Title of Invention	PHENYLALKANOIC ACID AND PHENYLOXYALKANOIC ACID DERIVATIVES AS HPPAR ACTIVATORS
Abstract	The present invention provides a compound of formula (I):wherein.Rl and R2 are independently H or C1-3 alkyl;X represents a O or (CH2)n where n is 0, 1 or 2;R3and R4 independently represent H, C1-3 alkyl, -OCH3, -CF3, allyl, or halogen;Xl represents O, S, SO2, SO, or CH2;R5 and R6 independently represent hydrogen, C1-6 alkyl (including branched alkyl and optionally substituted by one or more halogens or Cl-6alkoxy), or together with the carbon atom to which they are bonded form a 3-6 membered cycloalkyl ring;R7 represents aphenyl or a 6 membered heteroaryl group containing 1, 2 or 3 nitrogen atoms wherein the phenyl or heteroaryl group is substituted by 1. 2 or 3 moieties selected from the group consisting of halogen, C1-6 alkoxy, C1-6 alkyl, CF3, hydroxy, or phenyl (which may be optionally substituted by one or more C1-3 alkyl, -OC1-3 alkyl, CN, acetyl, hydroxy, halogen or CF3).

Title of Invention

PHENYLALKANOIC ACID AND PHENYLOXYALKANOIC ACID DERIVATIVES AS HPPAR ACTIVATORS

Abstract

The present invention provides a compound of formula (I):wherein.Rl and R2 are independently H or C1-3 alkyl;X represents a O or (CH2)n where n is 0, 1 or 2;R3and R4 independently represent H, C1-3 alkyl, -OCH3, -CF3, allyl, or halogen;Xl represents O, S, SO2, SO, or CH2;R5 and R6 independently represent hydrogen, C1-6 alkyl (including branched alkyl and optionally substituted by one or more halogens or Cl-6alkoxy), or together with the carbon atom to which they are bonded form a 3-6 membered cycloalkyl ring;R7 represents aphenyl or a 6 membered heteroaryl group containing 1, 2 or 3 nitrogen atoms wherein the phenyl or heteroaryl group is substituted by 1. 2 or 3 moieties selected from the group consisting of halogen, C1-6 alkoxy, C1-6 alkyl, CF3, hydroxy, or phenyl (which may be optionally substituted by one or more C1-3 alkyl, -OC1-3 alkyl, CN, acetyl, hydroxy, halogen or CF3).

Full Text	PHENYLALKANOIC ACID AND PHENYLOXYALKANOIC ACID DERIVATIVES AS HPPAR ACTIVARORS Chemical Compounds The present invention relates to certain novel compounds. In particular, the present invention relates to compounds that activate human peroxisome proliferator activated receptors ("hPPARs"). The present invention also relates to method for preparing the compounds, their use in medicine, pharmaceutical compositions containing them and methods for the prevention or treatment of PPAR mediated diseases or conditions. Several independent risk factors have been associated with cardiovascular disease. These include hypertension, increased fibrinogen levels, high levels of triglycerides, elevated LDL cholesterol, elevated total cholesterol, and low levels of HDL cholesterol. HMG CoA reductase inhibitors ("statins") are useful for treating conditions characterized by high LDL-c levels. It has bean shown that lowering LDL-c is not sufficient for reducing the risk of cardiovascular disease in some patients, particularly those with normal LDL-c levels. This population pool is identified by the independent risk factor of low HDL-c. The increased risk of cardiovascular disease associated with low HDL-c levels has not yet been totally successfully addressed by drug therapy (Bisgaier, C. L.; Pape, M. E. Curr. Pharm. Des. 1998, 4, 53-70). Syndrome X (including metabolic syndrome) is loosely defined as a collection of abnormalities including hyperinsulemia, obesity, elevated levels of the following: triglycerides, uric acid, fibrinogen, small dense LDL particles, and plasminogen activator inhibitor 1 (PAI-1), and decreased levels of HDL-c. NlDDK/I is described as insulin resistance, which in turn causes anomalous glucose output and a decrease in glucose uptake, by skeletal muscle. These factors eventually lead to impaired glucose tolerance (IGT) and hyperinsulinemia. Peroxisome Proliferator Activated Receptors (PPARs) are orphan receptors belonging to the steroid/retinoid receptor superfamily of ligand-activated transcription factors. See, for example Willson T.M. and Wahli, W., Curr. Opin. Chem. B!ol., 1, pp235-241 (1997) and Willson T.M. et. al., J. Med. Chem., 43, p527-549 (2000). The binding of agonist ligands to the receptor results in changes in the expression level of mRNAs encoded by PPAR target genes. Three mammalian Peroxisome Proliferator Activated Receptors have been isolated and termed PPAR alpha, PPAR gamma, and PPAR delta (also known as NUC1 or PPAR beta). These PPARs regulate expression of target genes by binding to DNA sequence elements, termed PPAR response elements (PPRE). To date, PPREs have been identified in the enhancers of a number of genes encoding proteins that regulate lipid metabolism suggesting that PPARs play a pivotal role in the adipogenic signalling cascade and lipid homeostasis (H. Keller and W. Wahli, Trends Endocrinol. Metab 291 -296, 4 (1993)). It has now been reported that the thiazolidinedione class of drugs are potent and selective activators of PPAR gamma and bind directly to the PPAR gamma receptor (J. M. Lehmann et. al., J. Biol. Chem. 12953-12956, 270 (1995)), providing evidence that PPAR gamma is a possible target for the therapeutic actions of the thiazolidinediones. Activators of the nuclear receptor PPAR?, for example rosiglitazone, have been shown in the clinic to enhance insulin-action, reduce serum glucose and have small but significant effects on reducing serum triglyceride levels in patients with Type 2 diabetes. See, for example, D. E. Kelly et al., Curr. Opin. Endocrinol. Diabetes, 90-96, 5 (2), (1998); M. D. Johnson et al., Ann. Pharmacother., 337-348,32 (3), (1997); and M. Leutenegger et al., Curr. Ther. Res., 403-416, 58 (7), (1997). The mechanism for this triglyceride lowering effect appears to be predominantly increased clearance of very low density lipoproteins (VLDL) through induction of lipoprotein lipase (LPL) gene expression. See, for example, B. Staels et al., Arterioscler. Thromb., Vase. Biol., 1756- 1764,17 (9), (1997). Fibrates are a class of drugs which may lower serum triglycerides 20-50%, lower LDLc 10- 15%, shift the LDL particle size from the more atherogenic small dense to normal dense LDL, and increase HDLc 10-15%. Experimental evidence indicates that the effects of fibrates on serum liplds are mediated through activation of PPARa. See, for example, B. Staels et al., Curr. Pharm. Des., 1-14,3 (1), (1997). Activation of PPARa results in transcription of enzymes that increase fatty acid catabolism and decrease de-novo fatty acid synthesis in the liver resulting in decreased triglyceride synthesis and VLDL production/secretion. In addition, PPARa activation decreases production of apoC-lll. Reduction in apoC-lll, an inhibitor of LPL activity, increases clearance of VLDL. See, for example, J. Auwerx et al., Atherosclerosis, (Shannon, Ire!.), S29-S37,124 (Suppl), (1996). Certain compounds that activate or otherwise interact with one or more of the PPARs have been implicated in the regulation of triglyceride and cholesterol levels in animal models. See, for example, U.S. Patents 5,847,008 (Doebber et al.) and 5,859,051 (Adams et al.) and PCT publications WO 97/28149 (Leibowitz et al.), WO99/04815 (Shimokawa et al.) and WO 01/00603 (Glaxo Group Ltd.). Oliver et al, Proc Natl Acad Sci, 98, 5306-5311 (2001) reports raising of HDLc and lowering of serum triglycerides in the obese rhesus monkey following administration of a PPAR delta agonist. Accordingly the invention provides a compound of formula 1 and pharmaceutically acceptable salts and solvates and hydrolysable esters thereof. wherein: R1 and R2 are independently H or C1-3 alkyl; X represents a O or (CH2)n where n is 0,1 or 2; R3and R4 independently represent H, C1-6 alkyl, -OCH3, -CF3, allyl, or halogen; XI represents O, S, SO2, SO, or CH2; R5 and R6 independently represent hydrogen, C1-6alkyl (including branched alkyl and optionally substituted by one or more halogens or C1-6alkoxy), or together with the carbon atom to which they are bonded form a 3-6 membered cycloalkyl ring; R7 represents a phenyl or a 6 membered heteroaryl group containing 1, 2 or 3 nitrogen atoms wherein the phenyl or heteroaryl group is substituted by 1,2 or 3 moieties selected from the group consisting of halogen, C1-6alkoxy, C1-6 alkyl, CF3, hydroxy, or phenyl (which may be optionally substituted by one or more C1-3 alkyl, -OC1-3 alkyl, CN, acetyl, hydroxy, halogen or CF3). In another aspect, the present invention discloses a method for prevention or treatment of a disease or condition mediated by one or more human PPAR alpha, gamma or delta ("hPPARs") comprising administration of a therapeutically effective amount of a compound of this Invention. hPPAR mediated diseases or conditions include dyslipidemia including associated diabetic dyslipidemia and mixed dyslipidemia, syndrome X (as defined in this application this embraces metabolic syndrome), heart failure, hypercholesterolemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridemia, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, Alzheimers disease and other cognitive disorders, inflammation, epithelial hyperproliferative diseases including eczema and psoriasis and conditions associated with the lung and gut and regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia, and anorexia nervosa. In particular, the compounds of this invention are useful in the treatment and prevention of diabetes and cardiovascular diseases and conditions including atherosclerosis, arteriosclerosis, hypertriglyceridemia, and mixed dyslipidaemia. In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, preferably in association with a pharmaceutically acceptable diluent or carrier. In another aspect, the present invention provides a compound of the invention for use in therapy, and in particular, in human medicine. In another aspect, the present invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment of a hPPAR mediated disease or condition. As used herein, "a compound of the invention" means a compound of formula (I) or a pharmaceutically acceptable salt, or solvate, or hydrolysable ester thereof. While hydrolyzable esters are included in the scope of this invention, the acids are preferred because the data suggests that while the esters are useful compounds, it may actually be the acids to which they hydrolyse that are the active compounds. Esters that hydrolyse readily can produce the carboxylic acid in the assay conditions or in vivo. Generally the carboxylic acid is active in both the binding and transient transfection assays, while the ester does not usually bind well but is active in the transient transfection assay presumably due to hydrolysis. Preferred hydrolysable esters are C1-6alkyl esters wherein the alkyl group may be straight chain or branched chain. Methyl or ethyl esters are more preferred. Preferably R1 and R2 are both H or both Me. More preferably both R1 and R2are H. Preferably R3 and R4 are independently H or C1-3 alkyl. More preferably, at least one of R3 and R4 are hydrogen and when one of R4 and R3 is hydrogen and the other is not, then the one that is not hydrogen is preferably ortho to the depicted moiety X. Most preferably the one that is not hydrogen is methyl. Preferably X is O. Preferably X1 is O or S. Preferably R5 and R8 are independently hydrogen or C1-6 alkyl (optionally substituted by C1-6 alkoxy). More preferably one of R5 and R6 is H. Most preferably one of R5 and R6 is H the other is butyl or ethyloxymethyl (CH3CH2OCH2). Preferably R7 is phenyl or a 6 membered heterocycle selected from pyrimidine, pyridine, pyridazine, pyrazine, each of which phenyl or heterocycle is substituted by phenyl (optionally substituted by one or more C1-3 alkyl, CN, CF3, halogen). More preferably R7 is a phenyl or pyridine ring which is substituted meta to the depicted moiety X1 by para -C6H4CF3, para -C8H4Me, para -C6H4CN or para -C8H4CI. Preferred compounds of formula (I) include: {[2-Methyl-4-({[4'-(trifluoromBthyl)-3-biphenylyl]methyl}thio)phenyl]oxy}acetic acid {[2-Methyl-4-({[4-methyl-4'-(trifluoromethyl)-3-biphenylyl]methyl}thio)phenyl]oxy}acetic acid 3-t2-Methyl-4-({[4'-(trifluoromethyl)-3-biphenylyl]methyl}oxy)phenyl]propanoic acid [(2-Methyl-4-{2-[4'-(trifluoromethyl)-3-biphenylyl]ethyl}phenyl)oxy]acetic acid ({2-Methyl-4-[({6-[4-(trifluoromethyI)phenyl]-2-pyridinyl}methyl)thlo]phenyl}oxy)acetic acid {[2-Methyl-4-({1-[4'-(trifluoromethyl)-3-biphenylyl]ethyl}thio)phenyl]oxy}acetic acid {[2-Methyl-4-({1-[4'-(trifluoromethyl)-4-biphenylyl]ethyI}thio)phenyl]oxy}acetic acid 2-Methyl-2-({2-methyl-4-[(1-{6-[4-(trifluoromethyl)phenyi]-2- pyridinyl}pentyl)oxy]phenyl}oxy)propanoic acid {[2-Methyl-4-({1-[4'-(trifluoromethyl)-3-biphenylyl]pentyl}oxy)phenyl]oxy}acetic acid [(4-{[1-(4'-Chloro-3-blphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetic acid {[2-Methyl-4-({1-[4'-(trifluoromethyl)-4-biphenylyl]pentyl}oxy)phenyl]oxy}acetic acid [(4-{[1-(4'-Chloro-4-biphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetic acid {[2-Methyl-4-({(1 R)-1 -[4'-(trifluoromethyl)-4-biphenylyl]pentyl}thio)phenyl]oxy}acetic acid {[2-Methyl-4-({(1 S)-1 -[4'-(trifluoromethyl)-4-biphenylyl]pentyl}thio)phenyl]oxy}acetic acid ({2-Methyl-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetic acid ({2-Methyl-4-[((1/?)