1 H), 4.0 (m, 1 H), 3.70 (m, 1 H), 3.60 (m, 1 H), 3.37 (m, 1 H)₁ 3.20 (dq, 1 H), 2.80 (brdq, 1 H), 2.0 (m, 1 H), 1.25 (m, 1H), 1.20 (t, 3H), 0.8 (d, 6H). MS (ES⁺) CaIc 600.18, Found 601.23 (M+1).

Example 48: (4R.5S)-4-r3.5-bisαrifluoromethvnphenyll-1-{2-r(S)- cvclohexyl(methoxy)methyll-5-(trifluoiOmethvnbenzyl)-3.5-dimethylimidazolidin-2-one

To a solution of (4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{2-[(S)- cyclohexyKmethoxyJmethyq-δ^trifluoromethyObenzylJ-S-methylimidazolidin^-one (Example 32, 14 mg, 0.024 mmol) in THF (0.5 ml) was added methyl iodide (34 mg,

0.015 ml, 0.24 mmol) followed by KHMDS (20 mg, 0.15 ml of 0.5 M solution, 0.08 mmol). The mixture was stirred at room temperature for 30 min. Water was added and the mixture was extracted with ethyl acetate. Combined organic layer was washed with brine, dried with Na₂SO₄ and concentrated in vacuo. The residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-35% ethyl acetate in heptane) to afford a colorless oil (12.0 mg, 82%). ¹H NMR (400 MHz, CDCI₃) δ 7.89 (s), 7.68 (s), 4.81 (d, J=16.1Hz), 4.69 (d, J=8.8Hz), 4.36 (d, J=15.5Hz), 4.25 (d, J=6.9Hz), 3.17 (S), 2.80 (S), 0.66 (d, J=6.6Hz). (ES⁺) CaIc: 610.2, Found: 611.4 (M +1).

Example 49: (3S.4R)-4-r3.5-bis(trifluoromethvnphenyll-2-l2-r(SV cvclohexyl(methoxy)methyll-5-(trifluoromethyl)benzylK3-methyl-1 ,2.5-thiadiazolidine 1.1- dioxide

A mixture of (1R,2S)-1-[3_I5-bis(trifluoromethyl)phenyl]-N~2~-{2-[(S)- cyclohexyl(methoxy)methyl]-5-(trifluoromethyl)benzyl}piOpane-1 ,2-diamine (EΞxample 32, Step D, 12 mg, 0.021 mmol), sulfamide (4 mg, 0.042 mmol) in pyridine (0.4 ml) was heated at 12O⁰C for 2h. Solvent was removed in vacuo. The residue was dissolved in ethyl acetate (4 mL) and washed with water (1 ml_), 1N HCI (1 ml_), and brine (1 mL) and filtered through a short pad of sodium sulfate. The filtrate was concentrated in vacuo and purified by chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in heptane) to afford a colorless oil (9.3 mg, 70%). ¹H NMR (400 MHz, CDCI₃) δ 7.91 (s), 7.75 (S), 5.07 (m), 4.93 (d, J=4.9Hz), 4.46 (d, J=16.1Hz), 4.31 (d, J=15.2Hz), 4.21 (d, J=7.2Hz), 3.17 (s), 0.85 (d, J=6.6Hz). (ES⁺) CaIc: 632.2, Found: 631.4 (M-1).

Throughout this application, various publications are referenced. The disclosures of the; publications in their entireties are hereby incorporated by reference into this application for all purposes.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

What is claimed is:

1. A compound of Formula I

Formula I or a pharmaceutically acceptable salt of said compound; wherein

B iS -OR⁶Or-NR⁷R⁸;

M and J are each independently CH₂ or a bond wherein at least one of M and J are CH₂;

W is hydrogen or a fully saturated, partially unsaturated or fully unsaturated straight or branched chain having 1 to 6 carbon atoms wherein each carbon atom of said chain is optionally replaced by a heteroatom selected from nitrogen, oxygen or sulfur, and said carbon atom of said chain is optionally mono-, di- or tri-substituted with amino, halo, cyano, (Ci-C₆)alkyl, (CrC₆)alkoxy, hydroxy or oxo and said nitrogen atom of said chain is optionally mono- or disubstituted with (Ci-C₆)alkyl, cyano or oxo and said sulfur atom of said chain is optionally substituted with one or two oxo,

