Abstract:
This invention provides compounds of formula I, having the structure 
                         
 
wherein R 1 , R 2 , R 3 , R 4 , A, and B are as defined in the specification, or a pharmaceutically acceptable salt thereof, that are useful in treating metabolic disorders mediated by insulin resistance or hyperglycemia.

Description:
This application claims the benefit under 35 U.S.C§119(e) to U.S. provisional application Ser. No. 60/371,540 filed Apr. 10, 2002, which is hereby incorporated by reference in its entirety. 
    
    
     BACKGROUND OF THE INVENTION 
     This invention relates to novel compounds of general formula I or pharmaceutically acceptable salts thereof, which lower plasma glucose levels and/or insulin levels in vivo and/or inhibit the production of PEPCK enzyme and/or lower glucose and/or insulin levels in cultured cells and are therefore useful in the treatment of non-insulin dependent diabetes mellitus (NIDDM). Diabetes mellitus is a syndrome characterized by abnormal insulin production, increased urinary output and elevated blood glucose levels. There are two major subclasses of diabetes mellitus. One is the insulin-dependent diabetes mellitus (IDDM or Type 1), formerly referred to as juvenile onset diabetes since it was evident early in life, and non-insulin dependent diabetes mellitus (NIDDM or Type 2), often referred to as maturity-onset diabetes. Exogenous insulin by injection is used clinically to control diabetes but suffers from several drawbacks. Insulin is a protein and thus cannot be taken orally due to digestion and degradation but must be injected. It is not always possible to attain good control of blood sugar levels by insulin administration. Insulin resistance sometimes occurs requiring much higher doses of insulin than normal. Another shortcoming of insulin is that while it may control hormonal abnormalities, it does not always prevent the occurrence of complications such as neuropathy, retinopathy, glomerulosclerosis, or cardiovascular disorders. Insulin regulates glucose homeostasis mainly by acting on two targets tissues: liver and muscle. Liver is the only site of glucose production and skeletal muscle the main site of insulin mediated glucose uptake. 
     Orally effective antihyperglycemic agents are used to reduce blood glucose levels and to reduce damage to the nervous, retinal, renal or vascular systems through mechanisms affecting glucose metabolism. Such agents act in a variety of different mechanisms including inhibition of fatty acid oxidation, a-glycosidase inhibition, antagonism of a 2 -receptors and inhibition of gluconeogenesis. Two classes of compounds have predominated: the biguanides as represented by phenformin and the sulfonylureas as represented by tolbutamide (Orinase®). A third class of compounds which has shown antihyperglycemic activity are the thiazolidinediones. Recently a member (troglidazone) of this family was introduced for the treatment of Type 2 diabetes. 
     PEPCK is present at relatively high specific activity in liver, renal cortex, and white fat (R. M. O&#39;Brien,  Diabetes Care , 1990, 13, 327-339). It catalyzes the conversion of oxaloacetate to phosphonoenolpyruvate, the rate-limiting step in hepatic and renal gluconeogenesis, and it is essential for the synthesis of a-glycerophosphate in adipose tissue. Given that PEPCK catalyzes the rate-limiting step in gluconeogenesis, it is reasonable to conclude that the activity of the PEPCK gene determines the rate of this important metabolic process (E. Sharfir,  Frontiers In Diabetes Research , 1998, John Libbey &amp; Company, Ltd, pp 304-315). PEPCK activity is altered in vivo by glucagon, glucocorticoids, insulin, epinephrine, thyroxine and glucose. The primary effectors are glucagon and glucocorticoids, which increase the synthesis of PEPCK, and insulin, which decreases its synthesis. All of these effects appear to result from alterations in the amount of PEPCK mRNA, which in turn result from changes in the rate of transcription of the PEPCK gene. Gluconeogenesis rates are increased two- to three-fold in patients with NIDDM, and gluconeogenesis is the predominant mechanism responsible for fasting hyperglycemia in NIDDM (A. Consoli, et.al.  Diabetes , 1989, 38, 550-557). Modulation of the transcription of the PEPCK gene may lead to glucose lowering in NIDDM patients. 
     Clinical Correlation: Compounds that inhibit or modulate glucose production in cultured hepatocytes from gluconeogenic precursors should inhibit gluconeogenesis in man and cause a reduction in the circulating plasma glucose level. Known gluconeogenic inhibitors that cause decreases in blood glucose in vivo have been shown to be active in this assay. (References: Berry M N, Edwards A M, Barritt G J. Isolated hepatocytes, preparation properties and applications in laboratory techniques in Biochemistry and Molecular Biology. 1983; 65:55-63; Exton, J. H. The perfused rat liver in Methods in Enzymology XXXIX, part D (Hormone Action), pp 25-36 (1975). Eds.; J. G. Hardman and B. W. O&#39;Malley. Goodman M N. Effect of 3-mercaptopicolinic acid on gluconeogenesis and gluconeogenic metabolite concentrations in the isolated perfused rat liver. Biochem. J. 1975; 150:137-139; Jomain-Baum M, Schramm V L, Hanson R W. Mechanism of 3-mercaptopicolinic acid inhibition of hepatic phosphoenol pyruvate carboxykinase (GTP). J. Biol. Chem. 1976; 251:37-44; Lowry O H, Rosebrough N J, Farr A L, Randall R J: Protein measurement with the Folin phenol reagent. J. Biol. Chem. 1951; 193:265-275; Musmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Meth. 1983; 65: 55-63). 
    
    
     DESCRIPTION OF THE INVENTION 
     The compounds of the present invention, represented by Formula I below, act to inhibit the production of PEPCK enzyme and/or PEPCK mRNA, and/or lower glucose and/or insulin levels in cultured cells, and/or demonstrate oral antihyperglycemic activity in an animal model of NIDDM, namely the ob/ob mouse, and are useful in the treatment of non-insulin dependent diabetes mellitus (NIDDM). 
                        
 
wherein:
     Y is selected from O, S, N, C═C, or C═N;   R 1  is selected from —SO 2 CF 3 , —SO 2 Ar, —SO 2 CH 3 , —SO 2 CH 2 CF 3 , —CONH 2 , —CSNHCH 3 , —CONHAr, —COAr, —COCCl 3 ;   Ar is phenyl, naphthyl, pyridyl, or quinolyl, which may be optionally mono- or di-substituted with alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, halogen, hydroxyl, alkoxy of 1-6 carbon atoms, —CN, —NO 2 , amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, thio, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, alkylcarbonyl of 2-7 carbon atoms, or benzoyl;   R 2  and R 3  are independently selected from hydrogen, halogen, hydroxy, alkoxy of 1-6 carbon atoms, —CF 3 , —CN, alkyl of 1-6 carbon atoms, or —CH═CHPh; or R 2  and R 3  may be taken together as —C(CH 3 ) 2 CH 2 CH 2 —C(CH 3 ) 2 —, —OCH 2 CH 2 O—, or —CH═CH—CH═CH—;   R 4  is hydrogen, halogen, or alkoxy of 1-6 carbon atoms;   A is a bond; or 
                         
 
wherein R 6 , and R 7  are each, independently, hydrogen, hydroxy, alkoxy of 1-6 carbon atoms, CF 3 , CN, or alkyl of 1-6 carbon atoms;
   R 8  is hydrogen or alkyl of 1-6 carbon atoms;   B is —CH 2 —, —CH 2 —CHR 5 —, —CHR 5 CH 2 —, or —CH 2 R 9 R 10 —;   R 5 , R 9  and R 10  are each, independently, alkyl of 1-6 carbon atoms, fluorine, or hydrogen;
 
or a pharmaceutically acceptable salt form thereof.
   

     Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable aids when a compound of this invention contains a basic moiety. Salts may also be formed from organic and inorganic bases, such as alkali metal salts (for example, sodium, lithium, or potassium) alkaline earth metal salts, ammonium salts, alkylammonium salts containing 1-6 carbon atoms or dialkylammonium salts containing 1-6 carbon atoms in each alkyl group, and trialkylammonium salts containing 1-6 carbon atoms in each alkyl group, when a compound of this invention contains an acidic moiety. 
     The term alkyl includes both branched and straight chain moieties. Examples include methyl, ethyl, propyl, butyl, isopropyl, sec-butyl, tert-butyl and the like. The term halogen includes bromine, chlorine, fluorine, and iodine. The term alkylthio means —S-alkyl. 
     As used in accordance with this invention, the term “providing,” with respect to providing a compound or substance covered by this invention, means either directly administering such a compound or substance, or administering a prodrug, derivative, or analog which will form the effective amount of the compound or substance within the body. 
     Preferred compounds of the present invention are those of formula II: 
                        
 
wherein, 
                         
 
Y is —C═C—;
 
or a pharmaceutically acceptable salt form thereof.
 
     Particularly preferred compounds of this invention are:
         a) N-{3-[2-(3-Chloro-4′-chloro-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoromethane sulfo   b) N-{3-[2-(4′-chloro-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro methane sulfonamide;   c) N-{3-[2-(4′-Chloro-3-methoxy-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro methane sulfonamide;   d) N-{3-[2-(3′,4′-dichloro-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro methane sulfonamide;   e) N-{3-[2-(4′-Chloro-3-fluoro-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro methane sulfo   f) N-(3-{2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethoxy]-ethyl}-phenyl)-C,C,C-trifluoro-methanesulfonamide;   g) N-(3-{2-[2-(5-trifluoromethyl-pyridin-2-yl)-thiazol-4-yl-methoxy]ethyl}-phenyl)-C,C,C-trifluoro-methanesulfonamide;   h) N-{3-[2-(4′-Fluoro-4-methoxy-biphenyl-3-ylmethoxy)-ethyl]-phenyl)-C,C,C-trifluoro-methanesulfonamide; or   i) N-{3-[2-(4′-Chloro-2-methoxy-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoromethane sulfonamide.       

     The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. The compounds of the present invention can be generally prepared according to the following synthetic scheme. 
                        
 
     The synthesis of the title products is depicted in Scheme I. Amino alcohols of type (II) are reacted with a halo compound of type (III) (prepared as described or obtained from commercial sources) in the presence of a strong base and crown ether to provide the coupled product of type (IV). This intermediate is then reacted with the appropriate electrophile to provide the title compounds (I). These processes are well known in the art. 
     The compounds of this invention are useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. The compounds of this invention are therefore, particularly useful in the treatment or inhibition of type II diabetes. The compounds of this invention are also useful in modulating glucose levels in disorders such as type I diabetes. Additionally, because an association exists between insulin resistance and hypertension and between insulin resistance, hypertension and coronary artery disease, the compounds of this invention are also useful for the treatment of primary (essential) hypertension and atherosclerosis. 
     The ability of compounds of this invention to treat or inhibit disorders related to insulin resistance or hyperglycemia was established with representative compounds of this invention in the following pharmacological test procedures. 
     Inhibition of Glucose Output from Hepatocytes Isolated and Cultured from Obese Zucker (fa/fa) Rats and their Lean Controls 
     Culturing of Hepatocytes: Isolated hepatocytes were plated on 12 well rat-tail collagen coated plates at a cell density of 5×10(5) cells/ml (approximately 1 ml of cell suspension per well). Following a one hour attachment period in which plates were incubated in a CO 2  incubator at 37 deg C. (95% O 2 , 5% CO 2 ), the supernatant containing unattached hepatocytes was removed and replaced with fresh media (1 ml/well) containing 1 μM dexamethasone and 100 pM insulin. Cells were maintained at 37 deg C. for 48 hours in a 95% O 2 , 5% CO 2  environment. At the end of the first 24 hours, the media was aspirated off of the wells and replaced with fresh media containing the same concentrations of dexamethasone and insulin as described earlier. Treatment with Drugs and Assessment of Glucose Output: Drugs were routinely added with fresh media 24 hours after the initial attachment period. Eighteen hours later, media was aspirated and 500 μl of fresh Hank&#39;s buffer, Buffer D (glucose-free) supplemented with hormones, gluconeogenic substrates and drug(s) was added to each well and incubated for 4 hours. At the end of the 4 hour incubation, media from each well was removed and assayed for glucose content using the hexokinase/glucose-6-phosphate dehydrogenase coupled assay on the Boehringer Mannheim model 911 auto analyzer. Glucose concentration was expressed as μg/ml. Three of the plates from each treated group were frozen for subsequent determination of protein content. Two plates from each treatment group were used to assess the cytotoxicity of drug(s) and other agents as determined by the MTT (tetrazolium) dye reduction method (see below). 
     Assessment of Cytotoxicity using MTT Dye Reduction Assay: Two plates with no insulin treatment and two plates with 10 −8  M insulin treatment were used for the MTT dye reduction assay. Following removal of media from the plates for measurement of glucose output, wells were washed once with 1 ml of Hank&#39;s buffer (0.5% BSA). Aliquots of 500 ml of Hank&#39;s buffer (1.1% BSA) and 50 ml MTT solution (5 mg MTT/ml in phosphate buffered saline (PBS) filtered through 0.45 micron syringe filter) were added to each well. Plates were incubated for one hour at 37 deg C. After one hour incubation, the MTT dye solution was aspirated off and 300 ml of HCL/isopropanol solution (8 ml of 1 N HCL and 192 ml of isopropanol) was added to each well. HCL/isopropanol solution was mixed by drawing liquid into a pipetman 2 to 3 times and then carefully transferred into a 96 well flat bottom plate. The 96 well plate was read on a plate reader (UV max kinetic microplate reader, Molecular Devices) at 570 nm test wavelength and 650 nm reference wavelength. The results were expressed as % inhibition from the control (lactate and glucagon treated) well. 
     Protein test procedure: Three plates with no insulin treatment and three plates with 10 −8  M insulin treatment were used for protein determination. After supernatant has been removed for determination of glucose output the plates were frozen and stored at −20 deg C. until ready to assay for protein content. Prior to determination of protein the plates were defrosted at room temperature for 15 minutes. An aliquot of 1 ml 0.1 N NaOH was added to each well. Plates were incubated at 4 deg C. overnight. Solutions for measurement of protein content were mixed by pipetting the NaOH solution up and down several time with a 1 ml pipette and then transferring to a small polyethylene tube. Protein determination was based on that of the Pierce BCA protein assay protocol (Pierce cat. no. 23223). A set of protein standards (0.2, 0.4, 0.6, 0.8, and 1 mg/ml BSA) was prepared by serial dilution of 1 mg/ml bovine serum albumin with 0.1 N NaOH, and 40 μl of each standard, or control blank was pipetted into a 96-well plate in duplicate. Each unknown protein sample (40 μl) was tested in triplicate. An aliquot of 200 μl of BCA protein assay reagent (consisting of 50 parts Reagent A with 1 part Reagent B) was added to each well. Samples were mixed with a Titertek pipette. The microtiter plate was covered with sealing tape and incubated at room temperature for 1 hour. After incubation, the sealing tape was removed and absorbance measured on a plate reader (Uvmax kinetic microplate reader, Molecular Devices) at 570 nm. A standard curve was prepared by plotting the blank-corrected absorbance against known protein concentrations, and protein concentrations were then determined for each unknown. 
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Buffers: 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Buffer A 
                 Buffer C 
               
               
                   
                   
               
               
                   
                 50 ml 10XHBSS 
                 (10 × solv.) 
               