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetic acid ({2-Methyl-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)thio]phenyl}oxy)acetic acid ({2-Methyl-4-[((1fl)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)thio]phenyl}oxy)acetic acid ({2-Methyl-4-[(1-{6-[4-{trifluoromethyl)phenyl]-2-pyridinyl}pentyl)sulfinyl]phenyl}oxy)acetic acid ({2-Methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)sulfonyl]phenyl}oxy)acetic acid {4-[(1-{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}aceticacid ({2-Methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}butyl)oxy]phenyl}oxy)aceticacid ({4-[(1-{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)aceticacid 3-{4-[(1-{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoicacid {[4-({1-[6-(4-Chlorophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}aceticacid ({2-Methyl-4-[(1-{6-[4-(methyloxy)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)aceticacid ({4-[(1-{6-[4-(Ethyloxy)phenyl]-2-pyridinyl}pentyl)oxy]-2-methylphenyl}oxy)aceticacid {t2-Methyl-4-({1-[6-(4-methylphenyl)-2-pyridinyl]pentyl}oxy)phenyl]oxy}aceticacid {[4-({1-l6-(3,4-Dichlorophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}aceticacid ({2-Methyl-4-[(1-{6-[3-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)aceticacid [(2-Methyl-4-{[1-(6-phenyl-2-pyridinyl)pentyl]oxy}phenyl)oxy]aceticacid {[4-({1-[6-(4-Acetylphenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}aceticacid {[4-({1-l6-(4-Fluorophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyI]oxy}aceticacid {[4-({1-[6-(4-Cyanophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}aceticacid ({2-Methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}hexyl)oxy]phenyl}oxy)aceticacid ({2-Methyl-4-[(4-methyl-1-{6-[4-(trifiuoromethyl)phenyl]-2- pyridinyl}penlyl)oxy]phenyl}oxy)aceticacid ({2-Methyl-4-[(3-methyl-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}butyl)oxy]phenyl}oxy)aceticacid [(4-{[1-(3-Biphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetic acid {[4-({1-[4'-(Ethyloxy)-3-biphenylyl]pentyl}oxy)-2-methylphenyl]oxy}acetic acid [(4-{[1-(4'-Cyano-3-biphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetic acid [(2-Ethyl-4-{[1-(6-phenyl-2-pyridinyl)pentyl]oxy}pheny!)oxy]acetic acid {[4-({1-t6-(4-Chlorophenyl)-2-pyridinyi]pentyl}oxy)-2-ethylphenyl]oxy}acetic acid ({2-Ethyl-4-[(1-{6-[4-(8thyloxy)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetic acid {[4-({1-[6-(4-Cyanophenyl)-2-pyridinyl]pentyl}oxy)-2-ethylphenyl]oxy}acetic acid ({2-Ethyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetic acid 4-{4-[(1-{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}pen1yl)oxy]phenyl}butanoic acid {[4-({(1R)-1-[6-(4-Chlorophenyl)-2-pyrldinyl]pentyl}oxy)-2-methylphenyl]oxy}acetic acid {[4-({(1R)-1-[6-(4-Cyanophenyl)-2-pyridinyl]pentyl}oxy)-2-methy!phenyl]oxy}acetic acid ({2-Methyl-4-[((1 fl)-1 -{6-l4-(methyloxy)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetic acid {[4-({(1R)-1 -[6-(4-Acetylphenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}acetic acid ({4-[((1R)-1-{6-[4-Acetyl-3-(msthyloxy)phenyl]-2-pyridinyl}pentyl)oxy]-2- methylphenyl}oxy)acetic add {[4-({(1S)-1 -[6-(4-Chlorophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}acetic acid {[4-({(1S)-1 -[6-(4-Cyanophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}acetic acid ({2-Methyl-4-[((1 S)-1 -{6-[4-(methyloxy)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetic acid {[4-({(1S)-1 -[6-(4-Acetylphenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}acetic acid ({4-[((1S)-1-{6-[4-Acetyl-3-(methyloxy)phenyl]-2-pyridinyl}pentyl)oxy]-2- methylphenyl}oxy)acetic acid ({2-Methyl-4-[((1R)-3-(methyloxy)-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}propyl)oxy]phenyl}oxy)aceticacld [(4-{[(1R)-1-[6-(4-Chlorophenyl)-2-pyridinyl]-3-(methytoxy)propyl]oxy}-2- methylphenyl)oxy]acetic acid ({2-Methyl-4-[((1S)-3-(methyloxy)-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}propyl)oxy]pheny!}oxy)aceticacid [(4-{[(1S)-1-[6-(4-Chlorophenyl)-2-pyridinyl]-3-(methyloxy)propyl]oxy}-2- methylphenyl)oxy]acetic acid ({4-[((1R)-2-(Ethyloxy)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}ethyl)oxy]-2- methylphenyl}oxy)acetic acid ({4-K(1R)-2-(Ethyloxy)-1-{6-[4-(methyloxy)phenyl]-2-pyridinyl}ethyl)oxy]-2- methylphenyl}oxy)acetic acid t(4-{[(1R)-1-[6-(4-Acetylphenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-methylphenyl)oxy]acetic acid [(4-{[(1R)-1-[6-(4-Cyanophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2- methylphenyl)oxy]acetic acid [(4-{[(1R)-1-[6-(4-Chlorophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2- methylphenyl)oxy]acetic acid ({4-[((1S)-2-(Ethyloxy)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}ethyl)oxy]-2- methylphenyl}oxy)acetic acid ({4-[((1S)-2-(Ethyloxy)-1-{6-[4-(methyloxy)phenyl]-2-pyridinyl}ethyl)oxy]-2- methylpheny!}oxy)acetic acid [(4-{[(1S)-1-[6-(4-Acetylphenyi)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-methylphenyl)oxy]acetic acid [(4-{[(1S)-1-[6-(4-Cyanophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2- methylphenyl)oxy]acetic acid [(4-{[(1S)-1-[6-(4-Chlorophsnyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2- methylphenyl)oxy]acetic acid {[4-({(1R)-2-(Ethyloxy)-1-[6-(3-fluoro-4-methylphenyl)-2-pyridinyl]ethyl}oxy)-2- methylpheny]oxy)acetic acid {[4-({(1R)-2-(Ethyloxy)-1-[6-(4-methylphenyl)-2-pyridinyl]ethyl}oxy)-2- methylphenyl]oxy}acetic acid ({4-[((1R)-2-(Ethyioxy)-1-{6-[4-(1-methylethyl)phenyl]-2-pyridinyl}©thyl)oxy]-2- methylphenyl}oxy)acetic acid [(4-{[(1R)-1-[6-(4-Cyano-3-fluorophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2- methylphenyl)oxy]acetic acid ({4-[((1R)-2-(Ethyloxy)-1-{6-l4-(ethyloxy)pheny!]-2-pyridinyl}ethy!)oxy]-2- methylphenyl}oxy)acetic acid {[4-({(1R)-2-(Ethyloxy)-1-[6-(2-fluoro-4-methylphenyl)-2-pyridinyl]ethyl}oxy)-2- methylphenyl]oxy}acetic acid {[4-({{1R)-2-(Ethyloxy)-1-t6-(4-fluorophenyl)-2-pyrldinyl]ethyl}oxy)-2-methylphenyl]oxy}acetic acid [(4-{[(1R)-2-(Ethy!oxy)-1 -(6-{4-[(1 -methylethyl)oxy]phenyl}-2-pyridinyl)ethyl]oxy}-2- methylphenyl)oxy]acetic acid [(4-{[(1R)-1-[6-(4-Chloro-3-methylphenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2- methylphenyl)oxy]acetic acid [(4-{[(1R)-1-[6-(3-Chloro-4-cyanophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2- methylphenyl)oxy]acetic acid [(4-{[(1ff)-1-[6-(4-Cyano-3-methylphenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2- methylphenyl)oxy]acetic acid ({4-[((1f5)-2-(Ethyloxy)-1-{6-[3-fIuoro-4-(methyloxy)phenyl]-2-pyridinyl}ethyl)oxy]-2- methylphenyl}oxy)acetic acid [(4-{[(1R)-1-[6-(4-Cyano-2-fluorophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2- methylphenyl)oxy]acetic acid t(4-{[(1R)-1-[6-(4-Cyano-2-methylphenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2- methylphenyi)oxy]acetic acid {[4-({(1S)-2-(Ethyloxy)-1-[6-(3-fluoro-4-methylphenyl)-2-pyridinyl]ethyl}oxy)-2- methylphenyl]oxy}acGtic acid {[4-({(1S)-2-(Ethyloxy)-1-[6-(4-me1hyiphenyl)-2-pyridinyl]ethyl}oxy)-2- methylphenyl]oxy}acetic acid ({4-[((1S)-2-(Ethyloxy)-1 -{6-[4-(1 -methylethyl)phenyl]-2-pyridinyl}ethyl)oxy]-2- methylphenyl}oxy)acetic acid [(4-{[(1S)-1-[6-(4-Cyano-3-fluorophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2- mGthylphenyl)oxy]acetic acid ({4-[((1S)-2-(Ethyloxy)-1-{6-[4-(ethyloxy)phenyl]-2-pyridinyl}ethyl)oxy]-2- methylphenyl}oxy)acetic acid {[4-({(1S)-2-(Ethyloxy)-1-[6-(2-fluoro-4-methylphenyl)-2-pyridinyl]ethyl}oxy)-2- methylphenyi]oxy}acetic acid {[4-({(1S)-2-(Ethyloxy)-1-[6-(4-fluorophenyl)-2-pyridinyl]ethyl}oxy)-2-methylphenyl]oxy}acetic acid [(4-{[(1 S)-2-(Ethyloxy)-1 -(6-{4-[(1 -methylethyl)oxy]phenyl}-2-pyridinyl)ethyl]oxy}-2- methylphenyl)oxy]acetic acid t(4-{[(1S)-1-[6-(4-Chloro-3-methylphenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2- methylphenyl)oxy]acetic acid [(4-{[(1S)-1-[6-(3-Chloro-4-cyanophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2- methylphenyl)oxy]acetic acid [(4-{[(1^-1-[6-(4-Cyano-3-methylphenyl)-2-pyridinyl]-2-(ethyloxy)ethylloxy}-2- methylphenyl)oxy]acetic acid ({4-[((1S)-2-(Ethyloxy)-1-{6-[3-fluoro-4-(methyloxy)phenyl]-2-pyridinyl}ethyl)oxy]-2- methylphenyl}oxy)acetic acid [(4-{[(1S)-1-[6-(4-Cyano-2-fluorophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2- methylphenyl)oxy]acetic acid [(4-{[(1S)-1-{6-[4-Cyano-3-(methyloxy)phenyl]-2-pyridinyl}-2-(ethyloxy)e1hyl]oxy}-2- methylphenyl)oxy]acetic acid 3-{2-Methyl-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyi]-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{2-Methyl-4-[((1S)-1-{6-[4-(methyloxy)phenyl]-2-pyridinyl}pentyl)oxy]phenyi}propanoic acid 3-[4-({(1 ^-1 -[6-(4-Acety\|phenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]propanoic acid 3-[4-({(1S)-1 -[6-(4-Cyanophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]propanoic acid 3-[4-({(1S)-1 -[6-(4-ChIorophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]propanoic acid 3-{2-Methyl-4-[((1R)-1-{6-[4-(trifluoromethyl)ph6nyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{2-Methyl-4-[((1R)-1-{6-[4-(methyloxy)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-[4-({(1R)-1 -[6-(4-Acetylphenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]propanoic acid 3-[4-({(1Rl)-1 -(6-(4-Cyanophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]propanoic acid 3-[4-({(1R)-1 -[6-(4-Chlorophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]propanoic acid 3-{3,5-Dimethyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{3-(Methyloxy)-5-propyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}propanoicacid 3-{3-Propyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoicacid 3-{3-(Ethyloxy)-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{4-[((1R)-1 -{6-[4-(Trif luoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{3-(Msthyloxy)-4-[((1R)-1 -{6-[4-(trif luoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}propanoic acid {4-[((1R)-1 -{6-[4-(trif luoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}acetic acid {3-Chloro-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]ph8nyl}aceticacid {3-(Methyloxy)-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl)2-pyridinyl}pentyl)oxy]phenyl}acetic acid 3-{4-[((1S)-1 -{6-[4-(Trif luoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{3-(Methyloxy)-4-[((1S)-1 -{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}propanoicacid {4-[((1S)-1 -{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}acetic acid {3-Chloro-4-[((1 S)-1 -{6-[4-(trifluoromethyi)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}acetic acid {3-(Wlethyloxy)-4-l((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}acetic acid 3-{3-Fluoro-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{3-Methyl-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyI}propanoic acid 3-{3,5-Bis(methyloxy)-4-[((1/:?)