WO2011028395A1 - Pyridyl oxazolidinone cetp inhibitor - Google Patents

Abstract

The compound of Formula I, including pharmaceutically acceptable salts, is a CETP inhibitor, and is useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis. In the compound of Formula 1, R is H or C_1-6alkyl optionally substituted with 1-3 halogens: (Formula I).

Description

TITLE OF THE INVENTION

PYRIDYL OXAZOLIDINONE CETP INHIBITOR

FIELD OF THE INVENTION

This invention relates to a chemical compound that inhibits cholesterol ester transfer protein (CETP) and is expected to have utility in raising HDL-C, lowering LDL-C, and in the treatment and prevention of atherosclerosis.

BACKGROUND OF THE INVENTION

Atherosclerosis and its clinical consequences, coronary heart disease (CHD), stroke and peripheral vascular disease, represent a truly enormous burden to the health care systems of the industrialized world. In the United States alone, approximately 13 million patients have been diagnosed with CHD, and greater than one half million deaths are attributed to CHD each year. Further, this toll is expected to grow over the next quarter century as an epidemic in obesity and diabetes continues to grow.

It has long been recognized that in mammals, variations in circulating lipoprotein profiles correlate with the risk of atherosclerosis and CHD. The clinical success of HMG-CoA reductase inhibitors, especially the statins, in reducing coronary events is based on the reduction of circulating low density lipoprotein cholesterol (LDL-C), levels of which correlate directly with an increased risk for atherosclerosis. More recently, epidemiologic studies have demonstrated an inverse relationship between high density lipoprotein cholesterol (HDL-C) levels and

atherosclerosis, leading to the conclusion that low serum HDL-C levels are associated with an increased risk for CHD.

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

In humans, CETP plays a role in reverse cholesterol transport, the process whereby cholesterol is returned to the liver from peripheral tissues, mtriguingly, many animals do not possess CETP, including animals that have high HDL levels and are known to be resistant to coronary heart disease, such as rodents (see Guyard-Dangremont, V., et. al., (1998)

Phospholipid and cholesteryl ester transfer activities in plasma from 14 vertebrate species. Relation to atherogenesis susceptibility, Comp. Biochem. Physiol. B Biochem. Mol Biol. 120(3), 517-525). Numerous epidemiologic studies correlating the effects of natural variation in CETP activity with respect to coronary heart disease risk have been performed, including studies on a small number of known human null mutations (see Hirano, K.-L, Yamashita, S. and Matsuzawa, Y. (2000) Pros and cons of inhibiting cholesteryl ester transfer protein, Curr. Opiri Lipidol 11(6), 589-596). These studies have clearly demonstrated an inverse correlation between plasma HDL-C concentration and CETP activity (see Inazu, A., et al. (2000) Cholesteryl ester transfer protein and atherosclerosis, Curr, Opin. Lipidol 11(4), 389-396), leading to the hypothesis that pharmacologic inhibition of CETP lipid transfer activity may be beneficial to humans by increasing levels of HDL-C while lowering LDL-C.

Despite the significant therapeutic advance that statins such as simvastatin and atorvastatin represent, statins only achieve a risk reduction of approximately one-third in the treatment and prevention of atherosclerosis and ensuing atherosclerotic disease events. Currently, few pharmacologic therapies are available that favorably raise circulating levels of HDL-C.

Certain statins and some fibrates offer modest HDL-C gains. Niacin provides an effective therapy for raising HDL-C but suffers from patient compliance issues, due in part to side effects such as flushing. Drugs that inhibit CETP (CETP inhibitors) have been under development with the expectation that they will effectively raise HDL cholesterol levels and also reduce the incidence of atherosclerosis in patients. Torcetrapib was the first drug that was tested in a long-term outcomes clinical trial. The clinical trial of torcetrapib was terminated early due to a higher incidence of mortality in patients to whom torcetrapib and atorvastatin were administered concomitantly compared with patients who were treated with atorvastatin alone. The cause of the increased mortality is not completely understood, but is not believed to be associated with the CETP inhibiting effects of the drug. Two other drug candidates, dalcetrapib and anacetrapib, are currently undergoing clinical trials. New drug candidates are still being sought that have improved properties compared with the CETP inhibitors that have so far been studied in the laboratory, in animal studies, or in clinical trials. These improved properties include, for example, higher potency, reduced off-target activity, better phannacodynamics, improved bioavailability, and a reduced "food effect" compared with many of the highly lipophilic compounds mat have so far been studied in the laboratory, in animal studies, or in clinical trials. "Food effect" refers to the variability in exposure to the active drug that occurs depending on when the patient had .last eaten when the drug is administered and whether or not the drug is administered with food.

The following published patent applications disclose CETP inhibitors that have structures that may contain a central oxazolidinone ring having aryl and biaryl substituent groups: WO 2006/014357, WO 2006/014413, WO 2007/079186, WO 2007/081569, and WO 2007/081571. SUMMARY OF THE INVENTION

The compound having Formula I, including pharmaceutically acceptable salts of the compound, is a potent CETP inhibitor, having the utilities described below:

In the compound of Formula I, R is H or Ci_6alkyl which is optionally substituted with 1-3 halogens. The preferred compound is the carboxylic acid (R = H) or a pharmaceutically acceptable salt of the compound. When R is alkyl, the preferred halogen substituent(s) on alkyl, if present, is F. Preferred alkyl groups are methyl, ethyl, and trifluoromethyl.

DETAILED DESCRIPTION OF THE INVENTION

The compound described above modulates CETP, and in particular is a CETP inhibitor. The compound thus has utility for treating diseases that are treated by modulation of CETP, and particularly inhibition of CETP.

This application describes a method for treating atherosclerosis and for treating dyslipidemia by administering to a patient in need of treatment a therapeutically effective amount of the compound of Formula I as described above, and more specifically of the compound of Formula I in which R is H, or a pharmaceutically acceptable salt thereof. This application also describes a method for raising HDL-cholesterol and/or lowering LDL-cholesterol by

administering to a patient in need of treatment a therapeutically effective amount of the compound of Formula I as described above, and more specifically of the compound of Formula I in which R is H, or a pharmaceutically acceptable salt thereof. The compound of Formula I as described above, and more specifically the compound of Formula I in which R is H, or a pliarmaceutically acceptable salt thereof, is also effective for treating other diseases and conditions that can be treated or controlled by inhibiting CETP.

