Title of Invention

TETRAHYDROPYRANYL CYCLOPENTYL TETRAHYDROPYRIDOPYRIDINE MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY

Abstract

The present invention is directed to compounds of the formula (I): (wherein R3 et R8 are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptor CCR-2. 1. A compound of the formula 1: wherein; R3 is oxygen or is absent; R8 is selected from: (a) hydrogen, (b) C1-3 alkyl, which is unsubstitated or substituted with 1-6 fluoro, (c) -O-C1-3alkyl, (d) fluoro, and (e) hydroxy; and pharmaceutically acceptable salts thereof and individual diastereomers thereof.

Full Text

TITLE OF THE INVENTION TETRAHYDROPYRAN^X CYCLOPENTYL TETRAHYDROPYRIDOPYRIDINE MODULATORS OF CHEMOKINE RECEPTOR ACTIVTIY BACKGROUND OF THE INVENTION The chemokines are a family of small (70-120 amino acids), proinflammatory cytoldnes, with potent chemotactic activities, Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract various cells, such as monocytes, macrophages, T cells, eosinophils, basophils and neutrophils to sites of infiammation (reviewed in Schall, Cytokine. 3, 165-1S3 (1991) and Murphy, Rev. Immun.. 12, 593-633 (1994)}. These molecules were originally defined by four conserved cysteines and divided into two subfamilies based on the arrangement of the first cysteine pair. In the CXC-chemoldne family, which includes IL-S, GROα, NAP-2 and IP-10, these two cysteines are separated by a single amino acid, while in the CC-chemoldne farnily, which includes RANTES, MCP-l, MCP-2, MCP-3, MlP-lα, MIP-IB and eotaxin, these two residues are adjacent. The chemoldnes are secreted by a wide varietv of cell types and bind to specific G-protein coupled receptors (GPCRs) (reviewed in Horuk, Trends Pharm. ScL, 15,159-165 (1994)) present on leukocytes and other cells. These chemokine receptors form a sub-family of GPCRs, which, at present, consists of fifteen characterized members and a number of orphans. Unlike receptors for promiscuous chemoattractants such as C5a, fMLP, PAF, and LTB4, chemokine receptors are more selectively expressed on subsets of leukocytes- Thus, generation of specific chemokines provides a mechanism for recruitment of particular leukocyte subsets. On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration. There are at least seven human chemokine receptors that bind or respond to P-chemokines with the following characteristic pattern: CCR-1 (or"CKR-l"or "CC-CKR-f'} [MlP-lct, M1P-1|3, MCP-3, RANTES] (Ben-Barruch, et al., J. Biol. Chem.. 270,22123-22128 (1995); Beote, et al. Cell, 72, 415-425 (1993)); CCR-2A and CCR-2E (or "CKR-2A"/"CKR-2A" or "CC-CKR-2A'V"CC-CKI1-2A") [MCP-1, MCP-2, MCP-3, MCP-4]; CCR-3 (or '^CKR-3" or "CC-CKR-3") [Eotaxin, Eotaxin 2, RANTES, MCP-2, MCP-3] (Rollins, et al., Blood, 90, 90S-92S (1997)); CCR-4 (or 'CKR-4" or "CC-CKR-4"} [MlP-la, RANTES, MCP-i] (Rollins, et al, Blood, 90, 90S-92S (1997)): CCR-5 (or immunoinflammatory and autoimmune diseases. Accordinsly. agents which modulate chemoldne receptors such as the CCR-2 receptor would be useful in such disorders and diseases. In addition, the recruitment of monocytes to inflammatory lesions in the vascular wall is a major component of the pathogenesis of atherogenic plaque formation. MCP-I is produced and secreted by endothelial cells and intimal smooth muscle cells after injury to the vascular wall in hypercholesterolemjc conditions. Monocytes recruited to the site of injury infiltrate the vascular wall and differentiate to foam cells in response to the released WCP-l. Several groups have now demonstrated that aortic lesion size, macrophage content and necrosis are attenuated in MCP-I -/- or CCR2 -/- mice backcrossed to APO-E -/-, LDL-R -I- or Apo B transgenic mice maintained on high fat diets (Boring et al. Nature, 394, 894-897 (1998); Gosling et al. J. Clin. Invest.. 103,773-77S (1999)). Thus, CCR2 antagonists may inhibit atherosclerotic lesion formation and pathological progression by impairing monocyte recruitment and differentiation in the arterial wall. SUMMARY OF THE INVENTION The present invention is further directed to compounds which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid aithritis and atherosclerosis. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which chemokine receptors are involved. DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to compounds of tiie formula T. The compounds of the instant invention have at least two asymmetric centers at the 1- and 3-positions of the cyclopentyl ring, one asymmetric center at the 4-position of the morpholine ring and optionally one asymmetric center at the 3-position of the morpholine ring. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The independent syntheses of diastereomers and enantiomers or their chromatographic separations may be achieved as known in the ait by appropriate modification of the methodology disclosed herein. Their absolute stereochemistn mav be deteraiined by the x-ray crystallography of crystalline products or crystalline inteimediates which are derivatized. if necessary, with a reagent containing an asymmetric center of known absolute configuration. As appreciated by those of skill in the art, C103alkyl is defined to identify the group as having I. 2 or 3 carbons in a linear or branched arrangement, such that C1-3aikyl specifically includes methyl, ethyl, n-propyl, and iso-propyl. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, "pharraaceuticaily acceptable salts" refer to derivatives wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfaniiic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. The pharmaceutically acceptable salts of the present invention can be prepared from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Suitable salts are found, e.g. in Remington's Pharmaceutical Sciences, I7th ed.. Mack Publishing Company, Easton, PA, 1985, p. 1418. Specific compounds within the present invention include a compound which selected from the group consisting of. the title compounds of the Examples; and phannaceutica]]y acceptable salts thereof and individual diastereomers thereof. The subject compounds are useful in a method of modulating chemokine receptor activity in a patient in need of such modulation comprising the administration of an effective amount of the compound. The present invention is directed to the use of the foregoing compounds as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors, in particular CCR-2. The utility of the compounds in accordance with the present invention as modulators of chemokine receptor activity may be demonstrated by methodology known in the art, such as the assay for chemokine binding as disclosed by Van Riper, et al-,J. Exp. Med.. 177. 