-1-{6-[4-(trifluoromethyl)phenyl3-2- pyridinyl}pentyl)oxy]phenyl}propanoicacid 3-{2-(Methyloxy)-4-[((1 fl)-1 -{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{3-Fluoro-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{3-Methyl-4-[((1S)-1-{6-[4-(trlfluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{3,5-Bis(methyloxy)-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{2-(Methyloxy)-4-l((1S)-1 -{6-[4-(trif luoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{3-Chloro-5-(methyloxy)-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{3-Chloro-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{2-Chloro-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{3-Chloro-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyll-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{2-Chloro-4-t((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid {[2-Methyl-4-({1-[2-methyl-4'-(trifluoromethyl)-3-biphenylyl]pentyl}oxy)phenyl]oxy}acetic acid [(4-{[1-(4'-Chloro-2-methyl-3-biphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetic acid [(4-{[1-(2,4'-Dimethyl-3-biphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetic acid [(4-{[1-(4'-Cyano-2-methyl-3-biphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetic acid {[2-Methyl-4-({1-[2-methyl-4'-(methyloxy)-3-biphenylyl]pentyl}oxy)phenyl]oxy}acetic acid [(4-{[1-(4'-Fluoro-2-methyl-3-biphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetic acid ({2-Methyl-4-[(2-(propyloxy)-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}ethyl)oxy]phenyl}oxy)aceticacid ({4-[(2-(Ethyloxy)-1-{6-[4-(trKluoromethyl)phenyl]-2-pyridinyl}ethyl)thio]-2- methylphenyl)oxy)acetic acid While the preferred groups for each variable have generally been listed above separately for each variable, preferred compounds of this invention include those in which several or each variable in Formula (I) Is selected from the preferred, more preferred, or most preferred groups for each variable. Therefore, this invention is intended to include all combinations of preferred and most preferred groups. Those skilled in the art will recognize that stereocentres exist in compounds of formula (I). Accordingly, the present invention includes all possible stereoisomers and geometric isomers of formula (I) and includes not only racemic compounds but this invention is also intended to cover each of these isomers in their racemic, enriched, or purified forms. When a compound of formula (I) is desired as a single enantiomer, it may be obtained either by resolution of the final product or by stereospecific synthesis using an optically active catalyst or a catalytic system with optically active ligands or isomerically pure starting material or any convenient intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Carbon Compounds by E. L. Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents by S. H. Wllen. Additionally, in situations where tautomers of the compounds of formula (I) are possible, the present invention is intended to include all tautomeric forms of the compounds. In particular, in many of the preferred compounds of this invention the carbon atom to which R5 and R6 are bonded is chiral. In some of these chiral compounds the activities at the various PPAR receptors varies between the S and R isomers. Which of these isomers is preferred depends on the particular desired utility of the compound. In other words, even with the same compound, it Is possible that the S isomer will be preferred for some uses, while the R isomer will be preferred for others. The hPPAR agonists of formula (I) may be agonists of only one type ("selective agonists"), agonists for two PPAR subtypes ("dual agonists"), or agonists for ail three subtypes ("pan agonists"). As used herein, by "agonist", or "activating compound", or "activator", or the like, is meant those compounds which have a pKi of at least 6.0 preferably at least 7.0 to the relevant PPAR, for example hPPARS in the binding assay described below, and which achieve at least 50% activation of the relevant PPAR relative to the appropriate indicated positive control in the transfection assay described below at concentrations of 10-5 M or less. More preferably, the agonists of this invention achieve 50% activation of at least one human PPAR in the relevant transfection assay at concentrations of 10-6 M or less. Preferably the compounds are hPPARS agonists. More preferably the compounds are selective hPPARS agonists. It will also be appreciated by those skilled in the art that the compounds of the present invention may also be utilised in the form of a pharmaceutically acceptable salt or solvate thereof. The physiologically acceptable salts of the compounds of formula (I) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium acid addition salts. More specific examples of suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric; fumaric, acetic, proplonlc, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene- 2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N.N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine salts. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvents". For example, a complex with water is known as a "hydrate". Solvates of the compound of formula (I) are within the scope of the invention. References hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable salts and solvates. The compounds of the invention and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients. While it is possible that compounds of the present invention may be therapeutically administered as the raw chemical, it is preferable to present the active Ingredient as a pharmaceutical formulation. The carriers) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Accordingly, the present invention further provides for a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients. The formulations include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot tablet, intradermal, intrathecal, Intramuscular e.g. by depot and intravenous), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compounds ("active ingredient") with the carrier, which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chewable tablets in particular for paediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a other conventional excipients such as binding agents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycollate) or wetting agents, such as sodium lauryl sulfate. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. The tablets may be coated according to methods well-known in the art. Alternatively, the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for example. Moreover, formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan mono- oleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid. Such preparations may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides. Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non- aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol. Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia. The compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. In addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents. It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established diseases or symptoms. Moreover, it will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, preferably 1-1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day. The formulations according to the invention may contain between 0.1-99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations. The compound of formula (I) for use in the instant invention may be used in combination with other therapeutic agents for example, statins and/or other lipid lowering drugs for example MTP inhibitors and LDLR upregulators. The compounds of the invention may also be used in combination with antidiabetic agents, e.g. metformln, sulfonylureas and/or PPAR gamma, PPAR alpha or PPAR alpha/gamma agonists (for example thiazolidinediones such as e.g. pioglitazone and rosiglitazone). The compounds may also be used in combination with antihypertensive agents such as angiotensin antagonists e.g. telmisartan, calcium channel antagonists e.g. lacidipine and ACE inhibitors e.g. enalapril. The invention thus provides in a further aspect the use of a combination comprising a compound of formula (I) with a further therapeutic agent in the treatment of a hPPAR mediated disease. When the compounds of formula (I) are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route. The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above optimally together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation and may be formulated for administration. When formulated separately they may be provided in any convenient formulation, conveniently in such a manner as are known for such compounds in the art. When a compound of formula (I) is used in combination with a second therapeutic agent active against the same hPPAR mediated disease, the dose of each compound may differ from that when the compound is used alone. Appropriate doses wilt be readily appreciated by those skilled in the art. Compounds of this invention may be conveniently prepared by a general process wherein a moiety like (A) is coupled to an alcohol (B) using the Mitsunobu protocol (O. Mitsunobu, 1981, Synthesis p1) or by alklylaton of (A) using a suitable non nucleophilic base such as K2CO3, Cs2CO3 or NaH, with an alkyl halide (C). Compounds of this invention may be conveniently prepared by a general process wherein a moiety like (A) is coupled to an alcohol (B) using the Mitsunobu protocol (O. Mitsunobu, 1981, Synthesis p1) or by alklylaton of (A) using a suitable non nucleophilic base such as K2CO3, Cs2CO3 or NaH, with an alkyl halide (C). Note this synthesis is preferably carried out with the acid group protected by R to give intermediate (D). Preferably R is C1-6alky! which can be hydrolysed to give an acid of formula (1), or if readily hydrolyzable, the resulting ester can be administered. The groups R1-R7 and X1 of intermediate (D) can be further modified to provide further compounds of formula (1) by standard chemistry. Intermediates of formulae (A), (B), (C) and (D) are commercially available or may be synthesised as outlined below. Alcohol (B) can be converted to alkyl halide (C) using standard halogenation conditions. For example, when X1 is O or S, the following synthetic schemes may be followed. Scheme 1 Mitsunobu followed by hydrolysis The following synthetic schemes may be followed to prepare intermediate (B) where R5 is H and 'ring" represents a phenyl or a 6 membered heteroaryl group containing 1, 2 or 3 nitrogen atoms: Scheme 8 Alkylation, then Suzuki followed by reduction (or reduction followed by Suzuki) of a carboxylic acid derivative (E). Scheme 9 Oxidation, then Suzuki followed by alkylation (or alkylation followed by Suzuki) of an alcohol derivative (F). Other intermediates may be prepared as described in text below or in published literature e.g. WO 01/00603 and their synthesis will be apparent to a person skilled in the art. The following illustrates Intermediates and Examples of Formula 1 which should not be construed as constituting a limitation thereto. General purification and analytical methods LC/MS refers to analysis by analytical HPLC which was conducted on a Supelcosil LCABZ+PLUS column (3um, 3.3cm x 4.6mm ID) eluting with 0.1% HCO2H and 0.01 M ammonium acetate in water (solvent A), and 95% acetonitrile and 0.05% HCO2H in water (solvent B), using the following elution gradient 0-0.7 minutes 0%B, 0.7-4.2 minutes 0-100%B, 4.2-5.3 minutes 100%B, 5.3-5.5 minutes 100?0%B at a flow rate of 3 ml/minute. The mass spectra (MS) were recorded on a Fisons VG Platform mass spectrometer using electrospray positive ionisation [(ES+veto give [M+H]+and [M+NH4]+molecular ions] or electrospray negative ionisation [(ES-ve to give [M-H]- molecular ion] modes. 