This application describes the compound of Formula I as described above, and more specifically the compound of Formula I in which R is H, or a pharmaceutically acceptable salt thereof, for use in treating atherosclerosis, or for use in raising HDL-C, or for use in lowering LDL-C, or for use in treating dyslipidemia. This application describes the use of the compound of Formula I as described above, and more specifically the use of the compound of Formula I in which R is H, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating atherosclerosis, or for the manufacture of a medicament for raising HDL-C, or for the manufacture of a medicament for lowering LDL-C, or for the manufacture of a medicament for treating dyslipidemia.

The compound as described above, or a compound where R is H, or a

pharmaceutically acceptable salt thereof, has improved properties compared with the properties of many of the CETP inhibitors that have so far been studied or are currently being studied in the laboratory, in animal studies, or in clinical trials. These improved properties include, for example, higher potency, little or no off-target activity, better pharmacodynamics, improved bioavailability, reduced lipophilicity, and a reduced "food effect" compared with many of the highly lipophilic compounds that have been studied or are currently being studied in the laboratory, in animal studies, or in clinical trials. "Food effect" refers to the variability in exposure to the active drug that occurs depending on whether the patient is in a fasted or fed state when the drug is administered. The exposure to active drug also may vary (usually increase) when the drug is administered with food, and especially with a high fat meal.

Optical Isomers - Diastereomers - Geometric Isomers - Tautomers

The compound of Formula I contains two asymmetric centers, with the possibility of an additional asymmetric center in the group R if R is alkyl, and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The stereochemical structure shown as Formula I is the most active stereoisomer and is the most preferred stereoisomer. However, other stereochemical structures are also claimed individually and collectively, including mixtures of stereoisomers. These may have less activity or no activity, but these still may be useful as research tools for studying the mechanism of action of CETP inhibition. The compound of Formula I also occurs as atropisomers (rotamers), which may be observable by NMR spectroscopy. Salts

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-<Ubenzylethylenediamine, diethylamine, 2- (tiemylammoethanol, 2-diraemylaminoethanoI, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, trometharnine, and the like.

When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

It will be understood that, as used herein, references to the compound of Formula

I are meant to also include the pharmaceutically acceptable salts.

Prodrugs

Prodrugs, which are compounds that are converted to the compound of Formula I as they are being administered to a patient or after they have been administered to a patient, are also compounds of Formula I in the sense that they provide the pharmaceutical ly active drug moiety to the patient.

Utilities

The compound of Formula I, including pharmaceutically acceptable salts thereof, is a potent inhibitor of CETP. The compound is therefore useful in treating diseases and conditions that are treated by inhibitors of CETP.

One aspect of the present invention provides a method for treating or reducing the risk of developing a disease or condition that may be treated or prevented by inhibition of CETP by administering a therapeutically effective amount of the compound of Formula I to a patient in need of treatment The patient is a human or mammal, but is most often a human. A

"therapeutically effective amount" is the amount of compound that is effective in obtaining a desired clinical outcome in the treatment of a specific disease.

Diseases or conditions that may be treated with the compound of this invention, or which the patient may have a reduced risk of developing as a result of being treated with the compound of this invention, include: atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial-hypercholesterolemia, cardiovascular disorders, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplasty restenosis, hypertension, vascular complications of diabetes, obesity, endotoxemia, and metabolic syndrome.

The compound of this invention is particularly effective in raising HDL-C and/or increasing the ratio of HDL-C to LDL-C. The compound is also effective in reducing LDL-C and may be effective in treating dyslipidemia. These changes in HDL-C and LDL-C may be beneficial in treating atherosclerosis, reducing or reversing the development of atherosclerosis, reducing the risk of developing atherosclerosis, or preventing atherosclerosis. The compound of Formula I is thus expected to be beneficial in treating atherosclerosis, reducing or reversing the development of atherosclerosis, reducing the risk of developing atherosclerosis, or preventing atherosclerosis.

Adniinistration and Dose Ranges

Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of the compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably the compound of Formula I is administered orally.

When treating the diseases for which the compound of Formula I is indicated, generally satisfactory results are expected when the compound of the present invention is administered at a daily dosage of from about 0.1 milligram to about 1000 milligram in one dose daily or divided into more than one dose per day.

Oral administration will usually be carried out using tablets. Examples of doses in tablets include 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Other oral forms can also have the same dosages (e.g. capsules).

Pharmaceutical Compositions

Another aspect of the present invention provides pharmaceutical compositions which comprise the compound of Formula I and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention comprise the compound of Formula I or a pharmaceutically acceptable salt as an active ingredient, as well as a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids. A pharmaceutical composition may also comprise a prodrug, or a pharmaceutically acceptable salt thereof, if a prodrug is adrninistered. A pharmaceutical composition may also consist essentially of the compound of Formula L or a pharmaceutically acceptable salt of the compound, and a pharmaceutically acceptable carrier, without other thereapeutic ingredients.

The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

In practical use, the compound of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral

(including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid

preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.

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

The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin excipients such as dicalcium phosphate; a

disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as

magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

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

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

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

Combination Therapy

The compound of Formula I, including pharmaceutically acceptable salts, may be used in combination with other drugs that may also be useful in the treatment or amelioration of the diseases or conditions for which the compound of Formula I is useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with the compound of Formula I. When the compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred. However, the combination therapy also includes therapies in which the compound of Formula I and one or more other drugs are administered concomitantly, on the same or different schedules.

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

Examples of other active ingredients that may be administered in combination with a compound of this invention (e.g. Formula I), and either administered separately or in the same pharmaceutical composition, include, but are not limited to, other compounds which improve a patient's lipid profile, such as (i) HMG-CoA reductase inhibitors, (which are generally statins, including lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, pitavastatin, and other statins), (ii) bile acid sequestrants (cholestyramine, colestipol, dialkylaminoalkyl derivatives of a cross-linked dextran, Colestid®, or LoCholest®), (iii) niacin and related compounds, such as nicotinyl alcohol, nicotinamide, and nicotinic acid or a salt thereof, (iv) PP ARc agonists, such as gemfibrozil and fenofibric acid derivatives (fibrates), including clofibrate, fenofibrate, bezafibrate, ciprofibrate, and etofibrate, (v) cholesterol absorption inhibitors, such as stanol esters, beta-sitosterol, sterol glycosides such as tiqueside; and azetidinones, such as ezetimibe, (vi) acyl CoAxholesterol acyltransferase (ACAT) inhibitors, such as avasimibe and melinamide, and including selective ACAT-1 and ACAT-2 inhibitors and dual inhibitors, (vii) phenolic antioxidants, such as probucol, (viii) microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitors, (ix) anti-oxidant vitamins, such as vitamins C and E and beta carotene, (x) thyromimetics, (xi) LDL (low density lipoprotein) receptor inducers, (xii) platelet aggregation inhibitors, for example glycoprotein Ilb/IIIa fibrinogen receptor antagonists and aspirin, (xiii) vitamin B 12 (also known as cyanocobalamin), (xiv) folic acid or a pharmaceutically acceptable salt or ester thereof, such as the sodium salt and the methylglucamine salt, (xv) FXR and LXR ligands, including both inhibitors and agonists, (xvi) agents that enhance ABCA1 gene expression, and (xvii) ileal bile acid transporters.

