Background of the Invention CETP inhibitors, as a class, are characterized by high binding activity. Such CETP inhibitors are generally hydrophobic, however, with the consequence that they have extremely low aqueous solubility and have low oral bioavailability. Such compounds have generally proven to be difficult to formulate for oral administration such that high bioavailabilities are achieved.

Atherosclerosis and its associated coronary artery disease (CAD) is the leading cause of death 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-cholesterol may be the most recognized form of dyslipidemia, it is by no means the only significant lipid- associated contributor to CHD. Low HDL-cholesterol 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 exist. Niacin can significantly increase HDL, but has serious toleration issues that reduce compliance. Fibrates and the HMG CoA reductase inhibitors raise HDL-cholesterol only modestly (-10- 12%). As a result, there is a significant unmet medical need for a well-tolerated agent that can significantly elevate plasma HDL levels, thereby reversing or slowing the progression of atherosclerosis.

CETP inhibitors have been developed that inhibit CETP activity, and thus, if present in the blood, should result in higher HDL cholesterol levels and lower LDL cholesterol levels. To be effective, such CETP inhibitors must be absorbed into the blood. Oral dosing of CETP inhibitors is preferred because to be effective such CETP inhibitors must be taken on a regular basis, such as daily. Accordingly, it is preferred that patients be able to take CETP inhibitors by oral dosing rather than by injection.

However, it has proven to be difficult to formulate CETP inhibitors for oral administration such that therapeutic blood levels are achieved. CETP inhibitors, in general, possess a number of characteristics that render them poorly bioavailable when dosed orally in a conventional manner. CETP inhibitors tend to be quite hydrophobic and extremely water insoluble, with solubility in aqueous solution of usually less than about 10 gg/ml and typically less than 1 jj. g/mL Often the aqueous solubility of CETP inhibitors is less than 0.1 llg/ml. Indeed, the solubility of some CETP inhibitors is so low that it is in fact difficult to measure. Accordingly, when CETP inhibitors are dosed orally, concentrations of CETP inhibitor in the aqueous environment of the gastrointestinal tract tend to be extremely low, resulting in poor absorption from the GI tract to blood. The hydrophobicity of CETP inhibitors not only leads to low equilibrium aqueous solubility but also tends to make the drugs poorly wetting and slow to dissolve, further reducing their tendency to dissolve and be

absorbed from the gastrointestinal tract. This combination of characteristics has resulted in the bioavailability for orally dosed conventional crystalline or amorphous forms of CETP inhibitors generally to be quite low, often having absolute bioavailabilities of less than 1%.

Various attempts have been made to improve the aqueous concentration of CETP inhibitors, but generally have met with limited success. Conventional methods of formulation do not provide sufficient solubilities and thus poor oral bioavailabilities have been obtained. Pre-dissolving CETP inhibitors in hydrophilic solvents such as acetone or PEG followed by delivery as a solution have failed due to inadequate solubility in the solvent or precipitation upon dilution into the aqueous medium.

Suspensions of crystalline drug do not provide sufficient concentrations of drug in solution due to very low aqueous solubilities and therefore yield inadequate blood levels.

One approach that has been disclosed to formulate CETP inhibitors is the formation of CETP solutions in lipids. Solutions in medium chain triglycerides have been of value either as oral solutions or encapsulated in softgels. However, the solubility (65 mg/mL or less) for some of the most potent and useful CETP inhibitors known to the inventors has limited the dose to 30 mg in a reasonable sized softgel.

The efficacious dose is expected to be several multiples of this and therefore may require administration of more than 2 softgels per day.

It has also been found that it is necessary to administer triglyceride solutions with food in order to achieve efficacious blood levels of CETP inhibitors. Food effects of 20-30x have been observed in man for some CETP inhibitors, with considerable variability between patients. The food effect is the ratio of plasma AUC values measured for administration of drug with a meal vs. administration in the fasted state.

In addition, there is minimal CETP inhibition in the absence of food due to low fasted plasma exposure. As a result, labeling would need to indicate administration with food. This strong dependence of exposure on food could compromise the effectiveness of this medication in the treatment of atherosclerosis if there is a lack of compliance with labeling instructions.

Therefore, there remains a need to develop oral formulations of CETP inhibitors that would reduce the food effect substantially, primarily by improving fasted exposure, thereby minimizing patient-to-patient variability in clinical outcome. An increase in the dose per capsule would also be a desirable improvement.

Lack of mixing between oil formulations and the aqueous environment of the GI tract is known to lead to variable gastric emptying and thus variable absorption.

A frequent means of increasing fasted bioavailability of hydrophobic drugs is to use a surfactant or combination of surfactants to produce an emulsion, which, if of sufficiently small particle size can lead to enhanced absorption of the drug. Lipid solutions containing surfactants that spontaneously form emulsions when mixed with an aqueous medium are referred to in the literature as self-emulsifying drug delivery systems (SEDDS) (S, Charman, et. al., Pharm Res., vol. 9,87 (1992)). They are isotropic mixtures of oil, typically medium chain triglycerides, and non-ionic emulsifier that yield fine emulsions when gently mixed with aqueous fluid, such as in the stomach and intestine, and have the appropriate polarity for fast drug release (C. W.

Pouton, Adv. Drug Deliv. Rev, vol. 25,47 (1997); P. P. Constantinides, Pharm. Res., vol. 12,1561 (1995); A. Humberstone and W. Charman, Adv. Drug Del. Rev., vol 25, 103 (1997)). Early SEDDS were defined as forming an emulsion with particle size below 5 microns (S. Charman, et. al., Pharm Res., vol. 9,87 (1992)) and utilized MIGLYOLe and a single surfactant, Tagat TO, which has an HLB (hydrophilic- lipophilic balance) of 10, to form a emulsion with a droplet size of 3 microns. Tagat is not available for human use as are other excipients with the appropriate properties.

Much of the effort in both the open and patent literature has been invested in formulations of cyclosporin. A formulation of cyclosporin that was found to increase bioavailability by in situ generation of an emulsion utilized long chain triglyceride, a polyglycolyzed glyceride, and ethanol and was marketed as Sandimmune' (Cavanak (Sandoz)). See US 4,388,307 (1983). This had the disadvantage of considerable variability in oral bioavailability and PK profile. Subsequently, a self- microemulsifying system was developed (Meinzer, (Sandoz) WO 93/20833; Ritschel, Clin. Transplant., vol. 10,364 (1996)) using polyethoxylated hydrogenated castor oil (Cremophor RH40), corn oil mono-, di-and triglycerides, propylene glycol and ethanol. This softgel formulation, marketed as Neoralo, reduced variability in exposure and also reduced the moderate food effect (Mueller, Pharm. Res. vol 11, 151 (1994)).

Lipophilic solvents have been used in place of ethanol or propylene glycol which will not migrate to the shell and affect shell integrity and/or volatilize and thus impact on the concentration in the fill and on solubility. Triacetin has been used as a

lipophilic solvent for cyclosporin microemulsion preconcentrates with a long chain triglyceride and high HLB surfactant (Hong (Chong Kun Dang Corp.) WO 99/000002). It has also been used alone and in a mixture with propylene glycol dicaprylate/dicaprate and a high HLB surfactant for ketoprofen and related anti- inflammatory acids (Shelley and Wei (Scherer) WO 95/31979A).

US 5,993,858 discloses the use of an oil, high HLB surfactant, cosurfactant and triacetin as solvent for self-emulsifying formulations of hydrophobic drugs.

Propylene carbonate has also been used as a lipophilic solvent for cyclosporin self- emulsifying systems (Woo (Novartis) WO 97/48410 and US 5,958,876 (1999)). Use of ethyl lactate as a cosolvent for cyclosporin formulations, including clinical evaluation, has also been reported (WO 00/40219).

Summary Of The Invention This invention provides pharmaceutical compositions that are liquid solutions, suspensions, and (oil-in-water) emulsions of CETP inhibitors, said solutions being orally administrable. The solutions or dispersions may be administered, for example, as fill in encapsulated dosage forms such as hard or soft gelatin capsules. The CETP inhibitors can be dissolved or dispersed in a variety of lipophilic vehicles, as further described and discussed below, such as digestible oils, solvents and surfactants, including mixtures of any two or more of the aforementioned vehicles.

Reference to a compositional component such as a"digestible oil", to a "surfactant"and so forth, shall be understood as including mixtures of such components such as mixtures of digestible oils and surfactants.

In a first embodiment, the CETP inhibitor is dissolved or dispersed in a digestible oil such as a medium chain triglyceride oil or a mixture of digestible oils.

In a second embodiment, the CETP inhibitor is dissolved or dispersed in a digestible oil with one or more high HLB surfactants. The aforementioned solution or dispersion containing a high HLB surfactant or surfactant mixture may optionally contain one or more low HLB surfactants.

In a third embodiment, the CETP inhibitor is dissolved in a pharmaceutical acceptable lipophilic solvent optionally containing a digestible oil or digestible oil mixture. The CETP inhibitor solvent solution or dispersion or solvent/digestible oil solution or dispersion may optionally contain one or more high HLB surfactants and/or

one or more low HLB surfactants.

The presence of one or more surfactants can, upon contacting the pharmaceutical composition with water, yield an emulsion that is either preformed by mixing with an aqueous phase or that is generated in vivo by contacting the aqueous fluids of the gastrointestinal tract. Formation of an emulsion can improve fasted bioavailability and thus reduce the food effect in man (i. e., the effect of food upon absorption and/or bioavailability of a drug). It can also allow the oil to be consumed as a beverage in addition to being administered in capsules. Use of surfactants to provide an emulsion can also be of value for increasing exposures in toxicology species. Combination of a digestible oil with a solvent can have the advantage of higher solubility and thus a higher dose in a given volume of formulation than is obtainable with the digestible oil alone. It is advantageous for bioavailability to have the entire dose dissolved. The presence of a third component in any of the above embodiments may also improve miscibility between the first two components.

Thus, in a first embodiment, the invention provides an orally administrable pharmaceutical composition comprising a CETP inhibitor and a lipophilic vehicle selected from a digestible oil, a lipophilic solvent (also referred to herein as a "cosolvent", whether or not another solvent is in fact present), a lipophilic surfactant, and mixtures of any two or more thereof. Preferred embodiments include a CETP inhibitor and: (1) the combination of a pharmaceutical acceptable digestible oil and a surfactant; (2) the combination of a pharmaceutically acceptable digestible oil and a lipophilic solvent which is miscible therewith; and (3) the combination of a pharmaceutically acceptable digestible oil, a lipophilic solvent, and a surfactant.

In a particularly preferred embodiment, the invention provides a composition of matter for increasing the oral bioavailability of a CETP inhibitor. The composition comprises: 1. a CETP inhibitor; 2. a solvent ; 3. a surfactant having an HLB of from 1 to not more than 8; 4. a surfactant having an HLB of over 8 up to 20; and 5. optionally, a digestible oil.

In such formulations, all of the excipients are pharmaceutical acceptable. The above composition is sometimes referred to herein as a"pre- concentrate", in reference to its function of forming a stable emulsion when gently mixed with water or other aqueous medium, usually gastrointestinal fluids. It is also referred to herein as a"fill", referring to its utility as a fill for a softgel capsule.

Reference herein is frequently made to a softgel as a preferred dosage form for use with this invention,"softgel"being an abbreviation for soft gelatin capsules. It is understood that when reference is made to the term"softgel"alone, it shall be understood that the invention applies equally to all types of gelatin and non-gelatin capsules, regardless of hardness, softness, and so forth.

A solvent means a solvent in which the CETP inhibitor of interest is highly soluble, having, for any given CETP inhibitor, a solubility of at least 150 mg/mL.

As noted above, and as discussed further below, a digestible oil can form a part of the pre-concentrate. If no other component of the pre-concentrate is capable of functioning as an emulsifiable oily phase, a digestible oil can be included as the oil which acts as a solvent for the CETP inhibitor and which disperses to form the (emulsifiable) oil droplet phase once the pre-concentrate has been added to water.

Some surfactants can serve a dual function, however, i. e., that of acting as a surfactant and also as a solvent and an oily vehicle for forming an oil-in-water emulsion. In the event such a surfactant is employed, and, depending on the amount used, a digestible oil may be required in less of an amount, or not required at all.

The pre-concentrate can be self-emulsifying or self-microemulsifying.

The term"self-emulsifying"refers to a formulation which, when diluted by a factor of at least 100 by water or other aqueous medium and gently mixed, yields an opaque, stable oil/water emulsion with a mean droplet diameter less than about 5 microns, but greater than 100 nm, and which is generally polydisperse. Such an emulsion is stable for at least several (i. e., for at least 6) hours, meaning there is no visibly detectable phase separation and that there is no visibly detectable crystallization of CETP inhibitor.

The term"self-microemulsifying"refers to a pre-concentrate which, upon at least 100 x dilution with an aqueous medium and gentle mixing, yields a non-opaque, stable oil/water emulsion with an average droplet size of about 1 micron or less, said average particle size preferably being less than 100 nm. The particle size is primarily

unimodal. Most preferably the emulsion is transparent and has a unimodal particle size distribution with a mean diameter less than 50 nm as determined, for example, by dynamic light scattering. The microemulsion is thermodynamically stable and without any indication of crystallization of CETP inhibitor.

"Gentle mixing"as used above is understood in the art to refer to the formation of an emulsion by gentle hand (or machine) mixing, such as by repeated inversions on a standard laboratory mixing machine. High shear mixing is not required to form the emulsion. Such pre-concentrates generally emulsify nearly spontaneously when introduced into the human (or other animal) gastrointestinal tract.

The term"CETP inhibitor"implies any such compound that is sparingly or poorly water soluble. Generally, and as mentioned above, such compounds exhibit an aqueous solubility (e. g., in water) of less than about 10 ug/mL measured at about 22°C and at a physiologically relevant pH of from 1 through 8.

Combinations of 2 surfactants, one being a low HLB surfactant with an HLB of 1 to 8, the other being a high HLB surfactant with a higher HLB of over 8 to 20, preferably 9 to 20, can be employed to create the right conditions for efficient emulsification. The HLB, an acronym for"hydrophobic-lipophilic balance", is a rating scale which can range from 1-20 for non-ionic surfactants. The higher the HLB, the more hydrophilic the surfactant. Hydrophilic surfactants (HLB ca. 8-20), when used alone, provide fine emulsions which are, advantageously, more likely to empty uniformly from the stomach and provide a much higher surface area for absorption.

Disadvantageously, however, limited miscibility of such high HLB surfactants with oils can limit their effectiveness, and thus a low HLB, lipophilic surfactant (HLB ca. 1-8) is also included. This combination of surfactants can also provide superior emulsification. A combination of a medium chain triglyceride (such as Miglyole 812), Polysorbate 80 (HLB 15) and medium chain mono/diglycerides (Capmuls MCM, HLB =6) was found to be as efficient as Miglyole 812 and a surfactant with an HLB of 10 (Labrafac CM). N. H. Shah et al. Int. J. Pharm., vol 106,15 (1994). The advantages of using combinations of high and low HLB surfactants for self-emulsifying systems, including promotion of lipolysis, have been demonstrated by Lacy, US 6,096,338.

Detailed Description Suitable digestible oils, which can be used alone as the vehicle or in a vehicle which includes a digestible oil as part of a mixture, include medium chain triglycerides (MCT, C6-C12) and long chain triglycerides (LCT, C14-C20) and mixtures of mono-, di-, and triglycerides, or lipophilic derivatives of fatty acids such as esters with alkyl alcohols. Examples of preferred MCT's include fractionated coconut oils, such as Miglyol0 812 which is a 56% caprylic (C8) and 36% capric (C10) triglyceride, Miglyole 810 (68% C8 and 28% C10), Neobeee M5, Captez 300, Captez 355, and Crodamols GTCC. The Miglyols are supplied by Condea Vista Inc. (Huls), Neobees by Stepan Europe, Voreppe, France, Captez by Abitec Corp., and Crodamols by Croda Corp. Examples of LCTs include vegetable oils such as soybean, safflower, corn, olive, cottonseed, arachis, sunflowerseed, palm, or rapeseed. Examples of fatty acid esters of alkyl alcohols include ethyl oleate and glyceryl monooleate. Of the digestible oils MCT's are preferred, and Miglyol 812 is most preferred.

The vehicle may also be a pharmaceutical acceptable solvent, for use alone, or as a solvent in a mixture. Suitable solvents include any solvent that is used to increase solubility of the CETP inhibitor in the formulation in order to allow delivery of the desired dose per dosing unit. It is not generally possible to predict the solubility of CETP inhibitors in the individual solvents, but such can be easily determined by"trial runs". Suitable solvents include triacetin (1,2,3-propanetriyl triacetate or glyceryl triacetate available from Eastman Chemical Corp.) or other polyol esters of fatty acids, trialkyl citrate esters, propylene carbonate, dimethylisosorbide, ethyl lactate, N-methyl pyrrolidones, transcutol, glycofurol, peppermint oil, 1,2- propylene glycol, ethanol, and polyethylene glycols. Preferred as solvents are triacetin, propylene carbonate (Huntsman Corp.), transcutol (Gattefosse), ethyl lactate (Purac, Lincolnshire, NE) and dimethylisosorbide (sold under the registered trademark ARLASOLVE DMI, ICI Americas). A hydrophilic solvent is more likely to migrate to the capsule shell and soften the shell, and, if volatile, its concentration in the composition can be reduced, but with a potential negative impact on active component (CETP inhibitor) solubility.

More preferred are the lipophilic solvents triacetin, ethyl lactate and propylene carbonate. Most preferred is triacetin.

Hydrophilic surfactants having an HLB of 8-20, preferably having an HLB greater than 10, are particularly effective at reducing emulsion droplet particle size.

Suitable choices include nonionic surfactants such as polyoxyethylene 20 sorbitan

monooleate, polysorbate 80, sold under the trademark TWEEN 80, available commercially from ICI ; polyoxyethylene 20 sorbitan monolaurate (Polysorbate 20, TWEEN 20); polyethylene (40 or 60) hydrogenated castor oil (available under the registered trademarks CREMoPHoR@ RH40 and RH60 from BASF); polyoxyethylene (35) castor oil (CREMoPHoR@ EL) ; polyethylene (60) hydrogenated castor oil (Nikkole HCO-60); alpha tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS); glyceryl PEG 8 caprylate/caprate (available commercially under the registered trademark LABRASOL# from Gattefosse); PEG 32 glyceryl laurate (sold commercially under the registered trademark GELUCIRE° 44/14 by Gattefosse), polyoxyethylene fatty acid esters (availble commercially under the registered trademark MYRJ from ICI), polyoxyethylene fatty acid ethers (available commercially under the registered trademark BRIJ from ICI). Preferred are Polysorbate 80, CREMOPHOR# RH40 (BASF), and Vitamin E TPGS (Eastman). Most preferred are Polysorbate 80 and CREMOPHOR# RH40.

Lipophilic surfactants having an HLB of less than 8 are useful for achieving a balance of polarity to provide a stable emulsion, and have also been used to reverse the lipolysis inhibitory effect of hydrophilic surfactants. Suitable lipophilic surfactants include mono and diglycerides of capric and caprylic acid under the following registered trademarks: Capmule MCM, MCM 8, and MCM 10, available commercially from Abitec; and ImwitorX 988,742 or 308, available commercially from Condea Vista; polyoxyethylene 6 apricot kernel oil, available under the registered trademark Labrafil@ M 1944 CS from Gattefosse; polyoxyethylene corn oil, available commercially as Labrafils M 2125; propylene glycol monolaurate, available commercially as Lauroglycol from Gattefosse; propylene glycol dicaprylate/caprate available commercially as Captez 200 from Abitec or Miglyol 840 from Condea Vista, polyglyceryl oleate available commercially as Plurol oleique from Gattefosse, sorbitan esters of fatty acids (e. g. Span@ 20, Crill@ 1, Crible 4, available commercially from ICI and Croda), and glyceryl monooleate (Maisine, Peceol). Preferred from this class are Capmul@ MCM (Abitec Corp.) and Labrafilo M1944 CS (Gattefosse). Most preferred is Capmu) MCM.

In addition to the main liquid formulation ingredients previously noted, other stabilizing additives, as conventionally known in the art of softgel formulation, can be introduced to the fill as needed, usually in relatively small quantities, such as antioxidants (BHA, BHT, tocopherol, propyl galate, etc.) and other preservatives such

as benzyl alcohol or parabens.

The composition can be formulated as a fill encapsulated in a soft gelatin capsule, a hard gelatin capsule with an appropriate seal, a non-gelatin capsule such as a hydroxypropyl methylcellulose capsule or an oral liquid or emulsion by methods commonly employed in the art. The fill is prepared by mixing the excipients and CETP inhibitor with heating if required.

The ratio of CETP inhibitor, digestible oil, solvent, and surfactants depends upon the efficiency of emulsification and the solubility, and the solubility depends on the dose per capsule that is desired. A self-emulsifying formulation is generally useful if the primary goals are to deliver a high dose per softgel (at least 60 mg) with, generally, a much lower food effect than with an oil solution alone. In general, softgel preconcentrates having solubilities of CETP inhibitor of at least 140 mg/mL in the preconcentrate, and thus requiring higher amounts of solvent and lower levels of surfactants and oil, are preferred.

In general, the following ranges, in weight percent, of the components for a self-emulsifying formulation of CETP inhibitors are: 1-50 % CETP inhibitor 5-60 % solvent 5-75 % high HLB surfactant 5-75 % low HLB surfactant Preferred ranges which have advantageously low food effects include those stated immediately below : 1-33 % CETP inhibitor 0-30 % digestible oil 15-55 % cosolvent 5-40 % high HLB surfactant 10-50 % low HLB surfactant More preferred ranges include 1-25 % CETP inhibitor 10-25 % digestible oil 20-35 % solvent

10-30 % high HLB surfactant 15-35 % low HLB surfactant If a specific goal is a minimal food effect, then a self-microemulsifying formulation is advantageous. Such formulations generally require relatively high levels of surfactants and a reduced amount of solvent. These formulations can, however, result in lower solubilities and, accordingly, a lower dose per capsule.

These formulations have been found to increase fasted exposure.

General ranges, in weight percent, for the components for a self- microemulsifying formulation of CETP inhibitors are 1-40% CETP inhibitor 5-65 % digestible oil 5-60 % solvent 10-75 % high HLB surfactant 5-75 % low HLB surfactant Preferred ranges include those which follow 1-20 % CETP inhibitor 5-30 % digestible oil 5-45 % solvent 30-55%, high HLB surfactant 10-40 %, low HLB surfactant Specific examples of preferred formulations include: A composition comprising a compound which is [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)- methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro -2H-quinoline-1- carboxylic acid ethyl ester; or a compound which is [2R, 4S] 4- [acetyl- (3, 5-bis- <BR> <BR> <BR> trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1- carboxylic acid isopropyl ester; or a compound which is [2R, 4S] 4- [ (3, 5-Bis- trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-tri fluoromethyl-3, 4- dihydro-2H-quinoline-1-carboxylic acid isopropyl ester a solvent ; a high HLB surfactant; a low HLB surfactant; and

optionally, a digestible oil.

A more preferred composition is that noted immediately above, wherein said solvent is triacetin or ethyl lactate ; said high HLB surfactant comprises polysorbate 80 or a polyethylene hydrogenated castor oil ; said low HLB surfactant comprises a mixture of mono-and diglycerides of capric and caprylic acids; said digestible oil comprises a medium chain triglyceride, wherein each of the three hydrocarbon chains therein is predominantly C6-C12.

A more specific preferred composition is that noted immediately above, which comprises, by weight: 5-25% of said CETP inhibitor; 10-25% of said digestible oil ; 20-35% of said solvent : 10-35% of said high HLB surfactant ; and 10-35% of said low HLB surfactant; A still more specific preferred embodiment is that noted immediately above which comprises, by weight: 8-12% of [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2- ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester 10-20% of said digestible oil ; 25-35% of said solvent which comprises triacetin: 10-30% of said high HLB surfactant which comprises polysorbate 80; and 15-35% of said low HLB surfactant which comprises a mixture of medium chain mono-and di-glycerides.

Another still more specific preferred embodiment is one, which comprises, by weight: 8-12% of [2R, 4S] 4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; 10-20% of said digestible oil ; 25-35% of said solvent which comprises triacetin;

10-30% of said high HLB surfactant which comprises a polyethylene (40) hydrogenated castor oil ; 15-35% of said low HLB surfactant, which comprises a mixture of medium chain mono-and di-glycerides.

Another still more specific preferred embodiment is one which comprises, by weight 8-25% of [2R, 4S] 4- [ (3, 5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]- 2-ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; 10-25% of digestible oil ; 20-35% of said solvent which comprises triacetin; 10-30% of said high HLB surfactant which comprises polysorbate 80; and 15-35% of said low HLB surfactant which comprises a mixture of medium chain mono-and di-glycerides.

As indicated by the broadest range above, the digestible oil may be optionally omitted in order to further increase the amount of solvent and, therefore, solubility of the CETP inhibitor in the pre-concentrate.

In addition to the main softgel capsule ingredients previously noted, other stabilizing additives, as conventionally known in the art of softgel formulation, can be introduced to the fill as needed, usually in relatively small quantities, such as antioxidants (BHA, BHT, tocopherol, propyl galate, etc.) and other preservatives such as benzyl alcohol or parabens.

The composition can be formulated as a fill encapsulated in a soft gelatin capsule, a hard gelatin capsule with an appropriate seal, a non-gelatin capsule such as a hydroxypropyl methylcellulose capsule or an oral liquid or emulsion by methods commonly employed in the art. The fill is prepared by mixing the excipients and CETP inhibitor with heating if required.

Preferred embodiments comprise a CETP inhibitor with: (a) solubility less than 10 ug/ml ; (b) c log P greater than 5; and/or (c) dose greater than 10 mg, preferably at least 30 mg.

The invention is not limited by any particular structure or group of CETP inhibitors. Rather, the invention has general applicability to CETP inhibitors as a class, the class tending to be composed of compounds having low solubility. Compounds which may be the subject of the invention may be found in a number of patents and published applications, including DE 19741400 A1 ; DE 19741399 A1 ; WO 9914215 A1 ; WO 9914174 ; DE19709125A1 ; DE19704244A1 ; DE19704243A1 ; EP 818448 A1 ; WO 9804528 A2; DE 19627431 A1 ; DE 19627430 A1 ; DE 19627419 A1 ; EP 796846 A1 ; DE 19832159 ; DE 818197; DE 19741051; WO 9941237 A1 ; WO 9914204 A1 ; WO 9835937 A1 ; JP 11049743; WO 200018721 ; WO 200018723; WO 200018724; WO 200017164; WO 200017165; WO 200017166; EP 992496; and EP 987251, all of which are hereby incorporated by reference in their entirety.

Oral delivery of many CETP inhibitors is particularly difficult because their aqueous solubility is usually extremely low, typically being less than 2, ug/ml, often being less than 0.1, ug/ml. Such low solubilities are a direct consequence of the particular structural characteristics of species that bind to CETP and thus act as CETP inhibitors. This low solubility is primarily due to the hydrophobic nature of CETP inhibitors. Log P, defined as the base 10 logarithm of the ratio of the drug concentration in octanol to the drug concentration in water in a partitioning experiment, is a widely accepted measure of hydrophobicity. In general, Log P values for CETP inhibitors are greater than 4 and are often greater than 5 to 7. This property may also be calculated from the structure of the molecule and is designated"cLog P.". The calculation of cLog P values from chemical structures is given in Leo, A. J.; "Calculating log P from structures", Chem. Rev. 1993,93,1281. Thus, the hydrophobic and insoluble nature of CETP inhibitors as a class pose a particular challenge for oral delivery. Achieving therapeutic drug levels in the blood by oral dosing of practical quantities of drug generally requires a large enhancement in drug concentrations in the gastrointestinal fluid and a resulting large enhancement in bioavailability.