851-856 (1993) which may be readily adapted for measurement of CCR-2 binding. An equal concentration of test compound or DMSO was added to the bottom well to prevent dilution by diffusion. Following a 60 min incubation at 37- C, 5 % CO2, the filter was removed and the topside was washed with HESS containing 0.1 mg/tnl BSA to remove cells that had not migrated into the filter. Spontaneous migration (chemolcinesis) was detemiined in the absence of chemoattractanr In particular, the compounds of the following examples had activity in binding to the CCR-2 receptor in the aforementioned assays, generally with an IC50 of Jess than about 1 [.iM. Such a result is indicative of the intrinsic activity of the compounds in use as modulators of chemokine receptor activity. Marmnalian chemolcine receptors provide a taiget for interfering with 01" promoting eosinophil and/or lymphocyte function in a mammal, such as a human. Compounds which inhibit or promote chemokine receptor function, are particularly useful for modulating eosinophil and/or lymphocyte function for therapeutic purposes. Accordingly, compounds which inhibit or promote chemokine receptor function would be useful in treating, preventing, ameliorating, controlling or reducing the risk of a wide VEtriety of inflammatory and immunoregulatory disorders and diseases, aliergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. For example, an instant compound which inhibits one or more functions of a mammalian chemokine receptor (e.g., a human chemokine receptor) may be administered to inhibit (i.e., reduce or prevent) inflammation. As a result, one or more inflammatory processes, such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, is inhibited. In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens). Diseases and conditions associated with inflammation and infection can be treated using the compounds of the present invention. In a preferred embodiment, the disease or condition is one in which the actions of lymphocytes are to be inhibited or promoted, in order to modulate the inflammatory response. Diseases or conditions of humans or other species which can be treated with inhibitors of chenioldne receptor function, include, but are not limited to: inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, particularly bronchial asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), delayed-type hypersentitivity, interstitial lung diseases (ILD) (e.g., idiopatiaic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic Jupus erythematosus, ankylosing spondylitis, systeniic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., 10 penicillin, cephalosporins), insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis, Behcet's disease; graft rejection (e.g., in transplantation), including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory deimatoses such an dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eosinphilic myositis, eosinophilic fasciitis; cancers with leukocyte infiltradon of the viscera! larva migraines (e.g., Toxocaia), eosinophilic gastroenteritis (e.g.. Anisald sp., Fhocanema sp.), and cutaneous iarva inigraines (Anoylostona braziliense, Ancylostoma caninum). In addition, treatment of tiie aforementioned inflammator}, allergic and autoimmune diseases can also be contemplated for promoters of chemoldne receptor function if one contemplates the delivery- of sufficient compound to cause the loss of receptor expression on cells through the induction of chemokine receptor mtermalization or delivery of compound in a manner thai results in the misdirection of the migriUion of cells. The compounds of the present invention are accordingly useful in treating, preventing, ameliorating, controlling or reducing the risk of a wide variety of inflammatory and immunoregulatory disorders and diseases, allergic conditions, atopic conditions, as well as autoimmune pathologies. In a specific embodiment, the present invention is directed to the use of the subject compounds for treating, preventing, ameliorating, controlling or reducing the risk of autoimmune diseases, such as rheumatoid arthritis or psoriatic arthritis. In another aspect, the instant invention may be used to evaluate putative specific agonists or antagonists of chemoidne receptors, including CCR-3. Accordingly, the present invention is directed to the use of these compounds in the preparation and execution of screening assays for compounds which modulate the activity of chemokine receptors. For example, the compounds of this invention are useful for isolating receptor mutants, which are excellent screening tools for more potent compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other compounds to chemokine receptors, e.g., by competitive inhibition. The compouads of the instant invention are also useful for the evaluation of putative specific modulators of the chemokine receptors, including CCR-2. As appreciated in the ait, thorough evaluation of specific agonists and antagonists of the above chemokine receptors has been hampered by the lack of availability of non-peptidyl (metabolically resistant) compounds with high binding affinity for these receptors. Thus the compounds of this invention are conunercial products to be sold for these purposes. The present invention is further directed to a method for the manufacture of a medicament for modulating chemokine receptor activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent. The present invention is further directed to the use of the present compounds in treating, preventing, ameliorating, controiling or reducing the risk of infection by a retrovirus, in particuiar, herpes virus or the human immunodeficiency virus (HIV) and the treatment of, and delaying of the onset of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HTV is defined as including, but not limited to, treating a wide range of states of HTV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actua] or potential exposure to HTV. For example, the compounds of this invention are useful in treating infection by HTV after suspected past exposure to HTV by, e.g., blood transfusion, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery. In a preferred aspect of the present invention, a subject compound may be used in a method of inhibiting the binding of a chemokine to a chemokine receptor, such as CCR-2, of a target cell, which comprises contacting the target cell with an amount of the compound which is effective at inhibiting the binding of the chemokine to the chemokine receptor. The subject treated in the methods above is a mammal, preferably a-human being, male or female, in whom modulation of chemokine receptor activity is desired. "Modulation" as used herein is intended to encompass antagonism, agonism, partial antagonism, inverse agonism and/or partial agonism. In a preferred aspect of the present invention, modulation refers to antagonism of chemokine receptor activity. Combined therapy to moduiate chemoldne receptor activity for thereby treating, preventing, ameliorating, controlling or reducing the risi; of inflarmnatory and immoreregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arttiritis and atheroscierosis, and those pathologies noted above is illustrated by the combination of the compounds of this invention and other compounds which are known for such utilities- For example, in treating, preventing, ameliorating, controlling or reducing the risk of inflammation, the present compounds may be used in conjunction with an antiinflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleulcin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine-suppressing antiinflammatory agent, for example with a compound such as acetaminophen, aspirin, codeine, embrel, fentanyl, ibuprofen. indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like. Similarly, the instant compounds may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazohne, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, ot dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of the pressent invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention. Examples of other active ingredients that may be combined with a compound of the present invention, either administered separately or in the same pharmaceutical compositions, include, but are not hmited to: (a) VLA-4 antagonists such as those described in US 5,510,332, W095/15973, WO96/01644, WO96/0610S, WO96/20216, W096/22966, WO96/31206, WO96/40781, WO97/03094, WO97/02289, WO 98/42656, W098/53S14. W09S/53S17, W09S/53S1S, WO9S/54207, and WO98/58902; (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone. and hydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus, rapamycin and other FK-506 type immunosuppressants; (d) antihistamines (Hl-histamine antagonists) such as bromopheniramine, chlorpheniramine, dexchiorpheniramine, triprolidine, clemastine, diphenhydramine, diphenyipytaline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, desloratadine, cetirizine, fexofenadine, descartwethoxyloratadine, and the like; (e) non-steroidal anti-asthmatics such as b2-agonists (terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitoJterol, and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (zafirlukast, montelukast, pranlukast, iralukast, pobilukast, SKB-106,203), leukotriene biosynthesis inhibitors (zileuton, BAY-I005); (f) nonsteroidal antiinflammatory agents (NSAIDs) such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, oxyphenbutazone, phenylbutazone); (g) cycIooxygenase-2 (COX-2) inhibitors; (h) inhibitors of phosphodiesterase type IV (PDE-IV); (i) other antagonists of the chemokine receptors, especially CCR-1, CCR-2, CCR-3, CXCR-3 and CCR-5; (j) cholesterol lowering agents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, rosuvastaiin, and other statins). sequestrants (cholestyramine and colestipol), cholesterol absorption inhibitors (ezecimibe), nicotinic acid, fenofibric acid derivatives (gemfibrozii, clofibrat. fenofibrate and benzafibrate), and probucol; (k) anti-diabetic agents such as insulin, sulfonylureas, biguanides (metformin), a-glucosidase inhibitors (acarbose) and gIita2ones (troglitazona and pioglitazone); (!) pveparations of mierferon beta (interferon beta-la, interferon beta-l|3); (m) other compounds such as 5-aminosalicylic acid and prodrugs thereof, antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxic cancer chemotherapeutic agents. The weight ratio of the compound of the present invention to the second active ingredient may be varried and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSAID the weight ratio of the compound of the present invention to the NSAID will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each acdve ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction, in addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s). The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemai injecdon or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invenrion are effective for use in humans. The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the an of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispeisible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and :r Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carhoxymethylcellulose, methylcellulose, hydroxy- propyimethylcellulose. sodium alginate, polyvjnyl-pyiTolidone, gum tvagacanth and gura acacia; dispersing OY wetting agents may be a natiiraUy-occLimng phosphatide, for example iecithin, or condensation products of an alkylene oxide with fatty acids, for example pohoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethy[ene-oxycetano[, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyechyiene sorbitol monooleare, or condensation products of ethylene oxide with pania] esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydros.yben2oate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water piovide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oJl-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occuning phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbiian monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formuiations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringeris solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds of the present invention may also be administered in the form of suppositories for rectal administrarion of the drug. These composirions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles.) rag/kg per day; more preferably about 0.5 to about 100 n^/I^ per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg JKI day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of die active ingredient, preferably 2.0 to 500, more preferably 3.0 to 200, particularly 1, 5, 10, 15, 20, 25, 30, 50,75, 100, 125, 150,175,200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administei-ed on a regimen of 1 to 4 times per day, preferably once or twice per day. It will be understood, hov\ever, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a vaiiety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex. diet, mode and time of administration, rate of excretion, drug combmation, the severity of the paiticular condition, and the host undergoing therapy. Several methods for preparing the compounds of this invention are illustrated in the following Examples. The subject compounds may be prepared by modification of the procedures disclosed in the Examples as appropriate. Starting materials are made by known procedures or as illustrated. The following examples are provided for the purpose of further illusti-ation only and are not intended to be limitations on the disclosed invention. The following are representative procedures for the preparation of the cotnpounds used in the following Examples or which can be substituted for the compounds used in the following Examples which may not be conmercially available. Concentration of solutions was generally carried out on a rotary evaporator under reduced pressure. Flash chromatography was