Preferred classes of therapeutic compounds that can be used with the compound of this invention for use in improving a patient's lipid profile (i.e. raising HDL-C and lowering LDL-C) include one or both of statins and cholesterol absorption inhibitors. Particularly preferred are combinations of the compound of this invention with a statin, or with ezetimibe, or with both a statin and ezetimibe. Statins that may be used in these combinations include simvastatin, lovastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, and itavastatin. Preferred statins for use in combination therapy include simvastatin, atorvastatin,- and rosuvastatin.

Finally the compound of this invention can be used with compounds that are used for treating other diseases, such as diabetes, hypertension and obesity, as well as other anti- atherosclerostic compounds. Such combinations may be used to treat one or more of such diseases as diabetes, obesity, atherosclerosis, and dyslipidemia, or more than one of the diseases associated with metabolic syndrome. The combinations may exhibit synergistic activity in treating these disease, allowing for the possibility of administering reduced doses of active ingredients, such as doses that otherwise might be sub-therapeutic.

Examples of other active ingredients that may be administered in combination with a compound of this invention include, but are not limited to, compounds that are primarily anti-diabetic compounds, including: (a) PPAR gamma agonists and partial agonists, including glitazones and non- glitazones (e.g. pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, T-131, LY-300512, and LY-818;

(b) biguanides such as metformin and phenformin;

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

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

(e) insulin or insulin mimetics, such as for example insulin lispro, insulin glargine, insulin zinc suspension, and inhaled insulin formulations;

(f) sulfonylureas, such as tolbutamide, glipizide, glimepiride, acetohexamide, chlorpropamide, glibenclamide, and related materials;

(g) a-glucosidase inhibitors, such as acarbose, adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin;

(h) PPARα y dual agonists, such as muraglitazar, tesaglitazar, farglitazar, and naveglitazar;

(i) PPARδ agonists such as GW501516 and those disclosed in W097/28149; (j) glucagon receptor antagonists;

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

(l) GIP-l; and

(m) Non-sulfonylurea insulin secretagogues, such as the meglitinides (e.g.nateglinide and rapeglinide).

These other active ingredients that may be used in combination with the current invention also include antiobesity compounds, including 5-HT(serotonin) inhibitors,

neuropeptide Y5 (NPY5) inhibitors, melanocortin 4 receptor ( c4r) agonists, cannabinoid receptor 1 (CB-1) antagonists/inverse agonists, and β₃ adrenergic receptor agonists. These are listed in more detail later in this section.

These other active ingredients also include active ingredients that are used to treat inflammatory conditions, such as aspirin, non-steroidal antiinflammatory drugs, glucocorticoids, azulfidine, and selective cyclooxygenase-2 (COX-2) inhibitors, including etoricoxib, celecoxib, rofecoxib, and Bextra.

Antihypertensive compounds may also be used advantageously in combination therapy with the compounds of this invention. Examples of antihypertensive compounds that may be used with the compounds of this invention include (1) angiotensin II antagonists, such as losartan; (2)angiotensin converting enzyme inhibitors (ACE inhibitors), such as enalapril and captopril; (3) calcium channel blockers such as nifedipine and dUtiazam; and (4) endothelian antagonists. Anti-obesity compounds may be administered in combination with the compounds of this invention, including: (1) growth hormone secretogogues and growth hormone secretogogue receptor agonists/antagonists, such as NN703 and hexarelin; (2) protein tyrosine phosphatase-lB (PTP-1B) inhibitors; (3) cannabinoid receptor ligands, such as cannabinoid CB₁ receptor antagonists or inverse agonists, such as rimonabant (Sanofi Synthelabo), AMT-251 , and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319 (Solvay), BAY 65-2520 (Bayer); (4) anti-obesity serotonergic agents, such as fenfluramine, dexfenfluramine, phentermine, and sibutramine; (5) β3 -adrenoreceptor agonists, such as AD9677 TAK677 (Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, Trecadrine, Zeneca D7114, and SR 59119A; (6) pancreatic lipase inhibitors, such as orlistat (Xenical®), Triton WR1339, RHC80267, lipstatin, tetrahydrolipstatin, teasaponin, and diethylumbelliferyl phosphate; (7) neuropeptide Yl antagonists, such as BIBP3226, J-l 15814, BIBO 3304, LY-357897, CP-671906, and GI-264879A; (8) neuropeptide Y5 antagonists, such as GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR- 120819A and JCF-104; (9) melanin-concentrating hormone (MCH) receptor antagonists; (10) melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such as T-226296 (Takeda); (11) melanin-concentrating hormone 2 receptor (MCH2R) agonist antagonists; (12) orexin-1 receptor antagonists, such as SB-334867-A; (13) melanocortin agonists, such as Melanotan Π; (14) other Mc4r (melanocortin 4 receptor) agonists, such as CHI 86036 (Chiron), ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141, and PT-14 (Palatin); (15) 5HT-2 agonists; (16) 5HT2C (serotonin receptor 2C) agonists, such as BVT933, DPCA37215,

WAY161503, and R-1065; (17) galanin antagonists; (18) CCK agonists; (19) CCK-A

(cholecystokinin-A) agonists, such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 and SR146131 ; (20) GLP-1 agonists; (21) corticotropin-releasing hormone agonists; (22) histamine receptor-3 (H3) modulators; (23) histamine receptor-3 (H3) antagonists inverse agonists, such as hioperamide, 3 -(1 H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan, and GT2394 (Gliatech); (24) β-hydroxy steroid dehydrogenase-1 inhibitors (11β-HSD-l inhibitors), such as BVT 3498 and, BVT 2733, (25) PDE (phosphodiesterase) inhibitors, such as meophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram, and cilomilast; (26) phosphodiesterase-3B (PDE3B) inhibitors; (27) NE (norepmephrine) transport inhibitors, such as GW 320659, despiramine, talsupram, and nomifensine; (28) ghrelin receptor antagonists; (29) leptin, including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen); (30) leptin derivatives; (31) BRS3 (bombesin receptor subtype 3) agonists such as [D-Phe6,beta- Alal l,Phel3,Nlel4]Bn(6-14) and [D-Phe6,Phel3]Bn(6-13)propylamide; (32) CNTF (Ciliary neurotrophic factors), such as GI-181771 (Glaxo-Smith line), SR146131 (Sanofi Synthelabo), butabindide, PD 170,292, and PD 149164 (Pfizer); (33) CNTF derivatives, such as axokine (Regeneron); (34) monoamine reuptake inhibitors, such as sibutramine; (35) UCP-1