The formulations of this invention will be administered in such an amount that an effective dose of the CETP inhibitor of interest is administered to the patient. The amount of CETP inhibitor will generally be known or determined by the attending physician. Thus the amount or volume of preconcentrate administered will be determined by the amount of CETP inhibitor prescribed and/or otherwise desired as a

dose and the solubility of the CETP in the preconcentrate. In general, an effective dose for most CETP inhibitors is in the range of from 5 to 500 mg, preferably 10-300 mg, more preferably 10-200 mg per day, in single or divided doses. The compositions of the invention are pre-concentrates for emulsification which are generally administered orally, in soft or hard gelatin capsules, gelatin encapsulation technology being well known to the pharmaceutical arts. Such pre-concentrates can also be administered in aqueous oral emulsions by adding the pre-concentrate to water or other aqueous liquid (e. g., soda). They can be mixed with an aqueous liquid and sold as pre-formed emulsions, or added to food such as ice cream.

Turning now to the chemical structures of specific CETP inhibitors, one class of CETP inhibitors that finds utility with the present invention consists of oxy substituted 4-carboxyamino-2-methyl-1, 2,3,4-tetrahydroquinolines having the Formula I Formula I and pharmaceutically acceptable salts, enantiomers, or stereoisomers of said compounds; wherein RI-1 is hydrogen, Y, W-X, Wl-Yl ; wherein W, is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl ; X, is-0-Yi,-S-Y,,-N (H)-Y, or-N-(Y) 2 ; wherein Y, for each occurrence is independently Z, or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di-substituted with oxo,

said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Z ; wherein Z, is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said Z, substituent is optionally mono-, di-or tri-substituted independently with halo, (C2-C6) alkenyl, (Cl-C6) alkyl, hydroxy, (Ci-Ce) alkoxy, (Cl- C4) alkylthio, amino, nitro, cyano, oxo, carboxyl, (C1-C6) alkyloxycarbonyl, mono-N-or di- N, N- (CI-Cr,) alkylamino wherein said (Cl-CE ;) alkyl substituent is optionally mono-, di-or tri-substituted independently with halo, hydroxy, (C1-C6) alkoxy, (C1-C4) alkylthio, amino, nitro, cyano, oxo, carboxyl, (Ci-C6) alkyloxycarbonyl, mono-N-or di-N, N- (Ci- C6) alkylamino, said (Ci-Ce) alkyl substituent is also optionally substituted with from one to nine fluorines; Rif 3 is hydrogen or Q, ; wherein Q, is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di- substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V, ; wherein V, is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said V, substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (Ci-Ce) alkyl, (C2-C6)alkenyl, hydroxy, (Ci-Ce) alkoxy, (C,- C4) alkylthio, amino, nitro, cyano, oxo, carbamoyl, mono-N-or di-N, N- (Cl-C6)

alkylcarbamoyl, carboxyl, (C1-C6) alkyloxycarbonyl, mono-N-or di-N, N- (Ci- Ce) alkylamino wherein said (Ci-C6) alkyl or (C2-C6) alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C1-C6) alkoxy, (C,-C4) alkylthio, amino, nitro, cyano, oxo, carboxyl, (Ci-C6) alkyloxycarbonyl, mono-N-or di-N, N- (Ci- C6) alkylamino, said (Ci-C6) alkyl or (C2-C6) alkenyl substituents are also optionally substituted with from one to nine fluorines ; Rl4 is QI-1 or VM wherein Qu-1 ils a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di- substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V,; wherein VI-1 is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said Vl 1 substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C1-C6) alkyl, (C1-C6) alkoxy, amino, nitro, cyano, (Cl- C6) alkyloxycarbonyl, mono-N-or di-N, N-(C1-C6) alkylamino wherein said (Ci-C6) alkyl substituent is optionally mono-substituted with oxo, said (Ci-Ce) alkyl substituent is also optionally substituted with from one to nine fluorines ; wherein either R must contain V, or RI-4 must contain V. i ; and RI-5, RI-6, RI-7 and RI-8 are each independently hydrogen, hydroxy or oxy wherein said oxy is substituted with T, or a partially saturated, fully saturated or fully unsaturated one to twelve membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono- substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di-substituted with oxo, said nitrogen is optionally mono-or di-substituted with oxo, and said carbon chain is optionally mono-substituted with TI ;

wherein T, is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said T, substituent is optionally mono-, di-or tri-substituted independently with halo, (Ci-C6) alkyl, (C2-C6) alkenyl, hydroxy, (d-Ce) alkoxy, (Ci- C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-C6) alkyloxycarbonyl, mono-N-or di- N, N-(C,-C6) alkylamino wherein said (Ci-C6) alkyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C1-C6) alkoxy, (Ci-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6) alkyloxycarbonyl, mono-N-or di-N, N-(C1-C6) alkylamino, said (Ci-Ce) alkyl substituent is also optionally substituted with from one to nine fluorines.

Compounds of Formula I are disclosed in commonly assigned pending U. S.

Patent Application Serial No. 09/390,731, the complete disclosure of which is herein incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from one of the following compounds of Formula I : [2R, 4S] 4- [ (3, 5-dichloro-benzyl)-methoxycarbonyl-amino]-6, 7-dimethoxy-2-methyl-3, 4- dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4- [ (3, 5-dinitro-benzyl)-methoxycarbonyl-amino]-6, 7-dimethoxy-2-methyl-3, 4- dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4-[(2,6-dichloro-pyridin-4-ylmethyl)-mjethoxycarbonyl-amino] -6, 7-dimethoxy-2- methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6, 7-dimethoxy-2- methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-metho xy-2- methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-metho xy-2- methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6, 7-dimethoxy-2- methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-ethoxycarbonyl-amino]-6, 7-dimethoxy-2- methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6 , 7-dimethoxy-2- methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid 2,2,2-trifluoro-ethylester; [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6, 7-dimethoxy-2- methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6, 7-dimethoxy-2- methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester; [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methy l-6- trifluoromethoxy-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, [2R, 4S] (3,5-bis-trifluoromethyl-benzyl)- (1-butyryl-6, 7-dimethoxy-2-methyl-1,2,3,4- tetrahydro-quinolin-4-yl)-carbamic acid methyl ester; [2R, 4S] (3, 5-bis-trifluoromethyl-benzyl)-(1-butyl-6,7-dimethoxy-2-methy l-1, 2,3,4- tetrahydro-quinolin-4-yl)-carbamic acid methyl ester; [2R, 4S] (3, 5-bis-trifluoromethyl-benzyl)-[1-(2-ethyl-butyl)-6,7-dimetho xy-2-methyl- 1,2,3,4-tetrahydro-quinolin-4-yl]-carbamic acid methyl ester, hydrochloride Another class of CETP inhibitors that finds utility with the present invention consists of 4-carboxyamino-2-methyl-1, 2,3,4,-tetrahydroquinolines, having the Formula II Formula II and pharmaceutically acceptable salts, enantiomers, or stereoisomers of said compounds; wherein Rll 1 is hydrogen, YII, Wli-Xil, Wll-Yll ; wherein Wil is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl ; XII is -O-YII, -S-YII, -N(H)-YII or -N-(YII)2;

wherein Y, for each occurrence is independently Z ; ; or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Zil ; Zll is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said Zll substituent is optionally mono-, di-or tri-substituted independently with halo, (C2-C6) alkenyl, (C,-C6) alkyl, hydroxy, (Ci-Ce) alkoxy, (Cl- C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-C6) alkyloxycarbonyl, mono-N-or di- N, N- (Cl-C6) alkylamino wherein said (Ci-C6) alkyl substituent is optionally mono-, di-or tri-substituted independently with halo, hydroxy, (Ci-Ce) alkoxy, (C1-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-C6) alkyloxycarbonyl, mono-N-or di-N, N- (C,- C6) alkylamino, said (Ci-C6) alkyl is also optionally substituted with from one to nine fluorines ; Rllt is hydrogen or Qll ; wherein Q ; ; is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di- substituted with oxo, said nitrogen is optionally mono-or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Vil ; wherein Vj, is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected

independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said VII substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (Ci-C6) alkyl, (C2-C6) alkenyl, hydroxy, (C1-C6) alkoxy, (Cl- C4) alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N-or di-N, N- (Ci-Ce) alkylcarboxamoyl, carboxy, (Ci-C6) alkyloxycarbonyl, mono-N-or di-N, N- (Cl- C6) alkylamino wherein said (Ci-Ce) alkyl or (C2-C6) alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (Ci-Ce) alkoxy, (Ci-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-C6) alkyloxycarbonyl, mono-N-or di-N, N- (Ci- C6) alkylamino or said (C,-C6) alkyl or (C2-C6) alkenyl substituents are optionally substituted with from one to nine fluorines ; RII-4 is QII-1 or VII-1 wherein QII-1 a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di- substituted with oxo, said nitrogen is optionally mono-or di-substituted with oxo, and said carbon chain is optionally mono-substituted with VII-1 ; wherein VII-I is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said VII-1 substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C1-C6) alkyl, (C,-C6) alkoxy, amino, nitro, cyano, (C1- C6) alkyloxycarbonyl, mono-N-or di-N, N- (Cl-C6) alkylamino wherein said (Ci-Ce) alkyl substituent is optionally mono-substituted with oxo, said (C,-C6) alkyl substituent is optionally substituted with from one to nine fluorines ; wherein either R"_3 must contain Vll or Rll 1 must contain Vil 1 ; and RII-5, RII-6, RII-7 and RII-8 are each independently hydrogen, a bond, nitro or halo wherein said bond is substituted with T), or a partially saturated, fully saturated or fully unsaturated (Ci-Ci2) straight or branched carbon chain wherein carbon may optionally

be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di- substituted with oxo, said nitrogen is optionally mono-or di-substituted with oxo, and said carbon is optionally mono-substituted with Tll ; wherein Til is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said Tn substituent is optionally mono-, di-or tri-substituted independently with halo, (C,-C6) alkyl, (C2-C6) alkenyl, hydroxy, (C,-C6) alkoxy, (Cl- C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-C6) alkyloxycarbonyl, mono-N-or di- N, N-(C1-C6) alkylamino wherein said (Ci-Ce) alkyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (Ci-Ce) alkoxy, (C1-C4) aikylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6) alkyloxycarbonyl, mono-N-or di-N, N-(C1-C6) alkylamino, said (Ci-Ce) alkyl substituent is also optionally substituted with from one to nine fluorines ; provided that at least one of substituents RII-5, RII-6, RII-7 and Ril-8 is not hydrogen and is not linked to the quinoline moiety through oxy.

Compounds of Formula II are disclosed in commonly assigned pending U. S.

Patent 6,147,090 the complete disclosure of which is herein incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from one of the following compounds of Formula li : [2R, 4S] 4- [ (3, 5-Bis-t (ifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-7- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4- [ (3, 5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-chlor o-2-methyl- 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6 -chloro-2-methyl- 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4- [ (3, 5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2, 6,7-trimethyl-3,4- dihydro-2H-quinoline-1-carboxylic acid ethyl ester

[2R, 4S] 4- [ (3, 5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6, 7-diethyl-2- methyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4- [ (3, 5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-ethyl -2-methyl- 3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4- [ (3, 5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methy l-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester.

[2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methy l-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester.

Another class of CETP inhibitors that finds utility with the present invention consists of annulated 4-carboxyamino-2-methyl-1, 2,3,4,-tetrahydroquinolines, having the Formula III

Formula III and pharmaceutically acceptable salts, enantiomers, or stereoisomers of said compounds ; wherein R, is hydrogen, YIII, WIII-XIII, WIII-YIII; wherein W¢,, is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl ; Xill is -O-YIII, -S-YIII, -N(H)-YIII or -N-(YIII)2; Ylil for each occurrence is independently Zli, or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di-substituted with oxo,

said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with ZIII; wherein ZIII is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said Zll substituent is optionally mono-, di-or tri-substituted independently with halo, (C2-C6) alkenyl, (C-C6) alkyl, hydroxy, (Ci-Ce) alkoxy, (Cl- C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-C6) alkyloxycarbonyl, mono-N-or di- N, N- (Ci-Ce) a) kyiamino wherein said (Ci-Ce) alkyl substituent is optionally mono-, di-or tri-substituted independently with halo, hydroxy, (Ci-Ce) alkoxy, (Ci-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-C6) alkyloxycarbonyl, mono-N-or di-N, N-(C,- C6) alkylamino, said (C,-C6) alkyl optionally substituted with from one to nine fluorines; Rill-3 is hydrogen or Qlll ; wherein Qlil is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di- substituted with oxo, said nitrogen is optionally mono-or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Vill ; wherein VII, is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said VII, substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (CI'C6) alkyl, (C2-C6) alkenyl, hydroxy, (C1-C6) alkoxy, (Cl- C4) alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N-or di-N, N- (Ci-Ce) alkylcarboxamoyl, carboxy, (Ci-C6) alkyloxycarbonyl, mono-N-or di-N, N- (Ci-

C6) alkylamino wherein said (Ci-Ce) alkyl or (C2-C6) alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C1-C6) alkoxy, (Ci-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6) alkyloxycarbonyl, mono-N-or di-N, N- (Cl- C6) alkylamino or said (Ci-Ce) alkyl or (C2-C6) alkenyl are optionally substituted with from one to nine fluorines; RlX, -4 is QIII-1 or VIII-1 ; wherein QIII-1 a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di- substituted with oxo, said nitrogen is optionally mono-or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Vill-1 ; wherein Vlil 1 is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said Vl substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C1-C6)alkyl, (C1-C6)alkoxy, amino, nitro, cyano, (Cl- C6) alkyloxycarbonyl, mono-N-or di-N, N-(C1-C6) alkylamino wherein said (Ci-Ce) alkyl substituent is optionally mono-substituted with oxo, said (CI-C6) alkyl substituent optionally having from one to nine fluorines ; wherein either RIII-3 must contain VIII or RIII-4 must contain VIII-1; and Rill-5 and Rill-6, or RIII-6 and Rill-7, and/or Rill-7 and and Ræ are taken together and form at least one four to eight membered ring that is partially saturated or fully unsaturated optionally having one to three heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said ring or rings formed by Rill-5 and RIII-6, or RIII-6 and RIII-7, and/or RIII-7 and RIII-8 are optionally mono-, di-or tri-substituted independently with halo, (Ci- C6) alkyl, (C1-C4) alkylsulfonyl, (C2-C6) alkenyl, hydroxy, (C1-C6) alkoxy, (Ci-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-C6) alkyloxycarbonyl, mono-N-or di-N, N- (Cl- C6) alkylamino wherein said (Ci-Ce) alkyl substituent is optionally mono-, di-or tri- substituted independently with hydroxy, (C1-C6) alkoxy, (C1-C4) alkylthio, amino, nitro,

cyano, oxo, carboxy, (Ci-Ce) alkyloxycarbonyl, mono-N-or di-N, N- (Cl-C6) alkylamino, said (Ci-C6) alkyl substituent optionally having from one to nine fluorines ; provided that the Rill-5, RIII-6, RIII-7 and/or RIII-8, as the case may be, that do not form at least one ring are each independently hydrogen, halo, (CI-C6) alkoxy or (Ci- C6) alkyl, said (Ci-Ce) alkyl optionally having from one to nine fluorines.

Compounds of Formula III are disclosed in commonly assigned pending U. S. Patent 6,147,089 the complete disclosure of which is herein incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from one of the following compounds of Formula III : [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methy l- 2,3,4,6,7,8-hexahydro-cyclopenta [g] quinoline-1-carboxylic acid ethyl ester; [6R, 8S] 8- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methy l-3, 6,7,8- tetrahydro-1 H-2-thia-5-aza-cyclopenta [b] naphthalene-5-carboxylic acid ethylester ; [6R, 8S] 8- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methy l-3, 6,7,8- tetrahydro-2H-furo [2, 3-g] quinoline-5-carboxylic acid ethyl ester; [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methy l-3, 4,6,8- tetrahydro-2H-furo [3,4-g] quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methy l- 3,4,6,7,8,9-hexahydro-2H-benzo [g] quinoline-1-carboxylic acid propyl ester; [7R, 9S] 9- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methy l- 1,2,3,7,8,9-hexahydro-6-aza-cyclopenta [a] naphthalene-6-carboxylic acid ethyl ester; and [6S, 8R] 6- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-methy l- 1,2,3,6,7,8-hexahydro-9-aza-cyclopenta [a] naphthalene-9-carboxylic acid ethyl ester.

Another class of CETP inhibitors that finds utility with the present invention consists of 4-carboxyamino-2-substituted-1,2,3,4,-tetrahydroquinolines, having the Formula IV

Formula IV and pharmaceutically acceptable salts, enantiomers, or stereoisomers of said compounds; wherein Rlv 1 is hydrogen, Ylv, Wiv-Xiv or Wiv-Ylv ; wherein W, v is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl ; Xlv is -O-YIV, -S-YIV, -N(H)-YIV or -N-(YIV)2; wherein Ylv for each occurrence is independently Zlv or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Zlv ; wherein Zlv is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said Zlv substituent is optionally mono-, di-or tri-substituted independently with halo, (C2-C6) alkenyl, (C,-C6) alkyl, hydroxy, (Ci-Ce) alkoxy, (C,- C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-Ce) alkyloxycarbonyl, mono-N-or di- N, N-(C1-C6)alkylamino wherein said (C,-C6) alkyl substituent is optionally mono-, di-or tri-substituted independently with halo, hydroxy, (C,-C6) alkoxy, (C,-C4) alkylthio, amino,

nitro, cyano, oxo, carboxy, (C,-C6) alkyloxycarbonyl, mono-N-or di-N, N- (C,- C6) alkylamino, said (Ci-Ce) alkyl substituent is also optionally substituted with from one to nine fluorines ; Rlv2 is a partially saturated, fully saturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono-or di-substituted with oxo, said nitrogen is optionally mono-or di-substituted with oxo; or said Riv-2 is a partially saturated, fully saturated or fully unsaturated three to seven membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said Rlv-2 ring is optionally attached through (C,-C4) alkyl ; wherein said Rlv-2 ring is optionally mono-, di-or tri-substituted independently with halo, (C2-C6) alkenyl, (C,-C6) alkyl, hydroxy, (Ci-Ce) alkoxy, (Ci-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-C6) alkyloxycarbonyl, mono-N-or di-N, N- (Ci- C6) alkylamino wherein said (C,-C6) alkyl substituent is optionally mono-, di-or tri- substituted independently with halo, hydroxy, (C,-C6) alkoxy, (C,-C4) alkylthio, oxo or (Ci-Ce) alkyloxycarbonyl ; with the proviso that R, V 2 is not methyl ; Rlv-3 is hydrogen or Qlv ; wherein Qlv is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di- substituted with oxo, said nitrogen is optionally mono-or di-substituted with oxo, and said carbon chain is optionally mono-substituted with V, v ; wherein Viv is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken

independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said Vlv substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C1-C6) alkyl, (C2-C6) alkenyl, hydroxy, (C,-C6) alkoxy, (Cl- C4) alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N-or di-N, N-(C,-C6) alkylcarboxamoyl, carboxy, (C-C6) alkyloxycarbonyl, mono-N-or di-N, N-(C1- C6) alkylamino wherein said (C1-C6) alkyl or (C2-C6) alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (Ci-C6) alkoxy, (C,-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-C6) alkyloxycarbonyl, mono-N-or di-N, N-(C1- C6) alkylamino, said (Ci-Ce) alkyl or (C2-C6) alkenyl substituents are also optionally substituted with from one to nine fluorines ; RIV-4 is QIV-1 or VIV-1; wherein Qlv 1 a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di- substituted with oxo, said nitrogen is optionally mono-or di-substituted with oxo, and said carbon chain is optionally mono-substituted with VlV-1 ; wherein Vlv 1 is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said VIV-1 substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (Ci-C6) alkyl, (Cl-C6) alkoxy, amino, nitro, cyano, (Ci- C6) alkyloxycarbonyl, mono-N-or di-N, N- (CI-C6) alkylamino wherein said (Ci-C6) alkyl substituent is optionally mono-substituted with oxo, said (Ci-C6) alkyl substituent is also optionally substituted with from one to nine fluorines ; wherein either Rev 3 must contain V, v or Rev 1 must contain VIV-1 ; RIV-5, RIV-6, RIV-7 and RIV-8 are each independently hydrogen, a bond, nitro or halo wherein said bond is substituted with Tir or a partially saturated, fully saturated or fully unsaturated (CI-CI2) straight or branched carbon chain wherein carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur

and nitrogen wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di- substituted with oxo, said nitrogen is optionally mono-or di-substituted with oxo, and said carbon is optionally mono-substituted with Tlv ; wherein Tlv is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said Tlv substituent is optionally mono-, di-or tri-substituted independently with halo, (C1-C8)alkyl, (C2-C6)alkenyl, hydroxy, (C1-C6) alkoxy, (Ci- C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-C6) alkyloxycarbonyl, mono-N-or di- N, N-(C,-C6) alkylamino wherein said (C-C6) alkyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (Ci-C6) alkoxy, (Ci-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-Ce) alkyloxycarbonyl, mono-N-or di-N, N-(C1-C6) alkylamino, said (Ci-Ce) alkyl substituent is also optionally substituted with from one to nine fluorines ; and wherein Rv-5 and Rlv-6, or RIV-6 and Rev-7 and/or RIV-7 AND RIV-8 may also be taken together and can form at least one four to eight membered ring that is partially saturated or fully unsaturated optionally having one to three heteroatoms independently selected from nitrogen, sulfur and oxygen; wherein said ring or rings formed by RIV-5 and RIV06, or RIV-6 and Rlv-7 and/or RIV-7 and RIV-8 are optionally mono-, di-or tri-substituted independently with halo, (C1- C6) alkyl, (C,-C4) alkylsulfonyf, (C2-C6) alkenyl, hydroxy, (Ci-Ce) alkoxy, (Ci-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-C6) alkyloxycarbonyl, mono-N-or di-N, N-(C1- C6) alkylamino wherein said (CI-C6) alkyl substituent is optionally mono-, di-or tri- substituted independently with hydroxy, (C1-C6) alkoxy, (Ci-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-C6) alkyloxycarbonyl, mono-N-or di-N, N-(C1-C6)alkylamino, said (Ci-Ce) alkyl substituent is also optionally substituted with from one to nine fluorines ; with the proviso that when Riv-2 is carboxyl or (Ci-C4) alkylcarboxyl, then RIV-1 is not hydrogen.

Compounds of Formula IV are disclosed in commonly assigned pending U. S.

Patent 6,197,786 the complete disclosure of which is herein incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from one of the following compounds of Formula IV : [2S, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopr opyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chlor o-2- cyclopropyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 2-cyclopropyl-4- [ (3, 5-dichloro-benzyl)-methoxycarbonyl-amino]-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclo propyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ter-butyl ester; [2R, 4R] 4- [ (3, 5-bis-trifluoromethyl-benzyl)- methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3, 4-dihydro-2H- quinaline-1-carboxylic acid isopropyl ester; [2S, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclo propyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclo butyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester, [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl -6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-metho xymethyl- 6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl -6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid 2-hydroxy-ethyl ester; [2S, 4S] 4- [ (3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cy clopropyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl -6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2S, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclo propyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; and [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl -6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid propyl ester.

Another class of CETP inhibitors that finds utility with the present invention consists of 4-amino substituted-2-substituted-1, 2,3,4,-tetrahydroquinolines, having the Formula V

Formula V and pharmaceutical acceptable salts, enantiomers, or stereoisomers of said compounds; wherein Rv 1 is Yv, Wv-Xv or Wv-Yv ; wherein Wv is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl ; Xv is-0-Yv,-S-Yv,-N (H)-Yv or-N- (Yv) 2; wherein Yv for each occurrence is independently Zv or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Zv ; wherein Zv is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said Zv substituent is optionally mono-, di-or tri-substituted independently with halo, (C2-C6) alkenyl, (Cl-C6) alkyl, hydroxy, (Ci-Ce) alkoxy, (C,-

C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-C6) alkyloxycarbonyl, mono-N-or di- N, N-(C1-C6) alkylamino wherein said (Ci-Ce) alkyl substituent is optionally mono-, di-or tri-substituted independently with halo, hydroxy, (Ci-Ce) alkoxy, (C1-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (CI-C6) alkyloxycarbonyl, mono-N-or di-N, N- (Cr C6) alkylamino, said (Ci-Ce) alkyl substituent is also optionally substituted with from one to nine fluorines ; Rv-2 is a partially saturated, fully saturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with oxo, said carbon is optionally mono-substituted with hydroxy, said sulfur is optionally mono-or di-substituted with oxo, said nitrogen is optionally mono-or di-substituted with oxo; or said Rv-2 is a partially saturated, fully saturated or fully unsaturated three to seven membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said Razz ring is optionally attached through (Ci-C4) alkyl ; wherein said Rv-2 ring is optionally mono-, di-or tri-substituted independently with halo, (C2-C6) alkenyl, (Cl-C6) alkyl, hydroxy, (Ci-Ce) alkoxy, (C1-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-C6) alkyloxycarbonyl, mono-N-or di-N, N- (Cr C6) alkylamino wherein said (Ci-Ce) alkyl substituent is optionally mono-, di-or tri- substituted independently with halo, hydroxy, (Ci-C6) alkoxy, (C1-C4) alkylthio, oxo or (Ci-C6) alkyloxycarbonyl ; Rv 3 is hydrogen or Qv ; wherein Qv is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di- substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Vv ; wherein Vv is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently

from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said Vv substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (Ci-Ce) alkyl, (C2-C6) alkenyl, hydroxy, (Ci-Ce) alkoxy, (Cl- C4) alkylthio, amino, nitro, cyano, oxo, carboxamoyl, mono-N-or di-N, N- (Ci-Ce) alkylcarboxamoyl, carboxy, (C1-C6) alkyloxycarbonyl, mono-N-or di-N, N-(C1- C6) alkylamino wherein said (C,-C6) alkyl or (C2-C6) alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C1-C6) alkoxy, (C1-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6) alkyloxycarbonyl, mono-N-or di-N, N- (Cl- C6) alkylamino, said (Ci-Ce) alkyl or (C2-C6) alkenyl substituents are also optionally substituted with from one to nine fluorines ; Rv-4 is cyano, formyl, WV-1QV-1, WV-1VV-1, (C1-C4)alkyleneVV-1 or VV-2 ; wherein Wv 1 is carbonyl, thiocarbonyl, SO or SO2, wherein Qv a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono- substituted with Vv, ; wherein Vv 1 is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said Vv-i substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (Ci-C6) alkyl, (C1-C6) alkoxy, hydroxy, oxo, amino, nitro, cyano, (Ci-C6) alkyloxycarbonyl, mono-N-or di-N, N-(C1-C6) alkylamino wherein said (Cl- C6) alkyl substituent is optionally mono-substituted with oxo, said (Ci-Ce) alkyl substituent is also optionally substituted with from one to nine fluorines;

wherein Vv 2 is a partially saturated, fully saturated or fully unsaturated five to seven membered ring containing one to four heteroatoms selected independently from oxygen, sulfur and nitrogen; wherein said VV-2 substituent is optionally mono-, di-or tri-substituted independently with halo, (Cl-C2) alkyl, (Cl-C2) alkoxy, hydroxy, or oxo wherein said (Cl- C2) alkyl optionally has from one to five fluorines ; and wherein Rv-4does not include oxycarbonyl linked directly to the C4 nitrogen ; wherein either RvÆ must contain Vv or RV-4 must contain Vv, ; Rv, Rv-6, Rv-7and Rv- are independently hydrogen, a bond, nitro or halo wherein said bond is substituted with Tv or a partially saturated, fully saturated or fully unsaturated (C1-C12) straight or branched carbon chain wherein carbon may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen, wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono-or di- substituted with oxo, said nitrogen is optionally mono-or di-substituted with oxo, and said carbon chain is optionally mono-substituted with Tv ; wherein Tv is a partially saturated, fully saturated or fully unsaturated three to twelve membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said Tv substituent is optionally mono-, di-or tri-substituted independently with halo, (Ci-C6) alkyl, (C2-C6) alkenyl, hydroxy, (Ci-Ce) alkoxy, (Cl- C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-Ce) alkyloxycarbonyl, mono-N-or di- N, N-(C1-C6) alkylamino wherein said (Ci-Ce) alkyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (Ci-C6) alkoxy, (C1-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-Ce) alkyloxycarbonyl, mono-N-or di-N, N-(C1-C6) alkylamino, said (Ci-C6) alkyl substituent also optionally has from one to nine fluorines ; wherein RV-5 and RV-6, or RV-6 and RV-7, and/or Rv-7and Rv-8 may also be taken together and can form at least one ring that is a partially saturated or fully unsaturated four to eight membered ring optionally having one to three heteroatoms independently selected from nitrogen, sulfur and oxygen;

wherein said rings formed by RV-5 and Rv, or RvÆ and RV-7, and/or Rv-7 and Rv-8 are optionally mono-, di-or tri-substituted independently with halo, (C1-C6)alyl, (Ci-C4) alkylsulfonyl, (C2-C6) alkenyl, hydroxy, (C1-C6) alkoxy, (C1-C4) alkylthio, amino, nitro, cyano, oxo, carboxy, (Ci-C6) alkyloxycarbonyl, mono-N-or di-N, N- (Cr C6) alkylamino wherein said (Ci-C6) alkyl substituent is optionally mono-, di-or tri- substituted independently with hydroxy, (Ci-Ce) alkoxy, (C1-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6) alkyloxycarbonyl, mono-N-or di-N, N- (CI-C6) alkylamino, said (Ci-Ce) alkyl substituent also optionally has from one to nine fluorines.