carried out on silica gel {230-400 mesh). MPLC refers to medium pressure liquid chromatography and was carried out on a silica gel stationary phase unless otherwise noted. NMR spectra were obtained in CDCI3 solution unless otherwise noted. Coupling constants (J) are in hertz (Hz). Abbreviations: diethyl ether (ether), triethylamine (TEA), N,N-diisopropylethylamine (DIEA) saturated aqueous (sat'd), room temperature (rt), hour(s) (h), minute(s) (nain). In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention. Concentration of solutions was generally carried out on a rotary evaporator under reduced pressure. Flash chromatography was carried out on silica gel {230-400 mesh). NMR spectra were obtained in CDCI3 solution unless otherwise noted. Coupling constants (J) are in hertz (Hz). Abbreviations: diethyl ether (ether). triethyiamine (TEA), RN-diisopropylethylamine (DIEA) saturated aqueous (sat'd), room temperature (rl), hour(s) (h), miiiute(s) (min). The following are representative Procedures for the preparation of the compounds used in the following Examples or which can be substituted for the compounds used in the following Examples which may not be commercially available. INTERMEDIATE 1 Intermediate 1 was prepared according to the procedure described in J. Am. Chem. Soc, 1991,113, 2079-2089. INTERMEDIATE 2 To a solution of terahydro-4H-pycan-4-Qne (5.0 g, 50 mmol) and hexamethylphosphoramide (8.70 mL) in tetrahydrofuran (150 mL) was added slowly a solution of Kthium diisopropylamide (31.25 mL, 2 M solution) in 125 mL of tetrahydrofuran at -78 °C. The reaction mixture was stirred for 5 min and then ethyl iodide was added (16.0 mL, 200 mmol). The mixture was gradually wanned to 0 C over 2 h. The reaction mixture was quenched with a saturated solution of NH4C1 and then extracted with ether (4 x 100 mL). The ether layer was washed with brine, dried (anhydrous magnesium sulfate), concentrated, and purified by flash column chromatography eluting with hexanes/ethyl acetate (4:1) to give Intermediate 2 (1.20 g.20%). Step A To a mixture of 5,6-dihydro-4-methoxy-2H-pyran (10.0 g, 875mmol) in methanol (200 mL) at 0 °C was added dropwise a solution of 3-chloroperoxy-benzoic acid (30.2 g, 175 mmol) in methanol (50 µL) via an addition funnel. The resulting solution was stirred for 5 h allowing it to warm to room temperature. The methanol was removed under reduced pressure affording a white solid- The material was dissolved in 500 mL of dichloromethane and cooled to 0C. To the mixture, while stirring vigorously, was added in portions an excess of solid calcium hydroxide (50-60 g). After stirring an additional 30 min, the mixture was filtered through a plug of celite and the filtrate was evaporated under reduced pressure to afford 11.62 g (S2%) of the desired product as a clear oil, 'HNMR (500 MHz ,CDCl3) 5 3.8So.S0 (ra, 2H), 3.73-3.68 (m, 2H), 3.54-3.4S (m, IH), 3.2S (s, 3H), 3.27 (s. 3H), 2.00-1.93 (m, IH). l.S2-1.77(m, IH). StepB To a cooled (0 °C) solution of the product from Step A, Intermediate 3 (9.40 g, 58.0 mmol) in tetrahydrofuran (200 mL), under nitrogen, was slowly added NaH (2.32 g, 58.0 mmol) and the resulting slurry was stirred for 1 h at 0 °C. lodomethane (7.22 mL, 116 mmol) was then added via syringe to the slurry and the resulting mixture was stirred overnight allowing it to warm to room temperature. The reaction was quenched with a saturated solution of ammonium chloride (200 mL) and the organic layer was then removed using a separatory funnel. The aqueous layer was extracted with ether (3 x 150 mL) and all the organics were combined, dried over anhydrous sodium sulfate, filtered, and evaporated m vacuo. Purification was accomplished by flash column using a stepwise gradient eluant of 10-60% ether/hexanes to afford S.46 g (83%) of the desired product as a clear oil. ^H NMR (500 MHz,CDCl3) 5 3.98 (dd, ] = 2.5, 12.4 Hz, IH), 3.77 (ddd, J = 3.5,7.1, 10.8 Hz, IH), 3.57 (dd, J = 1.4, 12.4 Hz, IH), 3.50 (dd, J = 2.5, 11.7 Hz, IH), 3.46 (s. 3H), 3.25 (s, 3H;, 3.22 (s, 3H), 3.22-3.20 (m, IH), 1.96 (ddd, J = 4.7,11.8,16.5 Hz, IH), 1.75 (br dd, J = 1.7,14.2 Hz, IH). Slep C A solutioB of the product from Step B, Intermediate 3 (3.0 g, 17.04 mmol) in tetiahydrofuran/water (60 mL/10 mL) was treated with concentrated hydrochloric acid (6 mL) and the resulting solution was stined at room temperature for 1 h. The mixture was concentrated in vacuo to remove the tetrahydrofuran and the aqueous layer then extracted with ether (6 x 50 mL). The organics were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford intermediate 24 (L75 g, 79%) as a clear oil. "H NMR (500 IvIHz, CDCis) 5 4.23 (ddd, J = 1.2, 11.4, 12.4 Hz, IH), 4.15-4.09 {m, IH), 3.S2 (dd, J = 5.95, S.7 Hz, IH), 3.74 (ddd, J = 5.5, 8.5,13.6 Hz, IH), 3.56 (dd, J = 8.8, U.3 Hz, IH), 3.50 (s, 3H), 2.61 (app dd, J = 5.0, 8.9 Hz, 2H). INTERMEDIATE 4 This intermediate was prepared in an analogous fashion to that of Intermediate 3, except iodomethane was replaced with iodoethane. Purification by MPLC (gradient elution from 0-40% ethyl acetate/hexanes) afforded 683 mg (66%) of the final compound as a clear oil. USTERMEDMTES To a mixture of 5.6-dihydro-4-methoxy-2H-pyran (0.5 g, 4 mmol) in acetonitrile/water(15 mL, 1:1) at room temperature was added l-(chloromethyl)-4-f]uoro-l,4-dia2omabicyclo[2.2.2.]octane bis(tetrafluoroborate) (1.5 g, 4.4 mmol, SELECTFLUORTM) in one lot and the resulting reaction mixture was stirred at room tempeature until completion- Solid NaCl was then added and the reaction mixture was then extracted with ether (4 x 50 mL). The ether layer was dried (anhydrous magnesium sulfate) and concentrated to yield 0.34 g (65%) of the title compound that required no further purification. IH NMR (500 MHz, CDC]}): d 4.95 (m, IH), 4,4-4.21 (m, 2H), 3-72-3-65 (m, 2H), 2.75 (m. 2H). INTERMEDUTE 6 A mixture of tetrahydro-4i?-pyran-4-one (10.0 g, 100 mmol) and pyn'olidine (11 g, 150 mmol) was stirred at room temperature for 1 h. The excess pyrrolidine was removed in vacuo and the residue was dried overnight under high vacuum. The enanune was obtained i^ a yellow liquid (14.7 g) which was. used in the next step without further purification. StepB The enamine, prepared in Step A, Intermediate 6 (1.54 g, 10 mmol) and 4-N,N-dimethylpyridine (1.22 g) were treated with N,N-dimethylformamide (25 mL). The mixture was cooled to 0 °C and solid 5-(trifluoromethyl)dibenzothiophen-ium trifluoromethanesulfonate (4.0 g, 10 mmol) was added. The resuking mixture was stirred at 0 °C for 1 H, then quenched with 30 mL of concentrated aqueous HCI. The resulting mixture was stin-ed for 2 h and then extracted with ether (4 x 70 mL). The combined ether layers were washed with water (50 µL) and brine (50 mL), dried over Na2S04, filtered, and evaporated. The residne was purified on silica gel (eluant; 10% ether/hexanes) to yield two components. The more polar component (200 mg) was the desired product. 