               
                   
                 400 ml ddH 2 O 
                 1800 ml ddH 2 O 
               
               
                   
                 2.38 g Hepes 
                 95.2 g Hepes 
               
               
                   
                 95 mg EGTA 
                 142.6 g NaCl 
               
               
                   
                 900 mg glucose 
                 7.5 g KCL 
               
               
                   
                 2.36 ml 7.5% NaHCO 3   
                 4.8 g MgSO 4   
               
               
                   
                 pH to 7.4 with 1 N NaOH 
                 11.4 g K 2 HPO 4 .3H 2 O 
               
               
                   
                 q.s. to 500 ml with ddH 2 O 
                 qs to 2L 
               
               
                   
                   
               
               
                   
                 Buffer B 
                 Buffer D 
               
               
                   
                   
               
               
                   
                 50 ml 10XHBSS 
                 50 ml 10 × Buffer C 
               
               
                   
                 430 ml ddH 2 O 
                 400 ml ddH 2 O 
               
               
                   
                 2.45 mg Hepes 
                 59 mg CaCl 2 .2H 2 O 
               
               
                   
                 366.3 mg CaCl 2 .2H 2 O 
                 1.01 g NaHCO 3   
               
               
                   
                 891 mg glucose 
                 BSA (0.2-1.1%) if necessary 
               
               
                   
                 2.34 ml 7.5% NaHCO 3   
                 pH to 7.4 
               
               
                   
                 qs to 500 ml 
                 qs to 500 ml 
               
               
                   
                 100 mg collagenase 
               
               
                   
                   
               
             
          
         
       
     
     Measurements and Calculations: Glucose output was calculated as μg glucose/mg protein/hour, and inhibition of glucose output was calculated as percent inhibition of glucose output when compared to glucagon stimulated cells. Cytotoxicity was determined using the MTT dye reduction assay and data were expressed as percent inhibition of MTT dye reduction compared to control cells. For some compounds of interest multiple point dose response curves were assessed and half-maximal inhibitory concentrations (IC 50 ) were calculated for both inhibition of glucose output and MTT dye reduction. Insulin potentiation was assessed by calculating the difference in percent inhibition of glucose output with and without drug(s) in the presence of the same insulin concentration. 
     Statisical Analysis: Two factors ANOVA with interaction was used to compare different compounds to control and other compounds within each concentration of insulin. The same procedure was used to compare effects of insulin alone. The ICx (where x equals 25,50 etc.) was determined for insulin, drug and insulin+drug using multi point logistic four parameter dose response curves. In addition another parameter (insulin interaction with drug) was estimated using the same technique. Confidence intervals (Wald) were determined using student&#39;s t distribution. 
     Reference Compound:
     Mercaptopicolinc acid (inhibitor of PEPCK activity)   

     References: Berry M N, Edwards A M, Barritt G J. Isolated hepatocytes, preparation properties and applications in laboratory techniques in Biochemistry and Molecular Biology. 1983; 65:55-63.
     Exton, J H. The perfused rat liver in Methods in Enzymology XXXIX, part D (Hormone Action), pp 25-36 (1975). Eds. J. G. Hardman and B. W. O&#39;Malley.   Goodman M N. Effect of 3-mercaptopicolinic acid on gluconeogenesis and gluconeogenic metabolite concentrations in the isolated perfused rat liver. Biochem. J. 1975; 150:137-139.   Jomain-Baum M, Schramm V L, Hanson R W. Mechanism of 3-mercaptopicolinic acid inhibition of hepatic phosphoenol pyvrate carboxykinase (GTP). J. Biol. Chem.   Musmann T. Rapid calorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Meth. 1983; 65:55-63.   Smith P K, Krohn R I, Hermanson G T, Mallia A K, Gartner F H, Provenjano M D, Fujimoto E K, Goeke N M, Olson B J, and Klenk D C. Measurement of Protein Using Bincinchoninic Acid. Analo. Biochem. 1985; 150:76-85.
 
The following table summarizes the results obtained using representative compounds of this invention.
   

                                                               EXAMPLE   IC 50                                           6   2.3   μM            7   2.5   μM           11   10   μM           23   1.7   μM           22   2.2   μM           26   2.3   μM           43   6.9   μM           53   10   μM           56   15   μM           88   4   μM           19   8   μM           Na-Mercaptopicolinic acid   45   μM                        
Hypoglycemic Effect in Diabetic OB/OB Mice
 
     Procedure: In each study, male or female ob/ob (C57 B1/6J) mice and their mean litermates (ob/+ or +/+, Jackson Laboratories) ages 2 to 5 months (10 to 65 g) were randomized according to plasma glucose into 4 groups of 10 mice. The mice were housed 5 per cage and were maintained on normal rodent chow with water ad libitum. Mice receive compound daily by gavage (suspended in 0.5 ml of 0.5% methyl cellulose); dissolved in the drinking water; or admixed in the diet. The dose of compounds given ranges from 2.5 to 200 mg/kg body weight/day. Body weight of fed animals was measured at the beginning of each week and doses for the entire week were calculated using this weight and were expressed in terms of the active moiety of the compound. Control mice receive vehicle only. 
     On the morning of Day 4, 7 or 14 two drops of blood (approximately 50 ul) were collected into sodium fluoride containing tubes either from the tail vein or after decapitation. For those studies in which the compound was administered daily by gavage the blood samples were collected four hours after compound administration. 
     Measurements: The plasma was isolated by centrifugation and the concentration of glucose was measured enzymatically on an Abbott V. P. Analyzer and the plasma concentration of insulin was determined by radioimmunoassay (Heding, 1972) 
     Calculations: For each mouse, the percentage change in plasma glucose on Day 4, 7 or 14 was calculated relative to the mean plasma glucose of the vehicle treated mice. Analysis of variance followed by Dunnett&#39;s Comparison Test (one-tailed) was used to estimate the significant difference between the plasma glucose values from the control group and the individual compound treated groups (CMS SAS Release 5.18). A compound will be considered active if the difference has a p&lt;0.05. 
     Clinical Correlation: The non-insulin dependent diabetic (NIDDM) syndrome can be typically characterized by obesity, hyperglycemia, abnormal insulin secretion, hyperinsulinemia and insulin resistance. The genetically obese-hyperglycemic ob/ob mouse exhibits many of these metabolic abnormalities and is a useful model for hypoglycemic agents to treat NIDDM (Coleman, 1978). 
     Reference Compound: Ciglitazone (5-(4-(1-methylcyclohexylmethoxy)-benzyl)-2,4-dione, Upjohn) and sodium metavanadate (NaVO3) at doses of 100 and 20 mg/kg/day, respectively, produce a significant lowering in plasma glucose (Brichard et al. 1990; Chang et al. 1983. 
     References:
     Brichard, S., Bailey, C. and Henquin, J.: Marked improvement of glucose homeostasis in diabetic ob/ob mice given oral vanadate Diabetes 39: 1326-1332, 1990.   Chang, A., Wyse, B., Gilchrist, B., Peterson, T. and Diani, A.: Ciglitazone, a new hypoglcemic gent. I. Studies in ob/ob and db/db mice, diabetic Chinese hamsters, and normal and streptozotocin-diabetic rats. Diabetes 32: 830-838, 1983.   Coleman, D.: Obese and diabetes: Two mutant genes causing diabetes-obesity syndromes in ice. Diabetologia 14: 141-148, 1978.   Heding, L. G.: Determination of total serum insulin (IRI) in insulin-treated diabetic patients. Diabetologia 8:260-266, 1972.
 
The following table summarizes the results obtained using representative compounds of this invention.
   

     Reduction in Plasma Glucose 
     
       
         
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 EXAMPLE 
                 Day 1 (6 hr) p.o. 
                 Day 3 (6 hr) p.o. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 6 
                 −16% 
                 (5 mg/kg) 
                 −24% 
                 (5 mg/kg) 
               
               
                 7 
                 −8% 
                 (5 mg/kg) 
                 −22% 
                 (5 mg/kg) 
               
               
                 23 
                 −37% 
                 (5 mg/kg) 
                 −37% 
                 (5 mg/kg) 
               
               
                 26 
                 −20% 
                 (20 mg/kg) 
                 +1 
                 (20 mg/kg) 
               
               
                 53 
                 −36% 
                 (10 mg/kg) 
                 −26% 
                 (10 mg/kg) 
               
               
                 56 
                 −16% 
                 (5 mg/kg) 
                 −26% 
                 (5 mg/kg) 
               
               
                 2 
                 −8% 
                 (5 mg/kg) 
                 −34% 
                 (5 mg/kg) 
               
               
                 42 
                 −14% 
                 (10 mg/kg) 
                 −14% 
                 (10 mg/kg) 
               
               
                 88 
                 −71 
                 (25 mg/kg) 
                 −29 
                 (25 mg/kg) 
               
               
                   
               
             
          
         
       
     