Compounds of Formula V are disclosed in commonly assigned pending U. S. Patent 6,140,343 the complete disclosure of which is herein incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from one of the following compounds of Formula V: [2S, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; [2S, 4S] 4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester; [2R, 4S] 4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluorometh yl-3, 4- dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2R, 4S] 4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromet hyl-3, 4- dihydro-2H-quinoline-1-carboxylic acid ethyl ester, [2S, 4S] 4- [1- (3, 5-bis-trifluoromethyl-benzyl)-ureido]-2-cyclopropyl-6-triflu oromethyl-3, 4- dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2R, 4S] 4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6- trifluoromethyl-3, 4- dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2S, 4S] 4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl)-amino]-2-methoxymethyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2S, 4S] 4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid propyl ester; [2S, 4S] 4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-ethyl-6-triflu oromethyl-3, 4- dihydro-2H-quinoline-1-carboxylic acid isopropyl ester,

[2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-methyl-6-trifl uoromethyl-3, 4- dihydro-2H-quinoline-1-carboxylic acid ethyl ester ; [2S, 4S] 4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-ethyl-6-triflu oromethyl-3, 4- dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2S, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-methyl-6-trifl uoromethyl-3, 4- dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; and [2R, 4S] 4- [acetyl- (3, 5-bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromet hyl-3, 4- dihydro-2H-quinoline-1-carboxylic acid isopropyl ester.

Another class of CETP inhibitors that finds utility with the present invention consists of cycloalkano-pyridines having the Formula VI

Formula VI and pharmaceutical acceptable salts, enantiomers, or stereoisomers of said compounds; in which Av, denotes an aryl containing 6 to 10 carbon atoms, which is optionally substituted with up to five identical or different substituents in the form of a halogen, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy or a straight-chain or branched alkyl, acyl, hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or in the form of a group according to the formula -BNRVI-3RVI-4, wherein Ravi4 and Rvi-4 are identical or different and denote a hydrogen, phenyl or a straight-chain or branched alkyl containing up to 6 carbon atoms, Dv denotes an aryl containing 6 to 10 carbon atoms, which is optionally substituted with a phenyl, nitro, halogen, trifluoromethyl or trifluoromethoxy, or a radical according to the formula RVI-5-LVI-,

or Rvi-g-Tv,-VvnXvi, wherein Rot-5, RVI-6 and RVI-9 denote, independently from one another, a cycloalkyl containing 3 to 6 carbon atoms, or an aryl containing 6 to 10 carbon atom or a 5-to 7- membered, optionally benzo-condensed, saturated or unsaturated, mono-, bi-or tricyclic heterocycle containing up to 4 heteroatoms from the series of S, N and/or O, wherein the rings are optionally substituted, in the case of the nitrogen-containing rings also via the N function, with up to five identical or different substituents in the form of a halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, a straight- chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl containing up to 6 carbon atoms each, an aryl or trifluoromethyl-substituted aryl containing 6 to 10 carbon atoms each, or an optionally benzo-condensed, aromatic 5-to 7-membered heterocycle containing up to 3 heteoatoms from the series of S, N and/or O, and/or in the form of a group according to the formula BORVI-10, -SRVI-11, -SO2RVI-12 or BNRVI- 13RVI-14,wherein RVI-10, RVI-11 and RVI-12 denote, independently from one another, an aryl containing 6 to 10 carbon atoms, which is in turn substituted with up to two identical or different substituents in the form of a phenyl, halogen or a straight-chain or branched alkyl containing up to 6 carbon atoms, RVI-13 and RVI-14 are identical or different and have the meaning of Rvm and Rvm given above, or RVI-5and/or RVI-6 denote a radical according to the formula Rv-7 denotes a hydrogen or halogen, and RVIÆ denotes a hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, a straight-chain or branched alkoxy or alkyl containing up to 6 carbon atoms each, or a radical according to the formula -NRVI-15RVI-16,

wherein RVI-15 and RVI-16 are identical or different and have the meaning of RVI-3 and RVI-4 given above, or Rvl 7 and Rv, together form a radical according to the formula =O or =NRVI-17, wherein RVI-17 denotes a hydrogen or a straight-chain or branched alkyl, alkoxy or acyl containing up to 6 carbon atoms each, LVI denotes a straight-chain or branched alkylen or alkenylene chain containing up to 8 carbon atoms each, which are optionally substituted with up to two hydroxyl groups, Tv, and Xv, are identical or different and denote a straight-chain or branched alkylen chain containing up to 8 carbon atoms, or Tv or Xv, denotes a bond, VVI denotes an oxygen or sulfur atom or an BNRvj-is group, wherein RVI-18 denotes a hydrogen or a straight-chain or branched alkyl containing up to 6 carbon atoms or a phenyl, EVI denotes a cycloalkyl containing 3 to 8 carbon atoms, or a straight-chain or branched alkyl containing up to 8 carbon atoms, which is optionally substituted with a cycloalkyl containing 3 to 8 carbon atoms or a hydroxyl, or a phenyl, which is optionally substituted with a halogen or trifluoromethyl, Rvl-l and RVI-2 together form a straight-chain or branched alkylen chain containing up to 7 carbon atoms, which must be substituted with a carbonyl group and/or a radical according to the formula wherein a and b are identical or different and denote a number equaling 1,2 or 3, RVI-19 denotes a hydrogen atom, a cycloalkyl containing 3 to 7 carbon atoms, a straight-chain or branched silylalkyl containing up to 8 carbon atoms, or a straight- chain or branched alkyl containing up to 8 carbon atoms, which is optionally substituted with a hydroxyl, a straight-chain or a branched alkoxy containing up to 6 carbon atoms or a phenyl, which may in turn be substituted with a halogen, nitro,

trifluoromethyl, trifluoromethoxy or phenyl or tetrazole-substituted phenyl, and an alkyl that is optionally substituted with a group according to the formula BOR", 22, wherein Ravi-22 denotes a straight-chain or branched acyl containing up to 4 carbon atoms or benzyl, or Rvng denotes a straight-chain or branched acyl containing up to 20 carbon atoms or benzoyl, which is optionally substituted with a halogen, trifluoromethyl, nitro or trifluoromethoxy, or a straight-chain or branched fluoroacyl containing up to 8 carbon atoms, Rvi-2o and Roi-21 are identical or different and denote a hydrogen, phenyl or a straight-chain or branched alkyl containing up to 6 carbon atoms, or Roi-20 and Rv). 2i together form a 3-to 6-membered carbocyclic ring, and a the carbocyclic rings formed are optionally substituted, optionally also geminaAy, with up to six identical or different substituents in the form of trifluoromethyl, hydroxyl, nitrile, halogen, carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy containing 3 to 7 carbon atoms each, a straight-chain or branched alkoxycarbonyl, alkoxy or alkylthio containing up to 6 carbon atoms each, or a straight-chain or branched alkyl containing up to 6 carbon atoms, which is in turn substituted with up to two identical or different substituents in the form of a hydroxyl, benzyloxy, trifluoromethyl, benzoyl, a straight- chain or branched alkoxy, oxyacyl or carboxyl containing up to 4 carbon atoms each and/or a phenyl, which may in turn be substituted with a halogen, trifluoromethyl or trifluoromethoxy, and/or the carbocyclic rings formed are optionally substituted, also geminally, with up to five identical or different substituents in the form of a phenyl, benzoyl, thiophenyl or sulfonylbenzyl, which in turn are optionally substituted with a halogen, trifluoromethyl, trifluoromethoxy or nitro, and/or optionally in the form of a radical according to the formula c is a number equaling 1,2,3 or 4, d is a number equaling 0 or 1, RVI-23 and Ravi-24 are identical or different and denote a hydrogen, cycloalkyl containing 3 to 6 carbon atoms, a straight-chain or branched alkyl containing up to 6 carbon atoms, benzyl or phenyl, which is optionally substituted with up to two identical or different substituents in the form of halogen, trifluoromethyl, cyano, phenyl or nitro, and/or the carbocyclic rings formed are optionally substituted with a spiro-linked radical according to the formula

wherein Wvl denotes either an oxygen atom or a sulfur atom, YVI and Y=VI together form a 2-to 6-membered straight-chain or branched alkylene chain, e is a number equaling 1,2,3,4,5,6 or 7, f is a number equaling 1 or 2, RVI-25, RVI-26, RVI-27, RVI-28, RVI-29, RVI-30 and Rvl-31 are identical or different and denote a hydrogen, trifluoromethyl, phenyl, halogen or a straight-chain or branched alkyl or alkoxy containing up to 6 carbon atoms each, or RVI-25 and Rv !-26 or RVI-27 and Roi-28 each together denote a straight-chain or branched alkyl chain containing up to 6 carbon atoms or Ri-25 and Roi-26 or Roi-27 and Rv)-2s each together form a radical according to the formula wherein Wvl has the meaning given above, g is a number equaling 1,2,3,4,5,6 or 7, RVI42 and RVI-33 together form a 3-to 7-membered heterocycle, which contains an oxygen or sulfur atom or a group according to the formula SO, SO2 or BNRVI-34, wherein RVI-34 denotes a hydrogen atom, a phenyl, benzyl, or a straight-chain or branched alkyl containing up to 4 carbon atoms, and salts and N oxides thereof, with the exception of 5 (6H)-quinolones, 3-benzoyl-7, 8-dihydro-2,7,7-trimethyl-4-phenyl.

Compounds of Formula VI are disclosed in European Patent Application No.

EP 818448 A1, U. S. Patent 6,207,671 and U. S. Patent 6,064,148 the complete disclosures of which are herein incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from one of the following compounds of Formula VI : 2-cyclopentyl-4- (4-fluorophenyl)-7, 7-dimethyl-3- (4-trifluoromethylbenzoyl)-4,6,7,8- tetrahydro-1 H-quinolin-5-one ; 2-cyclopentyl-4- (4-fluorophenyl)-7, 7-dimethyl-3- (4-trifluoromethylbenzoyl)-7, 8-dihydro- 6H-quinolin-5-one ; [2-cyclopentyl-4- (4-fluorophenyl)-5-hydroxy-7, 7-dimethyl-5,6,7,8-tetrahydroquinolin-3- yl)-(4-trifluoromethylphenyl)-methanone; [5- (t-butyldimethylsilanyloxy)-2-cyclopentyl-4- (4-fluorophenyl)-7, 7-dimethyl-5,6,7,8- tetrahydroquinolin-3-yl]- (4-trifluoromethylphenyl)-methanone ; [5- (t-butyldimethylsilanyloxy)-2-cyclopentyl-4- (4-fluorophenyl)-7, 7-dimethyl-5,6,7,8- tetrahydroquinolin-3-yl]- (4-trifluoromethylphenyl)-methanol ; 5- (t-butyidimethylsilanyloxy)-2-cyclopentyl-4- (4-fluorophenyl)-3- [fluoro- (4- trifluoromethylphenyl)-methyl]-7, 7-dimethyl-5,6,7,8-tetrahydroquinoline; 2-cyclopentyl-4- (4-fluorophenyl)- 3- [fluoro- (4-trifluoromethylphenyl)-methyl]-7, 7- dimethyl-5,6,7,8-tetrahydroquinolin-5-ol.

Another class of CETP inhibitors that finds utility with the present invention consists of substituted-pyridines having the Formula VII Formula Vil or a pharmaceutically acceptable salt or tautomer thereof, wherein RVII-2 and Rv-e are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl ; provided that at least one of RVII-2 and Rvx-e is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl ; RVII-3 is selected from the group consisting of hydroxy, amido, arylcarbonyl, <BR> <BR> heteroarylcarbonyl, hydroxymethyl<BR> <BR> <BR> <BR> -CHO, -CO2RVII-7, wherein RVII-7 is selected from the group consisting of hydrogen, alkyl and cyanoalkyl ; and

wherein Rot 5a is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryfoxy, heteroaryloxy and heterocyclyloxy, and RVII-16a is selected from the group consisting of alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, and heterocyclyl, arylalkoxy, trialkylsilyloxy ; RVII-4 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, hetereoarylalkenyl, heterocyclylalkenyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, aryloyloxy, heteroaroyloxy, heterocyclyloyloxy, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, thio, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, <BR> <BR> <BR> <BR> cycloalkenylthio, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl,<BR> <BR> <BR> <BR> <BR> <BR> heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl,<BR> <BR> <BR> <BR> <BR> <BR> <BR> alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclythioalkenyl, alkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, <BR> <BR> <BR> <BR> heterocyclylamino, aryldialkylamino, diarylamino, diheteroarylamino, alkylarylamino, alkylheteroarylamino, arylheteroarylamino, trialkylsilyl, trialkenylsilyl, triarylsilyl, -CO(O) N (RVII-8aRVII-8b), wherein Rvii-8a and RVII-8b are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,-SO2RVn-9, wherein RVII-9 is selected from the group consisting of hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,-OP (O) (ORVII-10a) (ORVII-10b), wherein RVII-10a and RVII10b are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and-OP (S) (ORVII-11a) (ORVII-11b), wherein RVII-11a and RvjMib are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl ;

RVII-5 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl, arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl, heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, <BR> <BR> alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl,<BR> <BR> heterocyclylthioalkenyl, alkoxyalkyl, alkenoxyalkyl, alkynoxylalkyl, aryloxyalkyl,<BR> <BR> heteroaryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkenyl, alkenoxyalkenyl, alkynoxyalkenyl, aryloxyalkenyl, heteroaryloxyalkenyl, heterocyclyloxyalkenyl, cyano, hydroxymethyl, -CO2RVII-14, wherein RVII-14 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl ;

wherein Rv) p) 5b is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, aroyloxy, and alkylsulfonyloxy, and Rv) M6b is selected form the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy, and trialkylsilyloxy ;

wherein RVII-17 and RVII-18 are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl ;

wherein RVII-19 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,-SRvil-2o,-ORvil-21, and BRVII-22CO2RVII-23, wherein RVII-20 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl, aminoheterocyclyl, alkylheteroarylamino, arylheteroarylamino, RVII-21 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl, RVII-22 is selected from the group consisting of alkylen or arylen, and Rv-23 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl ; wherein RVII-24 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, aralkenyl, and aralkynyl ; wherein RVII-25 is heterocyclylidenyl ; wherein Rv-26 and Rv-27 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl ;

wherein RVII-28 and Rvil-29 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl ;

wherein RVII-30 and Ri are independently alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, and heterocyclyloxy ; and wherein RVII-32 and RVII-33 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl ; wherein RVII-36 is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl and heterocyclyl ; wherein Rvn-g and RVII-38 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl ;

wherein RVII-39 is selected from the group consisting of hydrogen, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio, and RVII-40 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenoxy, heterocyclylalkynoxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio ; -N=RVII-41, wherein RVII-41 is heterocyclylidenyl ;

wherein RVII-42 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl, and RVII-43 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, and hatoheterocydy ! ;

wherein Rv) is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl ; - N=S=0 ; - N=C=S ; - N = C = 0 ;

- Nez - SRVII-45 wherein RVII-45 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, <BR> <BR> <BR> heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl,<BR> <BR> <BR> <BR> <BR> heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl, aminocarbonylaryl, aminocarbonylheteroaryl, and aminocarbonylheterocyclyl, -SRVII-46, and -CH2RVII-47, wherein RVII-46 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and RVII-47 selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl ; and wherein RVII-48 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and RVII-49 is selected from the group consisting of alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl ; wherein RVII-50 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy ;

wherein R-si is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyi, haloaryl, haloheteroaryl and haloheterocyclyl ; and wherein Rvil-53 is selected from the group consisting of alkyl, alkenyl, alkynyul, aryl, heteroaryl and heterocyclyl ; provided that when RVII-5 is selected from the group consisting of heterocyclylalkyl and heterocyclylalkenyl, the heterocyclyl radical of the corresponding heterocyclylalkyl or heterocyclylalkenyl is other than 6-lactone ; and provided that when RVII-4 is aryl, heteroaryl or heterocyclyl, and one of RVII-2 and RVII-6 is trifluoromethyl, then the other of RVII-2 and RVII-6 is difluoromethyl.

Compounds of Formula Vil are disclosed in WO 9941237-A1, the complete disclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of Formula Vit : Dimethyl 5,5-dithiobis [2-difluoromethyl-4- (2-methylpropyl)-6- (trifluoromethyl)-3- pyridine-carboxylate3.

Another class of CETP inhibitors that finds utility with the present invention consists of substituted pyridines having the Formula VIII Formula VIII or a pharmaceutical acceptable salt, enantiomers, or stereoisomers thereof, in which

Avill stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula -NRVIII-1RVIII-2,wherein RVIII-1 and Rvill-2 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms, DVIII stands for straight-chain or branched alkyl with up to 8 carbon atoms, which is substituted by hydroxy, Evil, and Lvill are either identical or different and stand for straight-chain or branched alkyl with up to 8 carbon atoms, which is optionally substituted by cycloalkyl with 3 to 8 carbon atoms, or stands for cycloalkyl with 3 to 8 carbon atoms, or RVIII has the above-mentioned meaning and LVIII in this case stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula -NRVIII-3RVIII-4, wherein Rvill-3 and RVIII-4 are identical or different and have the meaning given above for Ravin-1 and RVIII-2, or Evil, stands for straight-chain or branched alkyl with up to 8 carbon atoms, or stands for aryl with 6 to 10 carbon atoms, which is optionally substituted up to 3 times in an identical manner or differently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, or by straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbon atoms each, or by a group of the formula -NRV « Rv wherein Rvlll-5 and Rvill-6 are identical or different and have the meaning given above for RVIII-1 and RVIII-2, and Lv in this case stands for straight-chain or branched alkoxy with up to 8 carbon atoms or for cycloalkyloxy with 3 to 8 carbon atoms, TVIII stands for a radical of the formula

RVIII-7 and Rv) M are identica) or different and denote cycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms, or denote a 5-to 7-member aromatic, optionally benzo-condensed, heterocyclic compound with up to 3 heteroatoms from the series S, N and/or O, which are optionally substituted up to 3 times in an identical manner or differently by trifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, by straight-chain or branched alkyl, acyl, alkoxy, or alkoxycarbonyl with up to 6 carbon atoms each, or by phenyl, phenoxy, or thiophenyl, which can in turn be substituted by halogen, trifluoromethyl, or trifluoromethoxy, and/or the rings are substituted by a group of the formula -NRVIII-11RVIII-12, wherein RVIII-11 and Rot 12 are identical or different and have the meaning given above for Rvttk) and RVIII-2, Xv"l denotes a straight or branched alkyl chain or alkenyl chain with 2 to 10 carbon atoms each, which are optionally substituted up to 2 times by hydroxy, RVIII-9 denotes hydrogen, and Rv !) !-io denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to 5 carbon atoms, or a radical of the formula -NRVIII-13RVIII-14, wherein RVIII-13 and RVIII-14 are identical or different and have the meaning given above for RVIII-1 and RVIII-2, or RvHt-9 and RVIII-10 form a carbonyl group together with the carbon atom.

Compounds of Formula Vill are disclosed in WO 9804528, the complete disclosure of which is incorporated by reference.

Another class of CETP inhibitors that finds utility with the present invention consists of substituted 1,2,4-triazoles having the Formula IX Formula IX or a pharmaceutically acceptable salt or tautomer thereof; wherein RIX-1 is selected from higher alkyl, higher alkenyl, higher alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, and cycloalkylalkyl ;

wherein RIX-2 is selected from aryl, heteroaryl, cycloalkyl, and cycloalkenyl, wherein RIX-2 is optionally substituted at a substitutable position with one or more radicals independently selected from alkyl, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, halo, aryloxy, aralkyloxy, aryl, aralkyl, aminosulfonyl, amino, monoalkylamino and dialkylamino ; and wherein RIX-3 is selected from hydrido,-SH and halo ; provided RIX-2 cannot be phenyl or 4-methylphenyl when Rlx-1 is higher alkyl and when R, x 3 is BSH.

Compounds of Formula IX are disclosed in WO 9914204, the complete disclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of Formula IX : 2,4-dihydro-4- (3-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione; 2, 4-dihydro-4-(2-fluorophenyl)-5-tridecyl-3H-1, 2,4-triazole-3-thione; 2,4-dihydro-4- (2-methylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione; 2,4-dihydro-4- (3-chlorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione; 2, 4-dihydro-4- (2-methoxyphenyl)-5-tridecyl-3H-1, 2,4-triazole-3-thione; 2,4-dihydro-4- (3-methylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione; 4-cyclohexyl-2, 4-dihydro-5-tridecyl-3H-1, 2,4-triazole-3-thione; 2,4-dihydro-4- (3-pyridyl)-5-tridecyl-3H-1,2,4-triazole-3-thione; 2, 4-dihydro-4-(2-ethoxyphenyl)-5-tridecyl-3H-1, 2,4-triazole-3-thione; 2, 4-dihydro-4-(2,6-dimethylphenyl)-5-tidecyl-3H-1, 2,4-triazole-3-thione; 2,4-dihydro-4- (4-phenoxyphenyl)-5-tridecyl-3H-1,2,4-triazole- 3-thione; 4- (1, 3-benzodioxol-5-yl)-2, 4-dihydro-5-tridecyl-3H-1,2,4- triazole-3-thione; 4- (2-chlorophenyl)-2, 4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione; 2,4-dihydro-4- (4-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione; 2,4-dihydro-5-tridecyl-4- (3-trifluoromethylphenyl)-3H-1,2,4-triazole-3-thione; 2,4-dihydro-5-tridecyl-4- (3-fluorophenyl)-3H-1,2,4-triazole-3-thione;

4- (3-chloro-4-methylphenyl)-2. 4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione; 2,4-dihydro-4- (2-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione; 4- (4-benzyloxyphenyl)-2, 4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione; 2,4-dihydro-4- (2-naphthyl)-5-tridecyl-3H-1,2,4-triazole-3-thione; 2,4-dihydro-5-tridecyl-4- (4-trifluoromethylphenyl)-3H-1,2,4-triazole-3-thione; 2, 4-dihydro-4-(1-naphthyl0-5-tridecyl-3H-1, 2,4-triazole-3-thione; 2,4-dihydro-4- (3-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione; 2,4-dihydro-4- (4-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione; 2,4-dihydro-4- (3, 4-dimethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione; 2,4-dihydro-4- (2, 5-dimethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione; 2,4-dihydro-4- (2-methoxy-5-chlorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-th ione; 4- (4-aminosulfonylphenyl)-2, 4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione; 2,4-dihydro-5-dodecyl-4- (3-methoxyphenyl)-3H-1,2,4-triazole-3-thione; 2,4-dihydro-4- (3-methoxyphenyl)-5-tetradecyl-3H-1,2,4-triazole-3-thione; 2,4-dihydro-4- (3-methoxyphenyl)-5-undecyl-3H-1,2,4-triazole-3-thione; and 2,4-dihydro- (4-methoxyphenyl)-5-pentadecyl-3H-1,2,4-triazole-3-thione.