'H-NMR showed that it might exist in a semi-ketal form. 'H NMR (500 MHz, CDC13) 5 4.43-3.38 (m, 5H), 3.24, 3.18 (ss, 3H) 2.52 (m, IH), 1.S2 (m, IH). The less polar product (100 mg) was confirmed as alpha-alpha' di-trifluoromethyl tetrahydro-4H-pyran-4-one. 'HNAVIR (500 MHz, CDCi-.) S4.59 (dd, 2H), 3.24, 3.80 (t, J = U.3 Hz, 2H) 3.42 (m, 2H). To a solution of 5-trifIuoromethyl-2-pyridinal (51 g, 310 mmol) and sodium acetate (26.2g. 319 mmol) in glacial acetic acid (200 mL) was added bromine (16.7 mL, 325 mmol) and the resulting mixture was heated at SO °C for 2.5 h. The reaction was allow to cool to room temperature and then was evaporated under reduced pressure. The residue was neutralized with saturated NaHCOs solution and extracted with ethyl acetate (3 x 200 mL). The organics were combined, dried overMgS04. filtered, and evaporated in vacuo to yield 74.45 g (98%) of the cmde prodiKt ^H NMR (400 MHz, CDCb) 5 8.04 (d, J=2.6 Hz, IH), 7.89 (m, IH). Step B Under nitrogen, the substituted pyridine described in Step A, Intermediate 7 (48.8g, 202 mmol) was added in small portions to a suspension of NaH (8.9 g, 220 mmol) in anhydrous tetrahydrofuran (500 mL). After complete addition of the intermediate, the reaction mixture was cooled to -78 °C and treated with rerr-butyilithium (260 mL, 444 mmol) added dropwise via synnge. After stirring for 5 min. N,N-dimethyiformamide (50 niL, 707 mmol) was added slowly to rnaintain the temperarure below -50 °C. The resulting mixture was then sdrred for 10 h allowing it to warm to room temperature. The mixture was quenched with 2 N HCl and then diluted with ethyl acetate (1000 mL). The organic layer was sepm-ated, washed with brine, dried over MgS04, and evaporated in vacuo. The desired product was precipitated out of ethyl acetate and hexanes and filtered to yield a light brown solid (2S,55 g. 74%). 'H NTVIR (500 MHz. CD:,OD) 5 10.13 (s, !H), S.2L (s,2H). SlepC A mixture of the intermediate from Step B, Intel-mediate 7 (18 g, 95 mmol), sodium formate (7.1 g, 110 mmol), hydroxylamine hydrochloride (7.3 g, 110 mmol), and fomuc acid (150 mL) was stirred at room temperature for 2 h and then heated to reflux Dvemight. The reaction mixture was cooled and allowed to stand at room temperature for 7 days. The reaction was poured into water and extracted with ethyl acetate (3 x). The combined organic layers were washed with water (2 x), saturated NaHC03 and brine, dried over Na2S04, filtered, and concentrated in vacuo to yield the desired product as a brown powder (17.84 g, 90%). 'H NMR (400 MHz, CD3OD) 5 8.37 (d, J=2.7 Hz, IH), S.19 (q, J=0.7 Hz, 0.3 Hz, IH). StepD To a mixture of phosphorous oxychloride (13.4 mL, 144 mmol) and quinoline (S.7 mL, 73 mmol) was added the product from Step C, Intermediate S, (24.6 g, 131 mmoi) and the resulting mixture was heated to reflux for 3 h. The reaction was cooled to 100 °C before water (70 niL) was slowly added. The mixture was further cooled to room temperature and neutralized carefully with samrated NaHCO3 solution. The aqueous layer was extracted with ethyl acetate (3 x) and the organic layers were combined, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography to afford (23.5 g, 87%) of the desired compound. 1H NMR (500 MHz, CDCl2) 6 8.SS (d, J=2.0 Hz, IH). S.26 (d, 1=2.5 Hz, IH). Step E To a suspension of NaH(7.8 g, l00mmol) in tetrahydrofuran (100 mL) under nitrogen was added dropwise a solution of tert-butyl methyl malonate (20 mL, 120 mmol) in anhydrous tetrahydrofuran (100 mL) via syringe. The reaction mixture was stirr'ed for 0,5 h before a solution of the intermediate prepared in Step D, Intermediate S (20.1 g. 97.6 mmol) in tetrahydrofuran (200 mL) was added slowly via syringe. The reaction was stirred at room temperalure overnight, then quenched with a saturated solution of NH4CI. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x). The combined organic layers were washed with water (3 x), dried over Na2SO4, filtered, and evaporated in vacuo. Flash chromatography afforded 31.76 g (95%) of the pure desired product. 1H NMR (500 MHz, CDCI3) 5 9.03 (d, 1=1.5 Hz, IH), 8.25 (d, J=2.0 Hz, IH), 5.25 (s, IH), 3.S6 (s, 3H), 1.52(s,9H). Step F A suspension of RaneyNi (1 g) and the product from Step E, Intennediate 7 (18.2 g, 52.9 mmol) in ethanol (130 mL) was placed on a Parr apparatus and hydrogenated at 40 psi H2 overnight. The suspension was filtered through celite and the filtrate was evaporated in vacuo to afford 16.35 g (98%) of the crude product. 'H NMR (500 MHz, CDCI3) 5 8.83 (s, IH), 7.89 (s, IH), 7.82 (s, IH), 4.83 (d, J=16 Hz, IH), 4.72 (s, IH), 4.49 (d, J=16 Hz, IH), 1.45 (s, 9H). StepG To the mixture of the product from Step F, Intermediate 7 (16 g, 51 mmo!) in dichloromethane (60 mL) was added TFA (30 mL) and the resulting mixture was stiiTed 0.1 room temperature for 0.5 h. The solution was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The mixture was neutralized by the slow addition of a solution of saturated sodium bicarbonate and the organic layer was removed. The aqueous layer was extracted with dichloromethane (4 x) and the combined organic layers were dried over NaiSO2. filtered, and evaporated in vacuo to afford 10.42 g (95%) of the desired product. 'H NISIR (400 MHz, CDCI3) 6 S.S 1 IS, IH), 7.78 (s, IH), 7,30 (s, IH), 4.63 (s, 2HX 3.90 (s. 2H). StepH To a solution of the product from Step G, Intermediate 7 (IS.O g, S3.3 mmol) in tetrahydrofuran (50 mL) was added 1.0 M borane in tetrahydrofuran (417 raL, 420 mmol) and the resulting solution was stirred at room temperature overnight. The solution was evaporated under reduced pressure and the residue was treated with 1% HCl/ methanol solution. The resutling mixture was heated at 50 °C overnight to breakdown the borane complex. Treatment with acidic methanol was repeated twice to insure that the borane complex was removed. A solution of this crude product (S3.3 mmol, assuming 100% conversion) and diisopropylethylamine (43 mL, 250 mmol) in dichloromethane was treated with di-tert-butyl dicarbonate (36.4 g, 167 mmol) and the resulting mixture was stirred at, room temperature overnight. The solution was washed with saturated sodium bicarbonate solution, water, and brine. The aqueous layers were combined and back-washed with dichloromethane (2 x). The combined organic layers were then dried over Na2S04, filtered, and evaporated to dryness. The crude product was purified by flash chromatography and MPLC to afford (11.89 g, 47%) as a yellow solid. 