     Based on the results obtained in the standard pharmacological test procedure, the compounds of this invention are useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. More particularly, the compounds of this invention are useful in the treatment or inhibition of type II diabetes, and in modulating glucose levels in disorders such as type I diabetes. The compounds of this invention are also useful in the treatment of primary (essential) hypertension and atherosclerosis. As used herein, the term modulating means maintaining glucose levels within clinically normal ranges. 
     Effective administration of these compounds may be given at a daily dosage of from about 1 mg/kg to about 250 mg/kg, and may given in a single dose or in two or more divided doses. Such doses may be administered in any manner useful in directing the active compounds herein to the recipient&#39;s bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally. For the purposes of this disclosure, transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal). 
     Compounds of this invention may be administered neat or with a pharmaceutical carrier to a patient in need thereof. The pharmaceutical carrier may be solid or liquid. 
     Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc. Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar. Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s). Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository&#39;s melting point, and glycerin. Water soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used. 
     It is understood that the dosage, regimen and mode of administration of these compounds will vary according to the malady and the individual being treated and will be subject to the judgment of the medical practitioner involved. It is preferred that the administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved. 
     The following procedures describe the preparation of representative examples of this invention. 
     EXAMPLE 1 
     Preparation of N-[3-(2-(4-bromophen-4-yl methoxy)]ethyl phenyl-methanesulfonamide 
     General Procedure for Ether Synthesis 
     Step 1. Preparation of 3-[(2-(4-bromophen-4-yl methoxy)]ethyl phenyl-amine 
     To a solution of 0.30 g (12.5 mmol) of 95% sodium hydride and 1 drop of 15-crown-5 in THF was added dropwise a solution of 1.39 g (10 mmol) of 3-(2-hydroxy ethyl)phenyl amine at 0° C. 5 min later 0.05-0.001 mmol of 15-crown-6 and/or (10% vol DMSO) is added. After stirring for 0.5 hr 2.67 g (13 mmol) of 4-bromobenzyl chloride was added in one portion. The mixture was stirred at room temperature for 5 hr. At the end of this time, the solution was concentrated and the residue washed with 15 ml of saturated ammonium chloride and extracted 2 times with 60 mL of ethyl acetate. The organic layers were combined, dried (MgSO 4 ) and concentrated. The crude solid was chromatographed on silica gel eluting with 40% ethyl acetate:hexane. Concentration yielded 1.89 g (63%) of the product as an oil, used in the next step without further purification. NMR (200 Mhz, CDCl 3 ) δ 7.45 (d, J=8 Hz, 2H ArH), 7.19 (d, J=8 Hz, 2H, ArH), 7.08 (t, J=8 Hz, 1H, H5), 6.64 (d, J=8 Hz, 1H, H4), 6.55 (s, 1H, H2), 6.47 (d, J=8 Hz, 1H, H6), 4.43 (s, 2H, OCH2), 3.65 (t, J=7 Hz, 2H, OCH2), 3.58 (bs, 2H, NH2), 2.85 (t, J=7 Hz, 2H, ArCH2). 
     Step 2 Preparation of the Title Compound 
     General Procedure for Synthesis of Triflamides. 
     To a 250 mL flask charged with 150 mL of methylene chloride is added 1.03 mL (7.41 mmol) of triethyl amine and 1.89 g (6.18 mmol) of the product from Step 1. The flask was cooled to −20° C. where upon a solution of 1.14 mL (6.80 mmol) of trifluoromethane sulfonic anhydride in 25 mL of methylene chloride was added dropwise under nitrogen atmosphere. After ½ hr, 2 mL of a 1M solution tetra n-butyl ammoniun flouride was added and the mixture stirred for 16 hr. At the end of this time, the solution was concentrated, diluted with 50 mL of saturated ammonium chloride and extracted 2 times with ethyl acetate. The organic layers were combined, dried (MgSO 4 ) and concentrated. The crude solid was chromatographed on silica gel eluting with 30% ethyl acetate:hexane. Concentration yielded 1.83 g (68%) of the title compound as a brown oil, used in the next step without further purification. NMR (400 MHz, DMSO-d6) δ 11.80 (bs, 1H, NH), 7.45 (d, J=8 Hz, 2H ArH), 7.18 (d, J=8 Hz, 2H, ArH), 7.7 (t, J=8 Hz, 1H, H5), 7.17 (d, J=8 Hz, 1H, H4), 7.15 (s, 1H, H2), 7.11 (d, J=8 Hz, 1H, H6), 4.51 (s, 2H, OCH2), 3.65 (t, J=7 Hz, 2H, OCH2), 2.85 (t, J=7 Hz, 2H, ArCH2). 
     EXAMPLE 2 
     Preparation of C,C,C-trifluoro-N-{3-[2-(4′-trifluoromethyl-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-methanesulfonamide 
     To a 50 mL flask charged with 20 mL toluene and 5 mL EtOH was added 250 mg (0.57 mmol) of the product from Example 1, 195 mg (0.80 mmol) of 4-trifluoromethyl benzene boronic acid, and 3 mL of aqueous 5% potassium carbonate solution. The flask was stirred and degassed for 5 minutes with a steady stream of nitrogen, after which 35 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) was added. The mixture was heated to 70° C. for 18 hr under an atmosphere of nitrogen. At the end of this time the solution was concentrated and diluted with 30 mL of saturated ammoniun chloride solution. The mixture was extracted 2× with ethyl acetate and the organic layers combined and dried (MgSO 4 ), then concentrated. The crude solid was chromatographed on silica gel eluting with 30% ethyl acetate:hexane. Concentration yielded 0.192 mg (68%) of the title compound as an oil, which was triturated with hexane at −78° C. to form a solid. The solid was recrystallized from ethyl acetate:hexane to yield 0.17 g of the title product as colorless crystals, m.p. 98-100° C. NMR (400 MHz, DMSO-d6) δ 11.80 (bs, 1H, NH), 7.45 (d, J=8 Hz, 2H ArH), 7.36 (d, J=8 Hz, 2H, ArH), 7.28 (d, J=8 Hz, 2H, ArH), 7.18 (d, J=8 Hz, 2H, ArH), 7.7 (t, J=8 Hz, 1H, H5), 7.17 (d, J=8 Hz, 1H, H4), 7.11 (s, 1H, H2), 7.01 (d, J=8 Hz, 1H, H6), 4.51 (s, 2H, OCH2), 3.65 (t, J=7 Hz, 2H, OCH2), 2.85 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C23H19F6N1O3S1: C, 54.87; H, 54.87; H, 3.80; N, 2.78. Found: C, 54.83; H, 3.88; N, 2.75. 
     EXAMPLE 4 
     C,C,C-Trifluoro-N-{3-[2-(4′-methoxy-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-methanesulfonamide was prepared as a white solid from the product of Example 1 using the procedure of Example 2 and 4-methoxy benzene boronic acid, m.p. 96-98° C. NMR (400 MHz, DMSO-d6) δ 11.80 (bs, 1H, NH), 7.58 (d, J=8 Hz, 2H ArH), 7.56 (d, J=8 Hz, 2H, ArH), 7.31 (d, J=8 Hz, 2H, ArH), 7.30 (t, J=8 Hz, 1H, H5), 7.17 (d, J=8 Hz, 1H, H4), 7.11 (s, 1H, H2), 7.01 (d, J=8 Hz, 1H, H6), 6.98 (d, J=8 Hz, 2H, ArH), 4.51 (s, 2H, OCH2), 3.78 (s, 3H, OCH3), 3.65 (t, J=7 Hz, 2H, OCH2), 2.85 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C23H22F3N1O4S1: C, 59.35; H, 4.76; N, 3.01. Found: C, 59.14; H, 4.72; N, 2.95. 
     EXAMPLE 5 
     N-{3-[2-(3′-Chloro-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoromethane sulfonamide was prepared as a white solid from the product of Example 1 using the procedure of Example 2 and 3-chloro benzene boronic acid, m.p. 105-107° C. NMR (400 MHz, DMSO) δ 11.81 (s, 1H, —NH); 7.40 (m, 12H); 4.51 (s, 2H); 3.65 (t, J=6.6 Hz, 2H); 2.87 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 22 H 19 ClF 3 NO 3 S: C, 56.23; H, 4.08; N, 2.98 Found: C, 55.56; H, 4.21; N, 2.87. EI m/z 469. 
     EXAMPLE 6 
     N-{3-[2-(3′,4′-Dichloro-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide was prepared as a white solid from the product of Example 1 using the procedure of Example 2 and 3,4-dichloro benzene boronic acid (64%), m.p. 74-75° C. NMR (400 MHz, DMSO) δ 7.91 (d, 1H, J=2.0 Hz); 7.40 (m, 10H); 4.51 (s, 2H); 3.65 (t, J=6.6 Hz, 2H); 2.87 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 22 H 18 C 12 F 3 NO 3 S: C, 52.39; H, 3.60; N, 2.78 Found: C, 51.76; H, 3.46; N, 2.68. EI m/z 504. 
     EXAMPLE 7 
     N-{3-[2-(4′-Chloro-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoromethane sulfonamide was prepared as a white solid from the product of Example 1 using the procedure of Example 2 and 4-chloro benzene boronic acid (66%), m.p. 69-70° C. NMR (400 MHz, DMSO) δ: 7.38 (m, 12H); 4.51 (s, 2H); 3.65 (t, J=6.6 Hz, 2H); 2.87 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 22 H 19 ClF 3 NO 3 S: C, 56.23; H, 4.08; N, 2.98 Found: C, 55.85; H, 3.83; N, 2.88. (−)ESI m/z 468 (M−H). 
     EXAMPLE 8 
     C,C,C-Trifluoro-N-{3-[2-(4-pyridin-2-yl-benzyloxy)-ethyl]-phenyl}-methane sulfonamide was isolated as a white solid from the product of Example 1 using the procedure of Example 2 and 2-tri-(n-butyl stannyl)pyridine (52%), m.p. 95-96° C. NMR (400 MHz, DMSO) δ 7.87 (m, 12H); 4.53 (s, 2H); 3.66 (t, J=6.6 Hz, 2H); 2.88 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 21 H 19 F 3 N 2 O 3 S: C, 57.79; H, 4.39; N, 6.42 Found: C, 57.42; H, 4.33; N, 6.15. EI m/z 436. 
     EXAMPLE 9 
     Preparation of N-{3-[2-(4-bromo,2-fluorophenyl-methoxy)-ethyl]-phenyl}-C,C,C-trifluoro methane sulfonamide 
     Step 1. Preparation of 3-[(2-(4-bromo,2fluoro,phenyl methoxy)]ethyl phenyl-amine 
     To a solution of 0.30 g (12.5 mmol) of 95% sodium hydride and 1 drop of 15-crown-5 in THF was added dropwise a solution of 1.39 g (10 mmol) of 3-(2-hydroxy ethyl)phenyl amine at 0° C. After stirring for 0.5 hr 3.48 g (13 mmol) of 4-bromo,3-fluoro benzyl bromide was added in one portion. The mixture was stirred at room temperature for 5 hr. At the end of this time, the solution was concentrated and the residue washed with 15 ml of saturated ammonium chloride and extracted 2 times with 60 mL of ethyl acetate. The organic layers were combined, dried (MgSO 4 ) and concentrated. The crude solid was chromatographed on silica gel eluting with 40% ethyl acetate:hexane. Concentration yielded 1.97 g (61%) of the product as an oil, used in the next step without further purification. NMR (200 Mhz, CDCl 3 ) δ 7.23 (m, 3H ArH), 7.14 (t, J=8 Hz, 1H, H5), 6.64 (d, J=8 Hz, 1H, H4), 6.55 (s, 1H, H2), 6.49 (d, J=8 Hz, 1H, H6), 4.48 (s, 2H, OCH2), 3.65 (t, J=7 Hz, 2H, OCH2), 3.62 (bs, 2H, NH2), 2.85 (t, J=7 Hz, 2H, ArCH2). 