Another class of CETP inhibitors that finds utility with the present invention consists of hetero-tetrahydroquinolines having the Formula X Formula X and pharmaceutical acceptable salts, enantiomers, or stereoisomers or N-oxides of said compounds; in which

Ax represents cycloalkyl with 3 to 8 carbon atoms or a 5 to 7-membered, saturated, partially saturated or unsaturated, optionally benzo-condensed heterocyclic ring containing up to 3 heteroatoms from the series comprising S, N and/or O, that in case of a saturated heterocyclic ring is bonded to a nitrogen function, optionally bridged over it, and in which the aromatic systems mentioned above are optionally substituted up to 5-times in an identical or different substituents in the form of halogen, nitro, hydroxy, trifluoromethyl, trifluoromethoxy or by a straight-chain or branched alkyl, acyl, hydroxyalkyl or alkoxy each having up to 7 carbon atoms or by a group of the formula BNRX-3Rx-4, in which RX-3 and Rx4 are identical or different and denote hydrogen, phenyl or straight- chain or branched alkyl having up to 6 carbon atoms, or Ax represents a radical of the formula

Dx represents an aryl having 6 to 10 carbon atoms, that is optionally substituted by phenyl, nitro, halogen, trifluormethyl or trifluormethoxy, or it represents a radical of the formula

n which Rxz, Rx-6 and Rx-9 independently of one another denote cycloalkyl having 3 to 6 carbon atoms, or an aryl having 6 to 10 carbon atoms or a 5-to 7-membered aromatic, optionally benzo-condensed saturated or unsaturated, mono-, bi-, or tricyclic

heterocyclic ring from the series consisting of S, N and/or O, in which the rings are substituted, optionally, in case of the nitrogen containing aromatic rings via the N function, with up to 5 identical or different substituents in the form of halogen, trifluoromethyl, nitro, hydroxy, cyano, carbonyl, trifluoromethoxy, straight straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl each having up to 6 carbon atoms, by aryl or trifluoromethyl-substituted aryl each having 6 to 10 carbon atoms or by an, optionally benzo-condensed, aromatic 5-to 7-membered heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N, and/or O, and/or substituted by a group of the formula BORX-10, -SRX-11, SO2RX-12 or BNRX- 13Rx-14, in which RX-10, RX-11 and RX-12 independently from each other denote aryl having 6 to 10 carbon atoms, which is in turn substituted with up to 2 identical or different substituents in the form of phenyl, halogen or a straight-chain or branched alkyl having up to 6 carbon atoms, RX-13 and RX-14 are identical or different and have the meaning of Rx-3and Rx-4 indicated above, or Rx-5 and/or RxÆ denote a radical of the formula RX-7 denotes hydrogen or halogen, and Rx-8 denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkyl having up to 6 carbon atoms or a radical of the formula BNRX15RX-16, in which RX-15 and Rx-16 are identical or different and have the meaning of Rx-3 and Rx-4 indicated above, or

Rx-7 and Rx-8 together form a radical of the formula =0 or =NRX 17, in which Rx-17 denotes hydrogen or straight chain or branched alkyl, alkoxy or acyl having up to 6 carbon atoms, Lx denotes a straight chain or branched alkylen or alkenylene chain having up to 8 carbon atoms, that are optionally substituted with up to 2 hydroxy groups, Tx and Xx are identical or different and denote a straight chain or branched alkylen chain with up to 8 carbon atoms or Tx or Xx denotes a bond, Vx represents an oxygen or sulfur atom or an BNRx-18-group, in which RX-18 denotes hydrogen or straight chain or branched alkyl with up to 6 carbon atoms or phenyl, Ex represents cycloalkyl with 3 to 8 carbon atoms, or straight chain or branched alkyl with up to 8 carbon atoms, that is optionally substituted by cycloalkyl with 3 to 8 carbon atoms or hydroxy, or represents a phenyl, that is optionally substituted by halogen or trifluoromethyl, Rx, and Rx-2 together form a straight-chain or branched alkylen chain with up to 7 carbon atoms, that must be substituted by carbonyl group and/or by a radical with the formula in which a and b are identical or different and denote a number equaling 1,2, or 3, Rx, 9 denotes hydrogen, cycloalkyl with 3 up to 7 carbon atoms, straight chain or branched silylalkyl with up to 8 carbon atoms or straight chain or branched alkyl with up to 8 carbon atoms, that are optionally substituted by hydroxyl, straight chain or branched alkoxy with up to 6 carbon atoms or by phenyl, which in turn might be substituted by halogen, nitro, trifluormethyl, trifluoromethoxy or by phenyl or by tetrazole-substituted phenyl, and alkyl, optionally be substituted by a group with the formula BORx22, in which Ru-22 denotes a straight chain or branched acyl with up to 4 carbon atoms or benzyl,

or Ru, 9 denotes straight chain or branched acyl with up to 20 carbon atoms or benzoyl, that is optionally substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or it denotes straight chain or branched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms, RX-20 and Rx-21 are identical or different and denote hydrogen, phenyl or straight chain or branched alkyl with up to 6 carbon atoms, or Rx-20 and Rx-21 together form a 3-to 6-membered carbocyclic ring, and the carbocyclic rings formed are optionally substituted, optionally also geminally, with up to six identical or different substituents in the form of triflouromethyl, hydroxy, nitrile, halogen, carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy with 3 to 7 carbon atoms each, by straight chain or branched alkoxycarbonyl, alkoxy or alkylthio with up to 6 carbon atoms each or by straight chain or branched alkyl with up to 6 carbon atoms, which in turn is substituted with up to 2 identically or differently by hydroxyl, benzyloxy, trifluoromethyl, benzoyl, straight chain or branched alkoxy, oxyacyl or carbonyl with up to 4 carbon atoms each and/or phenyl, which may in turn be substituted with a halogen, trifuoromethyl or trifluoromethoxy, and/or the formed carbocyclic rings are optionally substituted, also geminally, with up to 5 identical or different substituents in the form of phenyl, benzoyl, thiophenyl or sulfonylbenzyl, which in turn are optionally substituted by halogen, trifluoromethyl, trifluoromethoxy or nitro, and/or optionally are substituted by a radical with the formula in which c denotes a number equaling 1,2,3, or 4, d denotes a number equaling 0 or 1, Rx-23 and RX-24 are identical or different and denote hydrogen, cycloalkyl with 3 to 6 carbon atoms, straight chain or branched alkyl with up to 6 carbon atoms, benzyl or phenyl, that is optionally substituted with up to 2 identically or differently by halogen, trifluoromethyl, cyano, phenyl or nitro, and/or the formed carbocyclic rings are substituted optionally by a spiro-linked radical with the formula

in which Wx denotes either an oxygen or a sulfur atom Yx and Y'x together form a 2 to 6 membered straight chain or branched alkylen chain, e denotes a number equaling 1,2,3,4,5,6, or 7, f denotes a number equaling 1 or 2, RX-25, RX-26, Rx-27, Rx-28, Rx-29, Rx-3o and RX-31 are identical or different and denote hydrogen, trifluoromethyl, phenyl, halogen or straight chain or branched alkyl or alkoxy with up to 6 carbon atoms each, or RX-25 and RX-26 or RX-27 and Rx-2s respectively form together a straight chain or branched alkyl chain with up to 6 carbon atoms, or RX-25 and RX-26 or RX-27 and RX-28 each together form a radical with the formula in which Wx has the meaning given above, g denotes a number equaling 1,2,3,4,5,6, or 7, RX-32 and RX-33 form together a 3-to 7-membered heterocycle, which contains an oxygen or sulfur atom or a group with the formula SO, S02 or - NRX-34, in which Rx-34 denotes hydrogen, phenyl, benzyl or straight or branched alkyl with up to 4 carbon atoms.

Compounds of Formula X are disclosed in WO 9914215, the complete disclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of Formula X: 2-cyclopentyl-5-hydroxy-7, 7-dimethyl-4- (3-thienyl)-3- (4-trifluoromethylbenxoyl)-5,6,7,8- tetrahydroquinoline ; <BR> <BR> <BR> <BR> <BR> <BR> 2-cyclopentyl-3- [fluoro- (4-trifluoromethylphenyl) methyl]-5-hydroxy-7, 7-dimethy1-4- (3- thienyl)-5, 6,7,8-tetrahydroquinoline; and 2-cyclopentyl-5-hydroxy-7, 7-dimethyl-4- (3-thienyl)-3- (trifluoromethylbenxyl)-5, 6,7,8- tetrahydroquinoline.

Another class of CETP inhibitors that finds utility with the present invention consists of substituted tetrahydro naphthalines and analogous compound having the Formula xi Formula Xi and stereoisomers, stereoisomer mixtures, and salts thereof, in which AXI stands for cycloalkyl with 3 to 8 carbon atoms, or stands for aryl with 6 to 10 carbon atoms, or stands for a 5-to 7-membered, saturated, partially unsaturated or unsaturated, possibly benzocondensated, heterocycle with up to 4 heteroatoms from the series S, N and/or O, where aryl and the heterocyclic ring systems mentioned above are substituted up to 5-fold, identical or different, by cyano, halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoro-methoxy, or by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio, alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy each with up to 7 carbon atoms, or by a group of the formula -NRxl-3Ryi-4, in which RXI-3 and Rxl-4 are identical or different and denote hydrogen, phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms Dx stands for a radical of the formula

inwhich RXI-5, Rxi. 6 and Ri-9, independent of each other, denote cycloalkyl with 3 to 6 carbon atoms, or denote aryl with 6 to 10 carbon atoms, or denote a 5-to 7- membered, possibly benzocondensated, saturated or unsaturated, mono-, bi-or tricyclic heterocycle with up to 4 heteroatoms of the series S, N and/or O, where the cycles are possibly substitutedCin the case of the nitrogen-containing rings also via the N-functionCup to 5-fold, identical or different, by halogen, trifluoromethyl. nitro, hydroxy, cyano, carboxyl, trifluoromethoxy, straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl with up to 6 carbon atoms each. by aryl or trifluoromethyl substituted aryl with 6 to 10 carbon atoms each, or by a possibly benzocondensated aromatic 5-to 7-membered heterocycle with up to 3 heteroatoms of the series S, N and/or O, and/or are substituted by a group of the formula -ORXI-10, -0SRXI-10, -SO2RXI-12 or -NRXI-13RXI-14, in which RxMo, Rx)-n and Rxl-12, independent of each other, denote aryl with 6 to 10 carbon atoms, which itself is substituted up to 2-fold, identical or different, by phenyl, halogen. or by straight-chain or branched alkyl with up to 6 carbon atoms, RXI-13 and RXI-14 are identical or different and have the meaning given above for RXI-3 and RXI-4, or RXI-5 and/or RXIX denote a radical of the formula RXI-7 denotes hydrogen, halogen or methyl, and RXIÆ denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkyl with up to 6 carbon atoms each, or a radical of the formula -NRXI-15RXI-16, in which

Roi-15 and RXI-16 are identical or different and have the meaning given above for Rx)-3 and Rxl-4, or RXI-7 and RXI-8 together form a radical of the formula =O or =NRXI-17, in which Roi-17 denotes hydrogen or straight-chain or branched alkyl, alkoxy or acyl with up to 6 carbon atoms each, LXI denotes a straight-chain or branched alkylene-or alkenylene chain with up to 8 carbon atoms each, which is possibly substituted up to 2-fold by hydroxy, TXI and Xxl are identical or different and denote a straight-chain or branched alkylen chain with up to 8 carbon atoms, or TXI and xxl denotes a bond, Vxl stands for an oxygen-or sulfur atom or for an -NRXI-18 group, in which RXI-18 denotes hydrogen or straight-chain or branched alkyl with up to 6 carbon atoms, or phenyl, EX, stands for cycloalkyl with 3 to 8 carbon atoms, or stands for straight-chain or branched alkyl with up to 8 carbon atoms, which is possibly substituted by cycloalkyl with 3 to 8 carbon atoms or hydroxy, or stands for phenyl, which is possibly substituted by halogen or trifluoromethyl, Rxn and RXI-2 together form a straight-chain or branched alkylen chain with up to 7 carbon atoms, which must be substituted by a carbonyl group and/or by a radical of the formula in which a and b are identical or different and denote a number 1, 2 or 3 Roi-19 denotes hydrogen, cycloalkyl with 3 to 7 carbon atoms, straight-chain or branched silylalkyl with up to 8 carbon atoms, or straight-chain or branched alkyl with up to 8 carbon atoms, which is possibly substituted by hydroxy, straight-chain or branched alkoxy with up to 6 carbon atoms, or by phenyl, which itself can be substituted by halogen, nitro, trifluoromethyl, trifluoromethoxy or by phenyl substituted

by phenyl or tetrazol, and alkyl is possibly substituted by a group of the formula-ORXI 22. in which Roi-22 denotes straight-chain or branched acyl with up to 4 carbon atoms, or benzyl, or Rxl 19 denotes straight-chain or branched acyl with up to 20 carbon atoms or benzoyl, which is possibly substituted by halogen, trifluoromethyl, nitro or trifluoromethoxy, or denotes straight-chain or branched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms, RXI-20 and Roi-21 are identical or different, denoting hydrogen, phenyl or straight- chain or branched alkyl with up to 6 carbon atoms, or Rx)-2o and RXI-21 together form a 3-to 6-membered carbocycle, and, possibly also geminally, the alkylen chain formed by RXI-1 and RXI-2, is possibly substituted up to 6-fold, identical or different, by trifluoromethyl, hydroxy, nitrile, halogen, carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy with 3 to 7 carbon atoms each, by straight-chain or branched alkoxycarbonyl, alkoxy or alkoxythio with up to 6 carbon atoms each, or by straight-chain or branched alkyl with up to 6 carbon atoms, which itself is substituted up to 2-fold, identical or different. by hydroxyl, benzyloxy, trifluoromethyl, benzoyl, straight-chain or branched alkoxy, oxyacyl or carboxyl with up to 4 carbon atoms each, and/or phenyl- which itself can be substituted by halogen, trifluoromethyl or trifluoromethoxy, and/or the alkylen chain formed by RXI 1 and RXI-2 is substituted, also geminally, possibly up to 5-fold, identical or different, by phenyl, benzoyl, thiophenyl or sulfobenzyl-which themselves are possibly substituted by halogen, trifluoromethyl, trifluoromethoxy or nitro, and/or the alkylen chain formed by RXI-1 and RXI-2 is possibly substituted by a radical of the formula in which c denotes a number 1,2,3 or 4,

d denotes a number 0 or 1, RXI-23 and Roi-24 are identical or different and denote hydrogen, cycloalkyl with 3 to 6 carbon atoms, straight-chain or branched alkyl with up to 6 carbon atoms, benzyl or phenyl, which is possibly substituted up to 2-fold identical or different, by halogen, trifluoromethyl, cyano, phenyl or nitro, and/or the alkylen chain formed by RXI-1 and RXI-2 is possibly substituted by a spirojointed radical of the formula

in which WXI denotes either an oxygen or a sulfur atom, YXI and Xi together form a 2-to 6-membered straight-chain or branched alkylen chain, e is a number 1, 2,3,4,5,6 or 7, f denotes a number I or 2, RXI25,RXI-26, RXI-27, RXI-28, RXI-29, RXI-30 and RXI-31 are identical or different and denote hydrogen, trifluoromethyl, phenyl, halogen, or straight-chain or branched alkyl or alkoxy with up to 6 carbon atoms each, or Roi-25 and RXI-26 or Rx,-27 and Rut-28 together form a straight-chain or branched alkyl chain with up to 6 carbon atoms, or RXI-25 and RXI-26 or RXI-27 and RXI-28 together form a radical of the formula

in which Wxl has the meaning given above, g is a number 1, 2,3,4,5,6 or 7, RXI-32 and RXI-33 together form a 3-to 7-membered heterocycle that contains an oxygen-or sulfur atom or a group of the formula SO, SO2 or -NRXI-34, in which

Rxi-34 denotes hydrogen, phenyl, benzyl, or straight-chain or branched alkyl with up to 4 carbon atoms.

Compounds of Formula XI are disclosed in WO 9914174, the complete disclosure of which is incorporated by reference.

Another class of CETP inhibitors that finds utility with the present invention consists of 2-aryl-substituted pyridines having the Formula (XII) Formula XII or pharmaceutically acceptable salts, enantiomers, or stereoisomers of said compounds, in which Axe and EXII are identical or different and stand for aryl with 6 to 10 carbon atoms which is possibly substituted, up to 5-fold identical or different, by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, nitro or by straight-chain or branched alkyl, acyl, hydroxy alkyl or alkoxy with up to 7 carbon atoms each, or by a group of the formula-NRx, Rxn-2, where RXII-1 and Rxn-2 are identical or different and are meant to be hydrogen, phenyl or straight-chain or branched alkyl with up to 6 carbon atoms, Dx"stands for straight-chain or branched alkyl with up to 8 carbon atoms, which is substituted by hydroxy, Lxh stands for cycloalkyl with 3 to 8 carbon atoms or for straight-chain or branched alkyl with up to 8 carbon atoms, which is possibly substituted by cycloalkyl with 3 to 8 carbon atoms, or by hydroxy, TXII stands for a radical of the formula Rxn-3-Xxn-or where RXII-3 and RXII-4 are identical or different and are meant to be cycloalkyl with 3 to

8 carbon atoms, or aryl with 6 to 10 carbon atoms, or a 5-to 7-membered aromatic, possibly benzocondensated heterocycle with up to 3 heteroatoms from the series S, N and/or O, which are possibly substituted. up to 3-fold identical or different, by trifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, nitro, by straight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl with up to 6 carbon atoms each. or by phenyl, phenoxy or phenylthio which in turn can be substituted by halogen. trifluoromethyl or trifluoromethoxy, and/or where the cycles are possibly substituted by a group of the formula -NRXII-7RXII-8, where RXII-7 and RxilÆ are identical or different and have the meaning of Rxx-i and Rxjj-2 given above, Xi ils a straight-chain or branched alkyl or alkenyl with 2 to 10 carbon atoms each, possibly substituted up to 2-fold by hydroxy or halogen, Rail-5 stands for hydrogen, and RXII4 means to be hydrogen, halogen, mercapto, azido, trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branched alkoxy with up to 5 carbon atoms, or a radical of the formula BNRXII-9RXII-10, where RXII-9 and RXII-10 are identical or different and have the meaning of Rail-, and Rxn-2 given above, or Rxii-5 and Rxjj-e, together with the carbon atom, form a carbonyl group.

Compounds of Formula XII are disclosed in EP 796846-A1, U. S. Patent 6,127,383 and U. S. Patent 5,925,645 the complete disclosures of which are incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of Formula XII : 4,6-bis-(p-fluorophenyl)-2-isopropyl-3-[(p-trifluoromethylph enyl)-(fluoro)-methyl]-5-(1- hydroxyethyl) pyridine ; 2, 4-bis-(4-fluorophenyl)-6-isopropyl-5-[4-(trifluoromethylphen yl)-fluoromethyl]-3- hydroxymethyl) pyridine; and 2,4-bis- (4-fluorophenyl)-6-isopropyl-5- [2- (3-trifluoromethylphenyl) vinyl]-3- hydroxymethyl) pyridine.

Another class of CETP inhibitors that finds utility with the present invention consists of compounds having the Formula (xi1) Formula XII or pharmaceutically acceptable salts, enantiomers, stereoisomers, hydrates, or solvates of said compounds, in which RXIII is a straight chain or branched C1-10 alkyl ; straight chain or branched C210 alkenyl ; halogenated C11 lower alkyl ; C3-10 cycloalkyl that may be substituted; C54 cycloalkenyl that may be substituted; C3-10 cycloalkyl c1-10 alkyl that may be substituted; aryl that may be substituted; aralkyl that may be substituted ; or a 5-or 6- membered heterocyclic group having 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms that may be substituted, XXIII-1, XXIII-2, XXIII-3, XXIII-4 may be the same or different and are a hydrogen atom; halogen atom; C1-4 lower alkyl ; halogenated C » lower alkyl ; C11 lower alkoxy ; cyano group; nitro group; acyl ; or aryl, respectively ; Yxt is-CO- ; or BSO2-; and Zxul is a hydrogen atom; or mercapto protective group.

Compounds of Formula Xill are disclosed in WO 98/35937, the complete disclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of Formula XIII : N, N'- (dithiodi-2, 1-phenylene) bis [2, 2-dimethyl-propanamide] ; N, N'-(dithiodi-2,1-phenylene) bis [1-methyl-cyclohexanecarboxamide] ;

N, N'- (dithiodi-2, 1-phenylene) bis [1- (3-methylbutyl)-cyclopentanecarboxamide] ; N, N'- (dithiodi-2, 1-phenylene) bis [1- (3-methylbutyl)-cyclohexanecarboxamide] ; N, N'-(dithiodi-2,1-phenylene) bis [1-(2-ethylbutyl)-cyclohexanecarboxamide] ; N, N'-(dithiodi-2,1-phenylene)bis-tricyclo [3.3.1.13,'] decane-1-carboxamide; propanethioic acid, 2-methyl-, S- [2[[[1-(2-ethylbutyl)cyclohexyl]carbonyl] amino] phenyl] ester; propanethioic acid, 2,2-dimethyl-, S- [2- [ [ [1- (2- ethyl butyl) cyclohexyl] carbonyl] amino] phenyl] ester; and ethanethioic acid, S-[2-[[[1-(2-ethylbutyl0cyclohexyl]carbonyl]amino]phenyl] ester.

Another class of CETP inhibitors that finds utility with the present invention consists of polycyclic aryl and heteroaryl tertiary-heteroalkylamines having the Formula XIV

and pharmaceutical acceptable forms thereof, wherein: nx ! v is an integer selected from 0 through 5; RXIV-1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl ; Xxlv is selected from the group consisting of O, H, F, S, S (O), NH, N (OH), N (alkyl), and N (alkoxy) ; Rev-, is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonyialkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenylm, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl, monocarboalkoxy, dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, dialkoxyphosphonoalkyl, trialkylsilyl, and a spacer selected from the group consisting of a covalent single bond and a linear spacer moiety having from 1 through 4 contiguous atoms linked to the point of bonding of an aromatic substituent selected from the group consisting of RXIV-4, RXIV-8, RXIV-9, and RX, v-3 to form a heterocyclyl ring having from 5 through 10 contiguous members with the provisos that said spacer moiety is other than a covalent single bond when R xlv-2 is alkyl and there is no RXIV-16 wherein X is H or F; DXIV-1, DXIV-2, JXIV-1, JXIV2 and KXIV-1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of DXIV-1, DXIV-2, JXIV-1, JXIV-2 and KXIV-1 is a covalent bond, no more than one of DXIV-1, Dxlv-2, Jxlv-,, J lv-2 and Kxn-, is O, no more than one of Dxjv-i, DXIV-2, JXIV-1, JXIV-2 and Kan-, is S, one of DXIV-1, DXIV-2, JXIV-1, JXIV-2 and Kxlv-, must be a covalent bond when two of Dxn-, 1, DXIV-2, JXIV-1, JXIV-2 and KXIV-1 are O and S, and no more than four of DXIV-1, DXIV-2, JXIV-1, JXIV-2 and Kxlv-1 are N; DXIV-3, DXIV-4, JXIV-3, JXIV-4 and KXIV-2 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one

of DXIV-3, DXIV-4, JXIV-3, JXIV-4 and Kxlv-2 is a covalent bond, no more than one of Dxtv-s.

DXIV-4, JXIV-3, JXIV-4 and Kxlv-2 is O, no more than one of DXSIV-3, DXIV-4, JXIV-3, and KXIV-2 is S, one of DXIV-3, DXIV-4,. JXIV-3, JXIV-4 and KXIV 2 must be a covalent bond when two of DxIV-3. DXIV-4, JXIV-3, JXIV-4 and KXIV-2 are O and S, and no more than four of DXIV-3, DXIV-4, Jx) JXIV-4 and KXIV-2 and KXIV-2 are N; Rev-2 is independently selected from the group consisting of hydrido, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, <BR> <BR> <BR> <BR> alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, aloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloaikenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfinylalkyl, alkylsulfonylalkyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl ; Rev-2 and RxIV-3 are taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members; Rev-3 is selected from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, acyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroarylthio, aralkylthio, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aroyl, heteroaroyl, aralkylthioalkyl,

heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, <BR> <BR> <BR> arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl ; Y ! v is selected from a group consisting of a covalent sing) e bond, (C (Rx ! v- 14) 2) qXIV wherein qXIV iS an integer selected from 1 and 2 and (CH(RXIV-14))gXIV-WXIV- (CH (RXIV t4)) pXIV wherein gxlv and pxlv are integers independently selected from 0 and 1; Rev-14 is independently selected from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, <BR> <BR> <BR> cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, <BR> <BR> <BR> halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,<BR> <BR> <BR> <BR> <BR> perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, <BR> <BR> <BR> haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl,<BR> <BR> <BR> <BR> <BR> aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl,<BR> <BR> <BR> <BR> <BR> cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,

carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected from a moiety having a chain length of 3 to 6 atoms connected to the point of bonding selected from the group consisting of Rxlv-9 and Rev-13 to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a heterocyclyl ring having from 5 through 8 contiguous members and a spacer selected from a moiety having a chain length of 2 to 5 atoms connected to the point of bonding selected from the group consisting of Rxlv-4 and Rxn$ to form a heterocyclyl having from 5 through 8 contiguous members with the proviso that, when YXIV is a covalent bond, an RXIV-14 substituent is not attached to YXIVì RXIV-14 and RXIV-14, when bonded to the different atoms, are taken together to form a group selected from the group consisting of a covalent bond, alkylen, haloalkylene, and a spacer selected from a group consisting of a moiety having a chain length of 2 to 5 atoms connected to form a ring selected from the group of a saturated cycloalkyl having from 5 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members; RXIV-14 and Rx<v-i4, when bonded to the same atom are taken together to form a group selected from the group consisting of oxo, thiono, alkylene, haloalkylene, and a spacer selected from the group consisting of a moiety having a chain length of 3 to 7 atoms connected to form a ring selected from the group consisting of a cycloalkyl having from 4 through 8 contiguous members, a cycloalkenyl having from 4 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members; Wxlv is selected from the group consisting of O, C (O), C (S), C (O) N (Rev-14), C (S) N (RXIV-14), (RXIV-14) NC (O), (Rev-14) NC (S), S, S (O), S (O) 2, S (0) 2N (XIV-14), (RXIV- 14) NS (0) 2, and N (Rev-14) with the proviso that Rxiv-14 is selected from other than halo and cyano; Zxlv is independently selected from a group consisting of a covalent single bond, (C (RXIV-15) 2) qXIV-2 wherein qxlv-2 is an integer selected from 1 and 2, (CH (Rev- 15))jXIV-W-(CH(RXIV-15))kXIV wherein jXIV and jkXIV are integers independently selected from 0 and 1 with the proviso that, when Zxlv is a covalent single bond, an Rxlv-15substituent is not attached to ZXIV ;

Rx) v-i5 is independently selected, when Zxlv is (C (RX v-15) 2) qxn wherein qxIV is an integer selected from 1 and 2, from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl,aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, <BR> <BR> <BR> heteroarylsulfinyl,<BR> <BR> <BR> <BR> <BR> heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected from a moiety having a chain length of 3 to 6 atoms connected to the point of bonding selected from the group consisting of Rx) v-4 and RXIVÆ to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a heterocyclyl ring having from 5 through 8 contiguous members, and a spacer selected from a moiety having a chain length of 2 to 5 atoms connected to the point of bonding selected from the group consisting of Rev-9 and RXIV-13 to form a heterocyclyl having from 5 through 8 contiguous members; RXIV-15 and Run-15, when bonded to the different atoms, are taken together to form a group selected from the group consisting of a covalent bond, alkylen, haloalkylene, and a spacer selected from a group consisting of a moiety having a chain length of 2 to 5 atoms connected to form a ring selected from the group of a

saturated cycloalkyl having from 5 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members; Rev-15 and Rev-15, when bonded to the same atom are taken together to form a group selected from the group consisting of oxo, thiono, alkylene, haloalkylene, and a spacer selected from the group consisting of a moiety having a chain length of 3 to 7 atoms connected to form a ring selected from the group consisting of a cycloalkyl having from 4 through 8 contiguous members, a cycloalkenyl having from 4 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members; Rev 15 is independently selected, when Zxtv is (CH (Rev 1s)) ; (CH (Rxlv 15)) kXIV wherein jXIV and kXIV are integers independently selected from 0 and 1, from the group consisting of hydrido, halo, cyano, aryloxy, carboxyl, acyl, aroyl, heteroaroyl, hydroxyalkyl, heteroaryloxyalkyl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, <BR> <BR> <BR> alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, aralkoxyalkyl,<BR> <BR> <BR> <BR> <BR> <BR> heteroaralkoxyalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, <BR> <BR> <BR> <BR> halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthiialkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, <BR> <BR> <BR> <BR> carboalkoxycyanoalkyl, alkylsulfihyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl,<BR> <BR> <BR> <BR> <BR> <BR> arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsuffonyl, heteroary (sulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected from a linear moiety having a chain length of 3 to 6 atoms connected to the point of bonding selected from the group consisting of Rx) v and Rx ! v- $ to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a heterocyclyl ring having from 5 through 8 contiguous members, and a spacer

selected from a linear moiety having a chain length of 2 to 5 atoms connected to the point of bonding selected from the group consisting of Rxlv-9 and RXIV-13 to form a heterocyclyl ring having from 5 through 8 contiguous members; RXIV-4, ERXIV-5, RXIV-6, RXIV-7, RXIV-8, RXIV-9, RXIV-10, RXIV-11, RXIV-12, and RXIV-13 are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, <BR> <BR> <BR> alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, <BR> <BR> <BR> aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido,<BR> <BR> <BR> <BR> <BR> N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsuffonylalkyl, heteroarylamino, N- heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, <BR> <BR> <BR> halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, <BR> <BR> <BR> arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl,<BR> <BR> <BR> <BR> <BR> alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,<BR> <BR> <BR> <BR> <BR> heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl,<BR> <BR> <BR> <BR> <BR> haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl ; haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyaikyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido,

alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyi, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl with the proviso that there are one to five non-hydrido ring substituents Run4, Rxtv-s, RXIV-6, RXIV-7, and Rx ; v-s present, that there are one to five non- hydrido ring substituents RXIV-9, RXIV-10, RXIV-11, RXIV-12, and Rxlv-13 present, and Ru) viz RXIV-5, XIV-6, RXIV-7, RXIV-8, RXIV-9, RXIV-10, RXIV-11, RXIV-12, and Rev-13 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; RXIV-4 and RXIV-5, RXIV-5 and RXIV-6, RXIV-6 and RXIV-7, RXIV-7 and RXIV-8, RXIV-8 and RXIV9, Rxlv-9 and Rxiv-1o, Rxlv-lo and RXIV-11, RXIV-11 and RXIV-12, and RXIV-12 and RXIV-13 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs RXIV-4 and RXIV-5, RXIV-5 and RXIV-6, RXIV-6 and Run-7, and RXIV-7 and RXIV-8 are used at the same time and that no more than one of the group consisting of spacer pairs Run-9 and RXIV-10, RXIV-10 and RXIV-11, RXIV-11 and Rx) v-i2, and RXIV-12 and RXIV-13 are used at the same time; RXIV-4 an dRXIV-9, RXIV-4 and RXIV-13, RXIV-8 and RXIV-9, and RXIV-8 and RXIV-13 are independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear moiety wherein said linear moiety forms a ring selected from the group consisting of a partially saturated heterocyclyl ring having from 5 through 8 contiguous members and a heteroaryl ring having from 5 through 6 contiguous members with the proviso that no more than one of the group consisting of spacer pairs RXIV-4 and RXIV-9m, RXIV-4 and RXIV-13, RXIV-8 and Rxv-9, and RXIV-8 and RXIV-13 is used at the same time.