'H NMR (500 MHz, CDCI3) 5 8.69 (s, IH), 7.66 (s, IH), 4.67 (s, 2H), 3.79 (t, J=6.0 Hz, 2H), 3.08 (t, J=5.5 Hz, 2H), 1.51 (s, 9H). Step I The product described in Step R Intermediate S (11.S9 g) was treated with a solution of 4 N HCl in dioxane. The solution was stirred at room temperature for 2 h and then evaporated in vacuo to afford Intermediate 8 {10.85 g, 99%) as a yellow powder. LC-MS for C9H10F3N2 calculated 202.07, found [M+H] + 203.0. INTERMEDIATE 8 Procedure A: Step A A mixture of (15)-(+)-2-azabicyclo[2.2.1]hept-5-en-3-one (10.3 g, 94.4 mmol) in ethyl acetate (200 mL) and 10% Pd/C (0.5 g), was hydrogenated at room temperature. After 24 h the reaction mixture was filtered and evaporated leaving behind 10.4 g (100%) of the product that was taken in 250 mL methanol and HCl (12 M, 6 mL). The resultant mixture was stirred at room temperature, until the reaction was complete (72 h). Evaporation of methanol followed by drying under high vacuum, yielded title compound as an offwhite solid (16.0 g, 96%). 'HNMR(500MH2,D20): 5 3.70 (s, 3H), 3.01 (m, IH), 2.38 (m, IH), 2.16-1.73 (m, 6H). Step B' To a suspension of the intermediate from Step A (10.2 g, 56,8 mmol) in dry dichloromethane (200 mL) was added benzophenone imine (10.2 g, 56.8 mmol) at room temperature and the resultant mixture was stirred for 24 h. The reaction mixture was filtered and the filtrate was evaporated, to leave behind a yellow oil that was triturated with ether (l00 mL), filtered and evaporated. This operation was repeated twice to ensure that the product was free of ammonium chloride impurities. The resultant oil was thoroughly dried under vacuum to yield the title compound (18.03 g, >100%) and required no further purification. IH NMR (500 MHz, CDC13): 5 7.5-7.18 (m. lOH), 3.75 (m, IH), 3.7 (s. 3H), 2,78 (m. IH), 2.26-1.71 (m, 6H). Step C To a solution of lithium diisopropylamide (prepared from diisopropylamine (7.7 g, 16 mmol) andn-butyllilhium (30.4 mL. 2.5 Min hexanes, 76 mnMl) in telrahydrofuran (120 mL) at -78 °C was added the ester from step B (IS.O g. 58.6 mmol). The resultant burgundy colored solution was stirred for 20 min after which it was quenched with 2-iodopropane (14.9 gm, SS mmol). The reaction mixture was gradually warmed over 3 h to 0 °C and this temperature was maintained for an addidonal 3 h. Reaction was quenched with water and extracted with ethyi acetate. The organic layer was washed with water, brine, dried (anhydrous magnesium sulfate) and concentrated to yield an oil. To the solution of the crude Schiff base (20.0 g) in tetrahydrofuran (100 mL) was added HCl (5.0 mL, 12 M). The resulting reaction mixture was allowed to stir at room temperature for 3 h. After the removal of all volatiies, the hydrochloride salt was taken up into dichloromethane (250 mL), saturated solution of sodium bicarbonate (250 mL) and di-tert-butyl dicarbonate (26.0 g, 1.4 Eq.) were added. The resultant mixture was vigorously stirred overnight at room temperature. The organic layer was sepai-ated and washed with water, brine, dried (anhydrous magnesium sulfate) and concentrated to yield an oil. Purification by flash column chromatography (eluent: hexanes/ethy! acetate 19 : 1) gave the desired product (4.91 g, 30%). IH NMR (500 MHz, CDC13): 4.79 (br, IH), 4.01 (m, IH), 3.71 (s, 3H), 2.1S-1.60 (m, 6H), 1.44 (s, 9H), 0.87 (d, J = 6.9 Hz, 3H), 0.86 (d, J = 6.9 Hz,3H). StepD To a solurion of .the ester from Step C (4.91 g, 17.2 mmol) in methanol (100 mL) was added a solurion of LiOH (3.6 g, 85 mmol) in water (20 mL) and tetrahydrofuran (10 mL). The resultant mixture was heated at 80C until the reaction was complete (IS h). The methanol was removed in vacuo and the crude product was taken up with water/ethyl acetate (200 mL, 1:4) and cooled to 0 °C. The acidity of the mixture was adjusted to pH 6. The ethyl acetate layer was separated, washed with water, brine, dried (anhydrous magnesium sulfate) and concentrated to yield an oil. Purirication by flash column chromatography (eluent: hexanes/ethyl acetate 1:1 + 2% AcOH) gave IntenTiediate8(3.9g, 84%). IHNMR (500 MHz, CDC13): 11.36 (br, IH), 6.49 (br, IH), 4,83 (m, IH), 3.71 (s, 3H), 2.30-1.55 (m, 6H), 1.46 (s, 9H), 0.94 (d, J = 6.9 Hz, 3H),0.933Cd,J = 6.9Hz,3H). Procedure B: Step A: Commercially available (lR,4S)-4-annnocyclopent-2-ene-l-carboxylic acid was converted to its methyl ester hydrochloride salt via classical procedures. Step B: To a suspension of amine from Step A (6.31 g, 35.5 mmol) in acetone (40 mL) and water (20 mL) was added solid NaHCOa (6.6 g, 78 mmol) in portions. After 5 min, a solution of di-/err-butyl dicarbonate (S.5 g, 39 mmol) in acetone (60 mL) was added and the reaction mixture was stirred at room temperature. After 3 h, acetone was removed in vacuo and the residue was partitioned between ether (500 mL) and saturated aqueous NaHC03 solution (120 mL). The ether layer was further washed with aqueous NaHCOa solution (1 x 100 mL), brine (1x100 mL), dried over anhydrous Na2S04, concentrated and purified by flash chromatography (15% ethyl acetate/hexanes) to afford the product (7.25 g, S5%). Step C: To a solution of lithium bis(trimethylsilyl)amide (10.4 g, 62.1 mmol) in tetrahydrofuran (100 mL) was added a solution of the intermediate from Step B (6.71 g, 27.8 mmol) in tetrahydrofuran (10 mL) over 10 min at-7S °C. The resulted solution was stirred at -78C for 30 min before isopropyl iodide (3.3 mL. 33 mmol) was added in one portion. The reaction was allowed to warm up to -25C and this temperatm*e was maintained overnight. The reaction was then quenched with an aqueous saturated NH4CI solution (250 mLV The organic layer was separated and the aqueous layer was further extracted with diethyl ether (3 x 100 mL). The combined organic layers were then washed with brine (1 x 100 mL), dried over anhydrous Na;SO.+ filtered, concentrated and purified by flash chromatography (5-10% ethyl acetate/hexanes) to give the product (5.66 g, 72%) as a clear oil (cis/trans = 4.3/1). H NMR (500 IvlHz, CDCh) cis-isomer 6 5.79 (s, 2H), 4.75 (m, IH), 3.72 (s, 3H), 2.28-2.20 (m. 2H), 2.0 (dd, J = 15,4 Hz, IH), 1.45 (s, 9H), 0.85 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 7 Hz, 3H). Step D: To a solution of the product from step C (1.6 g, 5.7 mmol) in tetrahydrofuran (50 mL), methanol (50 mL) and water (10 mL) was added LiOH monohydrate (400 mg) and the reaction was heated to reflux overnight until the TLC indicated that the reaction was complete. The organic solvents were removed in vacuo and the aqueous layer was washed with ether (1 x) and then acidified slowly with concentrated HCl until the pH reached 4. The resulting suspension was extracted with CH2CI2 (3 x). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated to give the product as a mixture of two cis/trans isomers (1.5 g) as a foaming yellow solid. This soHd was dissolved in ethyl acetate (2 mL) with heating and diluted with hexanes (50 mL) to give a cleai' solution. This solution was allowed to cool to room temperate slowly over 1 h and then maintained at -25 °C in a freezer overnight. The trans-isomer was crystalized out along with some of the desired cis-isomer (500 mg total). The mother solution was collected and concentrated to give the title compound (1 g, 66%, cis-isomer only). 