R¹, R², R³, and R⁴ are each independently hydrogen, halo, cyano, hydroxy, nitro, ((C_rC₆)alkyl optionally substituted with one to nine halo, one or two hydroxyl, one or two (d-CβJalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy), ((Cr Cβjalkoxy optionally substituted with one to nine halo, one or two hydroxyl, or cyano), or ((Ci-C₆)alkylthio optionally substituted with one to nine halo, one or two hydroxyl, or cyano); or R¹ and R² or R² and R³ are optionally taken together to form a 5 to 7-membered partially unsaturated or fully unsaturated ring wherein each carbon atom of said ring is optionally replaced with an oxygen atom, wherein the oxygen atoms are not connected to each other, wherein said ring is optionally mono-, di-, tri- or tetra-substituted with halo, and optionally mono- or di-substituted with hydroxy, amino, nitro, cyano, oxo, carboxy, ((Ci-Cβ)alkyl optionally substituted with one to nine halo, one or two hydroxyl, one or two (Ci-C₆)alkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy), or ((CrCe)alkoxy optionally substituted with one to nine halo, one or two hydroxyl, or cyano);

R⁵ is hydrogen or (CrCβJalkyl optionally substituted with one to nine halogen; R⁶ is -(Ci-C₆)alkyl-NR⁹R¹⁰, -(C₀-C₆)alkyl-CO-NR⁹R¹⁰, -(C₀-C₆)alkyl-CO-OR¹³, -(C₁- C₆)alkyl-NR¹⁰-(Co-C₆)alkyl-CO-0-R¹³, -(CrCeJalkyl-NR^Co-CeJalkyl-CO-R¹³, -(C₁- C₆)alkyl-NR¹⁰-(Co-C₆)alkyl-Sθ₂-R¹³ _P -(C₁-C6)alkyl-0-CO-NR⁹R¹⁰, -(C₂-C₆)alkenyl-CO-O- R¹³, -(CrCβJalkyl-aryl, -(d-CeJalkyl-heteroaryl, -(CrCeJalkyl-O-aryl, -(C_rC₆)alkyl-O- heteroaryl, -(C₀-C₆)alkyl-heterocycle, -(Co-C₆)alkyl-(C₃-C₆)cycloalkyl, -(C₀-C₆)alkyl-(C₃- C₆)cycloalkenyl, (C₂-C₆)alkynyl, (C₂-C₆)alkenyl, (CrCeJalkyl, or -CO-(C_rC₆)alkyl, wherein said aryl, heteroaryl, heterocycle, cycloalkenyl, cycloalkyl, alkynyl, alkenyl, and alkyl groups are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (Ci-C₆)alkyl, one to three (CrC₆)haloalkyl, one to three (C₁- C₆)alkoxy, one to three (C-i-CβJhaloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy; R⁷ and R⁸ are each independently hydrogen, -(CrC₆)alkyl-NR⁹R¹⁰, -(C₀-C₆)alkyl-CO- NR⁹R¹⁰, -(Co-C₆)alkyl-CO-OR¹³, -(CrCeJalkyl-NR^Co-CeJalkyl-CO-O-R¹³, -(C₁- C₆)alkyl-NR¹⁰-(Co-C₆)alkyl-CO-R¹³ _I -(C₁-C₆)alkyl-NR¹⁰-(Co-C6)alkyl-Sθ₂-R¹³, -(C₁- C₆)alkyl-O-CO-NR⁹R¹⁰, -(C₂-C₆)alkenyl-CO-O-R¹³, -(Co-C₆)alkyl-aryl, -(C₀-C₆)alkyl- heteroaryl, -(d-CeJalkyl-O-aryl, -(CrCeJalkyl-O-heteroaryl, -(C₀-C₆)alkyl-heterocycle, - (Co-C₆)alkyl-(C₃-C₆)cycloalkyl, -(C₀-C6)alkyl-(C3-C₆)cycloalkenyl, (C₂-C₆)alkynyl, (C₂- CβJalkenyl, (CrCβ)alkyl, cyano, or -CO^CrCeJalkyl, wherein said aryl, heteroaryl, heterocycle, cycloalkenyl, cycloalkyl, alkynyl, alkenyl, and alkyl substituents are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (C₁-Cβ)alkyl, one to three (CrCεJhaloalkyl, one to three (C₁-C₆JaIkOXy, one to three (CrC₆)haloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy; or R⁷ and R⁸ are optionally taken together to form a 3 to 8-membered fully saturated or partially unsaturated mono- or bi-cyclic ring having optionally one or two heteroatoms selected from oxygen, nitrogen and sulfur, wherein the ring is optionally mono-, di- or tri- substituted with R¹⁴; R⁹ and R¹⁰ are each independently hydrogen, aryl or ((CrC₆)alkyl optionally substituted with one to nine halo;