Compounds of Formula XIV are disclosed in WO 00/18721, the entire disclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of Formula XIV :

3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1, 1,2,2-tetrafluoroethoxy)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-isopropylphenoxy)phenyl][[3-(1, 1,2,2-tetrafluoroethoxy) phenyl]-methyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(1, 1,2,2-tetrafluoroethoxy) phenyl]- methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-(2-furylo) phenoxy) phenyl] [ [3- ( 1, 1,2,2-tetrafluoroethoxy) phenyl]- methyl] amino] 1,1,1-trifluoro-2-propanol; 3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(1,1, 2,2- tetrafluoroethoxy) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(4-fluorophenoxy)phenyl][[3-(1, 1,2,2-tetrafluoroethoxy) phenyl]-methyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(4-methylphenoxy)phenyl][[3-(1, 1,2,2-tetrafluoroethoxy) phenyl]-methyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(1, 1,2,2- tetrafluoroethoxy) phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol ; 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1, 1,2,2- tetrafluoroethoxy) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3- [ [3- [3- (1, 1,2,2- tetrafluoroethoxy) phenoxy] phenyl] [ [3- ( 1, 1,2,2-tetrafluoro- ethoxy) phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-[3-(pentafluoroeth7yl) phenoxy] phenyl] [ [3- ( 1, 1,2,2- tetrafluoroethoxy)-phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; 3- [ [3- (3, 5-dimethylphenoxy) phenyl] [ [3- (1, 1,2,2- tetrafluoroethoxy) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-ethylphenoxy)phenyl][[3-(1, 1,2,2-tetrafluoroethoxy) phenyl]-methyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(3-t-butylphenoxy))phenyl][[3-(1,1,2,2-tetrafluoroetho xy) phenyl]- methyl] amino] 1,1,1-trifluoro-2-propanol; 3-[[3-(3-methylphenoxy))phenyl][[3-(1, 1,2,2-tetrafluoroethoxy) phenyl]-methyl] amino]- 1,1,1-trifluoro-2-propanol; 3- [ [3- (5, 6,7,8-tetrahydro-2-naphthoxy) phenyl] fi- (1, 1,2,2- tetrafluoroethoxy) phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(phenoxy))phenyl][[3-(1,1,2,2-tetrafluoroethoxy) phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol;

3-[[3-(N,N-dimethylamino) phenoxy] phenyl] [ [3- (1, 1,2,2- tetrafluoroethoxy) phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; 3- [ [ [3- (1, 1,2, 2-tetrafluoroethoxyphenyl]methyl1][3-[[3- (trifluoromethoxy)-phenyl] methoxy] phenyl] amino]-1,1,1-trifluoro-2-propanoi; 3- [ [ [3- (1, 1,2, 2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethyl)- phenyl] methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[[3-(1, 1,2, 2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-dimethylphenyl]- methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; 3- [ [ [3- (1, 1,2,2-tetrafluoroethoxy) phenyl] methyl] [3- [ [3- (trifluoromethylthio)-phenyl] methoxy] phenyl] amino]-1, 1,-trifluoro-2-propanol ; 3- [ [ [3- (1, 1,2, 2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-difluorophenyl]- methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; 3- [ [ [3- (1, 1,2,2-tetrafluoroethoxy) phenyl] methyl] [3- [cyclohexylmethoxy]-phenyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(1, 1,2,2- tetrafluoroethoxy)-phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(1, 1,2,2- tetrafluoroethoxy)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-difluoromethoxyphenoy)phenyl][[3-(1, 1,2,2-tetrafluoroethoxy)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[[3-(3-trifluoromethylthio) phenoxy] phenyl] [ [3- (1, 1,2,2- tetrafluoroethoxy)-phenyl]methyl]amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(1, 1,2,2-tetrafluoroethoxy)- phenyl] methyl] amino]-1, 1,1,-trifluoro-2-propanol; 3-[[3-(3-trifluorometoxyphenoxy)phenyl][[3-(pentafluoroethyl methyl]amino]-1, 1,1- trifluoro-2-propanol ; 3-[[3-(3-isopropylphenoxy)phenyl][[3-(pentafluoroethyl)pheny l]methyl]-amino]-1, 1,1- trifluoro-2-propanol ; 3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(pentafluoroethyl)phe nyl]methyl]-amino]-1, 1,1- trifluoro-2-propanol ; 3-[[3-(3-(2-furyl) phenoxy) phenyl] [ [3- (pentafluoroethyl) phenyl] methyl]-amino]-1, 1,1- trifluoro-2-propanol ; 3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(pentafluoroethyl)phen yl]methyl]-amino]-1, 1,1- trifluoro-2-propanol ;

3-[[3-(4-fluorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]m ethyl] amino]-1,1,1- trifluoro-2-propanol ; 3-[[3-(4-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]m ethyl] amino]-1,1,1- trifluoro-2-propanol ; <BR> <BR> 3- [ [3- (2-fluoro-5-bromophenoxy) phenyl] [ [3- (pentafluoroethyl) phenyl] methyl]-amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl) phenyl]methyl]-amino]- 1,1,1-trifluoro-2-propanol; 3- [ [3- [3- (1, 1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [ [3- (pentafluoroethyl)-phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[3-[3-(pentafluoroethyl) phenoxy] phenyl] [ [3- (pentafluoroethyl) phenyl]-methyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(pentafluoroethyl)phen yl]methyl]-amino]-1, 1,1- trifluoro-2-propanol ; 3-[[3-(3-ethyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]met hyl] amino]-1,1,1- trifluoro-2-propanol ; 3- [P- (3-t-butylphenoxy) phenyl] [ [3- (pentafluoroethyl) phenyl] methyl] aminol-1, 1,1- trifluoro-2-propanol ; 3-[[3-(3-methylphenoxy)phenyl][[3-pentafluoroethyl)phenyl]me thyl] amino]-1,1,1- trifluoro-2-propanol ; 3- [ [3- (5, 6,7,8-tetrahydro-2-naphthoxy) phenyl] [ [3- (pentafluoroethyl) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl] amino]-1, 1, 1-trifluoro-2-propanol ; 3-[[3-[3-(N,N-dimethylamino) phenoxy] phenyl] [ [3- (pentafluoroethyl) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluorometh oxy)phenyl]- methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluorometh yl)phenyl]- methoxy] phenyl]amino]-1, 1,1-trifluoro-2-propanol; 3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3, 5- dimethylphenyl] methoxy]-phenyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-

(trifluoromethylthio) phenyl]-methoxy] phenyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[[3-(pentafluoroethyl)phenyl]methyl]]3-[[3, 5- difluorophenyl] methoxy]-phenyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[cyclohexylmethoxy ]phenyl]-amino]-1, 1,1- trifluoro-2-propanol ; 3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3- (pentafluoroethyl) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanot; 3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3- (pentafluoroethyl) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl )phenyl]methyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[[3-(3-trifluoromethylthio) phenoxy] phenyl] [ [3- (pentafluoroethyl) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(4-chloro-3-trifrluoromethylphenoxy)phenyl][[3-(pentaf luoroethyl)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3- (heptafluoropropyl) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-isopropylpheoxy)phenyl][[3-(heptafluoropropyl)pheny l]methyl]-amino]-1, 1,1- trifluoro-2-propanol ; 3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(heptafluoropropyl)ph enyl]methyl]-amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(3-(2-furyl) phenoxy) phenyl] [ [3-(heptafluoropropyl) phenyl] methyl]-amino]-1, 1,1- trifluoro-2-propanol ; 3- [ [3- (2, 3-dichlorophenoxy) phenyl] [ [3- (heptafluoropropyl) phenyl] methyl]-amino]-1,1,1- trifluoro-2-propanol ; 3-[[3-(4-fluorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl] methyl] amino]-1,1,1- trifluoro-2-propanol ; 3-[[3-(4-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl] methyl] amino]-1,1,1- trifluoro-2-propanol ; 3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(heptafluoropropyl )phenyl]methyl]-amino]- 1,1,1-trifiuoro-2-propanol; 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(heptafluoropropyl )phenyl]methyl]-amino]- 1, 1,1-trifluoro-2-propanol;

3- [ [3- [3- (1, 1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [ [3- (heptafluoropropyl)-phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[3-[3-(pentafluoroethyl) phenoxy] phenyl] [ [3- (heptafluoropropyl) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3- [P- (3, 5-dimethylphenoxy) phenyl] [ [3- (heptafluoropropy1) phenyl] methyl]-amino]-1,1,1- trifluoro-2-propanol ; 3-[[3-(3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]m ethyl]-amino]-1, 1,1- trifluoro-2-propanol ; 3-[[3-(3-t-butylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl ]methyl]-amino]-1,1, 1- trifluoro-2-propanol ; 3-[[3-(3-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl] methyl] amino]-1,1,1- trifluoro-2-propanol ; 3- [ [3- (5, 6,7,8-tetrahydro-2-naphthoxy) phenyl] [ [3- (heptafluoropropyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(phenoxy)phyenyl][[3-(heptafluoropropyl)phenyl]methyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[3-[3-(n,N-dimethylamino) phenoxy] phenyl] [ [3- (heptafluoropropyl) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3- (trifluoromethoxy) phenyl]-methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromet hyl)phenyl]- methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3, 5- dimethylphenyl] methoxy]-phenyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3- (trifluoromethylthio) phenyl]-methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3, 5- difluorophenyl] methoxy]-phenyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-[cyclohexylme thoxy]phenyl]-amino]-1,1,1- trifluoro-2-propanol ; 3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3- (heptafluoropropyl) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(2-trifluoromethyl-4-pyruidyloxy)phenyl][[3-(heptafluo ropropyl)phenyl]- methyl] amino]-1, 1,1-trifluoro-2-propanol;

3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(heptafluoropropy l)phenyl]-methyl]amino]- 1,1,1-trifluoro-2-propanol; 3-[[[3-(3-trifluoromethylthio) phenoxy] phenyl] [ [3- (heptafluoropropyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(heptafl uoropropyl)phenyl]- methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-5-(triflu oromethyl)-phenyl]- methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-5-(trifluorometh yl)phenyl]-methyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-5- (trifluoromethyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(3-(2-furyl) phenoxy) phenyl] [[2-fluoro-5-(trifluoromethyl) phenyl]-methyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-5-(trifluoromet hyl)phenyl]-methyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl) phenyl]-methyl][amino]- 1,1, 1-trifluoro-2-propanol ; 3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-5-(trifluor omethyl)- phyenyl]methyl]amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluor omethyl)- phyenyl]methyl]amino]-1,1,1-trifluoro-2-propanol; 3- [ [3- [3- (1, 1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[2-fluoro-5-(trifluoro- methyl) phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-[3-(pentafluoroethyl) phenoxy] phenyl] [[2-fluoro-5-(trifluoromethyl)-phenyl]- methyl] amino]-1,1,1-trifluoro-2-propanol; 3- [ [3- (3, 5-dimethylphenoxy) phenyl] [ [2-fluoro-5- (trifluoromethyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)p henyl]methyl]-amino]-1, 1,1- trifluoro-2-propanol ; 3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl )phenyl]methyl]-amino]- 1,1,1-trifluoro-2-propanol;

3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl) phenyl]methyl]-amino]- 1,1,1-trifluoro-2-propanol; 3- [ [3- (5, 6,7,8-tetrahydro-2-naphthoxy) phenyl] [[2-fluoro-5- (trifluoromethyl)-phenyl] methyl]amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]m ethyl] amino]-1,1,1-trifluoro- 2-propanol ; 3- [ [3- [3- (N, N-dimethylamino) phenoxy] phenyl] [[2-fluoro-5- (trifluoromethyl)-phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifl uoromethoxy)- phenyl] methoxy] phenyl] amino]-1,1,1-trifluoro-2-propanol; 3-[ [ [2-fluoro-5- (trifluoromethyl) phenyl] methyl] [3- [ [3- (trifluoromethyl)- phenyl] methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-dime thylphenyl]- methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3- (trifluoromethylthio)-phenyl] methoxy] phenyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-difl uorophenyl]- methoxy] phenyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[cyclohexy lmethoxy]-phenyl]amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(2-difluoromethoxy-4-pyridyloxy)phyenyl][[2-fluoro-5- (trifluoromethyl)-phenyl]methyl]amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-5- (trifluoromethyl)-phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluo romethyl)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; 3- [ [P- (3-tdfluoromethylthio) phenoxy] phenyl3 [ [2-fluoro-5- (trifluoromethyl)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-5 - (trifluoromethyl) phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-4-(triflu oromethyl)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-4-(trifluorometh yl)phenyl]-methyl] amino]- 1,1,1-trifluoro-2-propanol;

3- [ [3- (3-cyclopropylphenoxy) phenyl] [ [2-fluoro-4- (trifluoromethyl) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-(2-furyl phenoxy) phenyl] [[2-fluoro-4-(trifluoromethyl) phenyl]-methyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-4-(trifluoromet hyl)phenyl]-methyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl) phenyl]-methyl]amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(2-fluoro-5-bromophenoxy) phenyl] [[2-fluoro-4-(trifluoromethyl)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluor omethyl)- phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol ; 3-[[3-[3-(1,1, 2,2-tetrafluoroethoxy) phenoxy] phenyl] [ [2-fluoro-4- (trifluoro- methyl) phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-[3-(pentafluoroethyl) phenoxy] phenyl] [[2-fluoro-4-(trifluoromethyl)- phenyl]methyl]amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-4- (trifluoromethyl)phenyl]-methyl]amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl) phenyl]methyl]-amino]-1, 1,1- trifluoro-2-propanol ; 3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl ) phenyl]methyl]-amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl) phenyl]methyl]-amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(5, 6,7, 8- tetrahydro-2-naphthoxy)phenyl][[2-fluoro-4-(trifluoromethyl- phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl) phenyl]methyl] amino]-1,1,1-trifluoro- 2-propanol ; 3-[[3-[3-(N,N-dimethylamino) phenoxy] phenyl] [[2-fluoro-4- (trifluoromethyl)-phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol ; 3-[[[3-2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(tri fluoromethoxy)- phenyl] methoxy] phenyl]amino]-1, 1,1-trifluoro-2-propanol;

3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifl uoromethyl)- phenyl] methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[[3-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-dime thylphenyl]- methoxy] phenyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3- (trifluoromethylthio)-phenyl] methoxy] phenyl]amino]-1,1,1-trifluoro-2-propanol; 3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-difl uorophenyl]- methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[[3-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[cyclohexy lmethoxy]-phenyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-4- (trifluoromethyl)-phenyl]methyl]amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-4- (trifluoromethyl)-phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluo romethyl)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; 3- [ [ [3- (3-trifluoromethylthio) phenoxy] phenyl] [[2-fluoro-4- (trifluoromethyl)-phenyl]methyl]amino]-1, 1,1-trifluoro-2-propanol; and 3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-4 -(trifluoro- methyl) phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol.

Another class of CETP inhibitors that finds utility with the present invention consists of substitued N-Aliphatic-N-Aromatic tertiary-Heteroalkylamines having the Formula XV Formula XV and pharmaceutical acceptable forms thereof, wherein: nXV is an integer selected from 1 through 2; Axv and Qxv are independently selected from the group consisting of

with the provisos that one of Axv and Qxv must be AQ-1 and that one of Axv and Qxv must be selected from the group consisting of AQ-2 and-CH2 (CRXV-37RXV-38)xXV-(CRXV- 33RXV-34)uXV-TXV-(CRXV-35RXV-36)wXV-H; Txv is selected from the group consisting of a single covalent bond, O, S, S (O), S (0) 2, C (RXV-33)=C(RXV-35), and

vXV is an integer selected from 0 through 1 with the proviso thatxv is 1 when any one of RXV-33, RXV-34, RXV-35, and Rxv-36 is aryl or heteroaryl ; uxv and wxv are integers independently selected from 0 through 6; Axe 1 is C (RXV-30) ; DXV-1, DXV-2, JXV-1, JXV-2, and KXV-1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of DXV-1, DXV-2, JXV-1, JXV-2, and KXV-1 is a covalent bond, no more than one of DXV-1, DXV-2, JXV-1, JXV-2, and Kxv-i is O, no more than one of DXV-1, DXV-2, JXV-1, JXV-2, and Kxv-i is S, one of DXV-1, DXV-2, JXV-1, JXV-2, and KXV-1 must be a covalent bond when two of Dxv-,, DXV-2, JXV-1, JXV-2, and K) are O and S, and no more than four of DXV-1, DXV-2, JXV-1, JXV- 2, and KXV-1 are N ; BXV-1, BXV-2, DXV-3, DXV-4, JXV-3, JXV-4, and KXV-2 are independently selected from the group consisting of C, C (Rev40) N, O, S and a covalent bond with the provisos that no more than 5 of Bxv-1, -1, BXV-2, DXV-3, DXV-4, JXV-3, JXV-4, and KXV-2 are a covalent bond, no more than two of Bxv-i, BXV-2, DXV-3, DXV-4, JXV-3, JXV-4, and Kxv-s are O, no more than two of BXV-1, BXV-2, DXV-3, DXV-4, JXV-3, JXV-4, and Kxv-2 are S, no more than two of BXV-1, BXV-2, DXV-3, DXV-4, JXV-3, JXV-4, and Kxv-2 are simultaneously O and S, and no more than two of Bxv-1, Bxv-2, Dxv-3, Dxv-4, Jxv-3, Jxv-4, and Kxv-2 are N; BXV-1 and Dxv-3, Dxv-3 and Jxv-3, Jxv-3 and Kxv-2, Kxv-2 and Jxv-4, Jxv-4 and Dxv-4, and DXV-4 and BXV-2 are independently selected to form an in-ring spacer pair wherein said spacer pair is selected from the group consisting of C (RXV-33) =C (Rxv-35) and N=N with the provisos that AQ-2 must be a ring of at least five contiguous members, that no more than two of the group of said spacer pairs are simultaneously C (RXV-33) =C (Rxv-3s) and that no more than one of the group of said spacer pairs can be N=N unless the other spacer pairs are other than C (RXV-33) =C (Rxv-35), 0, N, and S; RXV-1 is selected from the group consisting of haloalkyl and haloalkoxymethyl ; Rxv-2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl and heteroaryl ; Rxv-3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl ;

Yxv is selected from the group consisting of a covalent single bond, (CH2) q wherein q is an integer selected from 1 through 2 and (CH2) j-O- (CH2) k wherein j and k are integers independently selected from 0 through 1; Zxv is selected from the group consisting of covalent single bond, (CH2) q wherein q is an integer selected from 1 through 2, and (CH2) j-O- (CH2) k wherein j and k are integers independently selected from 0 through 1; Rxv-4, Rxv-8, Rxv-9 and Rxv-13 are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl ; RXV-30 is selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso that Rxv-3o is selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; Rxv-30, when bonded to Axv-1, is taken together to form an intra-ring linear spacer connecting the Axv-1-carbon at the point of attachment of RXV 30 to the point of bonding of a group selected from the group consisting of RXV-10, RXV-11, RXV-12, RXV-31, and RXV-32 wherein said intra-ring linear spacer is selected from the group consisting of a covalent single bond and a spacer moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 10 contiguous members, a cycloalkenyl having from 5 through 10 contiguous members, and a heterocyclyl having from 5 through 10 contiguous members; Rev40, when bonded to Axv-1, is taken together to form an intra-ring branched spacer connecting the A) carbon at the point of attachment of Ru"40 to the points of bonding of each member of any one of substituent pairs selected from the group consisting of subsitituent pairs RXV-10 and RXV-11, RXV-10 and RXV-31, RXV-10 and RXV-32, RXV- 10 and RXV-12, RXV-11 and RXV-31, RXV-11 and RXV-32, RXV-11 and RXV-12, RXV-31 and RXV-32, RXV- 31 and Rxv-i2, and RXV-32 and Rxv-12 and wherein said intra-ring branched spacer is selected to form two rings selected from the group consisting of cycloalkyl having from 3 through 10 contiguous members, cycloalkenyl having from 5 through 10 contiguous members, and heterocyclyl having from 5 through 10 contiguous members; Rev-as RXV-5, RXV-6, RXV-7, RXV-8, RXV-9, RXV-10, RXV-11, RXV-12, RXV-13, RXV-31, RXV-32, RXV-33, RXV-34, RXV-35, and Rev46 are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl,

heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N- <BR> <BR> <BR> heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, <BR> <BR> <BR> haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy,<BR> <BR> <BR> <BR> <BR> haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, alkylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl with the provisos that RXV-4, RXV-5, RXV-6, RXV-7, RXV-8, RXV-9, Rxv-io. RXV-11, RXV-12, RXV-13, RXV-31, RXV-32, RXV-33, RXV-34, RXV-35, and RXV-36 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen, that no more than three of the Rxv-ss and Rxv-34 substituents are simultaneously selected from other than the group consisting of hydrido and halo, and that no more than three of the Rev45

and RXV-36 substituents are simultaneously selected from other than the group consisting of hydrido and halo ; RXV-9, XV-10, RXV-11, RXV-12, RXV-13, RXV-31, and Rxv 32 are independently selected to be oxo with the provisos that BXV-1, BXV-2, DXV-3, DXV-4, JXV-3, JXV-4, and Kxv-2 are independently selected from the group consisting of C and S, no more than two of Rx\/- 9, Rev Rxv-n, Rxv-12, Rxv-13, Rxv-31, and Rw 32 are simultaneously oxo, and that Rev-9, RXV-10, RXV-11, RXV-12, RXV-13, RXV-31, and Rev-32 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen ; RXV-4 and RXV-5, RXV-5 and RXV-6, RXV-6 and RXV-7, RXV-7 and RXV-8, RXV-9 and RXV-10, Rxv-10 and Rxv-n, Rxv-n and Rxv-si, Rxv-31 and RXV-32, RXV-32 and RXV-12, and RXV-12 and RXV-13 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs RXV-4 and RXV-5, RXV-5 and RXV-6, RXV-6 and RXV-7, RXV-7 and RXV-8 is used at the same time and that no more than one of the group consisting of spacer pairs Rev 9 and Rxv-io, R_, o and Rev-11, Rev 11 and RXV-31, RXV-31 and RXV-32, RXV-32 and RXV-12, and Rxv-12 and Rxv-13 are used at the same time; Rxv-9 and RXV-11, RXV-9 and RXV-12, RXV-9 and Rxv-13 Rxv-a and Rxv-31, RXV-9 and Rxv- 32, Rxv-io and RXV-12, RXV-10 and RXV-13, RXV-10 and RXV-31, RXV-10 and RXV-32, RXV-11 and RXV- 12, Rxv-n and RXV-13, RXV-11 and RXV-32, RXV-12 and RXV-31, RXV-13 and RXV-31, and RXV-13 and RXV42 are independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a moiety having from 1 through 3 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, a saturated heterocyclyl having from 5 through 8 contiguous members and a partially saturated heterocyclyl having from 5 through 8 contiguous members with the provisos that no more than one of said group of spacer pairs is used at the same time;

RXV-37 and RXV-38 are independently selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.