'H NMR (500 MHz, CDCI3) cis-isomen 6 5.S0 (m, 2H), 4.S0 (m, IH), 2.40-2.20 (m, 2H), 2.15-2.0 (m, IH), 1.5 (m, 9H), 1.0-O.S (m, 3H). Step E: To a solution of the product from Step D (1 g) in ethanol (30 mL) was added 10% Pd/C (100 mg) and the resulting mixture was agitated on a Parr apparatus at 50 lb pressure of H2 overnight. The mixture was filtered through celite and concentrated in vacuo to afford the title compound (1 g, 99%). lHNMR(500WHz, CDCD): 11.36 (br, IH), 6.49 (br, IH), 4.83 (m, IH), 3.71 (s, 3H), 2.30-1.55 (m, 6H), 1.46 (s, 9H), 0.94 (d, J = 6.9 Hz, 3H), 0.933 (d, J = 6.9 Hz, 3H), INTERMEDIATE 9 Step A Intermediate 8 (4.6 g, 16 mmol) and Intermediate 11 (4.0 g, 14 mmol) were first dried by azeotropic distillation with toluene (3x 50 mL) and placed under high vacuum for 30 min. Under nitrogen, 4-dimethylaminopyridine (1.08 g, 8.60 mmol), anhydrous dichloromethane (40 mL), and diisopropylethylamine (7.0 mL, 40 mmol) were added sequentially. After Intermediate S was in solution, bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (6.80 g, 14.3 mmol) was added, immediately followed by additional diisopropylethylamine (7.0 mL, 40 mmol). The reaction mixture was stirred at room temperature overnight and then quenched with saturated NaHCO3. The aqueous layer was back washed with dichloromethane (3 x 50 mL) and the organic layers were combined, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography (stepwise gradient 0-60%, ethyl acetate/hexanes) to afford the product (4.S0 g, 74%) a yellow foam. 'H NMR (500 MHz, CDCL3) 6 S.72 (s. IH), 7.70 (s, IH), 4.SS (br J = 17.0 Hz, IH), 4.7S (d, J = 17.6 Hz, IH), 4.04-3.S4 (ir.. 2 H>, 3.52 (br s, IH), 12(brt,J = 5.6Hz, IH), 2,32-2.06 (m, 3H), 1.98-1.70 (rr.4Hi. 1.64-1.54 (m. IH), 44 (s. 9H), 0.92-0.82 (m. 6H). LC-MS for C23H32F3N30= :alcu]ated 455,24, found ■1+H]+ 456.2. epB le from StepB, Intermediate 19 (1.2 g, 2.6 mmol) was dissolved with 4 NHCl in oxane (50 mL) and the resulting solulion was stilted at rocm temperature for 1 h. le reaction was evaporated under vacuum to afford the product (904 mg, 97%) as a lite powder. LC-MS calculated for C1SH24F3N3O is 355.20. found [M+H]^ 356.2. To a solution of the product described in Step A, Intermediale 19 (2.0 g, 4,4 mmol) in dichloromelhane (80mL) was added 3-chloroperoxybenzoic acid (2.11 g, 8.83 mmol) and the resulting solution was stirred overnight at room temperature. The mixture was cooled to 0 °C and while stirring vigorously, solid calcium hydroxide was added in portions (about 6 g). The suspension was stirred for an additional 30 min, then filtered through celite to remove all solids. The filtrate was evaporated in vacuo and the residue was purified by MIPLC (gradient eluant 40-100% ethyl acetate/hexanes) to afford 1.32 g (64%) of the desired compound. 'H NMIR (500 VlHz, CDCL3) 6 8.46 (s, IH), 7.28 (s, IH), 4.SS (br d. J = 17.2 Hz, IH), 4.78 (d, J = 17.7 Hz, IH), 4.05-3.84 (m, 2 H), 3.12 (bi- s, IH), 2.34-2.06 (ra, 3H), 1.88-1.70 (m, 4H), 1.62-1.54 (m. IH), 1.43 (s, 9H), 0.90-0.85 (m, 6H). LC-MS for C2SH32F3N3O5 calculated 471.20, found [M+H]^ 472.2. Steps The product from Step B, Intermediate 20 (1.32 g, 2.82 mmol) was dissolved in 4 N HCl in dioxane (50 mL) and the resulting solution was stirred at room temperature for 1 h. The reaction was evaporated under vacuum to afford the product (1.10 g, 98%) as a white powder. LC-MS for C18H24F3N3O2 calculated 371.20, found [M+H]"" 372.2. EXAMPLE 1 A solution of Intermediate 9 (890 mg, 2.08 mmol), tetrahydro-4H'-pyran-4-one (320 mg, 3.13 mmol), diisopropylethylamine (1.10 mL, 6.24 mmol) and crushed molecular sieves (4 A, 500 mg) in dichloromethane (50 mL) was treated with sodium triacetoxyborohydride (2.20 g, 10.4 mmol) and stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbcnate solution (50 mL) and diluted with an additional 25 mL of dichloromethane. The organic layer was separated and the aqueous layer was washed with dichloromethane (2 x 25 mL). The organics were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by reverse phase HPLC to yield Example 1 (915 mg, 86.0%). LC-MS for C23H31F3N3O2 calculated 439.24, found [M+H]^ 440.2. EXAMPLE 2 A solution of Intermediate 9 {304 mg, 0.712 mmol), Intermediate 1 (160 mg, 1.42 mmol). disopropylethylamine (370 µL.. 2.14 mmol) and crushed molecular sieves (4 A. 150 mg) in dichloromethane (25 mL) was treated with sodium triacetoxyboro-hydridc (755 mg. 3.56 mmoi) and stirred at room temperature o\ernight. The reaction v\ as quenched with saturated sodium bicarbonate solution (25 µL) and diluted with an additional 25 mL of dichloromethane. The organic layer was separated and the aqueous layer was washed with dichloromethane (2 x 20 mL), The organics were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by preparative TLC (eluant: 0.5% NH;OPI/5% methanol/94.5% CH2CI2) to yield 239 mg (74Tc) of the final product as a mixture of four diastereomers. Cis and trans racemate in reference to the pyran ring were resolved by HPLC equipped with a Preparative ChiralCel OD column (eluant: 59c ethanoI/95% hexanes). Cis racemate was further resolved by using the Preparative ChiralPak AD column (eluant: 5% ethanol/95% hexanes). LC-MS for C24H35F3N3O2 calculated 453.26, found [M+H]"" 454.3. EXAMPLE 3 This product was prepared in an analogous fashion to that of Example 2, except Intermediate 1 was replaced with Intermediate 2. Purification by preparative TLC (eluant: 0.5% NHjOH/ 5% methanoy94.5% CH2CI2) afforded 203 mg (92%) as a mixture of four diastereomers. The single isomers were obtained by purification on an HPLC equipped with a Preparative ChiralCel OD column eluting with 5% ethanol/95% hexmes with a flow rate of 9 mL/min. LC-MS for C25H36F3N3O2 calculated 467.2S, found [M+H]^ 468.3 for all 4 isomer. EXAMPLE 4 This product was prepared in an analogous fashion to Example 2, except Intermediate 1 was replaced with Intermediate 5. Purification by afforded 312 mg {88%) as a mixture of four diastereomers. LC-MS for C30H36CIF3N3O4 calculated 593.23, found [M+H]+ 594.3. To the solution of the product described in Example 4 (286 mg, 0.4S2 mmol) in methanol (5 mL) was added a solution of 0.5 M sodium methoxide in methanol (1.2 mL, 0.58 mmol) and the resulting mixture was stirred at room temperature for 2 h. After completion of reaction, the mixture was evaporated in vacuo and purified by preparative TLC (eluant: 1.0% NH4OH/10% methanol/89% CH2CI2) to yield Example 21 (201 mg, 91-6%) as a mixhire of four diastereomers. LC-MS for C23H33F3N3O3 calculated 455.24, found [M+H]+ 456.25. A solution of Intermediate 9 (500 mg, 1.17 mmol). Intermediate 3 (45S mg, 3.51 mmol), diisopropylethylamine (407 µL, 2.34 mmol) and crushed molecular sieves (4 A. 250 mg) in dichloromethane (25 raL) was treated with sodium tnacetoxyboro-hydride (,1.24- g, 5.85 nimol) and stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate solution (25 mL) and diluted with an additional 25 mL of dichloromethane. The organic layer was sepai-ated and the aqueou5 layer was washed with dichloromethane (2 x 20 mL\ The organics were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by preparative TLC (eiuant: 1.0% NH.OH/10% melhanol/89% CH.Cl:) to yield 210 mg (S6%) of the final product as a mixture of four diastereomers. The single isomers were obtained by using an HPLC equipped with a Preparative ChiraJCel OD column eluting with 20% ethanol and 80% hexanes with a flow rate of 9 mlVmin. LC-MS calculated for C;4H34F3N303 is 469.21, found [M+H]^47Q.2 for ail 4 isomer. S'"* isomer off OD ChiralCel Column: 'H NMR (500 IvIHz, CDCI3) d S.72 (s, IH), 7.69 (s, IH), 4.87 (br d. J = 17.2 Hz, IH), 4.75 (d. J = 17.4 Hz, IH), 4,12 (dd, J = 3,1, 12.4 Hz, IH), 3.99-3.S6 (m, 3H), 3.47-3.39 (m, IH), 3.41 (s, overlapped, 3H), 3.35-3.30 (m, 2H). 