(uncoupling protein- 1, 2, or 3) activators, such as phytanic acid, 4-[(E)-2-(5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-2-napthalenyl)- 1 -propenyl]benzoic acid (TTNPB), and retinoic acid; (36) thyroid hormone β agonists, such as KB-2611 (KaroBioBMS); (37) FAS (fatty acid synthase) inhibitors, such as Cerulenin and C7S; (38) DGAT1 (diacylglycerol acyltransferase 1) inhibitors; (39) DGAT2 (diacylglycerol acyltransferase 2) inhibitors; (40) ACC2 (acetyl-CoA carboxylase- 2) inhibitors; (41) glucocorticoid antagonists; (42) acyl-estrogens, such as oleoyl-estrone; (43) dicarboxylate transporter inhibitors; (44) peptide YY, PYY 3-36, peptide YY analogs, derivatives, and fragments such as BIM-43073D, BIM-43004C, (45) Neuropeptide Y2 (NPY2) receptor agonists such NPY3-36, N acetyl [Leu(28,31)] NPY 24-36, TASP-V, and cyclo-(28 32)- Ac-[Lys28-Glu32]-(25-36)-pNPY; (46) Neuropeptide Y4 (NPY4) agonists such as pancreatic peptide (PP); (47) Neuropeptide Yl (NPY1) antagonists such as BIBP3226, J-l 15814, BIBO 3304, LY-3S7897, CP-671906, and GI-264879A; (48) Opioid antagonists, such as nalmefene (Revex ®), 3-methoxynaltrexone, naloxone, and naltrexone; (49) glucose transporter inhibitors; (50) phosphate transporter inhibitors; (51) 5-HT (serotonin) inhibitors; (52) beta-blockers; (53) Neurokinin- 1 receptor antagonists (NK-1 antagonists); (54) clobenzorex; (55) cloforex; (56) clominorex; (57) clortermine; (58) cyclexedrine; (59) dextroamphetamine; (60)

diphemethoxidine, (61) N-emylamphetamine; (62) fenbutrazate; (63) fenisorex; (64)

fenproporex; (65) fludorex; (66) fluminorex; (67) furiurylmethylamphetamine; (68)

levamfetamine; (69) levophacetoperane; (70) mefenorex; (71) metamfepramone; (72)

methamphetamine; (73) norpseudoephedrine; (74) pentorex; (75) phendimetiazine; (76) phenmetrazine; (77) picilorex; (78) phytopharm 57; (79) zonisamide, (80) aminorex; (81) amphechloral; (82) amphetamine; (83) benzphetamine; and (84) chlorphentermine.

The combination therapies described above which use the compounds of this invention may also be useful in the treatment of the metabolic syndrome. According to one widely used definition, a patient having metabolic syndrome is characterized as having three or more symptoms selected from the following group of five symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low high-density lipoprotein cholesterol (HDL); (4) high blood pressure; and (5) elevated fasting glucose, which may be in the range characteristic of Type 2 diabetes if the patient is also diabetic. Each of these symptoms is defined clinically in the recently released Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III), National Institutes of Health, 2001, NTH Publication No.01-3670.

Patients with metabolic syndrome have an increased risk of developing the macro vascular and microvascular complications that are listed above, including atherosclerosis and coronary heart disease. The combinations described above may ameliorate more than one symptom of metabolic syndrome concurrently (e.g. two symptoms, three symptoms, four symptoms, or all five of the symptoms).

CETP ASSAY ID vitro radioactive assays of CETP-catalyzed CE and TG transfer

Sources of materials are: [3H] cholesteryl oleate (GE #TRK.886), [3H] Triolein (Perkin-Elmer NET-431), Butylated hydroxyl toluene (Aldrich, #D4740-4), DOPC (Sigma, # P63S4), Sodium Bromide (Fisher scientific #S255-500), PEG 8000 (Fisher, #BP233-1), and human HDL (Intracel Corp #RP-036).

An in vitro assay for determining ICso's to identify compounds that inhibit CETP transfer activity was performed based on a modification of the published method of Morton and Zilversmit, (1981), "A plasma inhibitor of triglyceride and cholesteryl ester transfer activities," J. Biol Chem. 256(23), 11992-11995. The ability of inhibitors to alter CETP activity was determined in 2% human serum by measuring the transfer of [3H] cholesteryl oleate or [3H] triolein from exogenous LDL to HDL. Radiolabeled donor particles were generated by first combining 100 ul of 200 uM butylated hydroxyl toluene in CHC1₃, 216 uL of 21.57 raM DOPC in EtOH, and either 500 μCi [3H]-triolein (Perkin Elmer #NET-431) or 500 μCi [3H]-cholesteryl oleate (GE #TRK886) in a glass tube. Reagents were mixed, dried under nitrogen, and then resuspened in 2 mL of 50 mM Tris, 27 uM EDTA at pH 7.4. After a brief vortex, the solution was sonicated until clear and mixed with 20 mL of fresh human serum. The mixture was incubated overnight at 37°C. The [3H] labeled LDL substrate was separated at 1.063 g ml density by sequential ultracentrifugal flotation in NaBr according to the method by (Havel, Eder et al. 1955; Chapman, Goldstein et al. 1981). Once isolated the particles were dialyzed 3x in CETP buffer (50 mM Tris, pH 7.4, 100 mM NaCl, 1 mM EDTA). Human HDL was purchased from Intracel and used as the acceptor particles.