     Step 2 Preparation of the Title Compound 
     To a 250 mL flask charged with 150 mL of methylene chloride is added 0.85 mL (7.0 mmol) of triethyl amine and 1.90 g (5.86 mmol) of the product from Step 1. The flask was cooled to −20° C. where upon a solution of 0.90 mL (6.0 mmol) of trifluoromathane sulfonic anhydride in 25 mL of methylene chloride was added dropwise under nitrogen atmosphere. After ½ hr, 2 mL of a 1M solution tetra n-butyl ammoniun flouride was added and the mixture stirred for 16 hr. At the end of this time, the solution was concentrated, diluted with 50 mL of saturated ammonium chloride and extracted 2 times with ethyl acetate. The organic layers were combined, dried (MgSO 4 ) and concentrated. The crude solid was chromatographed on silica gel eluting with 30% ethyl acetate:hexane. Concentration yielded 1.83 g (73%) of the title compound as a brown oil, used in the next step without further purification. NMR (200 MHz, CDCl3) δ 11.67 (bs, 1H, NH), (m, 3H, ArH), 7.45 (t, J=8 Hz, 1H, H5), 7.41 (d, J=8 Hz, 1H, H4), 7.28 (s, 1H, H2), 7.34 (d, J=8 Hz, 1H, H6), 4.57 (s, 2H, OCH2), 3.72 (t, J=7 Hz, 2H, OCH2), 2.86 (t, J=7 Hz, 2H, ArCH2). 
     EXAMPLE 10 
     Preparation of N-{3-[2-(3,4′-Difluoro-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide 
     To a 50 mL flask charged with 20 mL toluene and 5 mL EtOH was added 250 mg (0.54 mmol) of the product from Example 4, 195 mg (0.80 mmol) of 4-fluorobenzene boronic acid, and 3 mL of aqueous 5% potassium carbonate solution. The flask was stirred and degassed for 5 minutes with a steady stream of nitrogen, after which 35 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) was added. The mixture was heated to 70° C. for 18 hr under an atmosphere of nitrogen. At the end of this time the solution was concentrated and diluted with 30 mL of saturated ammoniun chloride solution. The mixture was extracted 2× with ethyl acetate and the organic layers combined and dried (MgSO 4 ), then concentrated. The crude solid was chromatographed on silica gel eluting with 30% ethyl acetate:hexane. Concentration yielded 0.188 mg (76%) of the title compound as an oil, which was triturated with hexane to form a solid. The solid was recrystallized from ethyl acetate:hexane to yield 0.14 g of the title product as colorless crystals, m.p. 65-67° C. NMR (400 MHz, DMSO-d6) δ 11.67 (bs, 1H, NH), 7.75 (m, 2H ArH), 7.44 (m, 3H, ArH), 7.32 (m, 3H, ArH), 7.17 (d, J=8 Hz, 1H, H4), 7.11 (s, 1H, H2), 7.01 (d, J=8 Hz, 1H, H6), 4.57 (s, 2H, OCH2), 3.65 (t, J=7 Hz, 2H, OCH2), 2.85 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C22H18F5N1O3S1: C, 56.05; H, 3.85; N, 2.97. Found: C, 55.87; H, 3.89; N, 2.84. 
     EXAMPLE 11 
     N-{3-[2-(4′-Chloro-3-fluoro-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro methane sulfonamide was prepared from the product of Example 4 with 4-chlor benzeneboronic acid using the procedure of Example 5 as a white solid (64%). m.p. 99-101° C. NMR (400 MHz, DMSO-d6) δ 11.77 (bs, 1H, NH), 7.73 (d, J=8 Hz, 2H ArH), 7.61 (d, J=8 Hz, 2H, ArH), 7.46 (m, 1H, ArH), 7.42 (m, 2H, ArH), 7.26 (t, J=8 Hz, 1H, H4), 7.14 (d, J=8 Hz, 1H, H5) 7.11 (s, 1H, H2), 7.03 (d, J=8 Hz, 1H, H6), 4.57 (s, 2H, OCH2), 3.65 (t, J=7 Hz, 2H, OCH2), 2.85 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C22H18Cl1F4N1O3S1: C, 54.16; H, 3.72; N, 2.87. Found: C, 53.93; H, 381; N, 3.21. 
     EXAMPLE 12 
     N-{3-[2-(3′,4′-Dichloro-3-fluoro-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro methane sulfonamide was prepared from the product of Example 4 and 3,4-dichlor benzeneboronic acid using the procedure of Example 5 as a white solid (65%), m.p. 102-104° C. NMR (400 MHz, DMSO-d6) δ 11.77 (bs, 1H, NH), 7.98 (s, 1H ArH), 7.72 (m, 2H, ArH), 7.61 (dd, J1=2 Hz, J2=8 Hz, ArH), 7.51 (dd, J1=2 Hz, J2=8 Hz, ArH), 7.41 (t, J=8 Hz, 1H), 7.31 (t, J=8 Hz, 1H, H4), 7.16 (d, J=8 Hz, 1H, H5) 7.11 (s, 1H, H2), 7.09 (d, J=8 Hz, 1H, H6), 4.57 (s, 2H, OCH2), 3.65 (t, J=7 Hz, 2H, OCH2), 2.85 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C22H17Cl2F4N1O3S1: C, 50.59; H, 3.28; N, 2.68. Found: C, 50.51; H, 3.43; N, 2.60. 
     EXAMPLE 13 
     C,C,C-Trifluoro-N-{3-[2-(3-fluoro-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro methane sulfonamide was prepared from the product of Example 4 and benzeneboronic acid using the procedure of Example 5 as a white solid (61%), 68-70° C. NMR (400 MHz, DMSO-d6) δ 11.80 (bs, 1H, NH), 7.71 (d, J=8 Hz, 2H, ArH), 7.44 (m, 6H, ArH), 7.31 (t, J=8 Hz, 1H, H4), 7.19 (d, J=8 Hz, 1H, H5) 7.11 (s, 1H, H2), 7.09 (d, J=8 Hz, 1H, H6), 4.57 (s, 2H, OCH2), 3.65 (t, J=7 Hz, 2H, OCH2), 2.85 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C22H19F4N1O3S1: C, 58.27; H, 4.22; N, 3.09. Found: C, 58.20; H, 4.21; N, 3.15. 
     EXAMPLE 14 
     C,C,C-Trifluoro-N-{3-[2-(3-fluoro-4′-trifluoromethyl-biphenyl-4-yl-methoxy)-ethyl]-phenyl}-methanesulfonamide was prepared from the product of Example 4 and 4-trifluoromethyl benzeneboronic acid using the procedure of Example 5 and isolated as a white solid (61%), m.p. 121-122° C. NMR (400 MHz, DMSO) δ 11.79 (s, 1H, —NH); 7.92 (d, J=8.3 Hz, 2H); 7.45 (m, 9H); 4.57 (s, 2H); 3.69 (t, J=6.6 Hz, 2H); 2.87 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 23 H 18 F 7 NO 3 S: C, 52.98; H, 3.48; N, 2.69. Found: C, 52.80; H, 3.48; N, 2.57. EI m/z 521. 
     EXAMPLE 15 
     N-{3-[2-(2′,4′-Dichloro-3-fluoro-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide was prepared according to the procedure of Example 5 from the product of Example 4 and 2,4-dichloro benzeneboronic acid and isolated as a white solid (61%), m.p. 65-66° C. NMR (400 MHz, DMSO) δ 11.82 (s, 1H, —NH); 7.43 (m, 12H); 4.59 (s, 2H); 3.71 (t, J=6.6 Hz, 2H); 2.89 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 22 H 17 C12F 4 NO3S: C, 50.59; H, 3.28; N, 2.68 Found: C, 50.30; H, 3.27; N, 2.52. EI m/z 521. 
     EXAMPLE 16 
     C,C,C-Trifluoro-N-{3-[2-(3-fluoro-3′-methyl-biphenyl-4-yl-methoxy)-ethyl]-phenyl}-methanesulfonamide was prepared according to the procedure of Example 5 from the product of Example 4 and 3-methyl benzeneboronic acid and isolated as a white solid (64%), m.p. 60-61° C. NMR (400 MHz, DMSO) δ 7.31 (m, 11H); 4.56 (s, 2H); 3.69 (t, J=6.6 Hz, 2H); 2.88 (t, J=6.6 Hz, 2H); 2.38 (s, 3H). Anal. Calcd. for C 23 H 21 F 4 NO 3 S: C, 59.09; H, 4.53; N, 3.00 Found: C, 58.87; H, 4.54; N, 2.96. EI m/z 467. 
     EXAMPLE 17 
     C,C,C-Trifluoro-N-{3-[2-(3-fluoro-3′-trifluoromethyl-biphenyl-4-yl-methoxy)-ethyl]-phenyl}-methanesulfonamide was prepared from the product of Example 4 and 3-trifluoro methyl benzeneboronic acid using the procedure of Example 5 and isolated as a white solid (67%), m.p. 60-61° C. NMR (400 MHz, DMSO) d: 11.79 (s, 1H, —NH); 7.55 (m, 11H); 4.57 (s, 2H); 3.69 (t, J=6.6 Hz, 2H); 2.87 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 23 H 18 F 7 NO 3 S: C, 52.98; H, 3.48; N, 2.69 Found: C, 53.22; H, 3.69; N, 2.48. EI m/z 521. 
     EXAMPLE 18 
     C,C,C-Trifluoro-N-{3-[2-(3-fluoro-4′-trifluoromethoxy-biphenyl-4-yl-methoxy)-ethyl]-phenyl}-methanesulfonamide was prepared from the product of Example 4 and 3-trifluoro methoxy benzeneboronic acid using the procedure of Example 5 and isolated as a white solid (66%), m.p. 114-115° C. NMR (400 MHz, DMSO) δ 7.45 (m, 11H); 4.56 (s, 2H); 3.68 (t, J=6.6 Hz, 2H); 2.87 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 23 H 18 F 7 NO 4 S: C, 51.40; H, 3.38; N, 2.61 Found: C, 51.38; H, 3.53; N, 2.49. El m/z 537. 
     EXAMPLE 19 
     N-{3-[2-(4′-tert-Butyl-3-fluoro-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide was prepared from the product of Example 4 and 4-t-butyl benzeneboronic acid using the procedure of Example 5 and isolated as a white solid (61%), m.p. 89-90° C. NMR (400 MHz, DMSO) δ 7.35 (m, 11H); 4.54 (s, 2H); 3.68 (t, J=6.6 Hz, 2H); 2.87 (t, J=6.6 Hz, 2H); 1.30 (s, 9H). Anal. Calcd. for C 26 H 27 F 4 NO 3 S: C, 61.29; H, 5.34; N, 2.75 Found: C, 60.08; H, 5.25; N, 2.80. EI m/z 509. 
     EXAMPLE 20 
     C,C,C-Trifluoro-N-{3-[2-(3-fluoro-3′-methoxy-biphenyl-4-yl-methoxy)ethyl]-phenyl}-methanesulfonamide was prepared from the product of Example 4 and 3-methoxy benzeneboronic acid using the procedure of Example 5 and isolated as a white solid (61%), m.p. 80-82° C. NMR (400 MHz, DMSO) δ 7.18 (m, 11H); 4.55 (s, 2H); 3.81 (s, 3H) 3.68 (t, J=6.6 Hz, 2H); 2.87 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 23 H 21 F 4 NO 4 S: C, 57.14; H, 4.38; N, 2.90 Found: C, 56.13; H, 4.73; N, 2.69 C 23 H 21 F 4 NO 4 S: C, 57.14; H, 4.38; N, 2.90 Found: C, 56.13; H, 4.73; N, 2.69. (−)ESI m/z 482 (M−H). 
     EXAMPLE 21 
     Preparation of N-{3-[2-(4-Bromo-2-chloro-phenylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro methane sulfonamide 
     Step 1 Preparation of 3-[2-(4-bromo,3-chloro methoxy)-ethyl]-phenyl amine 
     The 3-[2-(4-bromo,3-chloro methoxy)-ethyl]-phenyl amine was prepared from 3-(2-hydroxy ethyl)phenyl amine and 4-bromo,2-chloro benzyl chloride following the procedure of step 1 of Example 4. The compound was isolated as an oil used in the next step without further purification (71%). 
     Step 2 Preparation of the Title Compound 
     The title compound was prepared from 3-[2-(4-bromo,3-chloro methoxy)-ethyl]-phenyl amine according to the procedure followed for step 2 of Example 1 
     EXAMPLE 22 
     Preparation of N-3-[2-(3-Chloro-4′-fluoro-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro methane sulfonamide 
     The title compound was prepared from the product of Example 21 and 4-fluoro benzene boronic acid according to the procedure of Example 2 and isolated as a white solid (61%), m.p. 70-71° C. NMR (400 MHz, DMSO-d6) δ 11.80 (bs, 1H, NH), 7.75 (m, 3H, ArH), 7.58 (d, J=8 Hz, 1H, ArH), 7.44 (d, J=8 Hz, 1H, ArH), 7.31 (m, 3H, ArH), 7.19 (d, J=8 Hz, 1H, H5) 7.11 (s, 1H, H2), 7.09 (d, J=8 Hz, 1H, H6), 4.57 (s, 2H, OCH2), 3.65 (t, J=7 Hz, 2H, OCH2), 2.85 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C22H18Cl1F4N1O3S1: C, 54.16; H, 3.72; N, 2.87. Found: C, 54.45; H, 3.45; N, 2.78. 