3.20-3.0S (m, 3H), 2.87-2.S0 (m, IH), 2.62-2.54 (m, IH), 2.16-2.02 (m, 2H), 1.95 (br s, IH), 1.88-1.81 (m, IH). 1.78-1.57 (m, 6H), 1.41-1.32 (m, IH), 0.96 (d, J = 6.7 Hz, 3H), 0.S4 (d, J = 6.6 Hz. 3H). 4th isomer off OD ChiralCel Column; 'H NIV'IR (500 MHz, CDCI3) d'H NiVK (500 MHz, CDCI3) d8.72 (s, IH), 7.69 (s, IH), 4.S7 (br d, J = 17.6 Hz, IH), 4.75 (d. J = 17.5 Hz, IH), 4.10 (dd, J = 3.1, 12.3 Hz, IH), 3.99-3.SS (m, 3H), 3.46-3.39 (m, IH), 3.41 (s, overlapped, 3H), 3.35-3.30 (m, 2H), 3.17-3.09 (m, 3H), 2.S6-2.80 (ra, IH), 2.64-2.55 (m, IH), 2.16-2.10 (m, IH), 2.05 (br s, IH), 1.95-1.82 (m, 2H). 1.76-1.55 (m, 6H), 1.33-1.24 (ra, IH), 0,95 (d, J = 6.7 Hz, 3H), D.83 (d, J = 6.6 Hz,3H). This product was prepared in an analogous fashion to that of Example 2, except Intermediate 1 was replaced with Intermediate 4. The single isomers were obtained by using an HPLC equipped with a Preparative ChiralCel OD column eiuting with 15% ethanol and 85% hexanes with a flow rate of 9 mL/min. LC-MS for C25H36F3N3O3 calculated 483.23, found [M+H]^484.2 for all four isomers. EXAMPLE S This product was prepared in an analogous fashion to Example 2, except Intermediate 1 was replaced with Intermediate 5. LC-MS for C24H31F4N3O2 calculated 457.23, found [M+H]* 458.2 for all four isomers. EXAMPLE 9 This product was prepared in an analogous fashion to Example 2, except Intermediate 1 was replaced with Intermediate 6. The single isomers were obtained by using an HPLC equipped with a Preparative ChiralCel OD column eluting with 5% ethanol and 95% hexanes with a flow rate of 9 mL/min. LC-MS for C24H31F6N3O2 calculated 507.23, found [M+H]* 508.2 for all four isomers. EXAMPLE 10 A solution of Intermediate 10 (641 mg, 1.60 mmol), tetrahydro-4H-pyran-4-one (220 mg, 2.24 mmol). diisopropylethylamine (279 µL, L60 mmol) and crushed molecular sieves (4 A, 320 mg) in dichloromethane (20 mL) was treated with sodium triaceccxyborohydride (1.70 g. 8.00 mmo!) and stirred at room lemperature for no longer than 5 h. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and diluted with an additional 30 mL of dichloromethane. The organic layer was separated and the aqueous layer was washed with dichlororaechane (2 X 30 mL). The organics were combined, dried over anh\drous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by preparative TLC {eluant; 0.73% NH40H/7.5% methanol/9L7Drr CHrCl^) to yield 626 mg 1,86':^) of the final product. 'HNMR {500MHz, CDCI5) 0 S.45, (s, 3H), 7.25 (s, iH). 4.SS (br d, J = 17.4 Hz, IH), 4.77 (d, J = 17.6 Hz, IH). 4.00-3.S5 (m. 4H). 3.41 (app t. J ^ 11.7 Hz, 2H). 3.22.(p, J = 6.8 Hz, IH), 3.13-3.07 t m. 2H), 2.82-2.74 (m. IHn 2.54-2.47 (m, IH), 2.14 (dd, J = 6.8, 12.8 Hz, IH), 2.07-2.00 (m. IH), 1.94-1.86 (m, 2H). 1.S4-1.77 (m. 3H), 1.65-1.57 (m, 2H), 1.46-1.26 (m, 3H), 0.93 (d, J = 6.S Hz. 3H), 0.83 (d, J = 6.8 Hz, 3H), LC-MS for C23H32F3N3O3 calculated 455.24, found [M+Hl" 456.2. EXAMPLE 11 This product was prepared in an analogous fashion to Example 10, except tetrahydro-4if-pyran-4-one was replaced with Intermediate 1. The single isomers were obtained by using an HPLC equipped with a Preparative ChiralCel OD column eluting with 7% ethanol and 93% hexanes with a flow rate of 9 mL/min. LC-MS for C24H34F3N3O3 calculated 469.24, found [M+H]+470.2, for all four isomers. EXAMPLE 12 This product was prepared in an analogous fashion to Example 10, except tetrahydro-4H-pyran-4-one was replaced with Intermediate 2. The single isomers were obtained by using an HPLC equipped with a Preparative ChiralCel OD column eluting with 5% ethanol and 95% hexanes with a flow rate of 9 mL/min. LC-MS for C25H36F3N3O3 calculated 483.24, found [M+H]'4S4.2, for all four isomers. EXAMPLE 13 This product was prepared in an analogous fashion to Example 10, except tetrahydro-4H-pyran-4-one was replaced with Intermediate 3. The single isomers were obtained by using an HPLC equipped with a Preparative ChiralCel OD column eluting with 21% ethanol and 79% hexanes with a flow rate of 9 mL/min. LC-MS for C24H34F3N3O4 calculated 485.25, found pvl+H]4S6.3, for all four isomers. While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness ofttie mammal being treated for any of the indications with the ' compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable. WAHT IS CLAIMED IS: 1. A compound of the formula 1: wherein; R3 is oxygen or is absent; R8 is selected from: (a) hydrogen, (b) C1-3 alkyl, which is unsubstitated or substituted with 1-6 fluoro, (c) -O-C1-3alkyl, (d) fluoro, and (e) hydroxy; and pharmaceutically acceptable salts thereof and individual diastereomers thereof. 2. The compound of Claim 1 wherein R3 is absent. 3. The compound of Claim 1 wherein R3 is oxygen. 4. The compound of Claim 1 wherein R8 is selected from: (a) hydrogen, (d) trifluoromethyl, (c) methyl, (d) methoxy, (e) ethoxy, (f) ethyl, (g) fluoro, and (h) hydroxy. and pharmaceutically acceptable salts and individual diastereomers thereof. 6. A pharmaceutical composition which comprises an inert carrier and a compound of Claim 1. ^' 7. A method for modulation of chemokine receptor activity in a mammal which comprises the administration of an effective amount of the compound of Claim I. S. A method for the manufacture of a medicament: for modulating chemokine receptor activity in humans and animals comprising combining the compound of Claim 1 with a pharmaceutical carrier or diluent 9. A method for treating, ameliorating, controlling or reducing the risk of an inflammatory and immunoregulatory disorder or disease which' comprises the administration to a patient of an effective amount of the compound of Claim 1. 10. A method for treating, ameliorating, conttolling or reducing the risk of rheumatoid arthritis which comprises the administration to a patient of an effective amount of the compound of Claim 1. 11, A pharmaceutical composition substantially as herein described and exemplified. 12. .A method for the manufacture of a medicament substantially as herein described and exemplified.

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