Transfer assays were performed in a 96-well v-bottom polypropylene plate. An assay cocktail was prepared with the final concentrations 128 μg/mL HDL, 20 nM rCETP, 2% human serum, and 1 x CETP buffer. 1 uL of each test compound diluted in DMSO was added to 47 uL of assay cocktail per well and incubated at 37°C for 1 hour. To initiate the transfer reaction, 2 uL radiolabeled LDL was added. After an additional 60 min of incubation at 37°C, the transfer action was terminated by precipitation of LDL with an equal volume of 20% W/V PEG 8000. The plates were centrifuged at 2000 rpm for 30 minutes at 4°C. A 40 uL aliquot of the HDL- containing supernatant was transferred to a Packard Optiplate with 200 uL of MicroScint 20. After mixing, plates were counted by liquid scintillation. Counts present in the supernatant for blanks (wells containing only HDL acceptor, CETP buffer and DMSO) were subtracted from those containing test compounds and used to correct for non-specific transfer. Comparison of the counts of samples with inhibitors to an uninhibited (DMSO only) positive control yielded a percent inhibition. A plot of percent inhibition vs. log of inhibitor concentration, fit to a Sigmoidal 4 parameter equation was used to calculate IC50. Properties of the Compound of Formula I

The IC50 of the compound of formula I in which R is H is <2S nM, and typically is in the range 5-20 nM, when measured using the assay described above.

The compound has properties that may be advantageous in comparison with

CETP inhibitors that are currently known. These properties include a reduced food effect and reduced lipophilicity.

The food effect was determined by administering the compound of formula I as the carboxylic acid orally in methylcellulose with 1.1 equivalents of NaOH to male beagle dogs that had been fasted and to male beagle dogs that had been fed a high fat meal, and then measuring the plasma drug concentrations after dosing for 24 hours. The AUC was computed for the 24 hour period. The ratio of AUC values for the dogs that had been fed a high fat meal compared with the dogs that had been fasted was 0.9, whereas for compounds having a large food effect, this ratio is typically at least 2, and may be much greater than 2.

A commonly used indicator of lipophilicity of a drug is Log D, which is a measure of the partitioning of the drug between a lipophilic solvent, such as octanol, and water. Log D is often estimated using HPLC as a substitute for partitioning the drug between two solvents.

HPLC Log D for the compound having formula I as the carboxyic acid (R is H) is 4.5.

Compounds that are described as very lipophilic usually have higher Log D values (greater than

5). EXAMPLES

The following examples are provided to illustrate the invention but are not to be construed as limiting the scope of the invention in any way. The scope of the invention is defined by the appended claims

The Compound of Formula I may be made as follows:

INTERMEDIATE 1

(4£5.RV5-r3.S-bis(trifluoromemyDph^

The synthesis of intermediate 1 has been described previously. See, for example, Intermediate 1 of WO2007/081569 and Intermediate 11 of WO 2007/005572.

INTERMEDIATE 2

Methyl 3-[4-methoxv-3-(4.4.5.5 etramelhvl-

Step 1: methvl 3-f3-iodo-4-methoxyphenyl)propanoate

To a solution of methyl 3 -(4-methoxyphenyl)propanoate (100 g, 515 mmol) in

MeOH (2L) was added Ag≥S0₄ (161 g, 515 mmol) followed by . (131 g, 515 mmol). The reaction was stirred vigorously at room temperature for 1 hour and then the solids were removed by filtration. The filtrate was concentrated and the residue was taken up in EtOAc (4L), and washed with water (1L), saturated aq. NaHSC>3 (1L), and brine (1L). The organic layer was dried over MgS0_4> filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 0 to 30% EtOAc/heptanes afforded methyl 3-(3-iodo-4- methoxyphenyl)propanoate. Ή NMR (500 MHz, CDC ) 7.61 (d,J= 2.0 Hz, 1H), 7.14 (dd, J= 8.2, 2.0 Hz, 1H), 6.74 (d, J= 8.5 Hz, lH), 3.85 (s, 3H), 3.67 (s, 3H), 2.85 (t, J= 7.8 Hz, 2H), 2.59 (t,J= 7.8 Hz, 2H).

Step 2: methyl 3-[4-methoxv-3-(4.4.5.5-tetranethYl-1.3.2-d^ A flask was charged with methyl 3-(3-iodo-4-methoxyphenyl)propanoate (155 g, 484 mmol), bis(pinacolato)diboron (154 g, 605 mmol), KOAc (95 g, 968 mmol), dioxane (900 niL), and DMSO (3L). The reaction was degassed with N₂, and then PdCl₂(dr#f 'CH₂ ⁽¾ (39.5 g, 48.4 mmol) was added and the reaction was degassed further with N₂. The reaction was heated at 50 °C for 1 hour, and then at 80 °C for 16 hours. The reaction was then cooled to r.t., diluted with EtOAc (4L), and washed with water (2 x 1L) and brine (1L). The organic layer was dried over MgSC>4, filtered, and concentrated. Purification of the residue by flash chromoatography on silica gel (0 to 30% EtOAc hexanes) afforded methyl 3-[4-me1hoxy-3-(4,4,5,5-tetrame l- 1,3,2- dioxaborolan-2-yl)phenyl]propanoate. ^!H NM (CDCI₃, 500 MHz) δ 7.48 (d, 2.5 Hz, 1H), 7.21 (dd, J= 8.4, 2.3 Hz, 1H), 6.78 (d, = 8.5 Hz, 1H), 3.80 (s, 3H), 3.66 (s, 3H), 2.88 (t, J= 7.8 Hz, 2H), 2.59 (t, /= 7.8 Hz, 2H), 1.35 (s, 12H).

INTERMEDIATE 3

3 -bromc>-2-{ romomethvlV6-chloropvridine

Step 1: 3 -brorno-6-chloro-2-methvlpvridine

A solution of 6-amino-3-bromo-2-methylpyridine (239 g, 1278 mmol) in concentrated HC1 (1.0 L) was cooled to -5 °C. A solution of sodium nitrite (238 g, 3450 mmol) in water (1.0 L) was added dropwise over 1 hour while maintaining the temperature of the reaction between -5 and 5 °C. After the addition was complete, the reaction was stirred for 1 hour, and then the cooling bath was removed and the reaction was warmed to r.t. and stirred for 16 hours. The reaction was then poured onto ice and 5N NaOH (1.7 L) was added to adjust the pH of the solution to 13. The mixture was extracted 3 times with EtOAc (3 L and 2 x 2L). The combined organic layers were dried over NajSC^, filtered, and concentrated. Purification of the residue by flash

chromatography on silica gel with 100% methylene chloride afforded 3 -bromo-6-chloro-2- methylpyridine. 1H NMR (CDCI3, 500 MHz) δ 7.76 (d, J= 8.2 Hz, 1H), 7.07 (d, J - 8.1 Hz, 1H), 2.66 (s, 3H).