     EXAMPLE 23 
     N-{3-[2-(3-Chloro-4′-chloro-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro methane sulfonamide was prepared from the product of Example 21 and 4-chloro benzene boronic acid according to the procedure of Example 2 and isolated as a white solid (65%), 97-99° C. NMR (400 MHz, DMSO-d6) δ 11.80 (bs, 1H, NH), 7.75 (m, 3H, ArH), 7.61 (d, J=8 Hz, 1H, ArH), 7.54 (d, J=8 Hz, 2H, ArH), 7.42 (d, J=8 Hz, 1H, ArH), 7.31 (t, J=8 Hz, 1H, Ar5), 7.19 (d, J=8 Hz, 1H, H4) 7.11 (s, 1H, H2), 7.09 (d, J=8 Hz, 1H, H6), 4.57 (s, 2H, OCH2), 3.65 (t, J=7 Hz, 2H, OCH2), 2.85 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C22H18Cl2F3N1O3S1: C, 52.39; H, 3.60; N, 2.78. Found: C, 52.07; H, 3.47; N, 2.70. 
     EXAMPLE 24 
     Preparation of Methyl(2-methoxy,4-trifluoromethane sulfonyl)benzoate 
     To a flask charged with 3.0 g (16.5 mmol) of methyl(4-hydroxy,2-methoxy)benzoate and 2.72 ml (19.6 mmol) of triethyl amine dissolved in 200 mL of methylene chloride was added dropwise a solution of 3.02 ml (17.9 mmol) of trifluoromethane sulfonic anhydride in 50 mL of methylene chloride at 0° C. After 2 h, the solution was concentrated, and the residue washed with water and extracted twice with 100 mL of ethyl acetate. After upon drying and concentrating, the dark oil was subjected to flash chromatography on silica gel. Elution with 20% ethyl acetate:hexane yielded 3.56 g (71%) of product as a light yellow oil. NMR (200 MHz, CDCl3) δ 7.78 (d, J=8 Hz, 1H, H6) 6.45 (m, 2H, ArH) 3.84 (s, 3H, OCH3), 3.79 (s, 3H, OCH3). 
     EXAMPLE 25 
     Preparation of (2-methoxy,4-(4′chlorophenyl))benzyl chloride 
     Step 1. Preparation of Methyl(2-methoxy,4-(4′chlorophenyl))benzoate 
     2.03 g (6.37 mmol) of the product obtained from Example 24, 1.4 g (8.92 mmol) of 4-chlorobenzene boronic acid and 2.84 g (13.4 mmol) of potassium phosphate were placed in a flask along with 80 mL of dioxane. The solution was degassed with nitrogen, whereupon 85 mg of tetrakis(triphenylphosphine)palladium was added. The solution was heated to 70° C. for 24 hr. At the end of this time, the solution was concentrated, and the residue washed with water and extracted with ethyl acetate (2×50 mL). The combined extracts were dried and concentrated then the residue chromatographed over silica gel. Elution with 20% ethyl acetate:hexane yielded 1.04 g (60%) of product as a colorless solid. NMR (200 MHz, CDCl3) δ 7.84 (d, J=8 Hz, 1H, H6), 7.44 (dd, J=8 Hz, 4H), 7.18 (d, J=8 Hz, 1H, H5), 7.09 (s, 1H, H3), 3.96 (s, 3H, OCH3), 3.85 (s, 3H, OCH3). 
     Step 2 Preparation of the Title Compound 
     To a flask containing 300 mL of dry ether was added 0.53 g (14.4 mmol) of lithium aluminum hydride. 3.8 g of the product from step 1 was added portionwise over the course of 10 minutes at 0° C. After 1 hr, 3 ml of ethyl acetate was added, then 50 mL of a saturated solution of potassium sodium tartrate was cautiously added at 0° C. The layers were separated and the aqueous phase was extracted with 3×100 mL of ethyl acetate. The combined organic phases were combined, dried and concentrated to yield 2 g of product as an oil, which solidfied upon standing. 
     To a 200 mL THF solution of triphenyl phosphine (3.2 g, 12.2 mmol) and 1.74 g (13.8 mmol) of N-chlorosuccinimide was added 2.3 g (8.7 mmol) of the product from above. After stirring for 3 hr the solution was concentrated and the residue taken up in 30 mL of ether. The solution was filtered through a plug of SiO2 eluting with 20% ethyl acetate:hexane. After concentration, recovered 2.1 g of product as an oil, which solidified on standing. The product was used in the next step without further purification. 
     EXAMPLE 26 
     N-{3-[2-(4′-Chloro-3-methoxy-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro methane sulfonamide 
     Following the General procedure for ether synthesis of Example 1, the product from Example 25 was converted to the title product, m.p. 66-68° C. NMR (400 MHz, DMSO-d6) δ 11.80 (bs, 1H, NH), 7.70 (d, J=8 Hz, 2H, ArH), 7.50 (d, J=8 Hz, 2H, ArH), 7.35 (m, 3H, ArH), 7.19 (m, 4H, ArH), 7.09 (d, J=8 Hz, 1H, H6), 4.57 (s, 2H, OCH2), 3.84 (s, 3H, OCH3), 3.65 (t, J=7 Hz, 2H, OCH2), 2.85 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C23H21Cl1F3N1O4S1: C, 55.26; H, 4.23; N, 2.80. Found: C, 55.61; H, 4.15; N, 2.75. 
     EXAMPLE 27 
     Preparation of N-{4-[2-(Biphenyl-2-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoromethanesulfonamide 
     Step 1 Preparation of 4-[2-(Biphenyl-2-ylmethoxy)-ethyl]-phenyl amine 
     Using a procedure similar that of step 1 Example 4, 404 mg (2 mmol) of 2-phenyl benzyl chloride was reacted with 280 mg (2 mmol) of 3-(2-hydroxy ethyl)phenyl amine, to yield 206 mg (68%) of product as an oil, used in the next step without further purification. 
     Step 2 Preparation of the Title Compound 
     Using a procedure similiar to that of Example 4 step 2, 100 mg (0.33 mmol) of the product from step 1 was reacted with 0.06 ml (0.37 mmol) of trifluro methanesulfonic anhydride to yield 0.081 mg of the title compound as a solid, m.p 79-81° C. NMR (400 MHz, DMSO) δ 7.27 (m, 13H); 4.31 (s, 2H); 3.55 (t, J=6.6 Hz, 2H); 2.78 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 22 H 20 F 3 NO 3 S: C, 60.68; H, 4.63; N, 3.22 Found: C, 60.74; H, 4.89; N, 3.14 EI m/z 435. 
     EXAMPLE 28 
     C,C,C-Trifluoro-N-{3-[2-(4′-methoxy-biphenyl-3-ylmethoxy)-ethyl]-phenyl}-methanesulfonamide 
     Using a procedure similar to Example 24, 3-(4-methoxy phenyl)benzyl chloride was converted to the title compound (62 mg, 65%), m.p. 88-90° C.  1 H NMR (400 MHz, DMSO) δ 7.27 (m, 12H); 4.52 (s, 2H); 3.79 (s, 3H); 3.66 (t, J=6.6 Hz, 2H); 2.87 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 23 H 22 F 3 NO 4 S: C, 59.35; H, 4.76; N, 3.01 Found: C, 59.47; H, 5.02; N, 2.86. EI m/z 465. 
     Using the General Procedure of Example 1 the following compounds were synthesized from the corresponding biphenyl chlorides: 
     EXAMPLE 29 
     N-{3-[2-(4-Chloro-4′-fluoro-biphenyl-3-ylmethoxy)-ethyl]-phenyl)-C,C,C-trifluoro-methanesulfonamide, m.p. 80-82° C. DMSO: δ 11.8 (s, 1H), 7.0-7.7 (m, 11H, arom), 4.6 (s, 2H), 3.75 (t, 2H), 2.91 (t, 2H), CHN 54.16, 3.72, 2.87 Found 53.87, 3.57, 2.83. 
     EXAMPLE 30 
     N-{3-[2-(4′-Fluoro-4-methoxy-biphenyl-3-ylmethoxy)-ethyl]-phenyl)-C,C,C-trifluoro-methanesulfonamide, m.p. 55-57° C. DMSO: δ 11.7 (s, 1H), 7.0-7.6 (m, 11H, arom), 4.5 (s, 2H), 3.68 (t, 2H), 2.88 (t, 2H), CHN 57.14, 4.38, 2.90, Found 56.72, 4.25, 2.87. 
     EXAMPLE 31 
     N-{3-[2-biphenyl-4-ylmethoxy)-ethyl]-phenyl)-C,C,C-trifluoro-methane sulfonamide, m.p. 69-71° C. DMSO: δ 11.8 (s, 1H), 7.0-7.7 (m, 13H, arom), 4.5 (s, 2H), 3.64 (t, 2H), 2.87 (t, 2H), CHN 59.45, 4.76, 3.15 (0.5 MH 2 O) Found 59.48, 4.30, 3.03. 
     EXAMPLE 32 
     N-{3-[2-(3-fluoro-4′-methoxy-biphenyl-4-ylmethoxy)-ethyl]-phenyl)-C,C,C-trifluoromethanesulfonamide, m.p. 82-84° C. DMSO: δ 11.8 (s, 1H), 7.0-7.7 (m, 11H, arom), 4.54 (s, 2H), 3.64 (t, 2H), 2.85 (t, 2H) CHN 57.14, 4.38, 2.90 Found 56.96, 4.39, 2.86. 
     EXAMPLE 33 
     5-[3-(2-Methyl-biphenyl-3-ylmethoxymethyl)-phenyl]-2H-tetrazole, m.p. 112-114° C. DMSO: δ 7.1-8.1 (m, 12H, arom), 4.66 (m, 4H), 2.15 (s, 3H) CHN 73.21, 5.72, 15.52 (0.25 MH 2 O) Found 72.99, 4.96, 15.59. 
     EXAMPLE 34 
     N-{3-[2-(3′,5′-Dichloro-biphenyl-3-ylmethoxy)-ethyl]-phenyl)-C,C,C-trifluoro-methanesulfonamide, m.p. 52-54° C. DMSO: δ 11.8 (s, 1H), 7.0-7.7 (m, 11H, arom), 4.54 (s, 2H), 3.64 (t, 2H), 2.86 (t, 2H) CHN 52.39, 3.60, 2.78 Found 52.01, 3.53, 2.49. 
     EXAMPLE 35 
     N-{3-[2-(3′,5′-Dichloro-biphenyl-4-ylmethoxy)-ethyl]-phenyl)-C,C,C-trifluoro-methanesulfonamide, m.p. 70-72° C. DMSO: δ 11.8 (s, 1H), 7.0-7.8 (m, 11H, arom), 4.52 (s, 2H), 3.64 (t, 2H), 2.86 (t, 2H) CHN 52.39, 3.60, 2.78 Found 52.60, 3.67, 2.64. 
     EXAMPLE 36 
     N-{3-[2-(4′-Fluoro-biphenyl-3-ylmethoxy)-ethyl]-phenyl)-C,C,C-trifluoro-methanesulfonamide, m.p. 48-50° C. DMSO: δ 11.8 (s, 1H), 7.0-7.8 (m, 12H, arom), 4.5 (s, 2H), 3.66 (t, 2H), 2.86 (t, 2H) 58.27, 4.22, 3.09 Found 57.72, 4.08, 2.99. 
     EXAMPLE 37 
     N-{3-[2-(4′-Fluoro-biphenyl-4-ylmethoxy)-ethyl]-phenyl)-C,C,C-trifluoro-methanesulfonamide, m.p. 65-67° C. DMSO: δ 11.8 (s, 1H), 7.0-7.8 (m, 12H, arom), 4.5 (s, 2H), 3.66 (t, 2H), 2.86 (t, 2H) CHN 58.27, 4.22, 3.09 Found 57.60, 4.17, 3.03. 
     EXAMPLE 38 
     Preparation of {4-[2-(Biphenyl-2-ylmethoxy)-ethyl]-phenyl}-urea 
     To 100 mg (0.33 mmol) of the product of Example 27 step 1 in 15 mL of DMF was added 57 mg (0.50 mmol) of trimethylsilyl isocyanate the solution was heated to 50° C. for 1.5 hr. At the end of this time it was poured into 100 mL of water. The resulting precipitate was collected by filtration and taken up in hot ethyl acetate. The excess water was removed by decantation and the solution allow to cool. Hexane was introduced to cloudiness and the solution allow to cool further to yield 55 mg (48%) of product as a colorless solid, m.p. 143-144° C. NMR (400 MHz, DMSO) δ 8.42 (s, 1H); 7.34 (m, 10H); 7.10 (t, J=7.7 Hz, 1H); 6.73 (d, J=7.7 Hz, 1H); 5.77 (s, 2H); 4.30 (s, 2H); 3.53 (t, J=6.8 Hz, 2H); 2.72 (t, J=6.8 Hz, 2H). Anal. Calcd. for C 21 H 21 N O: C, 83.13; H, 6.98; N, 4.62 Found: C, 75.13; H, 6.41; N, 8.11. (+)FAB m/z 347 (M+H), 369 (M+Na). 
     EXAMPLE 39 
     {3-[2-(4′-Methoxy-biphenyl-3-ylmethoxy)-ethyl]-phenyl}-urea 
     Using a procedure similar to Example 38, 3-[2-(4′-Methoxy-biphenyl-3-ylmethoxy)-ethyl]-phenyl}-amine was converted to the title product (47 mg, 42%), m.p. 87-89° C. NMR (400 MHz, DMSO) δ 8.43 (s, 1H); 7.16 (m, 13H); 5.78 (s, 2H); 4.53 (s, 2H); 3.79 (s, 3H); 3.64 (t, J=7.0 Hz, 2H); 2.80 (t, J=7.0 Hz, 2H). Anal. Calcd. for C 23 H 24 N 2 O 3 : C, 73.38; H, 6.43; N, 7.44 Found: C, 72.03; H, 6.39; N, 7.54. EI m/z 376. 