Compounds of Formula XV are disclosed in WO 00/18723, the entire disclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of Formula XV: 3- [ [3- (4-chloro-3-ethylphenoxy) phenyl] (cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(4-chloro-3-ethylphenoxy)phenyl] (cyclopentylmethyl) amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(4-chloro-3-ethylphenoxy)phenyl] (cyclopropylmethyl)amino]-1, 1,1-trifluoro-2-propanol; 3- [ [3- (4-chloro-3-ethylphenoxy) phenyl] [ (3-trifiuoromethyl) cyclohexyl-methyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-pentafluoroethyl) cyclohexyl-methyl] amino]-1, 1, 1-trifluoro-2-propanol ; 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-trifluoromethoxy) cyclohexyl-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1, 1,2,2- tetrafluoroethoxy) cyclo-hexylmethyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethoxyphenoxy)phenyl] (cyclohexylmethyl) amino3-1,1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethoxyphenoxy)phenyl] (cyclopentylmethyl) amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethoxyphenoxy)phenyl] (cyclopropylmethyl)amino]-1, 1,1-trifluoro-2-propanol; 3- [[3-(3-trifluoromethoxyphenoxy)phenyl][(3-trifluoromethyl)cy clohexyl-methyl] amino]- 1,1,1-trifluoro-2-propanol ; 3-[[3-(3-trifluoromethoxyphenoxy)phenyl]](3-pentafluoroethyl )cyclohexyl-methyl]amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-

trifluoromethoxy) cyclohexyl-methyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1, 1,2,2- tetrafluoroethoxy) cyclohexyl-methyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(3-isopropylphenoxy)phenyl](cyclohexylmethyl]amino]-1, 1,1-trifiuoro-2-propanol: 3- [P- (3-isopropylphenoxy) phenyl] (cyclopentylmethyl] amino]-l,1,1-trifluoro-2-propanol; 3-[[3-(3-isopropylphenoxy)phenyl](cyclopropylmethyl)amino]-1 , 1,1-trifluoro-2-propanol; 3- [P- (3-isopropylphenoxy) phenyl] [ (3-trifluoromethyl) cyclohexyl-methyl] aminol-l,1,1- trifluoro-2-propanol ; 3-[[3-(3-isopropylphenoxy)phenyl][(3-pentafluoroethyl) cyclohexyl-methyl] amino]-1,1,1- trifluoro-2-propanol ; 3- [ [3- (3-isopropylphenoxy) phenyl] [ (3-trifluoromethoxy) cyclohexyl-methyl]amino]-1,1,1- trifluoro-2-propanol ; 3- [ [3- (3-isopropylphenoxy) phenyl] [3- (1, 1,2,2-tetrafluoroethoxy) cyclohexyl- methyl] amino]-1,1,1-trifluoro-2-propanol; 3- [ [3- (2, 3-dichlorophenoxy) phenyl] (cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(2,3-dichlorophenoxy)phenyl](cyclopentylmethyl) amino-1, 1,1-trifluoro-2-propanol; 3-[[3-(2,3-dichlorophenoxy)phenyl](cyclopropylmethyl)amino]- 1, 1,1-trifluoro-2-propanol; 3-[[3-(2,3-dichlorophenoxy)phenhyl][(3-trifluoromethyl) cyclohexyl-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(2,3-dichlorophenoxy)phenyl][(3-pentafluoroethyl) cyclohexyl-methyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(2,3-dichlorophenoxy)phenyl][(3-trifluoromethoxy) cyclohexyl-methyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(2,3-dichlorophenoxy)phenyl][3-(1, 1,2,2-tetrafluoroethoxy) cyclo-hexyl- methyl]amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(4-fluorophenoxy)phenyl](cyclohexylmethyl) amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(4-fluorophenoxy)phenyl](cyclopentylmethyl) amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(4-fluorophenoxy)phenyl](cyclopropylmethyl)amino]-1, 1,1-triflouro-2-propanol; 3-[[3-(4-fluorophenoxy)phenyl][(3-trifluoromethyl) cyclohexyl-methyl] amino]-1, 1,1-trifluoro-2-propanol;

3-[[3-(4-fluorophenoxy)phenyl][(3-pentafluoroethyl) cyclohexyl-methyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(4-fluorophenoxy)phenyl][(3-trifluoromethoxy) cyclohexyl-methyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(4-fluorophenoxy)phenyl][[3-(1, 1,2,2-tetrafluoroethoxy) cyclohexyl-methyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethoxybenzyloxy]phenyl] (cyclohexylmethyl) amino]-1,1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethoxybenzyloxy]phenyl] (cyclopentylmethyl) amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethoxybenzyloxy)phenyl] (cyclopropylmethyqamino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][(3- trifluoromethyl) cyclohexyl-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][(3- pentafluoroethyl) cyclohexyl-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethoxybenzyloxy]phenyl][(3- trifluoromethoxy) cyclohexyl-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][3-(1, 1,2,2- tetrafluoroethoxy)-cyclohexylmethyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethylbenzyloxy)phenyl] (cyclohexylmethyl) amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethylbenzyloxy)phenyl] (cyclopentylmethyl) amino]-1, 1,1-trifluoro-2-propanol; 3- [ (3- (3-trifluoromethylbenzyloxy) phenyl] (cyclopropylmethyl) amino]-1, 1,1-trifluoro-2-propanol; <BR> <BR> 3- [ (3- (3-trifluoromethylbenzyloxy) phenyl] [ (3-trifluoromethyl) cyclohexyl-methyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-pentafluoroethy l)cyclohexyl-methyl] amino]- 1,1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3- trifluoromethoxy) cyclohexyl-methyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[3-(3-trifluoromethylbenzyloxy)phenyl][3-(1, 1,2,2- tetrafluoroethoxy) cyclohexyl-methyl] amino]-1,1,1-trifluoro-2-propanol;

3-[[[(3-trifluoromethyl)phenyl]methyl](cyclohexyl)amino]-1, 1,1-trifluoro-2-propanol; 3-[[[(3-pentafluoroethyl)phenyl]methyl](cyclohexyl)amino]-1, 1,1-trifluoro-2-propanol; 3-[[[(3-trifluoromethoxy)phenyl]methyl](cyclohexyl)amino]-1, 1,1-trifluoro-2-propanol; 3- [ [ [3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] (cyclohexyl) amino]-1, 1,1-trifluoro-2-propanol; 3-[[[(3-trifluoromethyl)phenyl]methyl] (4-methylcyclohexyl) amino]-1, 1,1-trifluoro-2-propanol; 3- [ [ ( (3-pentafluoroethyl) phenyl] methyl] (4-methylcyclohexyl) amino]-1, 1,1-trifluoro-2-propanol; 3-[[[(3-trifluoromethoxy)phenyl]methyl] (4-methylcyclohexyl) amino]-1, 1,1-trifluoro-2-propanol; 3-[[[3-(1, 1,2,2-tetrafluoroethoxy) phenyl] methyl] (4- methylcyclohexyl) amino]-1, 1,1-trifluoro-2-propanol; 3-[[[(3-trifluoromethyl]phenyl]methyl] (3- trifluoromethylcyclohexyl) amino]-1,1,1-trifluoro-2-propanol; 3-[[[(3-pentafluoroethyl)phenyl]methyl] (3- trifluoromethylcyclohexyl) amino]-1,1,1-trifluoro-2-propanol; 3- [ [ ( (3-trifluoromethoxy) phenyl] methyl] (3- trifluoromethylcyclohexyl) amino]-1,1,1-trifluoro-2-propanol; 3- [ [ [3- (1, 1,2,2-tetrafluoroethoxy) phenyl] methyl] (3-trifluoromethylcyclohexyl) amino]- 1,1,1-trifluoro-2-propanol; 3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylph enoxy)cyclo-hexyl] amino]- 1,1,1-trifluoro-2-propanol; <BR> <BR> 3- [ [j (3-pentafluoroethyl) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy) cyclo-hexyl] aminoJ- 1,1,1-trifluoro-2-propanol; 3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3- ethylphenoxy) cyclo-hexyl] amino]-1, 1,1-trifluoro-2-propanol; 3- [ [ [3- (1, 1,2,2-tetrafluoroethoxy) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy)- cyclohexyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[[(3-trifluoromethyl]phenyl]methyl](3-phenoxycyclohexyl)a mino]-1, 1,1-trifluoro-2- propanol ; 3-[[[(3-pentafluoroethyl)phenyl]methyl](3-phenoxycyclohexyl) amino]-1, 1,1-trifluoro-2- propanol ;

3-[[[(3-trifluoromethoxy)phenyl]methyl](3-phenoxycyclohexyl) amino]-1, 1,1-trifluoro-2- propanol ; 3- [ [ [3- (1, 1,2,2-tetrafluoroethoxy) phenyl] methyl] (3- phenoxycyclohexyl) amino]-1,1,1-trifluoro-2-propanol; 3-[[[(3-trifluoromethyl)phenyl]methyl](3-isopropoxycyclohexy l)amino]-1, 1,1-trifluoro-2- propanol ; 3-[[[(3-pentafluoroethyl)phnyl]methyl](3-isopropoxycyclohexy l)amino]-1, 1,1-trifluoro-2- propanol ; 3-[[[(3-trifluoromethoxy)phenyl]methyl](3-isopropoxycyclohex yl)amino]-1, 1,1-trifluoro-2- propanol ; 3- [ [ [3- (1, 1,2,2-tetrafluoroethoxy) phenyl] methyl] (3- isopropoxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol; 3-[[[(3-trfluoromethyl)phenyl]methyl] (3- cyclopentyloxycyclohexyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[[(3-pentafluoroethyl]phenyl]methyl] (3- cyclopentyloxycyclohexyl) amino]-1,1,1-trifluoro-2-propanol; 3-[[[(3-trifluoromethoxy) phenyl] methyl] (3- cyclopentyloxycyclohexyl) amino]-1,1,1-trifluoro-2-propanol; 3- [ [ [3- (1, 1,2,2-tetrafluoroethoxy) phenyl] methyl] (3- cyclopentyloxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol; 3- ( [ (2-trifluoromethyl) pyrid-6-yl] methyl] (3- isopropoxycyclohexyl) amino]-1, 1,1-trifluoro-2-propanol; 3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-cyclopentyloxyc yclohexyl)-amino]-1, 1,1- trifluoro-2-propanol ; 3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-phenoxycyclohex yl)amino]-1, 1,1-trifluoro-2- propanol ; 3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3- trifluoromethylcyclohexyl) amino]-1,1,1-trifluoro-2-propanol; 3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(4-chloro-3-eth ylphenoxy)cyclo-hexyl]amino]- 1,1,1-trifluoro-2-propanol; 3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(1,1,2,2- tetrafluoroethoxy) cyclo-hexyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-pentafluoroeoth ylcycklohexyl)-amino]-1,1,1- trifluoro-2-propanol ;

3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-trifluoromethox ycyclohexyl)-amino]-1, 1,1- trifluoro-2-propanol ; 3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3- ethylphenoxy) propyl]-amino]-1,1,1-trifluoro-2-propanol; 3- ( [ ( (3-pentafluoroethyl) phenyl] methyl] (3- (4-chloro-3- ethylphenoxy) propyl]-amino]-1,1,1-trifluoro-2-propanol; 3- [ [ ( (3-trifluoromethoxy) phenyl] methyl] [3- (4-chloro-3- ethylphenoxy) propyl]-amino]-1,1,1-trifluoro-2-propanol; 3- [ [ [3- (1,1,2,2-tetrafluoroethoxy) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy)- propyl] amino]-1, 1,1-trifluoro-2-propanol; 3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylph enoxy)-2, 2,-di- fluropropyl] amino]-1, 1,1-trifluoro-2-propanol; 3[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-thylphe noxy)-2, 2-di- fluropropyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[[(3trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylph enoxy)-2, 2,-di- fluropropyl] amino]-1,1,1-trifluoro-2-propanol; 3-[[[3-(1,1, 2,2-tetrafluoroethoxy) phenyl] methyl] [3- (4-chloro-3-ethylphenoxy)-2,2,- difluropropyl] amino]-1, 1, 1-trifluoro-2-propanol ; 3-[[[(3-trifluoromethyl)phenyl]methyl][3-(isopropoxy)propyl] amino]-1, 1,1-trifluoro-2- propanol ; 3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(isopropoxy)propyl ]amino]-1, 1,1-trifluoro-2- propanol ; 3-[[[(3-trifluoromethoxcy)phenyl]methyl][3-(isopropoxy)propy l]amino]-1, 1,1-trifluoro-2- propanol ; 3-[[[3-(1, 1,2, 2-tetrafluoroethoxy)phnyl]methyl]]3- (isopropoxy) propyl] amino]-1, 1, 1-trifluoro-2-propanol ; and 3- [ [ [3- (1, 1,2,2-tetrafluoroethoxy) phenyl] methyl] [3- (phenoxy) propyl] amino-1, 1,1-trifluoro-2-propanol.

Another class of CETP inhibitors that finds utility with the present invention consists of (R)-chiral halogenated 1-substituted amino- (n+l)-alkanols having the Formula XVI

Formula XVI and pharmaceutical acceptable forms thereof, wherein: nazis an integer selected from 1 through 4; Xxv ! is oxy ; Rev_, is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the proviso that RXVI-1 has a higher Cahn-Ingold-Prelog stereochemical system ranking than both Rxv and (CHRXVI-3)n-N(AXVI)QXVI wherein AXVI is Formula XVI-(II) and Q is Formula XVI-(III) ;

RXVI-16 is selected from the group consisting of hydrido, alkyl, acyl, aroyl, heteroaroyl, trialkylsilyl, and a spacer selected from the group consisting of a covalent single bond and a linear spacer moiety having a chain length of 1 to 4 atoms linked to the point of bonding of any aromatic substituent selected from the group consisting of Rxv 4, Rev$, Rev-9, and Rev-, 3 to form a heterocyclyl ring having from 5 through 10 contiguous members; DXVI-1, DXVI-2, JXVI-1, JXVI-2 and KXVI-1 are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that no more than one of DXVI-1, DXVI-2, JXVI-1, JXVI-2 and KXVI-1 is a covalent bond, no more than one DXVI-1, DXVI-2, JXVI-1, JXVI-2 and Kxv)-i is be 0, no more than one of DXVI-1, DXVI-2, JXVI-1, JXVI-2 and KXVI-1 is S, one of DXVI-1, DXVI-2, JXVI-1, JXVI-2 and KXVI-1 must be a covalent bond when two of DXVI 11 DXVI-2, JXVI-1, JXVI-2 and KXVI-1 are O and S, and no more than four of Dxv)-i, DXVI-2, JXVI-1, JxVI-2 and Kxv is N; DXVI-3, DXVI-4, JXVI-3, JXVI-4 and Kx 2are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that no more than one is a covalent bond, no more than one of Dxv)-s. DXVI-4, JXVI-3, JXVI-4 and KXVI-2 is O, no more than one of DXVI-3, DXVI-4, JXVI-3, JXVI-4 and Kx"_2 is S, no more than two of DXVI-3, DXVI-4, JXVI_3, JXVI-4 and KXVI-2 is 0 and S, one of DXVI-3, DXVI-4, JXVI-3, JXVI-4 and Kil 2 must be a covalent bond when two of DXVI-3, DXVI-4, JXVI-3, JXVI-4 and KXVI-2 are O and S, and no more than four of DXVI-3, DXVI-4, JXVI-3, JXVI-4 and Kxvt-2 are N; Rev-2 is selected from the group consisting of hydrido, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl,

perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl, with the proviso that Rev-2 has a lower Cahn-Ingold-dPrelog system ranking than both Rxvi-i and (CHRXVI-3)n-N(AXVI)QXVI ; Rev-3 is selected from the group consisting of hydrido, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl, with the provisos that (CHR)) n- N (Adv) Qxvl has a lower Cahn-Ingold-Prelog stereochemical system ranking than Rxvn and a higher Cahn-lngold-Prelog stereochemical system ranking than Rev-2 ; Yxv) is seiected from a group consisting of a covalent single bond, (C (Rxvi-i4) 2) q wherein q is an integer selected from 1 and 2 and (CH (RXVI-14))g-WXVI-(CH(RXVI-14)) p wherein g and p are integers independently selected from 0 and 1; RXVI-14 is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl ; ZXVI is selected from a group consisting of a covalent single bond, (C (RXVI-15) 2) q, wherein q is an integer selected from 1 and 2, and (CH (RXVI-15))j-WXVI-(CH(RXVI-15)) k wherein j and k are integers independently selected from 0 and 1; W) M is seiected from the group consisting of O, C (O), C (S), C (O) N (RXVI-14), C (S) N (RXV-14),(RXVI-14)NC(O), (RXVI-14) NC (S), S, S (O), S (0) 2, S (O) 2N (RXV-14), (RXVI- raz NS (0) 2, and N (Rev4) with the proviso that RW, 14 is other than cyano ; Rx\/1-15 is selected, from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl ; RXVI-4, RXVI-5, RXVI-6, RXVI-7, RXVI-8, RXVI-9, RXVI-10, RXVI-11, RXVI-12, and RXVI-13 are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsu (finyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,

cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroaralkyl, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, <BR> <BR> <BR> arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl,<BR> <BR> <BR> <BR> <BR> arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl, amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl with the proviso that Rx"4, RXVI-5, RXVI-6, RXVI-7, RXVI-8, RXVI-9, RXVI-10, RXVI-11, RXVI-12, and Rev-13 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; Rxv,. 4 and Rx"_5, Rx"s and Rxv)-e, Rxvf-e and RXVI-7, Rev,-7 and RXVI-8, RXVI-9 and RXVI-10, RXVI-10 and Rev_", Rxv and Rev-129 and RXVI-12 and RXIV 13 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated

heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs Rxv, 4 and Rev-5 Rxvi-5 and RXVI-6, RXVI-6 and Rev-7, and Rev17 and Rev $ is used at the same time and that no more than one of the group consisting of spacer pairs RXIV-9 and RXVI-10, RXVI-10 and RXVI-11, RXVI-11 and RXvI-12, and RXVI-12 and Rxvt-13 can be used at the same time; RXVI-4 and RXVI-9, RXVI-4 and RXVI-13, RXVI-8 and Rev, 9, and RXVI-8 and RXVI-13 is independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear moiety wherein said linear moiety forms a ring selected from the group consisting of a partially saturated heterocyclyl ring having from 5 through 8 contiguous members and a heteroaryl ring having from 5 through 6 contiguous members with the proviso that no more than one of the group consisting of spacer pairs R,, 4 and RXVI-9, RXVI-4 and RXVI-13, RXVI-8 and RXVI-9, and RXVI-8 and Rxvt-ia is used at the same time.

Compounds of Formula XVI are disclosed in WO 00/18724, the entire disclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from the following compounds of Formula XVI : (2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1, 1,2,2- tetrafluoroethoxy) phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(1, 1,2,2- tetrafluoroethoxy) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3- [ [3- (3-cyclopropylphenoxy) phenyl) [ [3- (1, 1,2,2- tetrafluoroethoxy)phenyl]-methyl]amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(2-furyl) phenoxy) phenyl] [ [3- (1, 1,2,2-tetrafluoroethoxy) phenyl]- methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(1, 1,2,2- tetrafluoroethoxy) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(1, 1,2,2- tetrafluoroethoxy) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(1, 1,2,2- tetrafluoroethoxy) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(1, 1,2,2- tetrafluoroethoxy)phenyl]-methyl]amino]-1, 1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1, 1,2,2- tetrafluoroethoxy) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-[3-(1, 1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [ [3- (1,1,2,2-tetrafluoro-ethoxy) phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-[3-(pentafluorethyl)phenoxyl]phenyl][[3-(1, 1,2,2-tetrafluoroethoxy)- phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(3,5-dimethyl,phenoxy)phenyl][3-(1, 1,2,2- tetrafluoroethoxy) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-ethylphenoxy)phnyl][[3-(1, 1,2,2-tetrafluoroethoxy) phenyl]-methyl] amino]- 1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-t-butylphenoxy)phnyl][[3-(1, 1,2,2- tetrafluoroethoxy) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol: (2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(1, 1,2,2- tetrafluoroethoxy) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3- [ [3- (5, 6,7,8-tetrahydro-2-naphthoxy) phenyl] [ [3- (1, 1,2,2-tetrafluoro- ethoxy) phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(phenoxy)phenyl][[3-(1, 1,2,2- tetrafluoroethoxy) phenylJmethyl] amino]-1, 1, 1-trifluoro-2-propanol ; (2R)-3-[[3-[3-(N,N-dimethylamino) phenoxy] phenyl] [ [3- (1, 1,2,2-tetrafluoro- ethoxy) phenyl] methyl] amino-1, 1,1-trifluoro-2-propanol; (2R)-3-[[[3-(1, 1,2,2,-tetrafluoroethoxy) phenyl] methyl] [3-[[3-(trifluoromethoxy)- phenyl] methoxy] phenyl] amino]-1, 1, 1-trifluoro-2-propanol ; (2R)-3- [ [ [3- (1, 1,2,2-tetrafluoroethoxy) phenyl] methyls [3-[[3-(trifluoro- methyl) phenyl] methoxy] phenyl] amino3-1, 1,1-trifluoro-2-propanol; (2R)-3- [ [ [3- (1, 1,2, 2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-dimethylphenyl]- methoxy] phenyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3- [ [ [3- (1, 1,2, 2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethylthi o)- phenyl] methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3- [[[3-(1, 1,2, 2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-difluorophenyl]- methoxy] phenyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3- [ [ [3- (1, 1,2,2-tetrafluoroethoxy) phenyl] methyl] [3- [cyclohexylmethoxy]- phenyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-92-dfluoromethoxy-4-pyridyloxy)phenyl][[3-(1,1,2, 2-tetrafluoroethoxy)- phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(2-trifluoromethyl-4-pyridiyloxy)phenyl][[3-( 1,1,2,2-tetrafluoroethoxy)- phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-difluoromethoxpyphenoxy)phenyl][[3-(1,1,2,2- tetrafluoroethoxy)-phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-( 1,1,2,2-tetrafluoroethoxy)- phenyl] methyl]amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][33-( 1,1,2,2-tetrafluoroethoxy)- phenyl] methyl]amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3- (pentafluoroethyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3- (pentafluoroethyl) phenyl] methyl]-amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-cvyclopropylphenoxy)phnyl][[3- (pentafluoroethyl) phenyl] methyl]-amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-(2-furyl) phenoxy) phenyl] [ [3- (pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-pr opanol; (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3- (pentafluoroethyl) phenyl] methyl]-amino]-1,1,1-trifluoro-2-propanol; (2R)-3- [ (3- (4-fluorophenoxy) phenyl] [ [3- (pentafluoroethyl) phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(4-methylphenoxy)phenyl][[3- (pentafluoroethyl) phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3- (pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-pr opanol; (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3- (pentafluoroethyl) phenyl] methyl]-amino]-1,1,1-trifluoro-2-propanol; (2R)-3- [ [3- [3- (1, 1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [ [3- (pentafluoroethyl)- phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(pentafluoroethyl)phenoxy]phenyl][[3- (pentafluoroethyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(pentafluoroethyl ) phnyl]methyl]-amino]- 1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(pentafluoroethyl) phenyl]methyl]amino]-1, 1,1- trifluoro-2-propanol ; (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(pentafluoroethyl) phenyl]methyl amino]-1,1,1- trifluoro-2-propanol ; (2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(pentafluoroethyl) phenyl]methyl]amino]-1, 1,1- trifluoro-2-propanol ; (2R)-3- [ [3- (5, 6,7,8-tetrahydro-2-naphthoxy) phenyl] [ [3- (pentafluoroethyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(phenoxy)phnyl][[3(pentafluoroethyl) phenyl] methy amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-[3-(N,N-dimethylamino) phenoxy] phenyl] [[3- (pentafluoroethyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3- (trifluoromethoxy) phenyl]-methoxy] phenyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[[3-(pentafluoroethyl)phnyl]methyl][3-[3-(trifluorom ethyl)-phenyl]- methoxy] phenyl] amino-1, 1, 1-trifluoro-2-propanol ; (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3, 5- dimethylphenyl] methoxy]-phenyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3- (trifluoromethylthio) phenyl]-methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3, 5- difluorophenyl] methoxy]-phenyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl] [3- [cyclohexylmethoxy] phenyl]-amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3- (pentafluoroethyl) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(2-trifluoromethyl-4-pyridiyloxy)phenyl][[3- (pentafluoroethyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3- (pentafluoroethyl) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3- [3-(3-trifluoromethylthio) phenoxy] phenyl] [ [3- (pentafluoroethyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-

(pentafluoroethyl)-phenyl] methyl]amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-trfluoromethoxyphenoxy)phnyl][[3- (heptafluoropropyl) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-isopropylphnoxy)phenyl][[3- (heptafluoropropyl) phenyl] methyl]-amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-cycloopropylphenoxy)phenyl][[3-(heptafluoropyl )phenyl]methyl]-amino]- 1,1,1-trifluoro-2-propanol; (2R)-3- [ [3- (3- (2-furyl) phenoxy) phenyl] [ [3- (heptafluoropropyl) phenyl] methyl]-amino]- 1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(heptafluoropopyl ) phenyl]methyl]-amino]- 1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(4-fluorophnoxcy)phenyl][[3-(heptafluoropropyl) phenyl]methyl] amino]-1,1,1- trifluoro-2-propanol ; (2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(heptafluoropropyl) phenyl]methyl] amino]- 1,1,1,-trifluoro-2-propanol; (2R)-3-[[3-(2-fluoro-5-bromophenoxcy)phnyl][[3- (heptafluoropropyl)phenyl]-methyl]amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(4-chloro-3-ethylphenxoy)phenyl][[3- (heptafluoropropyl)phenyl]methyl]-amino]-1, 1,1-trifluoro-2-propanol; (2R)-3- [ [3- [3- (1, 1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [ [3- (heptafluoropropyl)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-[3-(pentafluoroethyl) phenoxy] phenyl [ [3- (heptafluoropropyl) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(heptafluoropropy l) phenyl]methyl]-amino]- 1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-ethylphenxoy)phnyl][[3-(heptafluoropropyl) phenyl]methyl]amino]-1, 1,1- trifluoro-2-propanol ; (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(heptafluoropropyl) phenyl]methyl] amino]-1,1,1- trifluoro-2-propanol ; (2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(heptafluoropyl) phenyl]methyl]amino]- 1,1,1-trifluoro-2-propanol; (2R)-3- [ [3- (5, 6,7,8-tetrahydro-2-naphthoxy) phenyl] [ [3- (heptafluoropropyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(phenyl][[3-(heptafluoropropyl) phenyl]methyl]amino]-1, 1,1-trifluoro- 2-propanol ; (2R)-3-[[3-[3-(N,N-dimethylamino) phenoxy] phenyl] [ [3- (heptafluoropropyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3- (trifluoromethoxy) phenyl]-methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3- (trifluoromethyl) phenyl]-methoxy] phenyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3, 5- dimethylphenyl] methoxy]-phenyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3- (trifluoromethylthio) phenyl]-methoxy] phenyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3, 5- difluorophenyl] methoxy]-phenyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl] [3- [cyclohexylmethoxfflphenyl]-amino]-1, 1, 1-trifluoro-2-propanol ; (2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3- (heptafluoropropyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3- (heptafluoropropyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3- (heptafluoropropyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[[3-(3-trifluoromethylthio) phenoxy] phenyl [ [3- (heptafluoropropyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3- (heptafluoropropyl)-phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-5- (trifluoromethyl)-phenyl] methyl] amino]- 1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-5- (trifluoromethyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-5- (trifluoromethyl) phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(3-(2-furyl) phenoxy) phenyl] [[2-fluoro-5-(trifluoromethyl)phenyl]- methyl]amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-5- (trifluoromethyl) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-5-9trifluorome thyl)phenyl]-methyl]amino]- 1,1,1-trifluoro-3-propanol; (2R)-3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-5- (trifluoromethyl) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-5-(tri fluoromethyl)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-5-(tri fluoromethyl)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3- [ [3- [3- (1, 1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[2-fluoro-5-(trifluoro-methyl)phenyl]methyl]amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-[3-(pentafluoroethyl) phenoxy] phenyl] [[2-fluoro-5-(trifluoromethyl)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluor-5- (trifluoromethyl) phenyl]-methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromet hyl)phenyl]methyl]-amino]- 1,1,1-trifluoro-2-propanol; (2R)-3- [ [3- (3-t-butyfphenoxy) phenyl] [ [2-fluoro-5- (trifluoromethyl) phenyl] methyl]-amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-5- (trifluoromethyl) phenyl] methyl]-amino]-1, 1,1-trifluoro-2-propanol; (2R)-3- [ [3- (5, 6,7,8-tetrahydro-2-naphthoxy) phenyl] [[2-fluoro-5-(trifluoromethyl)- phenyl]methyl]amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl) phenyl]methyl] amino]-1,1,1- trifluoro-2-propanol ; (2R)-3-[[3-[3-(N,N-dimethylamino,phenoxy]phenyl][[2-fluoro-5 -(trifluoromethyl)- phenyl] methyl] amino]-1, 1, 1-trifluoro-2-propanol ; (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3- (trifluoromethoxy)-phenyl]methoxy]pyhenyl]amino]-1, 1,1-trifluoro-3-propanol; (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3- (trifluoromethyl)-phenyl] methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol;

(2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5 -dimethylphenyl]- methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-( trifluoromethylthio)- phenyl] methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5 -difluorophenyl]- methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[[2-fluoro-5-(trifluoromethyl) phenyl] methyl] [3- [cyclohexylmethoxyl-phenyl]amino]-1,1,1-trifluoro-2-propanol ; (2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro -5-(trifluoromethyl)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3- [ (3- (2-trifluoromethyl-4-pyridyloxy) phenyl] [ [2-fluoro-5- (trifluoromethyl)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-5-(tr ifluoromethyl)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[[3-(3-trifluoromethylthio) phenoxy] phenyl] [[2-fluoro-5-(trifluoromethyl)- phenyl] methyl] amino-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(4-cyhloro-3-trifluoromethylphenoxy)phenyl][[2-fl uoro-5-(trifluoro- methyl) phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-4- (trifluoromethyl)-phenyl]methyl]amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-4- (trifluoromethyl)phenyl]-methyl]amino]I-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-4-(triflu oromethyl)phenyl]- methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-(2-furyl) phenoxy) phenyl] [[2-fluoro-4-(trifluoromethyl)phenyl]- methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-4- (trifluoromethyl) phenyl]-methyqamino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-4-(trifluorome thyl)phenyl]-methyl] amino]- 1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-4- (trifluoromethyl) phenyl]-methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-4- (trifluoromethyl)-phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-4- (trifluoromethyl)-phenyl]methyl]amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-[3-(1, 1,2,2-tetrafluoroethoxy) phenoxy] phenyl] [[2-fluoro-4-(trifluorometyyl)phenyl]methyl]amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-[3-(pentafluoroethyl) phenoxy] phenyl] [[2-fluoro-4-(trifluoromethyl)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-4- (trifluoromethyl) phenyl]-methyl] aminol-1,1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-4- (trifluoroemthyl)phenyl]methyl]-amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-4- (trifluoromethyl) phenyl] methyl]-amino]-1, 1, 1-trifluoro-2-propanol ; (2R)-3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-4- (trifluoromethyl) phenyl] methyl]-amino]-1,1,1-trifluoro-2-propanol; (2R)-3- ( [3- (5, 6,7,8-tetrahydro-2-naphthoxy) phenyl] [[2-fluoro-4-(trifluoromethyl)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl) phenyl]methyl] amino]-1,1,1- trifluoro-2-propanol ; (2R)-3-[[3-[3-(N,N-dimethylamino) phenoxy] phenyl] [[2-fluoro-4-(trifluoromethyl)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[[2-fluoro-4-(trifluoromethyl) phenyl] methyl] [3- [ [3- (trifluoromethoxy) phenyl] methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; (3R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl] [3- [ [3- (trifluoromethyl) phenyl] methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5 -dimethylphenyl]- methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3- (trifluoromethylthio)-phenyl] methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5 -difluorophenyl]- methoxy] phenyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl] [3- [cyclohexylmethoxy]-phenyliamino]-1,1,1-trifluoro-2-propanol ;

(2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro -4-(trifluoromethyl)- phenyl] methyl] amino]-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro -4-(trifluoromethyl)- phenyl] methyl] amino-1, 1,1-trifluoro-2-propanol; (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-4- (trifluoromethyl)-phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; (2R)-3-[[[3-(3-trifluoromethylthio) phenoxy] phenyl] [[2-fluoro-4-(trifluoromethyl)- phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol; and (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-flu oro-4- (trifluoromethyl) phenyl] methyl] amino]-1,1,1-trifluoro-2-propanol.