Step 2: 3-bromo-2- jromomethvlV6-chloropvridine

To a stirred solution of 3-bromo-6-c oro-2-me1hylpyridine (105 g, 509 mmol) in CCI4 (2 L) was added N-bromosuccinimide (95 g, 534 mmol) followed by AIBN (8.35 g, 50.9 mmol). The reaction was brought to reflux for 24 hours and then cooled to r.t, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 60% methylene chloride heptanes afforded 144.7 g of semi-pure product. Further purification by SFC on a Chiralpak AD-H column with 20% IPA/CO2 [the conditions of the preparative separation were as follows: column Chiralpak AD-H (2.1x25 cm, 5 um particle size) (Chiral Technologies, West Chester, PA, USA); mobile phase 20% 2-propanol/C02; elution mode isocratic pump-mixed; flow rate 50 mL rnin; pressure 100 bar.] gave 3-bromo-2-(bromomethyl)-6-cMoropyridine.

LCMS - 285.7 (M+l)⁺ *H NMR (CDC1_3> 500 MHz) δ 7.81 (d, J= 8.4 Hz, 1H), 7.15 (d, J= 8.3 Hz, 1H), 4.63 (s, 2H).

INTERMEDIATE 4

f4.9 .¾V5-f3.5-bisftrifluoromemvnphenyl1-3-rf3-bromo-6-chloro^

1.3-oxazolidin-2-one

To a solution of (45,5ii)-5-[3,5-bis( fluorome l)phenyl]-4-methyl-l,3- oxazolidin-2-one (254 g, 809 mmol) in THF (4L) was added NaH (60% dispersion in mineral oil) (27 g, 675 mmol). After stirring the reaction at room temperature for 10 minutes, 3-bromo- 2-(hromomethyl)-6-crdoropyridine (154 g, 540 mmol) was added as a solution in THF (500 rnL). The reaction was stirred at room temperature for 1 hours. The reaction was then diluted with EtOAc (8L) and washed with water (2 x 1L) and brine (1L), dried over Na₂SC^<4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 0 to 40% EtOAc/heptanes afforded (45,5>¾)-5-[3,5-bis(trifluoromethyl)phenyI]-3-[(3-bromo-6- chloropyridin-2-yl)m^ LCMS = 518.8 (M+l)⁺ 1HNMR (CDCI₃, 500 MHz) δ 7.90 (s, lH), 7.81-7.83 (m, 3H), 7.18 (d, J= 8.5 Hz, 1H), 5.87 (d, J= 8.5 Hz, 1H), 5.02 (d, J= 17.2 Hz, 1H), 4.42 (m, 1H), 4.32 (d, J= 17.1 Hz, 1H), 0.80 (d, J= 6.6 Hz, 3H).

EXAMPLE 1

3- f3-f2-fff4jS^r. 5ig>5-r3.5-bisitrifluorome^

vl I methyl V6-methoxvpvridin-3-vl] -4-methoxvphenvl \ propanoic acid

Step 1: (4£5.¾>5-r3.5-bis(trifluoro^

4- methvl-l .3-oxazolidin-2-one

A flask was charged with (4S,5J?)-5-[3,5-bis(trifliioromethyl)pheir/l]-3-[(^

cWoropyridin-2-yI)meth^^ (34.5g, 66.6 mmol). MeOH (1L) was added, followed by a solution of NaOMe in MeOH (91 mL of a 25% solution of NaOMe in MeOH, 400 mmol). The reaction was heated at reflux for 42 hours and then cooled to room temperature and diluted with EtOAc (4L). The organic layer was washed with water (1L) and brine (1L), dried over NajSO-i, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 0 to 25% EtO Ac heptanes afforded (4_*¼5Λ)-5-[3-5- bis(trifluoromethyl)phenyl] -3 - [(3 -bromo-6-methoxvpyridin-2-yl)methyl] -4-methyl- 1,3- oxazolidin-2-one. LCMS = 515.1 (M+l)⁺ 1H NMR (CDC1₃, 500 MHz) δ 7.90 (s, 1H), 7.78 (s, 2H), 7.69 (d, J= 8.7 Hz, 1H), 6.62 (d, J= 8.6 Hz, 1H), 5.77 (d, J= 8.5 Hz, 1H) 4.93 (d, J= 16.8 Hz, lH), 4.30-4.35 (m, 2H), 3.93 (s, 3H), 0.81 (d,J= 6.6 Hz, 3H).

Step2: methvl 3- ( 3-Γ2-( ί (45'.5.¾V5 3.5-bisftrifluoromethyl phenyl1-4-methyl-2-oxo- 1.3- oxazolidin-3 -yl } methyl V6-methoxvpvridin- 3 - vll-4-methoxvphenvl ) propanoate

A flask was charged with (4S,5ii)-5-[3,54>is(tefluoromethy

memoxypyridin-2-yl)methyl] -4-methyl- 1 ,3 -oxazolidin-2-one (25.45 g, 49.6 mmol), methyl 3-[4- methoxy-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl]propanoate (16.67 g, 52.1 mmol), THF (500 mL), and 1M KaC0₃ (20.5 g, 149 mmol) in water (400 mL). The reaction was degassed with N2 and then l, -bis(di-^urylphosphino)ferrocene palladium dichloride (129 mg, 0.198 mmol) was added. The reaction was degassed further with N₂ and stirred vigorously for 16 hours at room temperature. The reaction was then diluted with EtO Ac (4L) and washed with water (1L) and brine (1L). The organic layer was dried over MgSC>4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0 to 30% MTBE/heptanes) to afford methyl 3-{3-[2-({(4¾5J?)-5^3_J5-bis(trifluoromemyl)pheny¾

oxazolidin-3 -yl } methyl)-6-methoxypyridin-3 -yl] -4-methoxyphenyl } propanoate. LCMS = 627.1 (M+l)⁺ Ή NMR (CDC1₃, 500 MHz) δ 7.85 (s, lH), 7.72 (s, 2H), 7.43 (d, J- 8.4 Hz, lH), 7.19 (dd, J= 8.5, 2.1 Hz, 1H), 6.98 (bs, lH), 6.89 (d, J= 8.4 Hz, 1H), 6.74 (d, J= 8.4 Hz, 1H), 5.59 (bs, 1H), 4.73-4.86 (m, 1H), 3.83-4.31 (m, 2H), 3.98 (s, 3H), 3.76 (s, 3H), 3.64 (s, 3H), 2.92 (bs, 2H), 2.62 (bs, 2H), 0.57-0.67 (m, 3H).