R¹¹ and R¹² are optionally taken together to form (C4-C₇)cycloalkyl optionally mono-, di- or tri-substituted with R¹⁴;

R¹³ is hydrogen, aryl or ((CrC₆)alkyl optionally substituted with one to nine halo; each R¹⁴ is independently -(Co-C₆)alkyl-NR⁹R¹⁰, -(C₀-C₆)alkyl-CO- NR⁹R¹⁰, -(C₀- C₆)alkyl-CO-OR¹⁰, -O-(CrC₆)alkyl-CO-O-R¹⁰, halo, (Ci-C₆)alkyl, hydroxy, (C₁- C₆)alkoxy, cyano, oxo, or -CO-(CrC₆)alkyl, wherein said alkyl and alkoxy groups are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (Ci-C₆)alkyl, one to three (CrCβJhaloalkyl, one to three (Ci-C₆)alkoxy, one to three (C₁-C₆)haloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy; each R¹⁵ is independently -(C_rC₆)alkyl- NR⁹R¹⁰, -(C₀-C₆)alkyl-CO- NR⁹R¹⁰, -(C₀- C₆)alkyl-CO-OR¹⁰, or -CO-(C-ι-C₆)alkyl, wherein said alkyl groups are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (C_r C₆)alkyl, one to three (Ci-C₆)haloalkyl, one to three (Ci-C₆)alkoxy, one to three (C_r C₆)haloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy; each R¹⁶ is independently halo, nitro, cyano, hydroxyl, oxo, carboxyl, (Cr C₆)alkoxycarbonyl, ((Ci-C₆)alkyl optionally substituted with one to nine halo or one or two hydroxyl), ((CrCβJalkoxy optionally substituted with one to nine halo or one or two hydroxyl), or ((CrC₆)alkylthio optionally substituted with one to nine halo or one or two hydroxyl); and n is O, 1, 2, 3 or 4.

2. A compound according to claim 1, wherein A is

or a pharmaceutically acceptable salt of said compound.

3. A compound according to claim 2, wherein W is CH₃ or hydrogen, or a pharmaceutically acceptable salt of said compound.

4. A compound according to claim 3, wherein the compound has the formula Il

Formula Il or a pharmaceutically acceptable salt of said compound.

5. A compound according to claim 4, wherein M is a bond; J is CH₂; and R², R³, and R⁴ are each hydrogen, methyl, cyano, or CF_3; or a pharmaceutically acceptable salt of said compound.

6. A compound according to claim 5, wherein B is -OR⁶;

R¹¹ is a 5- or 6-membered fully saturated ring optionally having one heteroatom selected from oxygen and nitrogen and the carbon atoms of said ring are optionally mono- or di-substituted with R¹⁴ and the nitrogen atoms, if present, are optionally substituted with R¹⁵; each R¹⁴ is independently halo, (Ci-C₆)alkyl, hydroxy, (CrC₆)alkoxy, cyano, oxo, or - CO-(Cr C₆)alkyl, wherein said alkyl and alkoxy groups are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (C_rC₆)alkyl, one to three (CrC₆)haloalkyl, one to three (C-ι-C₆)alkoxy, one to three (CrCeJhaloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy; or a pharmaceutically acceptable salt of said compound.