Another class of CETP inhibitors that finds utility with the present invention consists of quinolines of Formula XVII

Formula XVII and pharmaceutically acceptable forms thereof, wherein: AXVII denotes an aryl containing 6 to 10 carbon atoms, which is optionally substituted with up to five identical or different substituents in the form of a halogen, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy or a straight-chain or branched alkyl, acyl, hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or in the form of a group according to the formula -NRXVII-4RXVII-5, wherein Rxvand Rxv) i-5 are identical or different and denote a hydrogen, phenyl or a straight-chain or branched alkyl containing up to 6 carbon atoms, DXVII denotes an aryl containing 6 to 10 carbon atoms, which is optionally substituted with a phenyl, nitro, halogen, trifluoromethyl or trifluoromethoxy, or a radical according to the formula

RXVII-6, RXVII-7, RXVII-10 denote, independently from one another, a cycloalkyl containing 3 to 6 carbon atoms, or an aryl containing 6 to 10 carbon atom or a 5-to 7- membered, optionally benzo-condensed, saturated or unsaturated, mono-, bi-or tricyclic heterocycle containing up to 4 heteroatoms from the series of S, N and/or O, wherein the rings are optionally substituted, in the case of the nitrogen-containing rings also via the N function, with up to five identical or different substituents in the form of a halogen, trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, a straight- chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl containing up to 6 carbon atoms each, an aryl or trifluoromethyl-substituted aryl containing 6 to 10 carbon atoms each, or an optionally benzo-condensed, aromatic 5-to 7-membered heterocycle containing up to 3 heteoatoms from the series of S, N and/or O, and/or in the form of a group according to the formula -ORXVII-11, -SRXVII-12, -SO2RXVII-13, or -NRXVII- 14RXVII-15 ; RXVII-11, RXVII-12, and Rxvll-13 denote, independently from one another, an aryl containing 6 to 10 carbon atoms, which is in turn substituted with up to two identical or different substituents in the form of a phenyl, halogen or a straight-chain or branched alkyl containing up to 6 carbon atoms, RXVII-14 and RXVII-15 are identical or different and have the meaning of RxV114 and Rxvx-5 given above, or XVII-6 and/or RXVII-7 denote a radical according to the formula

Rxvo-s denotes a hydrogen or halogen, and RXVII-9 denotes a hydrogen, halogen, azido, trifluoromethyl, hydroxyl, trifluoromethoxy, a straight-chain or branched alkoxy or alkyl containing up to 6 carbon atoms each, or a radical according to the formula NRXVII-16RXVII-17 ; Rxvx-ie and Rxv))-i7 are identical or different and have the meaning of Rev"4 and RXVII-5 above; or RXVII-8 and Rev, _9 together form a radical according to the formula =O or =NR 18; RXVII-18 denotes a hydrogen or a straight-chain or branched alkyl, alkoxy or acyl containing up to 6 carbon atoms each; LXVII denotes a straight-chain or branched alkylen or alkenylene chain containing up to 8 carbon atoms each, which are optionally substituted with up to two hydroxyl groups; Txvn and Xxvll are identical or different and denote a straight-chain or branched alkylen chain containing up to 8 carbon atoms; or Txv and XXVII denotes a bond; VXVII denotes an oxygen or sulfur atom or -NRXVII-19 ; RXVII-19 denotes a hydrogen or a straight-chain or branched alkyl containing up to 6 carbon atoms or a phenyl ; Ex", denotes a cycloalkyl containing 3 to 8 carbon atoms, or a straight-chain or branched alkyl containing up to 8 carbon atoms, which is optionally substituted with a cycloalkyl containing 3 to 8 carbon atoms or a hydroxyl, or a phenyl, which is optionally substituted with a halogen or trifluoromethyl ; Rxvo-1 and Rev"_2 are identical or different and denote a cycloalkyl containing 3 to 8 carbon atoms, hydrogen, nitro, halogen, trifluoromethyl, trifluoromethoxy, carboxy, hydroxy, cyano, a straight-chain or branched acyl, alkoxycarbonyl or alkoxy with up to 6 carbon atoms, or NRXVII-20RXVII-21 ;

RxvN-2oand Rxvo-21 are identical or different and denote hydrogen, phenyl, or a straight-chain or branched alkyl with up to 6 carbon atoms; and or RXVII-1 and/or R) 2are straight-chain or branched alkyl with up to 6 carbon atoms, optionally substituted with halogen, trifluoromethoxy, hydroxy, or a straight- chain or branched alkoxy with up to 4 carbon atoms, aryl containing 6-10 carbon atoms optionally substituted with up to five of the same or different substituents selected from halogen, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, straight- chain or branched alkyl, acyl, hydroxyalkyl, alkoxy with up to 7 carbon atoms and NU, ; RXVII-22 and RXVII-23 are identical or different and denote hydrogen, phenyl or a straight-chain or branched akyl up to 6 carbon atoms; and/or Rxv-i and R ;-2taken together form a straight-chain or branched alkene or alkane with up to 6 carbon atoms optionally substituted with halogen, trifluoromethyl, hydroxy or straight-chain or branched alkoxy with up to 5 carbon atoms; R ; denotes hydrogen, a straight-chain or branched acyl with up to 20 carbon atoms, a benzoyl optionally substituted with halogen, trifluoromethyl, nitro or trifluoromethoxy, a straight-chained or branched fluoroacyl with up to 8 carbon atoms and 7 fluoro atoms, a cycloalkyl with 3 to 7 carbon atoms, a straight chained or branched alkyl with up to 8 carbon atoms optionally substituted with hydroxyl, a straight-chained or branched alkoxy with up to 6 carbon atoms optionally substituted with phenyl which may in turn be substituted with halogen, nitro, trifluoromethyl, trifluoromethoxy, or phenyl or a tetrazol substitued phenyl, and/or an alkyl that is optionally substituted with a group according to the formula-ORx", -24 ; RXVII 24 is a straight-chained or branched acyl with up to 4 carbon atoms or benzyl.

Compounds of Formula XVII are disclosed in WO 98/39299, the entire disclosure is incorporated by reference.

Another class of CETP inhibitors that finds utility with the present invention consists of 4-Phenyltetrahydroquinolines of Formula XVIII

Formula XVIII , N oxides thereof, and pharmaceutical acceptable forms thereof, wherein: Axe", denotes a phenyl optionally substituted with up to two identical or different substituents in the form of halogen, trifluoromethyl or a straight-chain or branched alkyl or alkoxy containing up to three carbon atoms; DXVII denotes the formula Rxvot-sand Rxvare taken together to form =O ; or RXVIII-5 denotes hydrogen and Rxvto-e denotes halogen or hydrogen; or RXVIII-5 and RXVIII-6 denote hydrogen; RXVIII-7 and RXVIII-8 are identical or different and denote phenyl, naphthyl, benzothiazolyl, quinolinyl, pyrimidyl or pyridyl with up to four identical or different substituents in the form of halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy,- SO2-CH3 or NRXVIII-9RXVIII-10 ; RXVIII-9 and RXVIII-10 are identical or different and denote hydrogen or a straight- chained or branched alkyl of up to three carbon atoms; E, denotes a cycloalkyl of from three to six carbon atoms or a straight- chained or branched alkyl of up to eight carbon atoms ;.

Rxv ! h-i denotes hydroxy; RXVIII-2 denotes hydrogen or methyl ;

Rxn-3 and Rx"m are identical or different and denote straight-chained or branched alkyl of up to three carbon atoms; or Rxvand Rxv taken together form an alkenylene made up of between two and four carbon atoms.

Compounds of Formula XVIII are disclosed in WO 99/15504, the entire disclosure of which is incorporated by reference.

Emulsion pre-concentrates of CETP inhibitors, formulated as described above, are encapsulated in soft gelatin capsules, or are encapsulated in hard gelatin or non- gelatin capsules. If encapsulated in hard gelatin or non-gelatin capsules, it is preferred that the seam between the two capsule shell pieces be sealed, for example with a strip of gelatin, to prevent leakage. Encapsulation in soft-gelatin is well-known and is described in"The Theory and Practice of Industrial Pharmacy", by L. Lachman, H. Lieberman, and J. Kanig, Lea and Febiger, publisher, 3rd Edition, 1986.

The invention is further disclosed and described in the following examples, which are illustrative as opposed to limiting. In the examples,"mgA"is an abbreviation for"milligrams of active drug", the weight being expressed in mg of the non-salt, free acid or base. Other commonly employed and understood abbreviations have been employed : Me, methyl ; Cmpd, Compound; In the examples, the following shorthand notation means the corresponding structure listed and/or named below : Compound A- [2R, 4S] 4- [ (3, 5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2- ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, with a Clog P of 7.45 and having the following structure:

Compound B, Propanethioic acid, 2-methyl-, S-[2-[[[1-(2- ethylbutyl) cyclohexyl] carbonyl] amino] phenyl] ester with a Clog P of 7.15 having the structure:

Compound C, (S, S)-4'- (4-fluorophenyl)-3'- [fluoro [4- (trifluoromethyl) phenyl] methyl]-5', 8'- dihydro-2'- (1-methylethyl)-spiro [cyclobutane-1, 7' (6'H)-quinolin]-5'-ol, with a Clog P of 8.93 and having the following structure:

Compound D [2R, 4S] 4-[acetyl-(3, 5-bis-trifluoromethyl-benyl)-amino]-2-ethyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester, with a Clog P of 6.52 and the following structure:

Compound E- [2R, 4S] 4- [ (3, 5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2- ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester, with a Clog P of 7.76 and having the following structure:

Compound F- [2R, 4S] 4- [ (3, 5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2- ethyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid propyl ester, having a Clog P of 7.98 and having the following structure:

Compound G- [2R, 4S] 4- [ (3, 5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2- cyclopropyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester, having a Clog P of 7.58 and having the following structure:

Compound H- [2S, 4R] 4- [ (3, 5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2- cyclopropyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester, having a Clog P of 7.58 and having the following structure:

Compound I- [2R, 4S] 4- [ (3, 5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2- methyl-7-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, having a Clog P of 6.92 and having the following structure:

Compound J [2S, 4R] 4- [ (3, 5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2- methyl-2, 3,4,6,7,8-hexahydro-cyclopenta [g] quinoline-1-carboxylic acid ethyl ester, having a Clog P of 7.05 and having the following structure:

Compound K- [2R, 4S] 4- [ (3, 5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2- methyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, having a Clog P of 6.92 and having the following structure:

Compound L- [2R, 4S] 4- [ (3, 5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2- methyl-6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, having a Clog P of 6.92 and having the following structure:

Compound M- [2R, 4S] 4- [Acetyl- (3, 5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl- 6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid propyl ester, having a Clog P of 6.56 and having the following structure:

Compound N- [2R, 4S] 4- [ (3, 5-Bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl- 6-trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid propyl ester, having a Clog P of 6.33 and having the following structure:

Compound O- [2R, 4S] 4- [Acetyl- (3, 5-bis-trifluoromethyl-benzyl)-amino]-2-methyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, having a Clog P of 5.68 and having the following structure:

Compound P- [2R, 4S] 4- [ (3, 5-Bis-trifluoromethyl-benzyl)-formyl-amino]-2-ethyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, having a Clog P of 5.97and having the following structure:

Compound Q- [2R, 4S] 4- [ (3, 5-Bis-trifluoromethyl-benzyl)-formyl-amino]-2-methyl-6- trifluoromethyl-3, 4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, having a Clog P of 5.45 and having the following structure: Example 1 This Example (and Examples 2 through 5) illustrates making a composition according to the invention and using it to make softgel capsules containing it.

Capmul@ MCM was heated to 55 °C and mixed. To a 2 liter glass beaker was added 277 gm of Miglyol@ 812, 510 gm of triacetin, 318 gm of Polysorbate 80, and 442 gm of Capmul@ MCM. After stirring for one hour, this solution was added to 161 gm Compound A and the resulting mixture stirred at ambient temperature for 8 hours with scraping of walls as needed. It was then filtered to remove gross particulates. The amounts (in mg) of each component in the fill per gram of fill are set forth in Table 1.

The above 100 mgA/mL fill was encapsulated into &num 10 oval and #5 oval softgels to provide fill volumes of 0.6 mL and 0.3 mL respectively. The doses per softgel are therefore 60 mgA and 30 mgA, respectively. The shell was prepared from gelatin, glycerin, and water.

Table 1 Igredient mg/g Compound A 94 MiglyolS 812 162 Triacetin 299 Polysorbate 80 186 CapmulS MCM 259

Example 2 Capmu) MCM was heated to 55°C and mixed. Cremophor# RH40 was also heated to 65°C with stirring. Then 539 g of Miglyol 812,998 g of triacetin, 608 g of Cremophoe RH40, and 860 g of Capmul# MCM were combined and mixed for 20 min.

To this mixture was then added 312 gm of Compound D and the resulting mixture stirred at ambient temperature for 3 hours with scraping of walls as needed. It was then filtered to remove gross particulates. The amounts (in mg) of each component in the fill per gram of fill are set forth in Table 2.

The above 100 mgA/mL fill was encapsulated into #2 and #5 oval softgels to provide fill volumes of 0.1 mL and 0.3 mL, respectively. The doses per softgel were therefore 10 and 30 mgA, respectively. The shell was prepared from gelatin, glycerin, and water.

Table 2 Ingredient mg/g Compound D 94 Miglyol 812 163 Triacetin 301 Cremophor RH40 183 Capmul MCM 259

Example 3 Capmuls MCM was heated to 55°C and mixed. Alpha-tocopheryl polyethyleneglycol 1000 succinate (TPGS) was also heated to 55°C with stirring. Then 264 gm of Miglyol# 812,333 gm of propylene carbonate, 103 gm of TPGS, and 562 gm of Capmuls MCM were combined and mixed for 1 hr. This mixture was then added to 130.4 gm of Compound A and the resulting mixture stirred at ambient temperature for 8 hours with scraping of walls as needed. It was then filtered to

remove gross particulates. The amounts (in mg) of each component in the fill per gram of fill are set forth in Table 3.

The above 100 mgA/mL fill was encapsulated into #11 oblong softgels to provide a fill volume of 0.6 mL. The dose per softgel is therefore 60 mgA. The shell was prepared from gelatin, glycerin, and water.

Table 3 Inqredient mg/g Compound A 94 Miglyol"812 164 Propylene carbonate 207 Alpha-tocopheryl 185 polyethyleneglycol 1000 succinate Capmuls MCM 350

Example 4 Capmuls MCM was heated to 55°C and mixed. Then 264 gm of Miglyol 812, 333 gm of propylene carbonate, 303 gm of Polysorbate 80 and 562 gm of Capmul" MCM were combined and mixed for 1 hr. This mixture was then added to 130.5 gm of Compound A and the resulting mixture stirred at ambient temperature for 8 hours with scraping of walls as needed. It was then filtered to remove gross particulates. The amounts (in mg) of each component in the fill per gram of fill are set forth in Table 4.

The above 100 mgA/mL fill was encapsulated into #11 oblong softgels to provide a fill volume of 0.6 mL. The dose per softgel is therefore 60 mgA. The shell was prepared from gelatin, glycerin, and water.

Table 4

Ingredient mg/l Compound A 95 Miglyol# 812 163 Propylene carbonate 206 Polysorbate 80 188 Capmul# MCM 348

Example 5 Capmul# MCM was heated to 55°C and mixed. Then 271 gm of Miglyol# 812, 250 gm of triacetin, 779 gm of Polysorbate 80 and 217 gm of Capmuls MCM were combined and mixed for 20 min. This mixture was then added to 75.7 gm of COMPOUND A and the resulting mixture stirred at ambient temperature for 8 hours with scraping of walls as needed. It was filtered to remove gross particulates. The amounts (in mg) of each component in the fill per gram of fill are set forth in Table 5.

The above 50 mgA/mL fill was encapsulated into #11 oblong softgels to provide a fill volume of 0.6 mL. The dose per softgel is therefore 30 mgA. The shelf was prepared from gelatin, glycerin, and water.

Table 5 Ingredient mgig Compound A 48 Miglyol'D 812 170 Triacetin157 Polysorbate 80 489 Capmul MCM 136

Example This Example (and Example 7) illustrates the composition of fills according to the invention. The amounts (in mg) of each component in the fill per gram of fill are set forth in Table 6. This fill was prepared at a concentration of 50 mgA/mL in a manner similar to that described in Examples 1-5 but at a small volume for dog PK studies. It could be prepared at a larger scale for encapsulation into #11 oblong softgels to provide a fill volume of 0.6 mL and a dose of 30 mgA.

Table 6 Composition mg/g CompoundA 48 Miglyol 812 143 Triacetin 143 Cremophors RH 40 381 Capmu)MCM 286

Example 7 The amounts (in mg) of each component in the fill per gram of fill are set forth in Table 7. The fill was prepared at a concentration of 150 mgA/mL in a manner similar to that described in Examples 1-5, but at a small volume for dog PK studies. It could be prepared at a larger scale for encapsulation into #11 oblong softgels to provide a fill volume of 0.6 mL and a dose of 90 mgA. Composition mg/g Compound A 142 Miglyol@ 812 86 Ethyl lactate 429 Cremophoi-O RH 40 257 Capmul@ MCM 86 Example 8 To 80.1 g of Compound A was added 1451 gm Miglyole 812. The resulting mixture was stirred at ambient temperature for 8 hours with scraping of walls as needed. It was filtered to remove gross particulates. The amounts (in mg) of each component in the fill per gram of fill are set forth in Table 8.

The above 50 mgA/mL fill was encapsulated into #11 oblong and #4 oval softgels to provide fill volumes of 0.6 mL and 0.2 ml, respectively. The doses per sofgel were therefore 30 and 10 mgA, respectively. The shell was prepared from gelatin, glycerin, and water.

Table 8 Ingredient mg/g Compound A 52 MiglyolX 812 948 _

Example 9 This example describes the determination of solubility of CETP inhibitors in excipients and emulsion preconcentrates and also an initial assessment of emulsion quality (Table 9a-9d).

The solubility of CETP inhibitors in excipients and in formulations was determined by adding an excess of compound to the medium in question. The mixture was agitated by rotation over a period of days at ambient temperature until the concentration in solution had reached an equilibrium as judged by similar measurements for consecutive time points. Concentrations were measured by filtration of aliquots with a PTFE syringe filter and assay by HPLC as described in Example 11.

For CETP inhibitors where quantities were limited, an estimate of solubility was obtained by addition of vehicle to a known quantity of the compound and mixing in an ultrasonicator bath for 90 minutes, followed by overnight equilibration at ambient temperature. Addition of vehicle was repeated until a solution was achieved.

The extent of emulsification was determined by mixing the preconcentrate and water in a ratio of 1: 100 and 1: 10 by gentle inversion (5 x), visual inspection, and examination under an optical microscope, using a polarizing filter to check for the appearance of crystals. Droplet size determined by this approach is expressed as the upper limit for the average droplet size, since submicron droplets cannot be detected by this method.

The results in Table 9a show that the solubility of Compound A in Miglyol 812 is only sufficient for a 50 mgA/mL fill (30 mgA in a 0.6 mL softgel), while cosolvens such as triacetin and propylene carbonate provide ca. 4x higher solubility and those such as ethyl lactate and dimethyl isosorbide nearly double those levels. Solubility and emulsification data for preconcentrate solutions of Compound A is shown in Table 9c.

Use of propylene carbonate and triacetin as cosolvens allow solubilities suffcient in some cases for a 100 mgA/mL self-emulsifying fill. (e. g., Formulations M, O, Q, and R, see Table 9c)

Higher levels of surfactants are often required to yield self-microemulsifying formulations and in these cases solubilities only permit in general a 50 mgA/mL fill using triacetin as the solvent (e. g. Formulation EE, Y, and PP). Use of propylene carbonate or ethyl lactate as solvent can permit a 100mgA/mL fill (e. g., Formulations A, B, XX, YY, and ZZ) that has sufficient surfactant to yield microemulsions. However, triacetin has the advantage of good precedence in oral dosage forms (and has GRAS status). Dynamic light scattering was utilized to further characterize the sub-micron particle size distribution for microemulsions as described in Example 10.

The solubility in ethyl lactate permits a self-emulsifying 150 mgA/mL fill to be prepared (e. g Formulation WW). However, the solubilities of emulsion preconcentrates shown in Table 9a and 9c cannot reliably be predicted based on the solubilities of the components alone. This is exemplified by formulation WW (Table 9c), which exhibits considerably greater solubility than the corresponding formulation using dimethyl isosorbide (Formulation AAA), although the opposite would have been predicted based on solubilities in the individual cosolvents. Also, lack of data for excipients that are solids at room temperature also hinders prediction.

All of the emulsions prepared from these formulations exhibited good physical stability, i. e. there was no sign of crystallization or change in particle size based on microscopic examination after standing overnight at ambient temperature.

Results obtained for other CETP inhibitors are shown in Tables 9b and 9d. In case of Compound D (Table 9b), the average emulsion particle size is < 5 microns.

Table 9a. Equilibrium Solubility Data for Compound A in Oils, Solvents, and Surfactants Solubility (mgA/ml) Vehicle HLB Water < 0.00004 Oleic acid 8.5 Maisine 35-1 4 9 Peceol 3 10 Olive oil 17 Plurol Oleique CC 497617 Crmepophor# EL 20 Polysorbate 80 (Tween 80) 15 23 Labrafil"M 1944 4 26 Labrafil# M 2125 4 27 Tagat TO (Polyoxyethylene 11 32 glycerol trioleate) Pluronic# L-44 36 Capmul# MCM 6 41 Labrasol# 14 41 Mìglyols 812 65 Lauroglycol FCC 4 70 Gtycofuro) 99 Caprylic acid 145 Transcutol P 174 Propylene carbonate 227 Triacetin 235 Triethyl citrate 240 peppermint oil 266 Ethyl lactate 400 Dimethylisosorbide 439 N-methyl-2-pyrrolidone 813

Table 9b: Equilibrium Solubility Data for Other CETP inhibitors Vehicle Solubility (mgA/ml) Compound Compound D E Olive oil 13 39 Olive oil/Cremophors EL 80/20 14 Cremophor# EL 18 Miglyol# 812/Cremophor# EL 51 80/20 Capmul# MCM 58 Miglyol 812 61 167 Miglyol@/propylene 208 394 carbonate/Cremophor# EL (60/20/20) Triacetin 239

Table 9c. Solubility and emulsification data for Compound A in preconcentrates* Composition (% v/v) Solubility Ave Droplet (mgA/mL) Size (u) Formul. Miglyol# Cosolvent* Surfactants (1: 100 No. 812 dilution) Vitamin E TPGS/ Capmul #MCM A 20 20 P. C. 20/40 145 <1 H 20 20 triacetin 20/40 113 <2 20 30 P. C. 20/30 189 <2 S 10 30 triacetin 20/40 131 <5 Polysorbate 80/ Capmul# MCM B 20 20 P. C. 20/40 142 <5 O 20 30 triacetin 20/30 141 <2 EE 20 15 triacetin 50/15 64 <1 Vitamin E TPGS/ Labrafil@ M 1944 CS C 20 20 P. C. 20/40 114 <1 Q 10 40 triacetin 20/30 142 <2 Gelucire# 44/14/ Capmul# MCM D 20 20 P. C. 20/40 151 <5 Cremophor# RH40/ Capmul# MCM E 20 20 P. C. 20/40 147 <1 M 20 30 triacetin 20/30 145 <1 R 20 30 triacetin 35/15 122 <1 SS 0 28 triacetin 30/42 108 PP 17 13 triacetin 39/31 77 <1 Y 20 10 triacetin 50/20 67 <1 WW 11 50 29/10 203 <2 ethyl lactate XX 11 40 29/20 159 <1 ethyl lactate YY 16 35 39/10 142 <1 ethyl lactate ZZ 22 29 19/30 145 <1 ethyl lactate AAA 11 47 31/11 157 <1 dimethyl isosorbide

* P. C. = propylene carbonate Table 9d. Solubility and emulsification data for other CETP Inhibitor pre- concentrates Composition (% v/v) Compound Miglyol@8 Triacetin Surfactants Solubility Ave Droplet 12 (mgA/mL) Size (p) (1: 100 dilution) Polysorbate 80/ Capmul@MCM Compound B* 20 3020/30>1QQ<5 Compound C* 6 55 15/24 30 <5 Compound E 22 27 20/31 308 <2 Cremophor" RH40/ Capmule MCM Compound D I 20 30 20/30 172 cs

* Amorphous solids Example 10 Preliminary particle size analysis data has been obtained on selected formulations using a dynamic light scattering particle size analyzer (ZetaPals, Brookhaven Instruments, Inc.) for measurement of sub-micron particle distribution.

The formulation solutions were diluted 1: 100 in HPLC-grade water (previously filtered through a 0.22 um syringe filter). The resulting mixture was gently inverted five times to create the emulsion. Each emulsion sample was then analyzed at a temperature of 37°C. Triplicate measurements were made at each time point (0,30 min).

The results shown in Table 10 confirm that formulations O, Q and R are self- emulsifying formulations with a mean particle size above 100 nm. Formulations

such as A and B have mean particle sizes in the microemulsion range but with significant populations of larger particles and are slightly turbid. Formulation EE is very slightly turbid with a trace of larger particles. Use of Cremophor# RH 40 as the high HLB surfactant yielded formulations Y, PP, XX, and ZZ that form transparent microemulsions with all particles smaller than ca. 100 nm, as is the case for Neorale. Only formulation Y showed a stable unimodal distribution that did not change, even with stirring.