     EXAMPLE 40 
     Preparation of N-{3-[2-(4′-Chloro-4-methoxy-biphenyl-3-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoromethanesulfonamide 
     Using a procedure similar to Example 27, 2-methoxy, 5-(4-chlorophenyl)benzyl chloride was converted to the title compound (72 mg, 62%), m.p. 99-101° C. NMR (400 MHz, DMSO) δ 11.78 (s, 1H, —NH); 7.31 (m, 11H); 4.51 (s, 2H); 3.80 (3H, s) 3.69 (t, J=6.6 Hz, 2H); 2.87 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 23 H 21 ClF 3 NO 4 S: C, 55.26; H, 4.23; N, 2.80 Found: C, 54.88; H, 4.21; N, 2.66. EI m/z 499. 
     EXAMPLE 41 
     Preparation of {3-[2-(4′-Chloro-4-methoxy-biphenyl-3-ylmethoxy)-ethyl]-phenyl}-urea 
     Using a procedure similar to Example 38, 3-[2-(4′-Chloro-4-methoxy-biphenyl-3-ylmethoxy)-ethyl]-phenyl}-amine was converted to the title product (47 mg, 42%), m.p. 155° C. (dec.). NMR (400 MHz, DMSO) δ 8.44 (s, 1H); 7.18 (m, 10H); 5.79 (s, 2H); 4.52 (s, 2H); 3.81 (s, 3H); 3.67 (t, J=6.8 Hz, 2H); 2.80 (t, J=6.8 Hz, 2H). Anal. Calcd. for C 23 H 23 ClN 2 O 3 : C, 67.23; H, 5.64; N, 6.82 Found: C, 65.45; H, 5.15; N, 6.45. EI m/z 410. 
     EXAMPLE 42 
     Preparation of C,C,C-Trifluoro-N-{3-[2-(6-fluoro-4′-methoxy-biphenyl-3-yl-methoxy)-ethyl]-phenyl}-methanesulfonamide 
     Using a procedure similar to Example 27, 4-fluoro,3-(4-methoxy phenyl)benzyl chloride was converted to the title compound (338 mg, 65%), m.p. 70-71° C. NMR (400 MHz, DMSO) δ 11.82 (s, 1H, —NH); 7.24 (m, 11H); 4.50 (s, 2H); 3.81 (s, 3H) 3.66 (t, J=6.6 Hz, 2H); 2.87 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 23 H 21 F 4 NO 4 S: C, 57.14; H, 4.38; N, 2.90 Found: C, 56.13; H, 4.46; N, 2.87. (+)ESI m/z 501 (M+NH4). 
     EXAMPLE 43 
     Preparation of N-(3-{2-[2-(4-tert-Butyl-phenyl)-thiazol-4-ylmethoxy]-ethyl}-phenyl)-C,C,C-trifluoro-methanesulfonamide 
     Step 1. Preparation of 3-{2-[2-(4-tert-Butyl-phenyl)-thiazol-4-ylmethoxy]-ethyl}-phenyl amine 
     To a solution of 0.027 g (1 mmol) of 95% sodium hydride and 0.5 drop of 15-crown-5 in 20 mL of THF was added dropwise a solution of 0.139 g (1 mmol) of 3-(2-hydroxy ethyl)phenyl amine at 0° C. After stirring for 0.5 hr 0.28 g (1.1 mmol) of 4-chloromethyl-2-(4-tert-butyl phenyl)thiazole was added in one portion. The mixture was stirred at room temperature for 5 hr. At the end of this time, the solution was concentrated and the residue washed with 10 ml of saturated ammonium chloride and extracted 2 times with 30 mL of ethyl acetate. The organic layers were combined, dried (MgSO 4 ) and concentrated to recover an oil, which was purified by column chromatography on SiO2 with 30% ethyl acetate:hexane elution to provide 0.125 g of product as an oil, used in the next step without further purification. NMR (400 MHz, DMSO-d6) δ 7.83 (d, J=8 Hz, 2H, ArH), 7.50 (d, J=8 Hz, 2H, ArH), 7.45 (s, 1H, N═CH) 7.08 (t, J=8 Hz, 1H, H5), 6.63 (d, J=8 Hz, 1H, H4), 6.54 (s, 1H, H2), 6.51 (d, J=8 Hz, 1H, H6) 4.59 (s, 2H, OCH2), 3.71 (t, J=7 Hz, 2H, OCH2), 2.87 (t, J=7 Hz, 2H, ArCH2), 1.30 (s, 9H, t-bu). 
     Step 2. Preparation of the Title Compound 
     According to the procedure of Example 2, 0.125 g (0.34 mmol) of the product from step 1 was followed to yield a crude oil, which was chromatographed over SiO2 and 20% ethyl acetate:hexane solution to recover 0.16 g of a light yellow oil. Trituration with hexane and recrystallization of the resulting solid from ethyl acetate:hexane yielded 0.09 g of heavy yellow crystals, m.p. 110-112° C. NMR (400 MHz, DMSO-d6) δ 11.79 (bs, 1H, NH), 7.83 (d, J=8 Hz, 2H, ArH), 7.50 (d, J=8 Hz, 2H, ArH), 7.45 (s, 1H, N═CH) 7.31 (t, J=8 Hz, 1H, H5), 7.18 (d, J=8 Hz, 1H, H4), 7.15 (s, 1H, H2), 7.10 (d, J=8 Hz, 1H, H6) 4.59 (s, 2H, OCH2), 3.71 (t, J=7 Hz, 2H, OCH2), 2.87 (t, J=7 Hz, 2H, ArCH2), 1.30 (s, 9H, t-bu). Anal. Calcd. for C23H25F3N2O3S2: C, 55.41; H, 5.05; N, 5.62. Found: C, 55.49; H, 5.22; N, 5.24. 
     EXAMPLE 44 
     Preparation of 2-(4-t-butyl phenyl),4-chloro methyl thiazole 
     To a 100 ml flask was added 1.9 g (10 mmol) of 4-t-butyl phenyl thioamide and 5 g (40 mmol) of dichloroacetone. The flask was immersed in an oil bath pre-heated to 100° C. After heating 1 hour the dark viscous oil was allowed to cool, then subjected to column chormatography on silica gel. Elution with 20% ethyl acetate:hexane resulted in 0.95 g (36%) of the title compound as a light yellow oil, used without further purification. NMR (200 Mhz, CDCl 3 ) δ: 7.85 (d, J=8 Hz, 2H, ArH) 7.45 (d, J=8 Hz, 2H, ArH) 7.23 (s, 1H, N═CH), 4.74 (s, 2H, OCH2), 1.36 (s, 9H, C(CH3)). 
     In like manner, the following chloromethyl thiazoles were made. 
     EXAMPLE 45 
     2-(5-Trifluoromethylpyridin-2-yl)-4-chloromethylthiazole 
       1 H NMR (300 Mhz, DMSO) δ: 9.17 (1H, s); 8.35 (2H, m); 8.03 (1H, s); 4.93 (2H, s). 
     EXAMPLE 46 
     2-(4-Methoxyphenyl)-4-chloromethylthiazole 
       1 H NMR (300 Mhz, CDCl 3 ) δ: 7.40 (5H, m); 4.70 (2H, s); 3.82 (3H, s). 
     EXAMPLE 47 
     2-Phenyl-4-chloromethylthiazole 
       1 H NMR (300 Mhz, CDCl 3 ) δ: 7.86 (6H, m); 5.02 (2H, s). 
     EXAMPLE 48 
     2-(2-Chlorophenyl)-4-chloromethylthiazole 
       1 H NMR (300 Mhz, DMSO) δ: 8.63 (1H, m); 7.99 (1H, s); 7.47 (3H, m); 4.92 (2H, s). 
     EXAMPLE 49 
     2-(4-Trifluoromethoxyphenyl)-4-chloromethylthiazole 
       1 H NMR (300 Mhz, CDCl 3 ) δ: 7.62 (5H, m); 4.73 (2H, s). 
     EXAMPLE 50 
     2-(4-Fluorophenyl)-4-chloromethyl-5-bromothiazole 
       1 H NMR (300 Mhz, DMSO) δ: 7.98 (2H, m); 7.37 (2H, m); 4.83 (2H, s). 
     EXAMPLE 51 
     2-(4-Trifluoromethylphenyl)-4-chloromethyl-5-chlorothiazole 
       1 H NMR (300 Mhz, CDCl 3 ) δ: 7.83 (2H, m); 7.11 (2H, m); 4.73 (2H, s). 
     EXAMPLE 52 
     C,C,C-Trifluoro-N-(3-{2-[2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethoxy]-ethyl}-phenyl)-methanesulfonamide was prepared from 4-trifluoromethyl-2-(4-t-butyl phenyl thiazole following the procedure of Example 44 (69%), m.p. 117-119° C. NMR (400 MHz, DMSO-d6) δ 11.79 (bs, 1H, NH), 8.15 (d, J=8 Hz, 2H, ArH), 7.68 (d, J=8 Hz, 2H, ArH), 7.31 (t, J=8 Hz, 1H, H5), 7.26 (s, 1H, N═CH), 7.20 (d, J=8 Hz, 1H, H4), 7.16 (s, 1H, H2), 7.17 (d, J=8 Hz, 1H, H6) 4.65 (s, 2H, OCH2), 3.82 (t, J=7 Hz, 2H, OCH2), 2.95 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C20H16F6N2O3S2: C, 47.06; H, 3.16; N, 5.49. Found: C, 47.04; H, 3.17; N, 5.41. 
     EXAMPLE 53 
     N-(3-{2-[2-(4-Chloro-phenyl)-thiazol-4-ylmethoxy]-ethyl}-phenyl)-C,C,C-trifluoro-methanesulfonamide was prepared from 4-chloromethyl-2-(4-chloro)phenyl thiazole following the procedure of Example 44 (63%), m.p. 114-116° C. NMR (400 MHz, DMSO-d6) δ 11.79 (bs, 1H, NH), 7.93 (d, J=8 Hz, 2H, ArH), 7.58 (d, J=8 Hz, 2H, ArH), 7.31 (t, J=8 Hz, 1H, H5), 7.20 (d, J=8 Hz, 1H, H4), 7.18 (s, 1H, N═CH), 7.16 (s, 1H, H2), 7.17 (d, J=8 Hz, 1H, H6) 4.60 (s, 2H, OCH2), 3.72 (t, J=7 Hz, 2H, OCH2), 2.95 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C19H16Cl1F3N2O3S2: C, 47.85; H, 3.38; N, 5.87. Found: C, 47.99; H, 3.51; N, 5.68. 
     EXAMPLE 54 
     C,C,C-Trifluoro-N-(3-{2-[2-(4-fluoro-phenyl)-thiazol-4-ylmethoxy]-phenyl)-C,C,C-trifluoro-methanesulfonamide was prepared from 4-chloromethyl-2-(4-fluoro)phenyl thiazole following the procedure of Example 44 (64%), m.p. 110-111° C. NMR (400 MHz, DMSO-d6) δ 11.76 (bs, 1H, NH), 7.95 (m, 2H, ArH), 7.48 (s, 1H, N═CH), 7.36 (m, 3H, ArH), 7.20 (d, J=8 Hz, 1H, H4), 7.16 (s, 1H, H2), 7.17 (d, J=8 Hz, 1H, H6) 4.60 (s, 2H, OCH2), 3.72 (t, J=7 Hz, 2H, OCH2), 2.95 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C19H16F4N2O3S2: C, 49.56; H, 3.50; N, 6.08. Found: C, 48.22; H, 3.58; N, 5.78. 
     EXAMPLE 55 
     N-(3-{2-[2-(6-Chloro-pyridin-3-yl)-thiazol-4-ylmethoxy]-ethyl}-phenyl)-C,C,C-trifluoro-methanesulfonamide was prepared from 4-chloromethyl-2-(6-chloro-pyridine-3-yl)thiazole following the procedure of Example 44 (61%), 116-118° C. NMR (400 MHz, DMSO-d6) δ 11.82 (bs, 1H, NH), 8.75 (d, J=3 Hz, 1H, ArH), 8.20 (dd, J1=3 Hz, J2=8 Hz, 1H, ArH), 7.79 (s, 1H, N═CH), 7.37 (t, J=8 Hz, 1H, H5), 7.24 (d, J=8 Hz, 1H, H4), 7.20 (s, 1H, H2), 7.17 (d, J=8 Hz, 1H, H6), 6.89 (d, J=8 Hz, 1H, ArH), 4.85 (s, 2H, OCH2), 4.56 (t, J=7 Hz, 2H, OCH2), 3.16 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C18H15F3N3O3S2: C, 45.24; H, 3.16; N, 8.79. Found: C, 45.29; H, 3.31; N, 8.42. 
     EXAMPLE 56 
     N-(3-{2-[2-(3-Chloro-4-fluoro-phenyl)-thiazol-4-ylmethoxy]-ethyl}-phenyl)-C,C,C-trifluoro-methanesulfonamide was prepared from 4-chloromethyl-2-(3-chloro,4-fluoro-phenyl)thiazole following the procedure of Example 44 (58%), m.p. 141-143° C. NMR (400 MHz, DMSO-d6) δ 11.76 (bs, 1H, NH), 7.94 (s, 1H, ArH), 7.83 (d, J=8 Hz, 1H, ArH), 7.78 (s, 1H, N═CH), 7.36 (t, J=8 Hz, 1H, H5), 7.20 (d, J=8 Hz, 1H, H4), 7.16 (s, 2H, H2 and ArH), 7.17 (d, J=8 Hz, 1H, H6), 4.84 (s, 2H, OCH2), 4.35 (t, J=7 Hz, 2H, OCH2), 3.14 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C19H15ClN2O3S2: C, 46.11; H, 3.06; N, 5.66. Found: C, 45.819; H, 3.11; N, 5.24. 
     EXAMPLE 57 
     C,C,C-Trifluoro-N-(3-{2-[2-(5-trifluoromethyl-pyridin-2-yl)-thiazol-4-yl-methoxy]ethyl}-phenyl)-methanesulfonamide was prepared from 4-chloromethyl-2-(5-trifluoromethyl-pyridin-2-yl)thiazole following the procedure of Example 44 (56%), m.p. 116-117° C. NMR (400 MHz, DMSO) δ 9.03 (s, 1H); 8.31 (m, 2H); 7.73 (s, 1H); 7.21 (s, 4H); 4.51 (s, 2H); 3.69 (t, J=6.6 Hz, 2H); 2.88 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 19 H 15 F 6 N 3 O 3 S 2 : C, 44.62; H, 2.96; N, 8.22 Found: C, 44.91; H, 2.71; N, 7.86. EI m/z 511. 
     EXAMPLE 58 
     C,C,C-Trifluoro-N-{3-[2-(2-phenyl-thiazol-4-ylmethoxy)-ethyl]phenyl}-methane sulfonamide was prepared from 4-chloromethyl-(2-phenyl)thiazole following the procedure of Example 44 (59%), m.p. 112-113° C. NMR (400 MHz, DMSO) δ 7.51 (m, 10H); 4.61 (s, 2H); 3.72 (t, J=6.6 Hz, 2H); 2.87 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 19 H 17 F 3 N 2 O 3 S 2 : C, 51.58; H, 3.87; N, 6.33 Found: C, 51.55; H, 4.02; N, 6.24. EI m/z 442. 