1H NMR spectra were recorded using a Bruker DPX 400MHz spectrometer. Biotage™ chromatography refers to purification carried out using equipment sold by Dyax Corporation (either the Flash 40i or Flash 150i) and cartridges pre-packed with KP-Sil™ silica. OPTIX refers to purification using CombiFlash Optix 10 equipment provided by Isco Inc. Mass directed auto-prep HPLC refers to the method where the material was purified by high performance liquid chromatography on a HPLCABZ+ 5um column (5cm x 10mm i.d.) with 0.1% HCO2H in water and 95% MeCN, 5% water (0.5% HCO2H) utilising the following gradient elution conditions: 0-1.0 minutes 5%B, 1.0-8.0 minutes 5?30%B, 8.0-8.9 minutes 30%B, 8.9-9.0 minutes 30?95%B, 9.0-9.9 minutes 95%B, 9.9-10 minutes 95?0%B at a flow rate of 8ml/minute. The Gilson 202-fraction collector was triggered by a VG Platform Mass Spectrometer on detecting the mass of interest. Hydrophobic frits refers to filtration tubes sold by Whatman. SPE (solid phase extraction) refers to the use of cartridges sold by International Sorbent Technology Ltd. TLC (thin layer chromatography) refers to the use of TLC plates sold by Merck coated with silica gel 60 F254. Et2O: diethyl ether EtOAc: ethyl acetate MeCN: acetonitrile MeOH: methanol nBu3P: tributylphosphine R1: retention time TBAF: tetrabutylammonium fluoride THF: tetrahydrofuran br: broad s: singlet d: doublet dd : doublet of doublets t: triplet q: quartet m: multiplet rt: room temperature Intermediate 1 6-Bromo-N-methoxy-N-methylpyridine-2-carboxamlde To a slurry of 6-bromopicolinic acid (5.44 g, 26.93 mmol) in DCM (100 mL) was added a solution of CDI (5.67 g, 34.97 mmol) in DCM (70 mL) drop-wise over 15 minutes under nitrogen. The solution cleared a little during the addition but remained cloudy and after 1 hour at rt the mixture was treated drop-wise over 15 minutes with N,O-dimethylhydroxylamine [solution in DCM prepared by treating N,O-dimethylhydroxylamine hydrochloride (5.35 g, 53.82 mmol) with aqueous NaOH (2M, 100 mL) and extracting with DCM (2 x 100 mL)]. The mixture cleared during the addition and the resulting clear pale yellow solution was left to stir under nitrogen for 20 hours. The mixture was then reduced under vacuum and the residue partitioned between EtOAc (125 mL) and saturated aqueous NaHCO3 (125 mL). The layers were then separated and the organic layer washed with brine (125 mL), dried (MgSO4), filtered and reduced to give the title compound as a yellow oil (5.29 g). LC/MS: m/z 245.0 [M+H]+, R, 2.27 min. Intermediate 2 1-(6-Bromo-2-pyridinyl)-1-pentanone (Method A) To a solution of 6-bromo-/V-methoxy-/V-methylpyridine-2-carboxamide (5.29 g, 21.58 mmol) in dry THF (120 mL) at -78°C (dry ice/acetone bath) under nitrogen was added nBuMgCI (15.2 mL of a 20%wt solution in THF/toluene, 25.84 mmol) drop-wise over 15 minutes. The resulting yellow mixture was stirred at this temperature for 1 hour and was then allowed to warm to 0°C (ice/water bath) slowly over 1.5 hours and then to rt over 18 hours. The yellow cloudy mixture was then added portion-wise to a stirred solution of aqueous HCI (2M, 200 mL) and the resulting mixture partitioned with EtOAc (200 mL) and the layers separated. The aqueous was re- extracted with EtOAc (200 mL) and the combined organic layer washed with brine (300 mL), dried (MgSO4) filtered and reduced to give a yellow/orange oil. Purification by Biotage™ chromatography (silica) eluting with cyclohexane: EtOAc (gradient 20:1 to 1:2) afforded the title compound (2.51 g). LC/MS: m/z 242.0 [M+H]+, R1 3.57 min. A solution of 1-(6-bromo-2-pyridinyl)-1-pentanone (2.51 g, 10.37 mmol) in DME (13 mL) was treated with 4-(triflouromethyl)benzeneboronic acid (2.36 g, 12.43 mmol), Pd(PPh3)4 (1.19 g, 1.03 mmol) and then a slurry of Na2CO3 (3.29 g, 31.04 mmol) in water (13 mL). The resulting mixture was then heated to reflux over 30 minutes and then stirred at this temperature for 17 hours. The mixture was then allowed to cool to rt and was reduced and the residue partitioned between EtOAc (200 mL) and water (200 mL). The aqueous was re-extracted with EtOAc (100 mL) and the combined organic layer washed with saturated aqueous NaHCO3 (250 mL), brine (250 mL), dried (MgS04), filtered and reduced to give a brown orange solid residue. Purification by Biotage™ chromatography (silica) eluting with cyclohexane: EtOAc (gradient 1:0 to 10:1) afforded the title compound as a white solid (3.02 g). LC/MS: m/z 308.2 [M+Hf, R,4.14 min. A mixture of 1 -{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1 -pentanone (2.80 g, 9.11 mmol) In THF (61 mL) at 0°C (ice/water bath) was treated drop-wise with a mixture of sodium borohydride (689 mg, 18.21 mmol) in water (11 mL) over 5-10 minutes. The resulting mixture was stirred at this temperature for 2.5 hours and was then partitioned between EtOAc (200 mL) and water (200 mL) and the layers separated. The aqueous was re-extracted with EtOAc (200 mL) and the combined organic layer washed with brine (250 mL), dried (MgSO4), filtered and reduced. Purification by Biotage™ chromatography (silica) eluting with cyclohexane : EtOAc (gradient 20:1 to 5:1) afforded the title compound as a colourless oil (2.81 g). LC/MS: m/z 310.2 [M+H]+, R1 3.87 min. A solution of 6-bromo-2-pyridinecarboxaldehyde (512 mg, 2.75 mmol) and 4- (triflouromethyl)benzeneboronic acid (522 mg, 2.75 mmol) in DME (46 mL) was treated a slurry of Na2CO3 (875 mg, 8.26 mmol) in water (23 mL) followed by Pd(PPh3)4 (64 mg, 0.06 mmol). The resulting mixture was then heated to reflux, under nitrogen over 30 minutes and then stirred at this temperature for 17 hours. The mixture was then allowed to cool to rt, was reduced under vacuum and the residue partitioned between EtOAc (50 mL) and water (50 mL) and the layers separated. The aqueous was re-extracted with EtOAc (100 mL) and the combined organic layer washed with brine (100 mL), dried (MgSO4), filtered and reduced to give a yellow solid residue. Purification by SPE (silica) eluting with cyclohexane: EtOAc (gradient 1:0 to 10:1) afforded the title compound as a yellow foam (565 mg). LC/MS: m/z 251.9 [M+H]+, R1 3.57 min. Intermediate 4 1 -{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (Method B) A solution ot 6-\|4-(trifiuorometnyi)pnenyl]-2-pynainecarbaicienyde (2.50 g, 9.95 mmol) in dry THF (100 mL) was cooled to 0°C (ice/water bath) and treated with nBuLi (6.8 mL of a 1.6M solution in hexanes, 10.88 mmol) under nitrogen drop-wise over 20 minutes. The resulting deep red coloured solution was stirred at 0°C for 1.5 hours and then quenched by the addition of aqueous HCI (2M, 10 mL) and allowed to warm to rt over about 20 minutes. The solvents were then removed under vacuum and the residue partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 (150 mL) and the layers separated. The aqueous was re-extracted with EtOAc (100 mL) and the combined organic layer washed with water (200 mL), brine (200 mL), dried (MgSO4), filtered and reduced to give a pale yellow foam. Purification by Biotage™ chromatography (silica) eluting with cyclohexane : EtOAc (gradient 100:1 to 0:1) afforded the title compound as a pale yellow oil (1.99 g). LC/MS: m/z 310.2 [M+Hf, R1 3.87 min. A mixture 3-bromobenzyl alcohol (500 mg, 2.70 mmol), 4-(triflouromethyl)benzeneboronic acid (1.01 g, 5.35 mmol), Pd(PPh3) 4 (68 mg, 0.06 mmol) and Na2CO3 (740 mg, 7.02 mmol) in a mixture of DME (20 mL) and water (10 mL) was heated at reflux for 3 hours. The mixture was allowed to cool to rt, and then partitioned between EtOAc and water. The layers were separated and the aqueous re-extracted with EtOAc (2x) and the combined organic layer washed with water and then brine, dried (Na2SO4), filtered and reduced to give an oil. Purification by flash chromatography (silica) eluting with cyclohexane: EtOAc (5:2) afforded the title compound as a clear oil which crystallised on standing (654 mg). LC/MS: Ft, 3.58 min, no molecular ion observed. A solution of [4'-(trifluoromethyl)-3-biphenylyl]nnethanol (177 mg, 0.70 mmol) in dry DCM (10 mL) was cooled to 0°C (ice/water bath) under nitrogen and treated with CBr4 (256 mg, 0.77 mmol) in one portion. PPh3 (202 mg, 0.77 mmol) was then added portion-wise and the resulting mixture stirred for 1 hour at this temperature and was then allowed to warm to rt. The resulting mixture was then reduced and the residue purified directly by SPE (silica, 10 g cartridge) eluting with cyclohexane : DCM afforded the title compound as a colourless oil (220 mg). LC/MS: Rt 3.94 min, no molecular ion observed. A mixture of 3-(bromornethyl)-4'-(trifluoromethyl)biphenyl (200 mg, 0.63 mmol), ethyl (4- mercapto-2-methylphenoxy)acetate (144 mg, 0.63 mmol) and polymer supported diisopropylethylamine (3mmol/g, 423 mg, 1.27 mmol) in DCM (20 mL) was stirred at rt overnight. TLC (cyclohexane: DCM 1:1) indicated bromide still remaining so more thiol (100 mg, 0.44 mmol) was added and after 3 hours no change was observed by TLC. The mixture was then filtered, reduced and purified using SPE (silica, 10 g cartridge). The residue was dissolved in DCM (10 mL) and treated with polymer supported isocyante resin (1.43 mmol/g. 2 g, 2.46 mmol) and stirred at rt overnight. The mixture was then filtered, washing with DCM and reduced to give the title compound (209 mg). 1H NMR (400MHz; CDCI3) d:1.29 (3H, t, J 7 Hz), 2.25 (3H, s), 4.05 (2H, s), 4.26 (2H, q, J 7 Hz), 4.60 (2H, s), 7.59 (2H, d, J 8.5 Hz), 7.68 (2H, d, J 8.5 Hz). Borane (10.80 mL of a 1M solution in THF, 10.80 mmol) was added to a cooled solution of 5-bromo-2-methyl-benzoic acid (116 mg, 0.54 mmol) in THF (15 mL), under nitrogen, at 0°C (ice water bath) and the resulting mixture allowed to warm to rt overnight. The mixture was then treated with MeOH (10 mL) followed by aqueous HCl (2M, 20 mL) and the mixture stirred for about 15 minutes, concentrated under vacuum and then partitioned with EtOAc. The organic layer was washed with aqueous HCl (2M), water and brine, dried (MgSO4), filtered and reduced to give the title compound as a colourless oil (90 mg). LC/MS: Rt 3.09 min, no molecular ion observed. To a solution of [4'-(trifluoromethyl)-3-biphenylyl]methanol (121 mg, 0.48 mmol) in dry THF (5 mL) under nitrogen at 0°C (ice/water bath) was added nBu3P (240 uL, 0.96 mmol) followed by ethyl 3-(4-hydroxy-2-methylphenyl)propanoate (100 mg, 0.48 mmol) and then ADDM (246 mg, 0.96 mmol) portion-wise. The mixture was stirred at 0°C for 1 hour, allowed to warm to rt over 21 hours and then partitioned between water and EtOAc, and the layers separated. The aqueous layer was then extracted with EtOAc and the combined organic extract washed with water and then brine, dried (Na2SO4) and the solvent removed under vacuum. Purification by flash chromatography (silica) eluting with cyclohexane: EtOAc (15:1) afforded the title compound as a clear oil (141 mg). LC/MS: R14.43 min, no molecular ion observed. A suspension of [4-(2-ethoxy-2-oxoethoxy)-3-methylbenzyl](triphenyl)phosphonium chloride (500 mg, 0.99 mmol) in dry THF (10 mL) was cooled to 0°C (ice/water bath) and treated with NaH (44 mg of a 60% dispersion in mineral oil, 1.10 mmol) portion-wise over 5 minutes. The resulting yellow suspension was stirred for 15 minutes and was then treated with 3-bromobenzaidehyde (184 mg, 0.99 mmol) in dry THF (5 mL). The resulting white suspension was allowed to warm to rt over 3.5 hours and was then heated at reflux for 1 hour. The reaction mixture was then allowed to cool to rt, stirred overnight and was then reduced under vacuum. The residue was then partitioned between CHCI3 (20 mL) and water (20 mL) and the layers separated. The cloudy organic layer was dried through a hydrophobic frit and then concentrated to a cream coloured gum (700 mg). Purification by SPE (silica) eluting with cyclohexane: EtOAc (9:1) afforded the title compound (mixture of E:Zisomers) (258 mg). LC/MS: Rt 4.23 min and 4.31 min, no