Table 10a. Dynamic Light Scattering Particle Size Analysis of Emulsions from Compound A Self-Emulsifying Formulations* Form. Pre-concentrate Composition Mean Diam. Distribution# (% v/v) (nm) Peak Peak 2 Peak Miglyole 812/propylene carbonate/Vitamin E- 78.6 22 73 349 TPGS/Capmul MCM (20/20/20/40) Miglyole 812/propylene B carbonate/Polysorbate 80/Capmul@ 45.3 33 217 MCM(20/20/20/40 Miglyol# 812/ propylene carbonate/Vitamin E-2 TPGS/Labrafil M# 1944 CS (20/20120/40) Miglyole'81 2/Triacetin/ O Polysorbate 80/Capmul# MCM 256.6 257 (20/30/20/30) Miglyol# 812Triacetin/ Vitamin E-TPGS/ 440.9 259 537 Labrafil M# 1944 CS (10/40/20/30) Miglyol'812/Triacetin/ Cremophor# RH40/ 245.2 245 Capmul MCM (20/30/35/15) Neoral#/propylene carbonate 19.0 11 29 (90 : 10) Miglyol# 812/Triacetin/ Cremophor° RH40/ Capmul# MCM 22.3 22 (20/10/50/20) Miglyol# 812/Triacetin/ EE Polysorbate 80/Capmul@ MCM 19.6 13 64 (220) _ (20/15/50/15) Miglyol 812/Triacetin/ Cremophor# RH40/ PP 27.1 27 Capmul# MCM (17/13/39/31) Triacetin/Cremophor# RH40 /Capmulo MCM (28/30/42) Miglyol 812/Ethyl lactate/ WW Cremophore RH40/293. 8 324 Capful cm (11/50/29/10) Miglyol# 812/Ethyl lactate/ Cremophor# RH40/ 24.9 22 (107) Capmul° MCM (11/40/29/20) Miglyol# 812/Ethyl lactate/ Cremophor# RH40/ 31.5 28 (135) Capmu ! ° MCM (16/35/39/10) Miglyol# 812/Ethyl lactate/ Cremophor# RH40/ 36.3 34 (103) Capful cm (22/29/19/30) Neoral 27.4 27 (65)

# Parentheses indicate trace levels.

* Measured immediately after preparation unless indicated otherwise Table 10b. Dynamic Light Scattering Particle Size Analysis of Emulsions prepared for Other Compounds Cmpd. Conc. Pre-Concentrate Composition Mean Diam. (nm) # (mg/mL) (% v/v) Initial* 30 min. * D Miglyol 812/Triacetin/ 100 Cremophore RH40/182 17 Capmul# MCM (3) (20/30/20/30) Miglyol# 812/Triacetin/ E Polysorbate 80/Capmul 181 100 #MCM 181 175 (22/27/20/31) Miglyol# 812/Triacetin/ 251 ~ 45 E 200 Polysorbate 80/Capmul 239 ~ 17 (4) #MCM (4) (22/27/20/31)

Number of samples in parentheses

* Time after preparation of emulsion Example 11 The fills prepared in the above examples were hand-filled into hydrophobic softgel shells and heat sealed, and then placed on stability under accelerated conditions in sealed HPDE bottles with child-resistant caps. The fills were assayed at intervals by dilution of aliquots into acetonitrile and gradient HPLC analysis on a Water Symmetry C-8 column (3.9 x 150 mm, 5 micron) at 30 C at a flow rate of 1 mL/min. The mobile phase program was a 25 minute gradient from 100 % A to 50% A/50 % B (A = 400/300/300/0.8 v/v DI H20/Acetonitrile/2-Propanol/Phosphoric Acid and B = 2-Propanol), followed by a 5 minute hold at this condition and a 10 minute gradient to the initial condition. The detection method was UV absorbance at 210 nm.

There was no impurity formed at ! : 0.1 % peak area vs. parent for any formulation in Table 11. There was no sign of crystallization in the fill under any condition based on microscopic examination. There was also no indication of seal leakage.

Disintegration times in water at 37°C were less than 15 min for Formulations A, B, and O after storage under accelerated conditions for 6 weeks.

Formulation O softgels of Compound A manufactured by machine have been shown to be stable for 9 months under accelerated conditions. Formulation M softgels of Compound D have been shown to be stable for 6 months under accelerated conditions.

Table 11. Accelerated Stability data for selected formulations of Compound A in hand-filled soft gels

Test Assay of Fill Assay of Fill Potency Formulation A B C E M O # Initial 100. 6 ~ 0. 6 99.40.7 101. 3 ~ 0. 8 102. 0 ~ 0. 1 101. 6 ~ 0. 2 102. 6 ~ 0. 6 1 Week 5°C/75% RH 101.8 0.8 99. 5 ~ 2. 3 99.1 0. 4 101.5 0.4 30°C/60% RH 100.8 ~ 0. 6 98.8 ~ 0.6 100.5 ~ 0. 7 101.1 0. 1 40°C/75% RH 101. 4 ~ 0. 5 98. 6 ~ 1. 4 99. 7 ~ 0. 5 102. 6 ~ 0. 1 3 Week OR * * 4 Week 5°C/75% RH 99. 9 ~ 0. 4 99. 0 ~ 0. 3 99.31.0 100. 5 ~ 0. 6 100. 6 ~ 0. 5 101.1 ~ 0. 6 30°C/60% RH 100. 7 ~ 0. 8 98.4 0.7 100. 0 ~ 0. 6 99. 9 ~ 0. 5 100.3 0.6 101.4 1.3 40°C/75% RH 101. 3 ~0. 3 100.7 1. 0 101.8 ~ 0. 5 102. 3 ~ 0. 4 102. 9 ~ 0. 6 101. 7 ~ 0. 2 6 Week 5°C/75% RH 100.7 0.8 100.70.1 98.4 0.3 100. 0 ~ 0. 3 101.2 0.5 101.9 0.2 30°C/60% RH 100. 4 ~ 0. 8 100.5 0.4 101.1 0. 6 101.1 0. 2 101. 6 ~ 0. 6 101. ~ 0. 8 40°C/75% RH 102. 4 ~ 0. 7 102.1 1. 0 102.5 0.4 102. 7 ~ 0. 7 101. 6 ~ 0. 5 101. 9 ~ 0. 9 * 4 Week time point.

Example 12 Fills were prepared as described in above examples and then encapsulated in #00 hard gelatin capsules. Male Beagle dogs (n=6) between the ages of 2-5 and weighing 6-12 kg were dosed with capsules followed by 50 mL of water. Dogs were also dosed with 30 mgA Miglyol 812 softgels and aqueous, crystalline drug suspension. The dogs were either fasted or fed just prior to dosing with 14 g of dry dog food and 8 gm olive oil. The same set of dogs were used for all formulations, except where indicated. Blood samples were obtained from the jugular vein of each dog at 0,0.5,1,2,3,4,6,8 and 12 hr and analyzed by acidifying the plasma, solid phase extraction, and analysis by LC/MS/MS with a lower limit of quantitation of 25 ng/mL.

The results, in Table 12a and 12b are shown in terms of Area Under the Curve (AUC), Cmax, the maximum concentration of drug measured in the plasma, and Tmax, the time in hours it took to reach Cmax. Unless otherwise indicated, results are for the fasted state. Miglyole softgels have a very low fasted exposure and thus a high food effect. The fasted exposure is higher than that for crystalline suspension, while the fed exposure using this high oil meal is the same. Thus Miglyol softgels provide a lower food effect than crystalline drug. At the same dose of 90 mgA, formulations such as A, O, and C that include surfactants and solvent have much higher fasted exposures and only a ca. 3x food effect. The fed exposures are also higher than for Miglyole 812 softgels and crystalline drug.

Poorer fasted exposure was obtained for Formulation WW, which contains a high level of ethyl lactate as a solvent.

The transparent self-microemulsifying formulations EE and PP at a dose of 30 mgA have a food effect of only 2.2-2.4. For the stable, monodisperse microemulsion Y there is a much higher fasted exposure at 30 mgA than for the self- emulsifying formulation O. The fasted exposure for Y was the same as the fed, i. e. there was no food effect.

Similar results were obtained for formulation M for Compound D (Table 12b) as were observed for the same formulation of Compound A.

Table 12a. Pharmacokinetic results of Compound A Formulations in dogs Formulation Conc. Dose AUC 0-12h Cmax Tmax Composition n* (mg/ (mg) (µg*h/mL) (µg/mL) (hr) (v/v) mL) Miglyol# 812 soft gels 50 4 90 3.0 ~ 2.0 0.77 ~ 0.48 2.0 Fed 50 6 90 0.6 ~ 0.3 0.2 ~ 0.14 3.7 Crystalline drug suspension in 0. 1% Polysorbate 80/ 6# 90 0.16 0. 14 0.04 ~ 0. 11 1.3 0.5% methyl cellulose Fed 6--90 2. 9 ~ 1. 3 0. 98 ~ 0. 53 2.7 Miglyol# 812/Propylene carbonate/ Vitamin E- 6 100 90 2.7 0.9 0. 67 ~ 0. 17 1.2 TPGS/Capmul#MCM (20/20/20/40) Fed 5 100 90 9.6 ~ 3. 4 2.491.30 1.4 Miglyol# 812 /Propylene carbonate/ Polysorbate 100 6 90 2.3 ~ 0.5 0.73 ~0.16 1.8 80/Capmul #MCM (20/20/20/40) Miglyol# 812 /propylene carbonate/ C Vitamin E-TPGS/5 80 90 3.4 ~ 1. 3 1.2 ~ 0. 41 1.2 Labrafil# M 1944 (20/20/20/40) Fed 6 80 90 9. 3 ~ 3. 5 4. 31 ~ 1. 89 1.0 Miglyol# 812 /Propylene carbonate/VitaminE-125 TPGS/Capmul# MCM 6 90 1.6 ~ 0.5 0.61 ~ 0.27 0.9 (20/30/20/30) Miglyol# 812 /Propylene J carbonate/Vitamin E-6 125 90 2.0 ~ 0. 8 0.71 ~ 0. 36 1.7 TPGS 20/40/40 Miglyol# 812 /Triacetin/ Cremophor #RH40/ Capmul #MCM 5 100 90 2.6 ~ 1.2 0.73 0.26 1.2 20/30/20/30 Miglyol# 812 /Triacetin/ O Polysorbate 80/Capmul' MCM (20/30/20/30) 6 100 90 2.7~0.7 0.97 0.36 1.2 Fed 4 100 90 8.5 ~ 3. 6 2. 7 ~ 1. 0 1.5 6 100 30 1. 1 ~ 0. 5 0. 37 ~ 0. 22 1.0 Miglyol@ 812/Triacetin/ Vitamin E-TPGS/ 5** 100 90 2.9 ~ 0. 8 1.1 ~ 0. 2 1.0 Labrafil# M1944 (10/40/20/30) Miglyol° 812/Triacetin/ Cremophor# RH40/ Capmul #MCM 6 90 2.8 ~ 1.2 1.0 ~ 0.4 1.0 (20/30/35/15) 100 20/30/35/15 6 50 90 4. 011. 3 1.1 ~ 0. 4 1.5 Neoral#/propylene X carbonate 3 50 90 2. 4 ~ 1. 9 0.67 ~ 0. 23 1. 3 (90 : 10) Miglyol°812/Triacetin/ Cremophor #RH40/ Capmul #MCM 6 50 90 4.6 ~ 1.4 1. 35 ~ 0. 26 1. 7 20/10/50/20 4** 50 30 4.6 2.0 1. 32 ~ 0. 60 2.0 Fed 5 50 30 4. 7 ~ 1. 1 1. 94 ~ 0. 74 1.0 Miglyol# 812 /Triacetin/ Polysorbate 80/ EE 6 90 2.7 ~ 1.5 0.86 ~ 0.31 1.3 Capmul #MCM 50 (20/15/50/15) Fed 5 50 30 1. 7 ~ 0. 3 0.64 0.21 1.0 6 50 30 3. 8 ~ 1. 2 1. 6 ~ 0. 6 1.0 Miglyol# 812 /Triacetin/ PP Cremophor RH40/ 5 50 30 1. 6 ~ 0. 6 0. 61 ~ 0. 18 1.2 Capmul #MCM m Fed 5 50 30 3.8 0.8 1. 55~0. 38 1.4 Triacetin/Cremophor SS RH40 /Capmul# MCM 6 75 90 1. 9: 1. 7 0.44 ~0. 26 1.3 (20/30/42) Fed 4 90 7.3 ~1.3 1.8 ~ 0.5 75 Miglyol#812 /Ethyl lactate/Cremophor WW o 0 1. 50. 7 0. 540. 17 0.9 RH40 /Capmul MCM 5 150 90 11/50/29/10

* n < 6 due to emesis.

** Due to emesis and outlier # Different set of dogs Table 12b Pharmacokinetic results for Other Compounds in dogs Formulation Conc. Dose AUC 0-tlast# Cmax Tmax Cmpd Composition' (mg) (pg*h/mL) (pg/mL) (hr) Miglyol# 812 /Triacetin/ Cremophore RH40/ D* Capmul# MCM (20/30/20/30) 3* 100 90 3. 45 ~ 0. 96 0.86 0. 31 1.7 Fed 4* 100 gp 4. 841. 23 1.200.41 1.5 Miglyol 812/Triacetin/ E Polysorbate 4** 100 60 2.90 0.67 0.20 0.14 1.5 80/Capmul° MCM (22/27/20/31)

* Emesis in 1 fasted dog (data not included) and in 4 fed dogs (included) ; dosed with 50 mL water.

** Emesis in 3 dogs (included), dosed with 10 mL water. Different set of dogs from those receiving Compound D.

# Tlast = 24 hr for Compound D and 48 hr for Compound E.

Example 13: This example further illustrates the determination of equilibrium solubilities of CETP inhibitors in vehicles. For experimental methods, see Example 9.

The solubility of crystalline CETP inhibitors in representative vehicles was determined by adding an excess of compound to the vehicle in question. The mixture was agitated by rotation over a period of days at ambient temperature until the concentration in solution had reached equilibrium as judged by similar measurements for consecutive time points. Concentrations were measured by filtration of aliquots with a PTFE syringe filter and assayed by HPLC.

The concentrations of CETP inhibitor in each vehicle were assayed at intervals by dilution of aliquots into acetonitrile and gradient HPLC analysis on a Water Symmetry C-8 column (3.9 x 150 mm, 5 micron) at 30 C at a flow rate of 1 mL/min. The mobile phase program was a 25 minute gradient from 100 % A to 50% A/50 % B (A = 400/300/300/0. 8 v/v Di H20/Acetonitrile/2-Propanol/Phosphoric Acid and B = 2-Propanol), followed by a 5 minute hold at this condition and a 10 minute

gradient to the initial condition. The detection method was UV absorbance at 210 nm.

The results of the equilibrium solubility studies are given in Tables 13a-13c.

Table 13a. Equilibrium Solubilities of Compound A in Triglyceride/surfactant (s) Solubility (mgA/ml) Vehicle Cmpd A Miglyol# 812/Capmul# MCM (80/20 74 Miglyole 812/Capmul@ MCM/Polysorbate 80 58 (40/40/20) Miglyole 812/Capmule MCM/Polysorbate 80 63 (20/60/20) Miglyol# 812/Tagat# TO (80/20) 58 Miglyol# 812/Labrafil# M 1944 (80/20) 59 Miglyol# 812/Labrafil# M 2125 (80/20) 57 Miglyol# 812/Labrasol# (80/20) 69 Miglyol# 812/Cremophor# EL 80/20 68 Olive oil/Capmul# MCM (80/20 23

Table 13b. Equilibrium Solubility of Compound A in Triglyceride/solvent Vehicle Solubility (mgA/ml) Miglyole 812/triacetin (90/10) * 106 MigfyoF 812/Peppermint oi) (90/10) 79 Miglyol"812/Peppermint oil (80/20) 93 Olive oil/Peppermint oil (90/10) 25

* Not completely miscible Table 13c. Equilibrium Solubility of Compound A in Miglyol/Solvent/surfactant Vehicle Solubility (mgA/ml) Miglyol 812/Propylene carbonate/Cremophor# EL 72/8/20 108 60/20/20 146 55/25/20 158 40/40/20 209 30/50/20 228 Miglyol# 812/Ethyl lactate/Cremophor# EL 72/8/20 94 70/10/20 99 65/15/20 120 60/20/20 143 50/30/20 196 40/40/20 221 30/50/20 256 Miglyol# 812/Triacetin/Cremophor# EL 72/8/20 94 65/15/20 111 60/20/20 133 50/30/20 158 40/40/20 183 30/50/20 198 Miglyol# 812/Pepppermint Oil/Crempophor EL (72/8/20) 72 Miglyol# 812/EtOH/Cremophor# EL (76/4/20) 89 Miglyol'9 812/Ethyl lactate/Tagat# TO (72/8/20) 87 Miglyol# 812/Ethyl lactat/Labrasol# (72/8/20) 98 Miglyol# 812/Propylene carbonate/Tagat# TO (72/8/20) 111 Miglyo# 812/Propylene carbonate/Labrasol# (72/8/20) 116

Example 14 : For CETP inhibitors where quantities were limited or the samples were amorphous solids, an estimate of solubility was obtained by addition of vehicle to a known quantity of the compound and mixing in an ultrasonicator bath for 90 minutes, followed by overnight equilibration at ambient temperature. Addition of vehicle was repeated until a solution was achieved. From the total volume of vehicle added to solubilize the CETP inhibitor compound, the solubility value, or so-called microsolubility, was calculated by the equation : Weight of sample (mgA)/vehicle volume (mL) = Microsolubility (mgA/mL) The microsolubility values for CETP inhibitors in various vehicles are given in Tables 14a-14c.

Table 14a. Microsolubility Data for Crystalline Compounds Solubility m/mL Solvent Cmpd A Cmpd B Crodamo) GTCC < 75 <20 Miglyole 810 < 100 Long chain triglycerides <75 <100 (soy, peanut, corn, safflower, sesame) Cotton oil <75 Olive oil <100 Capmulo MCM <100 PEG 400 <100 Crodamole GTCC/Capmule MCM/Polysorbate 80 <100 (40/40/20) Linoleic acid < 60 Incromegae TG2671 <75 propylene glycol < 75 Glycerin < 75 mineral oil <75 Table 14b. Microsolubilities of amorphous compounds (mg/mL) Cmpd F Cmpd G Cmpd H CmpD I Cmpd JU Miglyol# 812 <100 Crodamol GTCC >300 >20 >100 Corn, Safflower, >300 <20 >100 Soybean oils Peanut oil <20 >100 Olive oil 303 >300 >300 <20 >100 Sesame oil >300 <20 >100 Cremophore EL >300 <160 CapmulR MCM >300 >20 >100 PEG 400 <160 <20 50-100 Corn >20 oil/Polysorbate80 (80/20) Corn oil/Labrafil <20 (80/20) Crodamol GTCC >300 >20 >100 /Capmul@ MCM/ Polysorbate 80 (40/40/20)

Table 14c. Microsolubilities of amorphous compounds (mg/mL) Olive oil Safflower oil Miglyol# 812 Capmul MCM Cmpd L <300 >300 >300 >300 Cmpd M <300 <300 >300 >300 Cmpd A >300 >300 >300 >300 Cmpd N >300 >300 >300 >300 Cmpd O <300 <300 >300 >300 Cmpd P >300 <300 >300 >300 Cmpd Q <300 <300 >300 >300

Example 15: To 1.41 mL of Miglyol 812, 0.471 mL of propylene carbonate and 0.471 mL of Cremophoro EL was added 900 mg of Compound E. The resulting mixture was stirred at ambient temperature for 20 minutes with scraping of the container walls as needed. It was then probe sonicated for 30 seconds with occasional mixing to completely dissolve the drug, and then stirred for 20 minutes at ambient temperature.

The amounts (in mg) of each component in the oil solution per gram of solution are set forth in Table 15.

Table 15 Ingredient mg/g Compound E 275 Miglyol@ 812 406 Propylene carbonate 166 Cremophor# EL 153 An emulsion was prepared by combining 1 volume of oil solution with an equal volume of de-ionized water. This mixture was stirred for 10 minutes and then vortex mixed for 1 minute to yield an emulsion with an average particle size less than 10 microns. The emulsion is then stirred continuously to maintain homogeneity. No chemical degradation based on HPLC analysis or crystallization based on microscopic examination was detected in the oil or emulsion after storage for 24 hr.

Example 16: Capmule MCM was heated to 55°C and mixed. Cremophoro RH40 was also heated to 65°C with stirring. Then 2.70 g of triacetin, 2.71 g of Cremophoe RH40, and 3.60 g of Capmu) MCM were combined and mixed for 20 min. To this mixture was then added 1. 01 gm of Compound A and the resulting mixture stirred at ambient temperature for 3 hours with scraping of walls as needed. The amounts (in mg) of each component in the fill per gram of fill are set forth in Table 16a.

Table 16a Ingredient mg/g Cmpd A 100 Triacetin 270 CremophorW RH40 270 Capmulq9 MCM 360

Example 17: To 495 mg of Miglyol@ 812, 203 mg of propylene carbonate and 187 mg of Cremophoro EL was added 115 mg of Compound A. The resulting mixture was stirred at ambient temperature for 20 minutes with scraping of the container walls as needed.

It was then probe sonicated for 3 minutes with occasional mixing to completely dissolve the drug, and then stirred for 20 minutes at ambient temperature. The amounts (in mg) of each component in the oil solution per gram of solution are set forth in Table 17a.

Table 17a Ingredient mg/g Cmpd A 115 Miglyol"812 495 Propylene carbonate 203 Cremophor"EL 187 An emulsion was prepared by combining 1 volume of oil solution with an equal volume of de-ionized water. This mixture was stirred for 10 minutes and then vortex mixed for 2 minutes. The emulsion had an average particle size of less than 10 microns. It was stirred continuously to maintain homogeneity. No chemical degradation based on HPLC analysis or crystallization based on microscopic examination was detected in the oil after storage for 8 days or the emulsion after storage for 24 hr.

Example 18 : To 764 mg of olive oil and 223 mg of Cremophoro EL was added 13 mg of Compound A. The resulting mixture was stirred at ambient temperature for 20 minutes with scraping of container walls as needed. It was then probe sonicated for 3 minutes with occasional mixing to completely dissolve the drug. The solution was then stirred for 20 minutes at ambient temperature. The amounts (in mg) of each component in the oil solution per gram of solution are set forth in Table 18a.

Table 18a Ingredient mg/g Compound A 13 Olive oil 764 CremophorW EL 223 An emulsion was prepared by combining combining 1 volume of oil solution with an equal volume of de-ionized water. This mixture was stirred for 10 minutes and then vortex mixed for 2 minutes. The emulsion had an average particle size of less than 10 microns. It was stirred continuously to maintain homogeneity. No chemical degradation based on HPLC analysis or crystallization based on microscopic examination was detected in the oil after storage for 8 days or the emulsion after storage for 24 hr.

Example 19 : To 485 mg of Miglyole 812,199 mg of propylene carbonate and 183 mg of Cremophore EL was added 133 mg of Compound D. The resulting mixture was stirred at ambient temperature for 20 minutes with scraping of container walls as needed. It was then probe sonicated for 3 minutes with occasional mixing to completely dissolve the drug. The solution was stirred for further stirred for 20 minutes at ambient temperature. The amounts (in mg) of each component in the oil solution per gram of solution are set forth in Table 19A.

Table 19A Ingredient mg/g Cmpd D 133 Miglyol"812 485 Propylene carbonate 199 Cremophorw EL 183

An emulsion was prepared by combining combining 1 volume of oil solution with an equal volume of de-ionized water. This mixture was stirred for 10 minutes and then vortex mixed for 2 minutes. The emulsion had an average particle size of less than 10 microns. It was stirred continuously to maintain homogeneity. No chemical degradation based on HPLC analysis or crystallization based on microscopic examination was detected in the oil after storage for 8 days or the emulsion after storage for 24 hr.

Example 20: Chemical and physical stability for the formulation of Example 8 was determined for 30 mgA Miglyol (&num 11 oblong) softgels stored in white HPDE bottles (child-resistant closures). After storage at 40°C/75% RH for 6 months there was no change in potency and no degradation was detected (peak area < 0.05 % relative to parent) as determined by HPLC analysis of the entire softgel. The appearance (color, shape, seal integrity) was unchanged, and disintegration occurred within 15 minutes in water (USP<701>). Softgels stored at 5°C and 25°C/60% RH were stable for 18 months.

Example 21: Either oils or preformed emulsions of Compound A were administered to Sprague Dawley rats by oral gavage and the results are shown in Table 21 a. Emulsions were prepared as indicated in Examples 17-19. Emulsions prepared from olive oil/surfactant provided the best results. The solubility and thus the accessible dose could be increased by using cosolvens (e. g. caprylic acid and/or triacetin) or using a triglyceride with improved solubility (Miglyole 812), but this did not provide any improvement in exposure over much lower doses in olive oil/Cremophore EL.

Administration of pre-formed emulsions gave superior results to the oil, especially at higher dose volumes where mixing of phases in vivo may be less efficient.

In contrast to the results in rats, emulsions in Miglyol@ 812/Cremophor# EL yielded far superior results to olive oil/Cremophor@ EL in cynomologous monkeys (Table 21 b), and much better results than for Miglyole alone. Use of an emulsion prepared from crystalline (ethanolate) drug allowed comparible exposures to be achieved to those for more soluble amorphous drug in Miglyol@ alone. Excellent dose proportionality was also obtained.

The need for the presence of a high concentration of the long chain triglyceride olive oil for efficient absorption in the rat, but not the monkey, suggests that the lymphatic pathway plays a more important role for absorption of this drug in rats. An important role for lymphatic absorption for Compound A is consistent with its very high lipophilicity.

Table 21 a. PK results in rat for Compound A Drug Vehicle Dose Conc. in Vol. Cmax AUC Form oil of oil (0-Tlast) (mg/kg) (mg/mL) (mg/kg) (µg/mL) (µg- hr/mL) Ethanol. Olive oil/ Cremophor# / 100 20 5 6. 2 33* water 40/10/50 Ethanol. Miglyol#/Cremophor# 500 100 5 4.6 18* /water 40/10/50 Ethanol. Olive oil/caprylic acid/375 75 5 4. 1 21 Cremophor#/water 10/30/10/50 Ethanol. Olive oil/caprylic 625 125 5 4.8 26* acid/triacetin/ Cremophor#/water 10/15/15/10/50 Ethanol. Olive oif/Cremophor'100 20 5 3. 6 45 80/20 Ethanol. Mig) 100 1 1. 9 23 water 40/10/50 Ethanol. Miglyol#/Cremophor#/ 100 100 1 1.6 15 0.5 % HPMCAS 40/10/50 Ethanol. Miglyol"500 100 5 2. 1 27 Amorph. Olive oil 300 60 5 7. 3 50

* Tlast = 9 hr. Otherwise, Tlast = 24 hr.

Amorph. = amorphous anhydrous Ethanol. = crystalline ethanolate HPMCAS=Hydroxpyropyl methyl cellulose acetate succinate Table 21 b. PK results in monkeys for Compound A Form* Vehicle Dose Conc. Vol. Cmax AUC in oil of oil (pg/mL) (jg-hr/mL) (mg/kg) (mg/mL) (mg/kg) Ethanol. Miglyolo/Cremophoro 100 100 1 1. 6-2. 3 24-29 water 40/10/50 (BID) Ethanol. Miglyol'/Cremopho'/50 50 1 0, 8-1. 1 13-15 water (BID) 40/10/50 Ethanol. Miglyol#/ Cremophor#/ 100 100 1 0. 4-1.8 water 40/10/50 Ethanol. Olive oil/CremophorW/20 20 1 0. 1,0.16 N. D. water 40/10/50 Ethanol. Miglyole 100 100 1 ca. 0.17 N. D. Amorph. Miglyol'100 100 1 ca. 1.6 ca. 29

Amorph. = amorphous anhydrous Ethanol. = crystalline ethanolat Example 22: A. 100 mgA/mL fill Capmule MCM was heated to 55°C and mixed. Then 48.5 gm of miglyol# 812, 72.8 gm of triacetin, 48.5 gm of Polysorbate 80, and 72.8 gm of Capmul# MCM were combined. To this mixture was then added 25.0 gm Compound E and the resulting mixture stirred at ambient temperature for 10 minutes with scraping of walls as needed. The amounts (in mg) of each component in the fill per gram of fill are set forth in Table 22. The fill could be prepared on a larger scale for encapsulation into #10 oval softgels to provide a fill volume of 0.6 mL and a dose per softgel of 60 mgA.

B. 200 mgA/mL fill Capmu) MCM was heated to 55°C and mixed. Then 650 mg of Miglyol"812, 976 mg of triacetin, 650 mg of Polysorbate 80, and 976 mg of Capmu) MCM were combined and mixed for 10 min. To this mixture was then added 748 mg Compound E and the resulting mixture stirred at ambient temperature for 10 minutes with scraping of wall as needed. The amounts (in mg) of each component in the fill per gram of fill are set forth in Table 22. The fill could be prepared on a larger scale for encapsulation into #10 oval softgels to provide a fill volume of 0.6 mL and a dose per softgel of 120 mgA.

Table 22 Ingredient m/g 100 mgA/mL 200 mgA/mL Compound E 94 184 Miglyolw 812 181 163 Triacetin 272 245 Polysorbate 80 181 163 CapmulR MCM 272 245