7. A compound according to claim 5, wherein B is -OR⁶; and R¹¹ and R¹² are optionally taken together to form (C₅-C₇)cycloalkyl optionally mono- or di-substituted with R¹⁴; and each R¹⁴ is independently halo, (Ci-C₆)alkyl, hydroxy, (CrCβJalkoxy, cyano, oxo, or- CO-(CrC₆)alkyl, wherein said alkyl and alkoxy groups are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (CrCβ)alkyl, one to three (CrC₆)haloalkyl, one to three (d-C₆)alkoxy, one to three (CrC₆)haloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy; or a pharmaceutically acceptable salt of said compound.

8. A compound according to claim 5, wherein B iS -NR⁷R⁸;

R⁷ and R⁸ are each independently hydrogen, -(Ci-C₆)alkyl-NR⁹R¹⁰, -(C₀-C₆)alkyl-CO- NR⁹R¹⁰, -(Co-C₆)alkyl-CO-OR¹³, -(Co-C₆)alkyl-(C₃-C₆)cycloalkyl, (C_rC₆)alkyl, cyano, or- CO-(C_rC₆)alkyl, wherein said cycloalkyl, and alkyl substituents are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (Cr C₆)alkyl, one to three (Ci-C₆)haloalkyl, one to three (Ci-Ce)alkoxy, one to three (C-r C₆)haloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy;

R¹¹ is hydrogen, aryl, ((C₃-C₆)cycloalkyl optionally substituted with aryl, one to three (CrC₆)alkyl, one to three (Ci-Cβjalkoxy, one to three (CrCβ)haloalkyl, one to three (C_r C₆)haloalkoxy, one or two hydroxyl, or one to nine halo) or ((Ci-C₆)alkyl wherein said (CrC₆)alkyl is optionally substituted with aryl, one to three (Ci-C₆)alkoxy, one to three (Ci-C₆)haloalkyl, one to three (CrC_e)haloalkoxy, one or two hydroxyl, or one to nine halo); and

R¹² is hydrogen; or a pharmaceutically acceptable salt of said compound.

9. A compound according to claim 5, wherein B is -NR⁷R⁸;

R⁷ and R⁸ are optionally taken together to form a 5 to 8-membered fully saturated or partially unsaturated mono- or bi-cyclic ring having optionally one heteroatoms selected from oxygen and nitrogen, wherein the ring is optionally mono- or di-substituted with R¹⁴;

R¹¹ is hydrogen, aryl, ((C₃-C₆)cycloalkyl optionally substituted with aryl, one to three (Ci-C₆)alkyl, one to three (C-|-C₆)alkoxy, one to three (C_rC₆)haloalkyl, one to three (C_r C₆)haloalkoxy, one or two hydroxyl, or one to nine halo) or ((Ci-C₆)alkyl wherein said (CrC₆)alkyl is optionally substituted with aryl, one to three (C-ι-C₆)alkoxy, one to three (Ci-C₆)haloalkyl, one to three (Ci-C₆)haloalkoxy, one or two hydroxyl, or one to nine halo);

R¹² is hydrogen; and each R¹⁴ is independently halo, (CrC₆)alkyl, hydroxy, (CrCβJalkoxy, cyano, oxo, or- CO-(Ci-C₆)alkyl, wherein said alkyl and alkoxy groups are each optionally substituted independently with one to nine halo, one or two hydroxy, one to three (C-ι-C₆)alkyl, one to three (CrCβJhaloalkyl, one to three (CrCβJalkoxy, one to three (Ci-Cβjhaloalkoxy, one or two amino, one or two nitro, cyano, oxo, or carboxy; or a pharmaceutically acceptable salt of said compound.