molecular ions observed. Ethyl ({4-[2-(3-bromophenyl)ethenyl]-2-methylphenyl}oxy)acetate (150 mg, 0.40 mmol), Na2CO3 (106 mg, 1.00 mmol), 4-(triflouromethyl)benzeneboronic acid (83.5 mg, 0.44 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) was dissolved in DME and water (2:1,6 mL) and the mixture heated at reflux for 4 hours. The mixture was allowed to cool to rt, was concentrated under reduced pressure and the residue partitioned between EtOAc (15 mL) and water (15 mL). The aqueous layer was then acidified with aqueous HCI (1N) and extracted with EtOAc and the combined organic layers dried (MgSO4), filtered and reduced to give the title compound (94 mg). LC/MS: m/z 411 [M-Hf, R1 4.45 min and 4.67 min. I A solution of the 2-(bromomethyl)-6-[4-(trifluoromethyl)phenyl]pyridine (238 mg, 0.75 mmol), ethyl (4-mercapto-2-methylphenoxy)acetate (84 mg, 0.37 mmol) and K2CO3 (57 mg, 0.41 mmol) in MeCN (5 mL) was stirred at rt, under nitrogen overnight. The mixture was then partitioned between water and EtOAc and the layers separated. The organic layer was then washed with water and brine, dried (MgSO4), filtered and reduced. Purification by SPE (silica, 2g cartridge) eluting with CHCI3: cyclohexane (5:1) afforded the title compound (160 mg). LC/MS: m/z 462.3 [M+H]+, R1 4.10 min. A solution of 3-bromoacetophenone (661 µL, 5.00 mmol) and 4- (triflouromethyl)benzeneboronic acid (950 mg, 5.00 mmol) in DME (50 mL) was added Na2CO3 (1.32 g, 12.50 mmoi) and Pd(PPh3)4 (283 mg, 0.24 mmol) and water (25 mL). The mixture was then stirred at 100oC for 20 hours, diluted with water and extracted with EtOAc. The organic layer was then washed with brine, dried (Na2SO4), filtered and reduced. Purification by flash chromatography (silica) eluting with petrol: EtOAc (gradient 19:1 to 9:1) afforded the title compound (1.01 g). LC/MS: R1 3.62 min, no molecular ion observed. A mixture of 1-[4'-(trifluoromethyl)-3-biphenylyl]ethanone (300 mg, 1.14 mmol) in water (1 mL) and EtOH (5 mL) was treated portion-wise with sodium borohydride (57 mg, 1.50 mmol) and then stirred at rt for 1.5 hours. The reaction was then quenched by the addition of saturated aqueous NH4CI, diluted with CHCI3 and the layers separated. The organic layer was then dried (Na2SO4), filtered and reduced to give the title compound (274 mg). LC/MS: Rt 3.50 min, no molecular ion observed. Zinc (229 mg, 3.50 mmol) was added to EtOAc (10 mL) followed by AcOH (115 µM, 2.00 mmol) and ethyl [4-(chlorosulfonyl)-2-methylphenoxy]acetate (293 mg, 1.00 mmol). After 2 hours, dichlorodimethylsilane (258 mg, 2.00 mmol) was added followed by 1 -[4'-(trifluoromethyl)-3- biphenylyl]ethanol (266 mg, 1.00 mmol) and the mixture stirred for a further 1 hour and then heated at 80°C for 5 hours. The mixture was then cooled, diluted with EtOAc and washed with saturated aqueous NaHCO3, saturated aqueous NH4CI, water and brine, and then reduced. Purification by Biotage™ chromatography (silica) eluting with petrol: EtOAc (9:1) afforded the title compound as a colourless oil (238 mg). LC/MS: m/z 492.2 [M+NH4]+, Rt 4.28 min. Prepared according to the procedure used for the preparation of Intermediate 14, starting from 4-bromoacetophenone (661 µL, 5.00 mmol), to give, after purification by Biotage™ chromatography (silica) eluting with petrol: EtOAc (8:1), the title compound (1.10 g). LC/MS: Rt 3.63 min, no molecular ion observed. Prepared from 1-[4'-(trifluoromethy!)-4-biphenylyl]ethanone (305 mg, 1.15 mmol) according to the procedure used for the preparation of Intermediate 15 to give the title compound (324 mg). LC/MS: Rt 3.54 min, no molecular ion observed. Prepared from 1-[4'-(trifluoromethyl)-4-biphenylyl]ethanol (324 mg, 1.15 mmol) according to the procedure used for the preparation of Intermediate 16, to give, after purification by Biotage™ chromatography (silica) eluting with petrol: EtOAc (8:1), the title compound as a colourless oil (333 mg). LC/MS: m/z 492.2 [M+NH4]+, Rt 4.31 min. To a solution of nBu3P (47 uL, 0.19 mmol) in dry THF (2 mL), at 0°C (ice/water bath) under nitrogen was added DIAD (37 mL, 0.19 mmol). After stirring for 10 minutes 1-{6-[4- (trifluoromethyl)phenyl]-2-pyridinyl}-1 -pentanol (50 mg, 0.16 mmol) was added, followed after another 20 minutes by ethyl 2-(4-hydroxy-2-methylphenoxy)-2-methylpropanoate (39 mg, 0.16 mmol). The mixture was then allowed to warm to rt over 16 hours and was then reduced under vacuum and the residue partitioned between EtOAc and water. The layers were separated and the organic layer washed with water (2 x) then brine, dried (Na2SO4) and reduced to give a brown gum. Purification by Biotage™ chromatography (silica, 40 g cartridge) eluting with cyclohexane: EtOAc (19:1) afforded the title compound as a colourless gum (9 mg). LC/MS: m/z 530.3 [M+H]+, Rt 4.61 min. To 3-bromobenzaldehyde (5.00 g, 27.02 mmol) in dry THF (100 mL), under nitrogen at - 78°C (dry ice/acetone bath) was added nBuMgCI (16.2 mL of a 2.0M solution in THF, 0.032 mol) and the reaction stirred for 1 hour at -78°C and then allowed to warm to rt overnight. The reaction was then quenched with water, extracted with EtOAc and the layers separated. The organic layer was washed with water then brine, dried (Na2SO4) and reduced under vacuum to give a colourless oil. Purification by Biotage™ chromatography (silica, 90 g cartridge) eluting with cyclohexane : EtOAc 9:1 afforded the title compound as a colourless oil (4.07 g). LC/MS: Rt 3.49 min, no molecular ion observed. To a solution of 1 -(3-bromophenyl)-1 -pentanol (1.00 g, 4.11 mmol) in dry THF (40 mL) at 0°C was added ethyl (4-hydroxy-2-methylphenoxy)acetate (865 mg, 4.11 mmol), PPh3 (1.30 g, 4.94 mmol) and ADDP (1.25 g, 4.94 mmol) and the reaction stirred for 30 minutes and then allowed to warm to rt overnight. The mixture was then reduced under vacuum and the residue partitioned between EtOAc and water and the layers separated. The organic layer was washed with water (2 x) then brine, dried (Na2SO4) and reduced under vacuum to give a brown oil. Purification by Biotage™ chromatography (silica, 90 g cartridge) eluting with petroleum ether 40- 60oC: EtOAc (gradient 1:0 to 9:1) afforded the title compound as colourless oil (1.15 g). LC/MS: 454.0/455.1 [M+NH4]+, R, 4.28 min. Ethyl [(4-{[1-(3-bromophenyl)pentyl]oxy}-2-methylphenyl)oxy]acetate (200 mg, 0.46 mmol) was dissolved in dry THF (3 mL), and treated with 4-(trifluoromethyl)benzeneboronic acid (104 mg, 0.55 mmol), Pd(PPh3)4 (53 mg, 0.046 mmol) and sodium carbonate (146 mg, 1.38 mmol) in water (2 mL). The mixture was then heated at 70°C for 3 hours, cooled to rt and partitioned between EtOAc and water. The layers were separated and the organic layer washed with brine, dried (Na2SO4) and concentrated to give a brown oil. Purification by Biotage™ qhromatography (silica, 40 g cartridge) eluting with petroleum ether 40-60°C : EtOAc (19:1) afforded the title compound as a colourless gum (142 mg). LC/MS: m/z 518.2 [M+NH4]+, R, 4.55 min. Prepared according to the procedure used for the preparation of Intermediate 23, starting from ethyl [(4-{[1-(3-bromophenyl)pentyl]oxy}-2-methylphenyl)oxy]acetate (200 mg, 0.46 mmol) and 4-chlorobenzene boronic acid (86 mg, 0.55 mmol) to give, after purification by Biotage™ chromatography (silica, 40 g cartridge) eluting with petroleum ether 40-60°C: EtOAc (19:1), the title compound (137 mg). LC/MS: m/z 484.2 [M+NH4]+, Rt 4.55 min. To a solution of 1-(4-methylphenyl)-1-pentanone (1.00 g, 4.15 mmol) in DME (20 mL) and water (10 mL) was added 4-(trifluoromethyl)benzeneboronic acid (870 mg, 4.57 mmol) and Na2CO3 (1.10 g, 10.38 mmol). After 10 minutes under nitrogen, Pd(PPh3)4 (480 mg, 0.42 mmol) was added portion-wise, and the mixture heated to reflux and stirred under nitrogen for 2 hours. The reaction mixture was then allowed to cool to rt and the solvents removed under vacuum. The resulting residue was partitioned between water and EtOAc, the layers separated and the aqueous re-extracted with EtOAc (3 x 30mL). The combined organic extract was separated and dried (MgSO4), and the solvent removed under vacuum. Purification by flash chromatography (silica), eluting with cyclohexane : EtOAc (19:1) afforded the title compound as a white solid (850 mg). LC/MS: m/z 307.1 [M+H]+, Rt 4.16 min. To a solution of 1-[4'-(trif!uoromethyl)-4-biphenylyl]-1-pentanone (500 mg, 1.63 mmol) in THF (16 mL) and water (8 mL) under nitrogen at 0°C (ice/water bath) was added sodium borohydride (74 mg, 1.96 mmol) portion-wise. After stirring the mixture for 1 hour at rt, the reaction was diluted with water (30 mL) and extracted into EtOAc (3 x 30 mL). The combined organic extract was separated, dried (MgSO4) and reduced under vacuum to afford the title compound as a colourless gum (490 mg). LC/MS: Rt 3.96 min, no molecular ion observed. To a solution of 1 -[4'-(trifluoromethyl)-4-biphenyiyl]-1-pentanol (250 mg, 0.81 mmol) in dry THF (20 mL) under nitrogen at 0°C (ice/water bath) was added nBu3P (0.41 mL, 1.64 mmol), followed by ethyl (4-hydroxy-2-methylphenoxy)acetate (170 mg, 0.81 mmol) and ADDM (420 mg, 1.64 mmol) portion-wise. After stirring the mixture for 18 hours at rt under nitrogen the solvent was removed under vacuum. The residue was partitioned between water and EtOAc and the aqueous re-extracted with EtOAc (3 x 30 mL). The organic combined extract was dried (MgSO4) and then reduced under vacuum. Purification by flash chromatography (silica), eluting with cyclohexane : EtOAc (9:1) afforded the title compound as a colourless gum (310 mg). LC/MS: m/z 518.2 [M+NH4]+, Rt 4.55 min. To a solution of 4 -chloro-4-biphenylcarbaldehyde (200 mg, 0.92 mmol) in anhydrous THF (10 mL) under nitrogen at -78°C (dry ice/acetone) was added nBuMgCI (550 uL of a 2M solution in THF, 1.10 mmol). The reaction mixture was stirred at -78°C for 1 hour and then at rt for 18 hours. The reaction was quenched by cautious addition of water (15 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extract was then dried (MgSO4) and reduced under vacuum. Purification by flash chromatography (silica), eluting with cyclohexane: EtOAc (9:1) afforded the title compound as a colourless gum (140 mg). LC/MS: Rt 3.98 min, no molecular ion observed. To a solution of 1-(4'-chloro-4-biphenylyl)-1-pentanol (140 mg, 0.51 mmol) in dry THF (15 mL) under nitrogen at 0oC (ice/water bath) was added nBu3P (250 µL, 1.02 mmol), followed by ethyl (4-hydroxy-2-methylphenoxy)acetate (110 mg, 0.52 mmol) and ADDP (260 mg, 1.03 mmol) portion-wise. After stirring the mixture for 18 hours at rt under nitrogen the solvent was removed under vacuum. The residue was partitioned between water and EtOAc and extracted with EtOAc (3 x 30 mL). The organic extract was separated and dried (MgSO4) and the solvent removed under vacuum. Purification by flash chromatography (silica) eluting with cyclohexane: EtOAc (9:1) afforded the title compound as a colourless gum (150 mg). LC/MS: m/z 484.2 [M+NH4]+, Rt 4.51 min. To a solution of 1-[4-(trifluoromethyl)-4-biphenylyl]-1-pentanol (250 mg, 0.81 mmol) in dry DCM (15 mL) under nitrogen at 0°C (ice/water bath) was added thionyl chloride (590 µL, 8.09 mmol) drop-wise. After stirring the mixture for 30 minutes at rt under nitrogen, the reaction was quenched by cautious addition of saturated aqueous NaHCO3 (20 mL) and extracted with DCM (3 x 30 mL). The organic extract was separated, washed with brine, dried (MgSO4) and the solvents removed under vacuum to afford the title compound as a yellow gum (251 mg). LC/MS: Rt 4.42 min, no molecular ion observed. To a solution of ethyl (4-mercapto-2-methylphenoxy)acetate (170 mg, 0.75 mmol) in anhydrous MeCN (15 mL) under nitrogen was added 4-(1 -chloropentyl)-4'- (trifluoromethyl)biphenyl (500 mg, 1.53 mmol) and caesium carbonate (500 mg, 1.53 mmol). After 18 hours stirring under nitrogen at room temperature, the reaction mixture was filtered and the solvent removed under vacuum. Purification by flash chromatography (silica), eluting with