     EXAMPLE 59 
     C,C,C-Trifluoro-N-(3-{2-[2-(4-methoxy-phenyl)-thiazol-4-ylmethoxy]-ethyl}-phenyl)-methanesulfonamide was prepared from 4-chloromethyl-2-(4-methoxy)phenyl thiazole following the procedure of Example 44 (62%), m.p. 112-113° C. NMR (400 MHz, DMSO) δ 7.44 (m, 9H); 4.57 (s, 2H); 3.81 (s, 3H) 3.71 (t, J=6.6 Hz, 2H); 2.87 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 20 H 19 F 3 N 2 O 4 S 2 : C, 50.58; H, 4.04; N, 5.89 Found: C, 50.23; H, 4.01; N, 5.72. (−)ESI m/z 471 (M−H). 
     EXAMPLE 60 
     N-(3-{2-[2-(2-Chloro-phenyl)-thiazol-4-ylmethoxy]-ethyl}-phenyl)-C,C,C-trifluoro-methanesulfonamide was prepared from 4-chloromethyl-2-(2-chloro phenyl)thiazole following the procedure of Example 44 (64%), m.p. 86-87° C. NMR (400 MHz, DMSO) d: 8.15 (dd, 1H, J 1 =4.8, J 2 =2.4); 7.38 (m, 8H); 4.64 (s, 2H); 3.73 (t, J=6.6 Hz, 2H); 2.87 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 19 H 16 ClF 3 N 2 O 3 S 2 : C, 47.85; H, 3.38; N, 5.87 Found: C, 45.12; H, 3.17; N, 5.53. (−)ESI m/z 475 (M−H). 
     EXAMPLE 61 
     C,C,C-Trifluoro-N-(3-{2-[2-(4-trifluoromethoxy-phenyl)-thiazol-4-yl-methoxy]-ethyl}-phenyl)-methanesulfonamide was prepared from 4-chloromethyl-2-(4-trifluormethoxy phenyl)thiazole following the procedure of Example 44 (64%), m.p. 115-116° C. NMR (400 MHz, DMSO) δ 7.58 (m, 9H); 4.62 (s, 2H); 3.73 (t, J=6.6 Hz, 2H); 2.88 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 20 H 16 F 6 N 2 O 4 S   2 : C, 45.63; H, 3.06; N, 5.32 Found: C, 45.82; H, 3.10; N, 5.22. EI m/z 526. 
     EXAMPLE 62 
     N-(3-{2-[5-Bromo-2-(4-fluoro-phenyl)-thiazol-4-ylmethoxy]-ethyl}-phenyl)-C,C,C-trifluoromethanesulfonamide was prepared from 4-chloromethyl-2-(4-trifluormethoxy phenyl)thiazole following the procedure of Example 44 (62%), m.p. 84-85° C. NMR (400 MHz, DMSO) δ 7.25 (m, 8H); 4.54 (s, 2H); 3.70 (t, J=6.6 Hz, 2H); 2.84 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 19 H 15 BrF 4 N 2 O 3 S 2 : C, 42.31; H, 2.80; N, 5.19 Found: C, 42.41; H, 2.66; N, 5.03. 
     EXAMPLE 63 
     N-(3-{2-[5-Chloro-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethoxy]-ethyl}-phenyl)-C,C,C-trifluoromethanesulfonamide was prepared from 4-chloromethyl-2-(4-trifluormethoxy phenyl)thiazole following the procedure of Example 44 (67%), m.p. 107-109° C. NMR (400 MHz, DMSO) δ 8.10 (d, J=8.3 Hz, 2H); 7.88 (d, J=8.3 Hz, 2H); 7.30 (t, J=7.7 Hz, 1H); 7.13 (m, 3H); 4.59 (s, 2H); 3.73 (t, J=6.6 Hz, 2H); 2.86 (t, J=6.6 Hz, 2H). Anal. Calcd. for C 20 H 15 ClF 6 N 2 O 3 S 2 : C, 44.08; H, 2.77; N, 5.14 Found: C, 41.22; H, 2.62; N, 4.65. (+)ESI m/z 545 (M+H). 
     EXAMPLE 64 
     Preparation of C,C,C-Trifluoro-N-(3-{2-[6-(4-fluoro-phenyl)-pyridin-2-ylmethoxy]-ethyl}-phenyl)-methanesulfonamide 
     Step 1 Preparation of 2-methyl,6-trifluoromethanesulfonyl pyridine 
     Using a procedure similar to that of EXAMPLE 24, 2.18 g (20 mmol) of 6-hydroxy,2-methyl pyridine was converted to 2-methyl,6-trifluoromethanesulfonyl pyridine as an oil and used immediately in subsequent steps without further purification 
     Step 2 Preparation of 2-methyl,6-(4-fluorophenyl)pyridine. 
     Using a procedure similar to EXAMPLE 25, 2.8 g (10.8 mmol) of the product of step 1 was reacted with 2.0 g (14.3 mmol) of 4-fluoroboronic acid. Purification yielded 1.8 g (89%) of a light yellow oil. NMR (200 MHz, CDCl3) δ 7.96 (m, 2H, ArH), 7.64 (t, J=8 Hz, 1H, ArH), 7.45 (d, J=8 Hz, 1H, ArH), 7.16 (m, 3H, ArH), 2.63 (s, 3H, CH3). 
     Step 3 Preparation of 2-chloromethyl,6-(4-fluorophenyl)pyridine 
     0.60 g (3.2 mmol) of the product of step 2 was dissolved in 50 mL of carbon tetrachloride, along with 0.54 g (3.5 mmol) of N-chloro succinimide and a catalytic amount of benzoyl peroxide. After refluxing for 20 hr, the solution was concentrated and filtered through a plug of silica gel eluting with 20% ethyl acetate:hexane. The resulting oil was contaminated with ˜10% of unreacted starting material and was used in the next step without further purification. NMR (200 MHz, CDCl3) δ 7.96 (m, 2H, ArH), 7.63 (m, 1H, ArH), 7.43 (m, 1H, ArH), 7.17 (m, 3H, ArH), 4.72 (s, 2H, CH2Cl). 
     Step 4 Preparation of 3-{2-[6-(4-fluoro-phenyl)-pyridin-2-ylmethoxy]-ethyl}-phenyl amine 
     Using a similar procedure to step 1 of Example 1 222 mg (1 mmol) of the product of step 3 above was reacted with 137 mg (1 mmol) of 3-(2-hydroxy ethyl)phenyl amine. After purification on silica with 40% ethyl acetate:hexane elution, recovered 0.21 g (65%) of an oil. NMR (200 MHz, CDCl3) δ 8.11 (m, 2H, ArH), 7.79 (m, 2H, ArH), 7.18-7.38 (m, 6H, ArH), 7.08 (d, J=8 Hz, 1H, ArH), 4.63 (s, 2H, OCH2), 4.53 (bs, 2H, NH2), 3.78 (t, J=7 Hz, 2H, OCH2), 2.92 (t, J=7 Hz, 2H, ArCH2). 
     Step 5 Preparation of the Title Compound 
     Using a similar procedure to step 2 of Example 1, 0.21 g (0.65 mmol) of the product from step 4 above was reacted with 0.12 mL (0.72 mmol) of trifluoromethane sulfonic anhydride to yield 210 mg (70%) of an oil after chromatogaphy. The oil was triturated with methylene chloride:hexane to induce solidification. The solid was recrystallized from ethyl acetate:hexane to yield 115 mg of colorless crystals m.p. 71-73° C. NMR (400 MHz, DMSO-d6) δ 11.80 (bs, 1H, NH), 8.16 (m, 2H, ArH), 7.81 (m, 2H, ArH), 7.18-7.38 (m, 6H, ArH), 7.12 (d, J=8 Hz, 1H, ArH), 4.63 (s, 2H, OCH2), 3.78 (t, J=7 Hz, 2H, OCH2), 2.92 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C21H18F4N2O3S1: C, 55.50; H, 3.99; N, 6.16. Found: C, 55.77; H, 3.90; N, 6.13. 
     EXAMPLE 65 
     C,C,C-Trifluoro-N-{3-[2-(6-phenyl-pyridin-2-ylmethoxy)-ethyl]-phenyl}-methane sulfonamide 
     In a sequence similar to that of Example 64 except that phenyl boronic acid was used in place of 4-fluoroboronic acid in step 2, 105 mg (58%) of the title compound was prepared, m.p. 75-77° C. NMR (400 MHz, DMSO-d6) δ 11.80 (bs, 1H, NH), 8.02 (d, J=8 Hz, 1H ArH), 7.83 (m, 2H, ArH), 7.41-7.60 (m, 3H, ArH), 7.35 (t, J=8 Hz, 1H, H5), 7.15-7.30 (m, 3H, ArH), 7.10 (d, J=8 Hz, 1H, ArH), 4.63 (s, 2H, OCH2), 3.78 (t, J=7 Hz, 2H, OCH2), 2.92 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C21H19F3N2O3S1: C, 57.79; H, 4.39; N, 6.42. Found: C, 57.63; H, 4.41; N, 6.28. 
     EXAMPLE 66 
     Preparation of N-{3-[2-(3-Chloro-benzo[b]thiophen-2-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide 
     Using a procedure similar to Example 1 3-Chloro,2-chloromethyl benzo[b]thiophene was converted to the title compound (73 mg, 58%), m.p. 85-87° C. NMR (400 MHz, DMSO) δ 7.54 (8H, m); 4.81 (2H, s); 3.73 (2H, t, J=6.6 Hz); 2.87 (2H, t, J=6.6 Hz); 2.03 (3H, s). Anal. Calcd. for C 18 H 15 ClF 3 NO3S 2 : C, 48.06; H, 3.36; N, 3.11 Found: C, 49.04; H, 3.49; N, 3.02. EI m/z 449. 
     EXAMPLE 67 
     Preparation of N-(3-{2-[Bis-(4-fluoro-phenyl)-methoxy]-ethyl}-phenyl)-C,C,C-trifluoro-methanesulfonamide 
     To a solution of 1 mmol of 4,4′-Difluoro-benzhydrol in 5-10 ml of dichloromethane (flame-dried RBF, nitrogen, stirring) is added 1.5-3 mmol of 2,6-Di-tert-butyl-4-methyl-pyridine. The solution is cooled down to −30° C. and 1-1.2 mmol of neat triflic anhydride added to the reaction mixture. After complete disappearance of starting material (may require additional 0.1-0.03 eq. of triflic anhydride) 1 mmol of 3-Nitro-phenethol added. The intermediate triflate disappeared in 4-6 hours. Standard acidic work-up followed by flash chromatography afforded the ether (˜75%), that was reduced into corresponding amine using sodium dithionite. The title compound was prepared using general procedure of triflation (Example 1, step 2) and isolated as an oil. NMR: DMSO: δ 11.8 (s, 1H), 7.0-7.4 (m, 12H, arom), 5.46 (s, 1H), 3.54 (t, 2H), 2.88 (t, 2H) CHN: 55.00, 3.99, 2.92 (0.5 MH 2 O) Found 54.95, 4.08, 2.88 El:471[M] + . 
     The following compounds were made from the corresponding benzyl chlorides according to the procedure of Example 1 and purified by crystallization from ethyl acetate:hexane. 
     EXAMPLE 68 
     N-{3-[2-(4-cyclohexyl-benzyloxy)-ethyl]-phenyl}-C,C,C-trifluoro-methane sulfonamide from 4-cyclohexylbenzylchloride m.p. 90-92° C. NMR: DMSO: δ 11.8 (s, 1H), 7.0-7.4 (m, 8H, arom), 4.4 (s, 2H), 3.6 (t, 2H), 2.83 (t, 2H), 1.2-1.8 (m, 10H), CHN 59.85, 5.94, 3.17 Found 59.55, 5.80, 2.96 +ESI:459 [M+NH 4 ] + . 
     EXAMPLE 69 
     N-{3-[2-(4-tert-Butyl-benzyloxy)-ethyl]-phenyl}-C,C,C-trifluoro-methane sulfonamide from 4-t-butyl benzyl chloride, m.p. 40-42° C. NMR DMSO: δ 11.8 (s, 1H), 7.0-7.4 (m, 8H, arom), 4.4 (s, 2H), 3.6 (t, 2H), 2.83 (t, 2H), 1.25 (s, 9H) CHN 57.82, 5.82, 3.37 Found 57.79, 5.74, 3.27 −ESI:414 [M−H] − . 
     EXAMPLE 70 
     N-{3-[2-(3-Chloro-4-methoxy-benzyloxy)-ethyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide from 3-chloro, 4-methoxy benzyl chloride, oil NMR: DMSO: δ 11.8 (s, 1H), 7.0-7.4 (m, 7H, arom), 4.4 (s, 2H), 3.81 (s, 3H), 3.6 (t, 2H), 2.8 (t, 2H) CHN 48.18, 4.04, 3.31 (contain Bu 4 N) Found 50.18, 4.59, 3.47. 
     EXAMPLE 71 
     N-{3-[2-(4-Bromo-phenoxy-benzyloxy)-ethoxy]-phenyl}-C,C,C-trifluoro-methanesulfonamide from 4-bromo benzyl chloride m.p. 92-93° C. NMR: DMSO: δ 11.9 (s, 1H), 6.8-7.5 (m, 8H, arom), 4.29 (m, 4H) CHN 40.92, 2.98, 3.18 Found 40.82, 2.75, 3.12. 
     EXAMPLE 72 
     N-{3-[2-(4-Bromo-2-fluoro-benzyloxy)-ethyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide from 4-Bromo, 2-fluoro benzyl bromide, m.p. 48-50° C. NMR: DMSO: δ 11.8 (s, 1H), 7.0-7.6 (m, 9H, arom), 4.46 (s, 2H), 3.66 (t, 2H), 2.85 (t, 2H) CHN 42.12, 3.07, 3.07 Found 42.02, 2.77, 2.99. 
     EXAMPLE 73 
     N-{3-[2-(3-benzyloxy-benzyloxy)-ethyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide from 3-benzyloxy benzyl chloride m.p. 62-63° C. NMR: DMSO: δ 11.8 (s, 1H), 6.8-7.5 (m, 13H, arom) 5.0 (s, 2H), 4.46 (s, 2H), 3.6 (t, 2H), 2.82 (t, 2H) CHN 58.22, 4.89, 2.95 (0.5 MH 2 O) Found 58.52, 4.60, 2.92. 
     EXAMPLE 74 
     N-{3-[2-(4-Iodo-benzyloxy)-ethyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide from 4-iodo benzyl chloride, m.p. 48-50° C. NMR: DMSO: δ 11.8 (s, 1H), 7.0-7.7 (m, 8H, arom), 4.4 (s, 2H), 3.62 (t, 2H), 2.85 (t, 2H) CHN 39.60, 3.12, 2.89 Found 39.91, 2.98, 2.82. 