10. A compound selected from the group consisting of:

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{2-[(S)-cyclohexyl(methoxy)methyl3-5- (trifluoromethyl)benzyl}-4-methyl-1,3-oxazolidin-2-one;

(4S,5R)-5-[3,5-Bis(trifluorOmethyl)phenyl]-3-{2-[(R)-cyclohexyl(methoxy)methyl]-5- (trifluoromethyl)benzyl}-4-methyl-1,3-oxazolidin-2-one; (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{2-[(S)-cyclohexyl(methoxy)methyl]-5- (trifluoromethyl)benzyl}-4-methyl-1 ,3-oxazolidin-2-one;

(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{2-[(R)-cyclohexyl(methoxy)methyl]-5- (trifluoromethyl)benzyl}-4-methyl-1 ,3-oxazolidin-2-one;

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

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{2-[cyclobutyl(methoxy)methyl]-5- (trifluoromethyl)benzyl}-4-methyl-1 ,3-oxazolidin-2-one;

(4S,5R)-5-[3_I5-bis(trifluoromethyl)phenyl]-3-{2-[cyclopentyl(methoxy)methyl]-5- (trifluoromethyl)benzyl}-4-methyl-1 ,3-oxazolidin-2-one; (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{2-[cyclopentyl(ethoxy)methyl]-5- (trifluoromethyl)benzyl}-4-methyl-1 ,3-oxazolidin-2-one;

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{2-[methoxy(tetrahydro-2H-pyran-4- yl)methyl]-5-(trifluoromethyl)benzyl}-4-methyl-1 ,3-oxazolidin-2-one;

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{2-[ethoxy(tetrahydiO-2H-pyran-4- yl)methyl]-5-(trifluoromethyl)benzyl}-4-methyl-1 ,3-oxazolidin-2-one;

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{2-[(4-chlorophenyl)(methoxy)methyl]-5- (trifluoromethyl)benzyl}-4-methyl-1 ,3-oxazolidin-2-one; Methyl 4-{[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1 ,3- oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl](methoxy)methyl}piperidine-1- carboxylate;

Ethyl 4-{[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3- oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl](methoxy)methyl}piperidine-1- carboxylate;

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

(4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{2-[(S)-cyclohexyl(methoxy)methyl]-5- (trifluoromethyl)benzyl}-5-methylimidazolidin-2-one;

(4S,5f?)-3-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)-5-(3,5- bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one;

(RSJ-S^^I-methoxycycloheptylJ-S-OrifluoromethyObenzyO-S^S.δ- bis(trifluoromethyl)phenyl)oxazolidin-2-one; rrans-S^S.S-bis^rifluoromethyObenzylJ-δ^-^SJ-cyclohexyKmethoxyJmethyO-δ- (trifluoromethyl)phenyl)-4-methyloxazolidin-2-one;

(4S,5S)-3-(3₎5-bis(trifluoromethyl)benzyl)-5-(2-((S)-cyclohexyl(methoxy)methyl)-5- (trifluoromethyl)phenyl)-4-methyloxazolidin-2-one; and

(4R,5R)-3-(3,5-bis(trifluoromethyl)benzyl)-5-(2-((S)-cyclohexyl(methoxy)methyl)-5- (trifluoromethyl)phenyl)-4-methyloxazolidin-2-one; or a pharmaceutically acceptable salt thereof.

11. A method for treating atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia or myocardial infarction in a mammal by administering to a mammal in need of such treatment an atherosclerosis, coronary artery disease, coronary heart disease, coronary vascular disease, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia or myocardial infarction treating amount of a compound of claim 1 or 10 or a pharmaceutically acceptable salt of said compound.

12. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 1 or 10, or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable vehicle, diluent or carrier.

13. A pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of claim 1 or 10, or a pharmaceutically acceptable salt of said compound; a second compound, said second compound being an HMG CoA reductase inhibitor, an MTP/Apo B secretion inhibitor, a PPAR modulator, a bile acid reuptake inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, a combination of niacin and lovastatin, a combination of niacin and simvastatin, a combination of niacin and atorvastatin, a combination of amlodipine and atorvastatin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant; and a pharmaceutical vehicle, diluent or carrier.

14. A pharmaceutical combination composition according to claim 13 wherein the second compound is an HMG-CoA reductase inhibitor, a PPAR modulator, or niacin.

15. A pharmaceutical combination composition according to claim 14 wherein the second compound is fenofibrate, gemfibrozil, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, rosuvastatin or pitavastatin.