Step 3: 3-i 3-Γ2-Π Γ4& 5Ji 5-r3 -bis(1rifluoromemv^

yl } methyl 6-methoxvpvridin-3 -vll -4-methoxvphenvl I propanoic acid

To a solution of methyl 3-{3-[2-({(4S,5 )-5-[3,5-bis(trifl^

l,3-oxazoHdin-3-yl}memyl)-6-memo^ (21 g, 33.5 mmol) in freshly distilled dioxane (340 mL) was added water (85 mL) followed by 1M LiOH (67 mL, 67 mmol). The reaction was stirred at room temperature for 3 hours and then quenched with HOAc (4.80 mL, 84 mmol), diluted with EtOAc (4L), and washed with water (350 mL) and brine (350 mL). The organic layer was dried over Na2SC> , filtered, and concentrated. Drying under high vacuum resulted in foam that was slurried with heptane for 2 hours. The solid was filtered off and washed with heptane. The solid was then dried in a vacuum oven for 4 days at 50 °C to afford 3-{3-[2-({(45, 5ie 5-t3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-l,3- oxazolidm-3-yl}memyl)-6-meraox acid. LCMS =

613.1 (M+l)⁺. 1HNMR (CD3OD, 500 MHz) 6 7.97 (s, 1H), 7.89 (s, 2H), 7.45 (d, J= 8.3 Hz, 1H), 7.24 (dd, J= 8.4, 2.1 Hz, lH), 7.05 (bs, 1H), 6.98 (d, J= 8.5 Hz, lH), 6.74 (d, J= 8.3 Hz, lH), 5.81 (bs, 1H), 4.56-4.72 (m, 1H), 3.90-4.34 (m, 2H), 3.95 (s, 3H), 3.75 (s, 3H), 2.89 (bs, 2H), 2.59 (bs, 2H), 0.56-0.64 (m, 3H).

Alternate Synthesis of Compound of Formula I

An alternate approach for the preparation of the CETP inhibitor of Formula I provided below. The conditions are provided below the scheme.

Scheme 1

Conversion of 1 to 2:

In a 1000 mL flask under nitrogen, ester 1 (35 g, 180 mol) was dissolved in 350 mL CH2CI2 and cooled to -30°C. Bromine (9.93 mL) was added dropwise without an exotherm. The reaction mixture was warmed slowly to - 15°C. The reaction was complete by LC. The product was diluted with 300 mL of 7% NaHC0₃ solution. Sodium thiosulfate (pentahydrate) solid (4.5 g) was added to decolorize. The layers were separated, and the organic layer was dried with MgSO.}. The solvent was removed by evaporation. The product was used directly in the next step.

Conversion of 2 to 3:

Aryl bromide 2 (45 g, 165 mmol), potassium acetate (48.5 g, 494 mmol), and

bis-pinacolatodiboron (50.2 g, 198 mmol) were placed in a 1000 mL flask under nitrogen.

Cyclopentylmethyl ether (CPME) (450 ml, 387.00 g) was added. The resulting slurry was sparged with nitrogen for 60 min. In a separate 100 mL flask, palladium(II) acetate (0.740 g, 3.30 mmol) was combined with X-phos (3.14 g, 6.59 mmol). Degassed CPME (45 mL) was added, and the mixture was warmed gently to dissolve the solids. The solution turned dark red. The solution was transferred to the flask containing the reactants via syringe. The vial was rinsed with 1 mL of CPME. The mixture was heated to 80°C and aged overnight. After 22h at 80°C, the reaction was nearly complete by LC assay (about 3% of starting material remained). The reaction was cooled to RT. The mixture was washed twice with 300 raL of 7% NaHC03 solution. The organic layer was dried with MgS(>4 and the solvents were removed by

evaporation. The residue (88g) was estimated to contain -57 wt% of the desired product 3 and was used directly in the next step. The structure of X-Phos (commercially available) is shown below:

Conversion of 4 to 5:

Bromopyridine 4 (5.7 g, 30.3 mmol) was dissolved in 28.5 mL of THF in a 250 mL flask. The solution was cooled to -65°C. n-Hexyllithium (14.50 mL of 2.3M solution, 33.3 mmol) was added while maintaining the temperature below -60°C. After addition, the solution was aged for 5 minutes at -65°C. LC analysis showed complete reaction. DMF (2.82 ml, 36.4 mmol) was added dropwise while maintaining the temperature below -60°C. After 5 minutes age, LC showed presence of the aldehyde product. The mixture was warmed to -30°C. Methanol (22.80 mL) was added. The low temperature bath was replaced with an ice bath. NaBl¾ (0.688 g, 18.19 mmol) was added. The temperature increased to 12°C, then dropped again. LC analysis showed that no aldehyde remained. The solution was concentrated to a final volume of -25 mL and was then diluted with MTBE and water. 3N HC1 was added to quench the excess NaBH₄ and bring the pH to 8. The layers were separated. The organic layer was dried with MgS0₄- The solvent was removed by evaporation. The product 5 was left under vacuum for the weekend. The product (4.4 g) was used directly in the next step without purification.

Conversion of 5 to 6:

In a 1000 ml flask, the pyridine compound 5 (23.3 g, 147 mmol) was dissolved in CH₂C1₂ (233 ml). The solution was cooled to -20°C. Bromine (8.30 ml, 161 mmol) was added dropwise. The solution was warmed slowly to room temperature, and then 350 mL of 7% NaHCC^<3 solution was added. The solution was aged at RT for lh. The reaction was then complete. Sodium thiosulfate (1 g) was added to decolorize the product. The layers were separated, and the organic layer was washed with 100 mL of 7% NaHCC>3 solution and dried with MgSC>4. The solvent was removed, yielding a yellow oil (32 g), which was used directly in the next step without further purification.

Conversion of 3 and 6 to 7:

The bromopyridine 6 (2.3 g, 10.55 mmol), pinacolborate 3 (3.04 g, 9.49 mmol), potassium carbonate (3.94 g, 28.5 mmol), and PdCl₂(DTBPF) (0.06 g, 0.092 mmol) were charged to a 100 mL flask which was purged with nitrogen. A solution of THF (8.05 ml) and water (5.75 ml) that had been degassed was then charged to the flask. The mixture was warmed to 45°C and aged for lh at 45°C. The mixture was then cooled to room temperature and diluted with MTBE and water. The layers were separated, and the organic layer was washed with water and dried with MgSC>4. The solvent was removed by evaporation. The residue was purified on a Biotage (isocratic, Hex/EtOAc 80/20 v/v), yielding a colorless oil (1.4g).