     EXAMPLE 75 
     N-{3-[2-(6-Chloro-benzo[1,3]dioxol-5-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide from 6-chloro,-benzo[3,4]dioxol methyl chloride oil DMSO: δ 11.8 (s, 1H), 6.8-7.3 (m, 6H, arom), 6.04 (s, 2H), 4.4 (s, 2H), 3.65 (t, 2H), 2.84 (t, 2H), CHN 46.64, 3.45, 3.20 Found 46.64, 3.39, 3.16. 
     EXAMPLE 76 
     N-{3-[2-(4-Phenoxy-benzyloxy)-ethyl]-phenyl}-C,C,C-trifluoro-methane sulfonamide from 4-phenoxy benzyl chloride m.p. 47-49° C. DMSO: δ 11.8 (s, 1H), 6.8-7.5 (m, 13H, arom), 6.04 (s, 2H), 4.45 (s, 2H), 3.65 (t, 2H), 2.82 (t, 2H), CHN 58.53, 4.46, 3.10 Found 58.09, 4.44, 2.96. 
     EXAMPLE 77 
     N-{3-[2-(4-Styryl-benzyloxy)ethyl]phenyl}-C,C,C-trifluoro-methane sulfonamide from 4-styrylbenzylchloride, oil NMR: DMSO: δ 11.8 (s, 1H), 7.0-7.7 (m, 15H, arom), 4.45 (s, 2H), 3.65 (t, 2H), 2.84 (t, 2H) CHN 62.46, 4.81, 3.03 Found 61.82, 4.79, 2.88. 
     EXAMPLE 78 
     N-{3-[2-(3,4-Dimethyl-benzyloxy)-ethyl]-phenyl}-C,C,C-trifluoro methanesulfonamide (mixture of isomers) from 3,4-dimethyl benzyl chloride m.p. 58-60° C. NMR: DMSO: δ 11.8 (s, 1H), 6.9-7.4 (m, 7H, arom), 4.4 (m, 2H), 3.6 (m, 2H), 2-2.3 (m, 6H) CHN 55.80, 5.20, 3.62 Found 55.44, 5.17, 3.55. 
     EXAMPLE 79 
     Preparation of N-{3-[2-(5-(4-Trifluoromethyl-phenyl)[1,2,4]oxadiazol-3-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide 
     General procedure for preparation of 3-chloromethyl,[1,2,4]oxadiazoles Step 1. To a solution of 13.8 g of hydroxylamine hydrochloride in 30 mL of water was added 10.6 g of sodium carbonate. The mixture was stirred until everything was dissolved. Then 15 mL of chloroacetonitrile was added dropwise over a 15 min period (with exterior cooling). Stirred 1 h and then worked up by extracting twice with ether. Concentrated to give 10.8 g of chloroacetamide oxime. Used without further purification on subsequent step. 
     Step 2. To a solution of 3.0 g (27.6 mmol) of chloroacetamide oxime in 50 mL of dry dichloromethane at 0° C. was added 4.6 mL (33.1 mmol) of triethylamine followed by the dropwise addition of 4.52 mL (30.4 mmol) of 4-trifluoromethylbenzoyl chloride. Monitored via TLC for complete reaction (˜2 h). Worked up by pouring into water and extracting with ethyl acetate several times. The combined organic layers were washed with 2 N hydrochloric acid, saturated sodium bicarbonate, and brine. Dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give a thick residue. Residue was dissolved in 100 mL of toluene and refluxed, removing water via a Dean-Stark trap. After reaction was complete, the solvent was removed in vacuo to give an orange residue. Flash chomatography of the residue on a silica column eluting with 5-20% ethyl acetate hexane, gave after concentration, 4.5 g (62%) of pure 3-chloromethyl-5-(4-trifluoromethylphenyl)-1,2,4-oxadiazole. 
     Following the General Procedures of Example 1, the product from step 2 above was converted to the title product. NMR: DMSO: δ 11.9 (s, 1H), 7.2-8.4 (m, 8H, arom), 4.8 (s, 2H), 4.62 (s, 2H). 
     The following compounds were synthesized from their corresponding acid chlorides according to the above procedure. 
     EXAMPLE 80 
     N-{4-[5-(4-Adamantan-1-yl-[1,2,4]oxadiazol-3-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide from adamantoyl chloride, m.p. 120-122° C. DMSO: δ 11.8 (s, 1H), 7.0-7.4 (m, 4H, arom), 4.56 (s, 2H), 3.7 (t, 2H), 2.85 (t, 2H), 1.7-2.1 (m, 13H) CHN 54.42, 5.40, 8.65 Found 54.21, 5.38, 8.33. 
     EXAMPLE 81 
     N-{3-[2-(5-(4-tert-Butyl-phenyl)-[1,2,4]oxadiazol-3-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide from 4-t-butyl benzoyl chloride m.p. 75-77° C. DMSO: δ 11.8 (s, 1H), 7.0-8.1 (m, 8H, arom), 4.66 (s, 2H), 3.78 (t, 2H), 2.85 (t, 2H), 1.3 (s, 9H) CHN 54.65, 5.00, 8.69 Found 54.44, 4.47, 8.60. 
     EXAMPLE 82 
     N-{2-[3-(5-(4-Trifluoromethyl-phenyl) [1,2,4]oxadiazol-3-ylmethoxy)-phenyl]-ethyl}-C,C,C-trifluoro-methanesulfonamide from 4-trifluoromethyl benzoyl chloride, m.p. 83-86° C. NMR: DMSO: δ 9.45 (s, 1H), 6.8-8.4 (m, 8H, arom), 5.4 (s, 2H), 3.4 (m, 2H), 2.8 (m, 2H). 
     EXAMPLE 83 
     N-{3-[2-(5-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-3-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide from 3-trifluoromethyl benzoyl chloride m.p. 62-64° C. DMSO: δ 11.8 (s, 1H), 7.0-8.5 (m, 8H, arom), 3.78 (t, 2H), 2.86 (t, 2H) CHN 45.24, 3.20, 8.33 (0.5 MH 2 O) Found 44.87, 3.08, 7.89. 
     EXAMPLE 84 
     N-{3-[2-(5-(3-methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide from 3-methoxy benzoyl chloride, m.p. 52-54° C. DMSO: δ 11.8 (s, 1H), 7.0-7.7 (m, 8H, arom), 4.66 (s, 2H), 3.85 (s, 3H), 3.75 (t, 2H), 2.86 (t, 2H) CHN 45.42, 4.61, 8.36 (2.5 MH 2 O) Found 45.32, 3.67, 8.07. 
     EXAMPLE 85 
     N-{3-[2-(5-(4-methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide from 4-methoxy benzoyl chloride m.p. 88-90° C. DMSO: δ 11.7 (s, 1H), 7.0-8.1 (m, 8H, arom), 4.65 (s, 2H), 3.85 (s, 3H), 3.75 (t, 2H), 2.86 (t, 2H) CHN 49.89, 3.57, CHN 9.19 49.89, 3.57, 9.19 Found 49.78, 4.09, 8.72. 
     EXAMPLE 86 
     N-{3-[2-(5-(2-methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide from 2-methoxy benzoyl chloride, oil DMSO: δ 11.8 (s, 1H), 7.0-8.1 (m, 8H, arom), 4.66 (s, 2H), 3.9 (s, 3H), 3.75 (t, 2H), 2.86 (t, 2H) CHN 47.10, 4.37, 8.67 (1.5 MH 2 O) Found 47.21, 3.82, 8.44. 
     EXAMPLE 87 
     N-{3-[2-(5-(4-trifluoromethylphenyl)-[1,2,4]oxadiazol-3-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro-methanesulfonamide was prepared from 3-Chloromethyl-5-[4-trifluoromethyl)phenyl-1,2,4-oxadiazole following the general procedure of EXAMPLE 1, m.p. 83-86° C. NMR: DMSO: δ 11.8 (bs, 1H, NH), 8.30 (m, 2H, ArH), 7.96 (d, J=8 Hz, 2H, ArH), 7.30 (t, J=8 Hz, 1H, ArH), 7.01-7.18 (m, 3H, ArH), 4.70 (s, 2H, OCH2), 3.77 (t, J=7 Hz, 2H, OCH2), 2.87 (t, J=8 Hz, 2H, CH2). Anal. Calcd. for C 19 H 14 F6N3O 4 S: C, 46.07; H, 3.05; N, 8.48 Found: C, 45.92; H, 3.09; N, 8.33. 
     EXAMPLE 88 
     Preparation of N-{3-[2-(4′-Chloro-2-methoxy-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoromethane sulfonamide 
     Preparation of 3-methoxy,4-(4′-chlorophenyl)benzaldehyde 
     Step 1 
     To a flask charged with 6.08 g (40.0 mmol) of Vanillin and 6.70 ml (48.0 mmol) of triethyl amine dissolved in 300 mL of methylene chloride was added dropwise a solution of 12.4 g (44.0 mmol) of trifluoromethane sulfonic anhydride in 100 mL of methylene chloride at 0° C. After 2 h, the solution was concentrated, and the residue washed with water and extracted twice with 100 mL of ethyl acetate. After upon drying and concentrating, the dark oil was subjected to flash chromatography on silica gel. Elution with 20% ethyl acetate:hexane yielded 8.91 g (71%) of product as a light yellow oil, used in the next step without further purification 
     Step 2 
     5.03 g (15.9 mmol) of the product obtained from step 1, 3.5 g (22.3 mmol) of 4-chlorobenzene boronic acid and 8.49 g (39 mmol) of potassium phosphate were placed in a flask along with 150 mL of dioxane. The solution was degassed with nitrogen, whereupon 185 mg of tetrakis(triphenylphosphine)palladium was added. The solution was heated to 70° C. for 5 hr. At the end of this time, the solution was concentrated, and the residue washed with 0.1N HCl and extracted with ethyl acetate (2×150 mL). The combined extracts were dried (MgSO 4 ) and filtered through a plug of silica gel. The solution was concentrated and the residue triturated with hexane. Removal of the solid by filtration yielded 2.04 g of product. A second crop of product crystallized from the hexane and was combined with the first for a combined yield of 3.8 g (90%) as a colorless solid. NMR (200 MHz, CDCl3) δ 10.03 (s, 1H, CHO), 8.14 (d, J=8 Hz, 1H, H6), 7.31-7.56 (m, 6H, ArH), 3.91 (s, 3H, OCH3). 
     Step 3 Preparation of 3-methoxy,4-(4′-chlorophenyl)benzyl chloride 
     To a flask containing 300 mL of dry ether was added 0.53 g (14.4 mmol) of lithium aluminum hydride. 3.8 g of the product from step 2 was added portionwise over the course of 10 minutes at 0° C. After 1 hr, 3 ml of ethyl acetate was added, then 50 mL of a saturated solution of potassium sodium tartrate was cautiously added at 0° C. The layers were separated and the aqueous phase was extracted with 3×100 mL of ethyl acetate. The combined organic phases were combined, dried and concentrated to yield 2 g of product as an oil, which solidfied upon standing. 
     To a 200 mL THF solution of triphenyl phosphine (3.2 g, 12.2 mmol) and 1.74 g (13.8 mmol) of N-chlorosuccinimide was added 2.3 g (8.7 mmol) of the product from above. After stirring for 3 hr the solution was concentrated and the residue taken up in 30 mL of ether. The solution was filtered through a plug of SiO2 eluting with 20% ethyl acetate:hexane. After concentration, recovered 2.1 g of product as an oil, which solidified on standing. The product was used in the next step without further purification. NMR: (200 MHz, CDCl3) δ 7.51-7.36 (dd, J=8 Hz, 4H, ArH), 7.28 (d, J=8 Hz, 1H, H5), 7.06 (d, J=8 Hz, 1H, H6), 7.01 (s, 1H, H2), 4.64 (s, 2H, CH2Cl), 3.85 (s, 3H, OCH3). 
     Step 4. Preparation of the Title Compound. 
     3.0 g (8.17 mmol) of the product obtained from step 3 was subjected to the general ether synthesis procedure described in Example 1. Recovered 3.95 g of an oil which was triturated with hexane to induce solidification. After recrystallization from ethyl acetate:hexane recovered 2.84 g of product as colorless crystals, m.p. 88-90° C. NMR (400 MHz, DMSO-d6) δ 11.80 (bs, 1H, NH), 7.42-7.51 (m, 4H, ArH), 7.34 (t, J=8 Hz, 1H, ArH), 7.16-7.28 (m, 4H, ArH), 7.12 (d, J=8 Hz, 1H, ArH), 6.98 (s, 1H, ArH), 9.92 (d, J=8 Hz, 1H, ArH), 4.48 (s, 2H, OCH2), 3.75 (s, 1H, 3H, OCH3), 3.68 (t, J=7 Hz, 2H, OCH2), 2.88 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C23H21Cl1F3N1O4S1: C, 55.26; H, 4.23; N, 2.80. Found: C, 54.97; H, 4.29; N, 2.71.