Conversion of 7 to 8:

In a SO ml flask, compound 7 (1.2 g, 3.62 mmol) was dissolved in DMF (6.00 ml), and the solution was cooled in an ice bath. Thionyl chloride (0.344 ml, 4.71 mmol) was added dropwise, causing the temperature to increase to 13°C. The ice bath was removed after the addition of the thionyl chloride. The mixture was aged for lh at RT. The reaction was assayed as complete by LC. The reaction was quenched with MTBE and 7% NaHC0₃ solution, resulting in an exotherm. The layers were separated. The organic layer was washed with 7% NaHC0₃ solution and dried with MgS(>4, followed by removal of the solvent. Compound 8 (1.25 g) was obtained. The product was used directly in the next step.

Conversion of 8 and 9 to 10:

Oxazolidinone 9 (81 mg, 0.257 mmol) was placed in a 5 mL vial, which was purged with nitrogen, and then dissolved in DMF (900 μΐ, 849.60 mg). The solution was cooled to -20°C. NaHMDS (129 μΐ, 0.257 mmol) was added slowly to maintain the reaction temperature at less than -15°C. The mixture was aged for 5 minutes, and then the pyridyl chloride 8 (90 mg, 0.257 mmol) was added as a solution in DMF (900 μΐ). The reaction was warmed to room temperature slowly. The reaction was complete after 2h at ambient temperature. The reaction was quenched with MTBE and water. The layers were separated. The organic layer was washed with water, then dried with MgSC^, and the solvent was removed by evaporation. Compound 10 (150 mg) was obtained, which could be used directly in the next step.

Conversion of 10 to 11:

Same as hydrolysis step provided in Example 1.

Claims

WHAT IS CLAIMED IS:

1. A compound having Formula I, or a pharmaceutically acceptable salt thereof:

wherein is H or Ci-galkyl optionally substituted with 1-3 halogens.

2. The compound of Claim 1 , wherein R is H, or a pharmaceutically acceptable salt thereof.

3. A method of treating atherosclerosis, raising HDL-C, lowering LDL-C, or treating dyslipidemia in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of Claim 1, or a pharmaceutically acceptable salt thereof, to said patient.

4. A method of treating atherosclerosis in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of Claim 1, or a

pharmaceutically acceptable salt thereof, to said patient.

5. A method of raising HDL-C in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of Claim 1, or a pharmaceutically acceptable salt thereof, to said patient.

6. A method of lowering LDL-C in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of Claim 1 , or a pharmaceutically acceptable salt thereof, to said patient.

7. A method of treating dyslipidemia in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of Claim 1, or a

pharmaceutically acceptable salt thereof, to said patient.

8. A method of treating atherosclerosis, raising HDL-C, lowering LDL-C, or treating dyslipidemia in a patient in need of treatment comprising the administration of a therapeutically effective amount of the compound of Claim 2, or a pharmaceutically acceptable salt thereof, to said patient.

9. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, for use in treating atherosclerosis, raising HDL-C, lowering LDL-C, or treating dyslipidemia.

10. The compound of Claim 2, or a pharmaceutically acceptable salt thereof, for use in treating atherosclerosis, raising HDL-C, lowering LDL-C, or treating dyslipidemia.

11. The use of the compound of Claim 1 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating atherosclerosis, raising HDL-C, lowering LDL- C, or treating dyslipidemia.

12. The use of the compound of Claim 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating atherosclerosis, raising HDL-C, lowering LDL- C, or treating dyslipidemia.

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

14. A pharmaceutical composition comprising the compound of Claim 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising the compound of Claim 1, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one or more active ingredients selected from the group consisting of:

(a) PPAR gamma agonists and partial agonists;

(b) biguanides;

(c) protein tyrosine phosphatase-lB (PTP-IB) inhibitors,

(d) dipeptidyl peptidase IV (DP-IV) inhibitors;

(e) insulin or insulin mimetics; (f) sulfonylureas;

(g) a-glucosidase inhibitors;

(h) one or more compounds selected from the group consisting of (a) HMG-CoA reductase inhibitors; (b) bile acid sequestrants; (c) niacin, nicotinyl alcohol, nicotinamide, and nicotinic acid or a salt thereof; (d) PPARcc agonists; (e) cholesterol absorption inhibitors; (f) acyl

CoA holesterol acyltransferase (ACAT) inhibitors; (g) phenolic anti-oxidants, such as probucol, and (h) a microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitor;

(i) PPARot/ydual agonists;

(j) PPARS agonists;

(k) antiobesity compounds;

(1) ileal bile acid transporter inhibitors;

(m) anti- inflammatory agents;

(n) glucagon receptor antagonists;

(o) GLP-1,

(p) GEP-l, and

(q) GLP-1 analogs.

16. A pharmaceutical composition comprising the compound of Claim 2, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one or more active ingredients selected from the group consisting of:

(a) PPAR gamma agonists and partial agonists;

(b) biguanides;

(c) protein tyrosine phosphatase-lB (PTP-IB) inhibitors,

(d) dipeptidyl peptidase IV (DP-TV) inhibitors;

(e) insulin or insulin mimetics;

(f) sulfonylureas;

(g) a-glucosidase inhibitors;

(h) one or more compounds selected from the group consisting of (a) HMG-CoA reductase inhibitors; (b) bile acid sequestrants; (c) niacin, nicotinyl alcohol, nicotinamide, and nicotinic acid or a salt thereof; (d) PPARa agonists; (e) cholesterol absorption inhibitors; (fj acyl

CoA holesterol acyltransferase (ACAT) inhibitors; (g) phenolic anti-oxidants, such as probucol, and (h) a microsomal triglyceride transfer protein (MTP)/ApoB secretion inhibitor;

(i) PPARaydual agonists;

0) PPARS agonists;

(k) antiobesity compounds;

(1) ileal bile acid transporter inhibitors;

(m) anti- inflammatory agents; (n) glucagon receptor antagonists;

(o) GLP-1,

(P) GIP-l, and

(q) GLP-1 analogs.

17. A pharmaceutical composition comprising the compound of Claim 1, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one or more active ingredients selected from the group consisting of a statin and ezetimibe.

The pharmaceutical composition of Claim 17, wherein the statin is selected from the group consisting of simvastatin, lovastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, and itavastatin.

19. A pharmaceutical composition comprising the compound of Claim 2, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one or more active ingredients selected from the group consisting of a statin and ezetimibe.

20. The pharmaceutical composition of Claim 19, wherein the statin is selected from the group consisting of simvastatin, lovastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, and itavastatin.