cyclohexane : EtOAc (9:1) afforded a colourless gum (230 mg). LC/MS: m/z 517.1 [M+H]+, Rt 4.64 min. Separation of a 20 mg sample by chiral HPLC (2 x 25cm chiralpak A) eluting with 5% IPA/heptane, 15ml/min, wavelength 215nm afforded ethyl {[2-methyi-4-({(1R)-1-[4'- (trifluoromethyl)-4-biphenylyl]pentyl}thio)phenyl]oxy}acetate as a colourless oil (10 mg, Rt 8.2 min) and ethyl {[2-methyl-4-({(1S)-1-[4'-(trifluoromethyl)-4-biphenylyl]pentyl}thio)phenyl]oxy}acetate as a colourless oil (9 mg, Rt 9.8 min). To a solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (711 mg, 2.30 mmol) in dry THF (46 ml_) at 0°C (ice/water bath) was added ethyl (4-hydroxy-2-methylphenoxy)acetate (483 mg, 2.30 mmol) followed one minute later by ADDM (1.18 g, 4.60 mmol) in one portion. The resulting slightly cloudy orange mixture was stirred at rt for 2-3 mins and the treated with nBu3P (1.15 mL, 4.61 mmol) drop-wise over about 4 minutes to give a clear pale yellow solution. After 2 hours of slow warming, the solution had become slightly cloudy and was allowed to warm further to rt over 20 hours. The resulting cloudy mixture was then reduced under vacuum and the residue partitioned between EtOAc (150 mL) and water (150 mL) and the layers separated. The aqueous was re-extracted with EtOAc (150 mL) and the combined organic layers washed with brine (250 mL), dried (MgSO4), filtered and reduced to give an oil. Purification by SPE (silica) eluting with cyclohexane: EtOAc (gradient 50:1 to 10:1) afforded a pale yellow foam (827 mg). LC/MS: m/z 501.9 [M+H]+, Rt 4.45 min. Separation by chiral HPLC (2' x 20 cm chiralpak) eluting with heptane : EtOH (98:2), 50mL/min, wavelength 230nM afforded ethyl ({2-methyl-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}oxy)acetate (367 mg, Rt 8.5 min) and ethyl ({2-methyl-4-[((1R)-1-{6-[4- (trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetate (360 mg, Rt 10.0 min). To a solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (1.50 g, 4.85 mmol) in dry DCM was added SOCI2 (3.53 mL, 48.50 mmol), and the resulting solution stirred under nitrogen for 3 hours at rt. The mixture was then reduced under vacuum to afford the title compound as an oily yellow solid (1.65 g). To a solution of 2-(1-chloropentyl)-6-[4-(trifluoromethyl)phenyl]pyridine (522 mg, 1.59 mmol) in dry THF (20 mL) was added caesium carbonate (621 mg, 1.91 mmol) and ethyl (4-mercapto-2- methylphenoxy)acetate (361 mg, 1.59 mmol). The resulting mixture was stirred under nitrogen for 60 hours at rt, then at 66°C for 18 hours. The cooled reaction mixture was then diluted with water (50 mL), extracted with EtOAc (100 mL), the layers separated and the organic layer washed with brine (50 mL), dried (Na2SO4) and the solvents removed under vacuum. Purification by Biotage™ chromatography (silica, 40 g cartridge) eluting with cyclohexane: EtOAc (19:1) afforded a colourless oil (376 mg). LC/MS: m/z 518.4 [M+H]+, Rt 4.51 min. Separation of a 100 mg sample by chiral HPLC (2cm x 25cm chiralcel OJ) eluting with 5% EtOH/heptane, 15ml/min, wavelength 215nm afforded ethyl ({2-methyl-4-[((1S)-1-{6-[4- (trifluoromethyl)phenyl]-2-pyridinyl}pentyl)thio]phenyl}oxy)acetate as a colourless oil (34 mg, Rt 12.4 min) and ethyl ({2-methyl-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)thio]phenyl}oxy)acetate as a colourless oil (29 mg, Rt 14.7 min). To a cooled (0°C, ice/water bath) solution of a racemic mixture of Intermediates 36 and 37 (130 mg, 0.25 mmol) in methanol (1 mL) was added Oxone (49.5% KHSO5,204 mg, 0.33 mmol) in water (1 mL). After 15 minutes the reaction was quenched with Na2S2O5 (237 mg, 1.24 mmol) and diluted with water (10mL). The aqueous layer was extracted with CHCI3 (3 x 10mL) and the combined organic layer washed with brine (10mL), dried (Na2SO4) and concentrated under vacuum. Purification by SPE (silica, 5 g cartridge) eluting with cyclohexane : EtOAc (gradient elution 10:1 to 2:1), afforded the title compound as a mixture of isomers (60 mg). LC/MS: m/z 534.4 [M+H], Rt 3.88 min. To a cooled 0°C (ice/water bath) solution of a racemic mixture of Intermediates 36 and 37 (43 mg, 0.08 mmol) in methanol (1 mL) was added Oxone (49.5% KHSO6,153 mg, 0.25 mmol) in water (1 mL). After 4 hours 10 minutes the reaction was quenched with Na2S2Os (80 mg, 0.42 mmol) and diluted with water (10 mL). The aqueous layer was extracted with CHCI3 (3 x 10mL) and the combined organic layers washed with brine (30 mL), dried (Na2SO4) and concentrated under vacuum. Purification by SPE (silica, 5 g cartridge), eluting with cyclohexane: EtOAc (gradient 10:1 to 2:1) afforded the title compound (28 mg). LC/MS: m/z 550.2 [M+H]+, Rt 4.09 min. To a solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridlnyl}-1 -pentanol (349 mg, 1.13 mmol) in dry THF (22.5 mL) at 0°C (ice/water bath) under nitrogen was added methyl-4- hydroxyphenylacetate (187 mg, 1.13 mmol) followed after 1 minute by ADDM (578 mg, 2.25 mmol) in one portion. The resulting orange cloudy mixture was stirred for 3 minutes and then treated with nBu3P (562 µL, 2.26 mmol) drop-wise over 1 minute. The resulting pale yellow/orange mixture was then allowed to warm slowly to rt over 64 hours. The cloudy mixture was then reduced under vacuum and the residue partitioned between EtOAc (50 mL) and water (50 mL) and the layers separated. The aqueous was then re-extracted with EtOAc (50 mL) and the combined organic layer washed with brine (100 mL) dried (MgSO4), filtered and reduced to give an oil which was purified by SPE (silica) eluting with cyclohexane: EtOAc (gradient 100:1 to 5:1) to give the title compound (330 mg). LC/MS: m/z 457.9 [M+H]+, Rt 4.32 min. A solution of 2,6-dibromopyridine (1.00 g, 4.22 mmol) in THF (40 mL) was cooled to -78°C (dry-ice/acetone bath) and treated with nBuLi (2.64 mL of a 1.6M solution in hexanes, 4.22 mmol) drop-wise over 10 minutes under nitrogen. After 30 minutes at this temperature the pale yellow/green solution was treated with butyraldehyde (400 uL, 4.44mmol) drop-wise over 5 minutes and the resulting orange/red solution stirred at this temperature for 1 hour. The solution was then allowed to warm slowly to 0°C (ice/water bath) over 20 minutes and was then quenched by the drop-wise addition of aqueous HCI (2M, 4 mL). The resulting pale yellow solution was reduced to an oil, partitioned between EtOAc (100 mL) and aqueous HCI (2M, 100 mL), and the layers separated. The aqueous was re-extracted with EtOAc (100 mL) and the combined organic layer washed with water (150 mL), brine (150 mL), dried (MgSO4), filtered and reduced to an orange/yellow oil. Purification by SPE (silica) eluting with cyclohexane : EtOAc (gradient 100:1 to 2:1) afforded the title compound (626 mg). To a stirred solution of 1-(6-bromo-2-pyridinyl)-1-butanol (626 mg, 2.72 mmol) and ethyl (4- hydroxy-2-methylphenoxy)acetate (539 mg, 2.56 mmol) in dry THF (51 mL) at 0°C (ice/water bath) under nitrogen was added ADDM (1.32 g, 5.13 mmol) followed by nBu3P (1.28 mL, 4.95 mmol) drop-wise. The mixture was stirred with slow warming to rt over 18 hours and then concentrated under vacuum, diluted with EtOAc (150 mL) and washed with water (3 x 75 mL), dried (Na2SO4), filtered and reduced to give a yellow oil. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane: EtOAc (gradient 20:1 to 10:1) afforded the title compound (388 mg). LC/MS: m/z 423.8 [M+H]+, Rt 3.92 min. To a solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (99 mg, 0.32 mmol) in dry THF (6.4 mL) at 0°C (ice/water bath) under nitrogen was added ethyl (4- hydroxyphenoxy)acetate (63 mg, 0.32 mmol) followed after 1 minute by ADDM (164 mg, 0.64 mmol) in one portion. The resulting orange slurry was stirred for 2 minutes and then treated with nBu3P (159 µL, 0.64 mmol) drop-wise over 1 minute. The resulting pale yellow/orange mixture was then allowed to warm slowly to rt over 69 hours. The cloudy mixture was then reduced under vacuum and the residue purified by SPE (silica) eluting with cyclohexane : EtOAc (gradient 100:1 to 1:1) to give the title compound (42 mg). LC/MS: m/z 487.9 [M+H]+, Rt 4.33min. To a stirred solution of the 1 -{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (50 mg, 0.16 mmol) and ethyl 3-(4-hydroxyphenyl)propanoate (31 mg, 0.16 mmol) in anhydrous THF (3.2 mL) under nitrogen at 0°C (ice/water bath) was added ADDM (83 mg, 0.32 mmol). After a few minutes, nBu3P (81 µL, 0.32 mmol) was added (drop-wise) and the solution was stirred at 0°C warming to rt overnight. After 17.5 hours the solvent was concentrated under vacuum and the solid residue dissolved in DCM (5 mL) and washed with water (5 mL) using a hydrophobic frit. The aqueous layer was re-extracted with DCM (5 mL) and the combined organic layers concentrated under vacuum. The resulting solid residue was then purified by SPE (silica, 5 g cartridge) eluting with cyclohexane : EtOAc (gradient 100:1 to 1:1) to afford the title compound (29 mg). LC/MS: m/z 486.1 [M+H]+, Rt 4.33 min. To a solution of nBuLi (26.40 mL of a 1.6M solution in hexanes, 42.24 mmol) in THF (25 mL) at -78°C (dry-ice/acetone bath) was added a solution 2,6-dibromopyridine (10.00 g, 42.21 mmol) in THF (60 mL) drop-wise over 45 minutes under nitrogen. The resulting dark green coloured solution was stirred at -78°C for 15 minutes and then valeraldehyde (6.70 mL, 63.01 mmol) was added drop-wise over 1 minute. The resulting dark purple coloured solution was stirred at -78CC for 15 minutes and was then treated in one portion with a mixture of methanol (42 mL) and AcOH (2.70 mL, 47.16 mmol). The resulting pale yellow coloured solution was then allowed to warm to rt slowly over 1 hour. The mixture was then diluted with saturated aqueous NH4CI (200 mL) and the product extracted with EtOAc (2 x 200 mL). The combined organic layer was then washed with brine (250 mL), dried (MgSO4), filtered and reduced to an orange oil (10.31g, 100%). Purification of 7.14 g of this material by Biotage™ chromatography (silica) eluting with cyclohexane : EtOAc (gradient 100:1 to 1:1) afforded the title compound as a clear, pale yellow oil (4.48 g). LC/MS: m/z 246.0 [M+H]+, Rt 3.03 min. To a stirred solution of 1-(6-bromo-2-pyridinyl)-1-pentanol (2.00 g, 8.19 mmol) and ethyl (4- hydroxy-2-methylphenoxy)acetate (1.89 g, 8.99 mmol) in dry THF (160 mL) at 0°C (ice/water bath) under nitrogen was added ADDP (4.13 g, 16.37 mmol) portion-wise over 5 min followed by nBu3P (1.07 mL, 4.30 mmol) drop-wise over 1 -2 min. The mixture was stirred with slow warming to rt over 21 h and then concentrated under vacuum, diluted with EtOAc (300 mL) and washed with water (200 mL). The aqueous layer was then re-extracted with EtOAc (300 mL) and the combined organic layer washed with brine (350 mL), dried (MgSO4), filtered and reduced to give a orange solid residue. Purification by SPE (silica, 20 g Cartridge) eluting with cyclohexane: EtOAc (gradient 1:0 to 1:1) afforded the title compound (2.31 g). A solution of 6-[4-(trifluoromethyl)phenyl]-2-pyridinecarbaldehyde (300 mg, 1.19 mmol) in dry toluene (12 mL) under nitrogen was cooled to 0°C (ice/water bath) and treated with n- pentylmagnesium bromide (0.66 mL of a 2M solution in Et20,1.31 mmol) and the resulting mixture was stirred at 0°C for 2 hours. The reaction was then quenched by the cautious addition of aqueous HCI (2M, 2 mL) and the solvent was removed under vacuum and the residue partitioned between EtOAc (2 x 50 mL) and aqueous HCI (2M, 50 mL). The organic solution was washed with water (60 mL) then brine (60 mL), dried (MgSO4) and reduced. Purification by SPE (silica, 20g cartridge) eluting with cyclohexane : EtOAc (gradient 99:1 to 19:1) afforded the title compound as a colourless oil (131 mg). LC/MS: m/z 324.1 [M+H]+, Rt, 3.88 min. A solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-hexanol (131 mg, 0.41 mmol) in dry THF (15 mL) under nitrogen was cooled to 0°C and treated with ethyl (4-hydroxy-2- methylphenoxy)acetate (85 mg, 0.41 mmol), ADDM (210 mg, 0.82 mmol) and nBu3P (204 µL, 0.82 mmol). The reaction mixture was then allowed to warm to rt slowly over 22 hours. The solvent was removed under vacuum and the residue partitioned between EtOAc (2 x 30 mL) and water (30 mL). The layers were separated and the organic layer dried (Na2SO4) and reduced. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane: EtOAc (49:1 to 24:1) afforded the title compound as a colourless oil (80 mg). A solution of 6-[4-(trif luoromethyl)phenyl]-2-pyridinecarbaldehyde (350 mg, 1.39 mmol) In Et2O (14 mL) was cooled to 0°C. To this was slowly added the freshly prepared Grignard reagent (1.26 mL, 1.53 mmol), prepared from magnesium turnings (500 mg, 0.02 mol) and 1-bromo-3- methyl butane (2.34 mL, 0.02 mol) in dry Et2O (16.5 mL). The resulting mixture was stirred under nitrogen at 0°C. After 1.5 hours, more Grignard reagent (0.3 mL, 0.36 mmol) was added and the resulting mixture stirred at 0oC for a further 1.5 hours. The reaction mixture was then quenched by cautious addition of aqueous HCI (2M, 3 mL) and the solvent removed under vacuum. The residue was partitioned between EtOAc (30 mL) and water (20 mL), the layers separated and the aqueous re-extracted with EtOAc (30 mL). The combined organic layer was washed with brine (50 mL), dried (MgSO4) and reduced under vacuum. Purification by SPE (silica, 20 g cartridge), eluting with cyclohexane: EtOAc (gradient 99:1 to 1:1) followed by EtOAc then MeOH afforded the title compound as a colourless oil (179 mg). LC/MS: m/z 324.1 [M+H]+, Rt 3.8 mln. Prepared from 4-methyl-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (80 mg, 0.25 mmol) according to the procedure used for the preparation of Intermediate 48 to give, after purification by SPE (silica, 10 g cartridge) eluting with cyclohexane: EtOAc (gradient 99:1 to 1:1) afforded the title compound as a colourless oil (13.2 mg). LCMS: m/z 516.2 [M+H], Rt 4.42 min. Prepared from 6-[4-(trifluoromethyl)phenyl]-2-pyridinecarbaldehyde (500 mg, 1.99 mmol) in Et2O (20 mL) and isobutylmagnesium bromide (1.1 mL of a 2M solution in Et20,2.2 mmol) according to the procedure used for the preparation of Intermediate 47 to give, after purification by SPE (silica, 10 g cartridge) eluting with cyclohexane : EtOAc (gradient 99:1 to 4:1) the title compound as a white crystalline solid (215 mg). LC/MS: m/z 310.1 [M+H]+, R, 3.74 min. A solution of 3-methyl-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-butanol (180 mg, 0.58 mmol) in dry THF (12 mL) under nitrogen was treated with ethyl (4-hydroxy-2- methylphenoxy)acetate(122 mg, 0.58 mmol) and cooled to 0°C. This was treated portion-wise with ADDP (0.3 g, 1.2 mmol), then drop-wise with nBu3P (0.29 mL, 1.2 mmol). The resulting pale yellow suspension allowed to warm to rt slowly over 16 hours. The solvent was removed under vacuum and the residue partitioned between EtOAc (60 mL) and water (60 mL) and the layers separated. The aqueous was re-extracted with EtOAc (60 mL) and the combined organic layer dried (Na2SO4) and reduced. Purification by SPE (silica, 10 g cartridge) eluting with cyclohexane : EtOAc (gradient 99:1 to 49:1) gave the title compound as a colourless oil (137 mg). LC/MS: m/z 502.1 [M+H]+, Rt 4.31 min. To a stirred solution of 1 -(6-bromo-2-pyridinyl)-1 -pentanol (250 mg, 1.02 mmol) and ethyl (4-hydroxy-2-ethylphenoxy)acetate (230 mg, 1.02 mmol) in dry THF (21 mlL at 0°C (ice/water bath) under nitrogen was added ADDP (517 mg, 2.04 mmol) followed by nBu3P (510 µL, 2.04 mmol) drop-wise. The mixture was stirred with slow warming to rt over 18 hours and then concentrated under vacuum, diluted with EtOAc (150 mL) and washed with water (3 x 75 mL), dried (MgS04), filtered and reduced to give an oil. Purification by SPE (silica, 10 g Cartridge) eluting with cyclohexane: EtOAc (gradient 20:1 to 5:1) afforded the title compound (307 mg). LC/MS: m/z 452.0 [M+H]+, Rt 4.03 min. To a stirred solution of 2-(trimethylsilyl) ethanol (0.56 mL, 3.91 mmol) in THF (1 mL) at rt under nitrogen, was added 4-DMAP (113 mg, 0.92 mmol) followed by EDC (177 mg, 0.92 mmol). After about 1 minute Et3N (170 µL, 1.22 mmol) was added, drop-wise followed by 4-(4- hydroxyphenyl)butanoic acid (150 mg, 0.83 mmol) in THF (4 mL) and the mixture stirred at rt for 18 hours. The mixture was then partitioned between Et2O (25 mL) and aqueous HCI (2M, 30 mL) and the layers separated. The aqueous layer was re-extracted with Et2O (20 mL) and the combined organic layer washed with brine (50 mL), dried (MgSO4) and concentrated under vacuum to give a 'chalk-white' milky oil. Purification by SPE (silica, 5 g Cartridge) eluting with cyclohexane: EtOAc (gradient 25:1 to 1:2) afforded the title compound (55mg). LC/MS: m/z 298.2 [M+NH4]+, Rt 3.63 min. To a stirred solution of 1 -{6-[4-(trifiuoromethyl)phenyl]-2-pyridinyl}-1-pentanol (62 mg, 0.20 mmol) and 2-(trimethylsilyl)ethyl 4-(4-hydroxyphenyl)butanoate (55 mg, 0.20 mtnol) in dry THF (4 mL) at 0°C (ice/water bath), under nitrogen, was added ADDP (102 mg, 0.40 mmol) followed by nBu3P (100 µL, 0.40 mmol), and the mixture stirred with slow warming to rt over 64.5 hours. The mixture was then concentrated under vacuum and the solid residue partitioned between DCM (5 mL) and water (5 mL) using a hydrophobic frit. The layers were separated and the aqueous layer re-extracted with DCM (5 mL) and the combined organic layer reduced. Purification by SPE (silica, 5 g Cartridge) eluting with cyclohexane : EtOAc (gradient 50:1 to 7.5:1) afforded the title compound (42 mg). LC/MS: m/z 572.2 [M+H]+, Rt 4.75 min. Separation of ethyl [(4-{[1-(6-bromo-2-pyridinyl)pentyl]oxy}-2-methylphenyl)oxy]acetate (Intermediate 46; 2.31 g, 5.29 mmol) by preparative chiral HPLC (1" x 25 cm Chiralpak AD) eluting with 2% IPA in heptane, f = 15 mL/min, afforded ethyl [(4-{[(1 f?)-1 -(6-bromo-2- pyridinyl)pentyl]oxy}-2-methylphenyl)oxy]acetate as a pale yellow oil (962 mg), R, 10.0 min. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 10% IPA in heptane, f = 1.0 mL/min, wavelength 215 nm, R, 5.3 min (96.3 %ee) and ethyl [(4-{[(1S)-1-(6-bromo-2-pyridinyl)pentyl]oxy}- 2-methylphenyl)oxy]acetate as a pale yellow oil (901 mg), Rt 14.5 min. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 10% IPA in heptane, f = 1.0 mL/min, wavelength 215 nm, Rt 6.0 min (96.2 %ee). To a solution of 1-[4-bromo-2-(methy!oxy)phenyl]ethanone(205 mg, 0.89 mmol), 4,4I4'>4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (250 mg, 0.98 mmol), potassium acetate (263 mg, 2.68 mmol) in DMF (5.3 mL) was added PdCI2(dppf) (73 mg, 0.09 mmol) and the resulting mixture heated under nitrogen at 85°C, overnight. The mixture was then reduced under vacuum and the residue purified by SPE (Si) possessing a layer of celite on the top, and eluting with cyclohexane:EtOAc (gradient 50:1 to 1:2) to afford the title compound as a solid (146 mg). LC/MS: m/z 277.1 [M+H]+, Rt 3.28 min. A suspension of 1,1 '-carbonyldiimidazole (23.20 g, 0.14 mol) in dry DCM (240 mL) was added portion-wise over 15 min to a solution of 3-methoxypropionic acid (10.00 mL, 0.11 mol) in DCM (100 mL) under nitrogen at room temperature. The resulting solution was stirred under nitrogen for 1 h and then treated with a solution of N-ethylbenzylamine (32.70 mL, 0.22 mol) in dry DCM (140 mL) drop-wise over 50 min. The resultant pale brown solution was stirred under nitrogen at room temperature for 16 h and then reduced in vacuo. The orange residue was partitioned between EtOAc (500 mL) and saturated aqueous NaHCO3 (500 mL), the layers separated and the organic layer washed with aqueous HCI (2M, 500 mL) and brine (350 mL). Each of the aqueous washings was then re-extracted with EtOAC (250 mL) and the combined organic layer dried (MgSO4), filtered and reduced In vacuo to give a yellow oil. Purification by Biotage (silica, 5 x 90 g cartridges), eluting with cyclohexane:EtOAc 95:5 then 3:2 afforded the title compound as a pale yellow oil (20.39 g). LC/MS: m/z 222.2 [M+H]+, Rt 2.54 min. To a solution of n-Butyllithium (1.6M in hexanes, 4.06 mL, 6.50 mmo!) in anhydrous THF (4.0 mL) under nitrogen at -78°C was added a solution of 2,6-dibromopyridine (1.54 g, 6.50 mmol) in anhydrous THF (9.5 mL) drop-wise over 45 min. The resulting dark green solution was stirred at -78°C for 15 min and then treated with N-ethyl-3-(methyloxy)-/v- (phenylmethyl)propanamide (2.16 g, 9.76 mmol), washing in with anhydrous THF (3.0 mL). The resulting green solution was stirred at -78°C for 15 min and was then treated with a solution of AcOH (0.40 mL) in MeOH (6.60 mL) to give a pale brown solution. This mixture was removed from the cooling bath and allowed to warm to room temperature, then stirred for 2 h. The mixture was then treated with saturated aqueous. NH4CI (40 mL) and the products extracted with EtOAc (2 x 50 mL). The combined organic layer was then washed with brine (60 mL), dried (MgSO4) and the reduced in vacuo to give an orange oil. Purification by Biotage (silica, 90 g cartridge) eluting with cyclohexane: EtOAc (10:1) afforded the title compound as a white solid (547 mg). LC/MS: m/z 244.1/246.1 [M+H]+, Rt 2.65 min. To a solution of 1-(6-bromo-2-pyridinyl)-3-(methyloxy)-1-propanone (547 mg, 2.24 mmol) in anhydrous MeOH (15 mL) under nitrogen at 0°C was treated portion-wise with sodium borohydride (127 mg, 3.36 mmol) over 10 min. The resulting solution was stirred under nitrogen and gradually allowed to warm to room temperature over 2 h. The reaction mixture was then diluted with aqueous HCI (0.5M, 20 mL) and the resulting mixture extracted with EtOAc (2 x 50 mL). The combined organic layer was dried (MgSO4) and reduced under vacuum to afford the title compound as an off-white gum (551 mg). LC/MS: m/z 246.0/248.0 [M+H]+, Rt 2.22 min. A solution of diisopropylazodicarboxylate (1.44 mL,7.31 mmol) in dry THF (50 mg was added drop-wise, under nitrogen, over 1.5 h (using a syringe pump) to a solution ethyl (4-hydroxy- 2-methylphenoxy)acetate (1.10 g, 5.21 mmol), 1-(6-bromo-z-pyridinyl)-3-(methyloxy)-1-propanol (1.29 g, 5.24 mmol) and triphenylphosphine (1.92 g, 7.32 mmol) in dry THF (50 mL) at 0°C. The resulting mixture was stirred under nitrogen and gradually allowed to warm to room temperature over 19 h. The solvent was then removed in vacua and the residue purified by Biotage (silica, 90 g cartridge), elutlng with cyclohexane:EtOAc 85:15 to afford the title compound as a pale yellow oil(1.32g). LC/MS: m/z 438.1/440.1 [M+H]+, Rt 3.47 min. Separation of ethyl [(4-{[1-(6-bromo-2-pyridinyl)-3-(methy!oxy)propyl]oxy}-2- methylphenyl)oxy]acetate (1.32 g, 3.01 mmol) by preparative chiral HPLC (2" x 20 cm Chiralpak AD) eluting with 5% EtOH in heptane, f = 40 mL/min, afforded ethyl [(4-{[(1R)-1-(6-bromo-2- pyridinyl)-3-(methyloxy)propyl]oxy}-2-methylphenyl)oxy]acetate as a colourless oil (556 mg), Rt 10.0 min. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 5% EtOH in heptane, f = 1.0 mL/min, wavelength 215 nm, R, 9.9 min (98.2 %ee) and ethyl [(4-{[(1S)-1-(6-bromo-2-pyridinyl)-3- (methyloxy)propyl]oxy}-2-methylphenyl)oxy]acetate as a colourless oil (566 rng), Rt 12.5 min. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 5% EtOH in heptane, f = 1.0 mL/min, wavelength 215 nm, Rt 11.7 min (94.9 %ee). A suspension of 1,1'-carbonyldiimidazole (4.68 g, 28.86 mmol) in dry DCM (15 mL) was added portion-wise over 15 min to a solution of ethoxyacetic acid (2.09 mL, 22.12 mmol) in DCM (30 mL) under nitrogen at room temperature. The resulting solution was stirred under nitrogen for 1 h and then treated with a solution of N-ethylbenzylamine (6.60 mL, 44.37 mol) in dry dichloromethane (30 mL) drop-wise over 15 min. The resultant solution was stirred under nitrogen at room temperature for 18 h and then partitioned with aqueous HCI (2M, 2 X 75 mL) and the combined organic layer dried (MgSO4), filtered and reduced in vacuo to give an oil. Purification by SPE (silica, 2 x 50 g cartridges), eluting with cyclohexane:EtOAc gradient 15:1 to 1:1 afforded the title compound as a pale yellow oil (4.36 g). LC/MS: m/z 222.2 [M+H], Rt 2.59 min. To a solution of n-butyllithium (1.6M in hexanes, 4.19 mL, 6.70 mmol) in anhydrous THF (4.0 mL) under nitrogen at -78°C was added a solution of 2,6-dibromopyridine (1.59 g, 6.71 mmol) in anhydrous THF (9.5 mL) drop-wise over 1 h. The resulting dark green solution was stirred at -78CC for 15 min and then treated with N-ethyl-2-(ethyloxy)-N-(phenylmethyl)acetamide (1.93 g, 8.70 mmol), washing in with anhydrous THF (1.0 mL). The resulting green solution was stirred at -78°C for 15 min and was then treated with a solution of AcOH (0.42 mL) in MeOH (7.00 mL) to give a orange solution which was then treated with NaBH4 (0.38 g, 10.04 mmol). This mixture was removed from the cooling bath and allowed to warm to room temperature over 2 h. The mixture was then treated with saturated aqueous. NH4CI (50 mL) and the products extracted with EtOAc (2 x 50 mL). The combined organic layer was then washed with brine (100 mL), driBd (MgSO,t} and the reduced in vacua to give a yellow oil. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to 1:1) afforded the title compound as a white solid (612 mg). LC/MS: m/z 246.0/248.0 [M+H]+, Rt 2.30 min. A solution of diisopropylazodicarboxylate (0.96 mL, 4.89 mmol) in dry THF (35 mL) was added drop-wise, under nitrogen, over 2 h (using a syringe pump) to a solution of ethyl (4- hydroxy-2-methy!phenoxy)acetate (735 mg, 3.50 mmol), 1-(6-bromo-2-pyridinyl)-2- (ethyloxy)ethanol (860 mg, 3.49 mmol) and triphenylphosphine (1.28 g, 4.88 mmol) in dry THF (35 mL) at 0°C. The resulting mixture was stirred under nitrogen and gradually allowed to warm to room temperature over 21 h. The solvent was then removed in vacuo and the residue purified by SPE (silica, 2 x 50 g cartridge), eluting with cyclohexane:EtOAc (gradient 20:1 to1:1) to afford the title compound as an oil (966 mg). LC/MS: m/z 438.1/440.0 [M+H]+, Rt 3.67 min. Intermediate 68 Intermediate 69 Separation of ethyl [(4-{[1-(6-bromo-2-pyridinyl)-2-(ethyloxy)ethyl]oxy}-2- methylphenyl)oxy]acetate (966 mg, 2.20 mmol) by preparative chiral HPLC (2" x 20 cm Chiralcel OD) eluting with 5% IPA in heptane, f = 50 mL/min, afforded ethyl [(4-{[(1R)-1-(6;bromo-2- pyridiny!)-2-(ethyloxy)ethyl]oxy}-2-methylphenyl)oxy]acetate as a colourless oil (284 mg), Rt 14.0 min. Analytical chiral HPLC (25 cm Chiralcel ODH) eluting with 5% IPA in heptane, f = 1.0 mL/min, wavelength 215 nm, Rt 12.1 min (94.7 %ee) and ethyl [(4-{[(1 S)-1-(6-bromo-2-pyridinyl)- 2-(ethyloxy)ethyl]oxy}-2-methylphenyl)oxy]acetate as a colourless oil (273 mg), Rt 16.0 min. Analytical chiral HPLC (25 cm Chiralcel ODH) eluting with 5% EtOH in heptane, f = 1.0 mL/min, wavelength 215 nm, Rt 14.0 min (99.3 %ee). To a stirring solution of 1-(6-bromo-2-pyridinyl)-1-pentanol (1.01g, 4.15 mmol) in chloroform (27 mL) was added manganese oxide (14.24g, 0.16 mol) portion-wise over 4 h. The mixture was then left to stir for an additional 3.5 h and was then filtered through celite placed directly on the top of a SPE (silica, 20 g cartridge) eluting with chloroform. The filtrate was reduce under vacuum and then purified further by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 100:1 to 5:1) afforded the title compound as an oil (625 mg). LC/MS: m/z 242.1/244.1 [M+H]\ R,3.50 min. To a stirring solution of (S)-(-)-a,a-diphenyl-2-pyrrolidinemethanol (a,a-diphenyl-L-prolinol) (840 mg, 3.32 mmol) in THF (3 mL) was added drop-wise trimethylborate (0.45 mL, 3.97 mmol) at ambient temperature under nitrogen. After stirring for 1 h at this temperature, borane dimethylsulfide (2M in THF, 2.5 mL, 5.00 mmol) drop-wise over 3-4 minutes. After the effervescence had stopped, 1-(6-bromo-2-pyridinyl)-1-pentanone (797 mg, 3.29 mmol) in THF (3.6 mL) was added over 1 h using a syringe pump. The mixture was stirred for an additional 5 minutes and the reaction was then quenched with aqueous HCI (2N, 5 mL) and the reaction mixture stirred overnight at ambient temperature. The mixture was then reduced under vacuum and the residue partitioned between EtOAc (30 mL) and water (30 mL) and the layers separated. The aqueous was then re-extracted with EtOAc (30 mL) and the combined organic layer washed with brine (50 mL) and then reduced under vacuum to give an oil. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 100:1 to 3:1) afforded the title compound as an oil (712 mg). LC/MS: m/z 244.1/246.1 [M+H]+, Rt 3.01 min. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 2% EtOH in heptane, f = 1.0 mL/min, wavelength 215 nm, Rt 11.7 min (97 %ee). To a gently shaking solution of 1-(6-bromo-2-pyridinyl)-1-pentanol (1.00 g, 4.10 mmol) in dry cyclohexane (100 mL) was added Lipase PS-C "Amano" {Pseudomonas cepacia) (9.97 g) followed by vinyl acetate (1.5 mL, 16.27 mmol). Shaking was continued for 7.5 h with continual monitoring by chiral HPLC. The mixture was then filtered and the filtrate reduced under vacuum to give an oil which was purified by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to 2:1) to afford (1 fl)-1-(6-bromo-2-pyridinyl)pentyl acetate as an oil (737 mg, 63%). LC/MS: m/z 286.1/288.1 [M+H]+, Rt 3.38 min. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 2% EtOH in heptane, f = 1.0 mL/min, wavelength 215 nm, (S-) R( 5.1 min and (R-) R, 5.4 min (43 %ee) and the title compound as an oil (349 mg). LC/MS: m/z 244.1/246.1 [M+H]+, Rt 3.01 min. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 2% EtOH in heptane, f = 1.0 mL/min, wavelength 215 nm, Rt 12.7 min (95 %ee). To a stirred solution of triethyl phosphonoacetate (1.40 mL, 7.06 mmol) in THF (40 mL) was added portion-wise NaH (60% dispersion in mineral oil, 399 mg, 9.98 mmol) over 2-3 mins. After effervescence had ceased, 2-methyl-4-benzyloxybenzaldehyde (1.50 g, 6.62 mmol) was added, washing in with THF (4 mL), and the resulting mixture heated to reflux. After 4 h at this temperature, the mixture was allowed to cool slowly to ambient temperature over night. Saturated aqueous NH4CI (45 mL) was then added carefully and the organic solvent removed under vacuum. The resulting aqueous mixture was then extracted with DCM (2 x 40 mL) and the combined organic layer washed with brine (60 mL) and then concentrated under vacuum to give a cream coloured solid. Purification by SPE (silica, 50 g cartridge) eluting with cyclohexane:EtOAc (gradient 20:1 to 0:1) then EtOAc:MeOH (gradient 95:5 to 90:10) afforded the title compound as an oil (1.22 g). LC/MS: m/z 297.2 [M+H]+, Rt 3.80 min. To a flask containing 10% Pd/C catalyst under nitrogen was added ethyl (2E)-3-{2-methyl- 4-[(phenylmethyl)oxy]phenyl}-2-propenoate (1.22 g, 4.12 mmol) in EtOH (15 mL) washing in with more EtOH (2 x 4 mL). The reaction vessel was placed under an atmosphere of hydrogen and stirred rapidly at ambient temperature for 19 h. The mixture was then filtered through a pad of ceiite washing with EtOH and the filtrate reduced under vacuum. The residua was the purified by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 10:1 to 2:1) to afford the title compound (548 mg). LC/MS: m/z 436.2 [M+H]+, P., 4.07 min. To a stirring solution of (1 R)-1 -(6-bromo-2-pyridinyl)-1 -pentanol (261 mg, 1.07 mmol) and ethyl 3-(4-hydroxy-2-methylphenyl)propanoate (329 mg, 1.58 mmol) in THF (13 mL) at 0°C under nitrogen was added ADDP (531 mg, 2.10mmol) followed by tri-N-butylphosphine (0.525 mL, 2.10 mmol) drop-wise. The resulting mixture was then stirred with slow warming to ambient temperature over 15 h. The reaction mixture was then concentrated under vaccgm and the solid residue purified directly by SPE (silica, 10 g cartridge) with a pad of celite on the top, eluting with cyclohexane:EtOAc (gradient 100:1 to 20:1) to afford the title compound (350 mg). LC/MS: m/z 434.1/436.1 [M+H]+, Rt 4.07 min. Analytical chiral HPLC (25 cm Chiralcel OD-H) eluting with 2% IPA in heptane, f = 1.0 mL/min, wavelength 215 nm, Rt 5.7 min (96 %ee). Prepared according to the procedure described for Intermediate 74, except starting from (1 S)-1-(6-bromo-2-pyridlnyl)-1-pentanol (237 mg, 0.97 mmol) to give the title compound as an oil (237 mg). LC/MS: m/z 434.1/436.1 [M+H]+, Rt 4.07 min. Analytical chiral HPLC (25 cm Chiralcel OD-H) eluting with 2% IPA in heptane, f = 1.0 mL/min, wavelength 215 nm, Rt 6.7 min (96 %ee). To a stirring solution of 3-fluoro-4-hydroxybenzaldehyde (508 mg, 3.63 mmol) and CsCO3 (1.25 g, 3.84 mmol) in dry MeCN (5.6 mL) under nitrogen at ambient temperature was added benzyl chloride (0.45 mL, 3.91 mmol) and the mixture heated at 40°C for 27 h. The mixture was then allowed to cool to rt, was quenched by the addition of aqueous NaOH (2N, 30 mL) and the product extracted with EtOAc (2 x 50 mL). The combined organic layer was then washed with brine (80 mL) and reduced under vacuum. The residue was then purified by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to 0:1) to afford the title compound as a colourless solid (623 mg). LC/MS: m/z 231.1 [M+H]+, Rt 3.26 min. Prepared according to the procedure used to prepare Intermediate 72 starting from 3- fluoro-4-[(phenylmethyl)oxy]benzaldehyde (620 mg, 2.69 mmol) except using 1.5 eq of triethyl phosphonoacetate and heating for 18 h. The product was isolated and purified as described for Intermediate 72, but contained some of the aldehyde starting material. Therefore, this crude material was re-subjected to the reaction conditions described above and was isolated and purified to give the title compound (605 mg). LC/MS: m/z 301.2 [M+H]+, Rt 3.66 min. A mixture of ethyl (2E)-3-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-2-propenoate (205 mg, 0.68 mmol) and 10% Pd/C catalyst (40 mg) in EtOH (4 mL) was stirred under an atmosphere of hydrogen at ambient temperature for 16.5 h. The mixture was then filtered through celite placed directly on the top of a SPE (silica, 5 g cartridge) eluting with EtOH. The filtrate was reduced under vacuum and the residue purified further by SPE (silica, 5 g cartridge) eluting with cyclohexane:EtOAc (gradient 25:1 to 3:1) to afford the title compound (140 mg). LC/MS: m/z 213.1 [M+H]+, Rt 2.80 min. Prepared according to the procedure used to prepare Intermediate 77 starting from 3- methyl-4-[(phenylmethyl)oxy]benzaldehyde (1.00 g, 4.44 mmol) except that the reaction was re- subjected to the reaction conditions twice before final purification. The title compound was isolated as a cream coloured solid (1.10 g). LC/MS: m/z 297.2 [M+H]+, Rt 3.86 min. Prepared according to the procedure used to prepare Intermediate 78 starting from ethyl (2E)-3-{3-methyI-4-[(phenylmethyl)oxy]phenyl}-2-propenoate (202 mg, 0.68 mmol) to give the title compound (136 mg). LC/MS: m/z 209.1 [M+H]+, Ft, 2.91 min. To a stirred solution of triethyl phosphonoacetate (0.60 mL, 3.02 mmol) in THF (5 mL) was added portion-wise NaH (60% dispersion in mineral oil, 360 mg, 9.00 mmol) over 2-3 mins. After effervescence had ceased, 4-hydroxy-3,5-dimethoxybenzaldehyde (547 mg, 3.00 mmol) was added portion-wise, washing in with THF (3 mL). More THF (2 x 2 mL) was added to the thick slurry and the resulting mixture was then heated to reflux for 21 hours. The mixture was then allowed to cool slowly to ambient temperature and the reaction quenched by the careful addition of saturated aqueous NH4CI (20 mL). The organic solvent was then removed under vacuum and the resulting aqueous mixture was then extracted with DCM (10 mL, 5 mL and then 2 mL) using hydrophobic frits. The filtrate was then treated with Polymer Supported-TsNHNH2 resin (loading 3.22 mmol/g, 1.62 g, 5.23 mmol (3 eq wrt unreacted aldehyde)) and the mixture stirred for 16 hours to remove any unreacted aldehyde. The resin was then removed by filtration washing with DCM (5 mL, 10 mL and then 5 mL) and the filtrate reduced under vacuum to give the title compound (221 mg). LC/MS: m/z 253.2 [M+H]+, Rt 2.76 min. Intermediate 82 Prepared according to the procedure for Intermediate 81 starting from 3-ethoxy-4- hydroxybenzaldehyde (500 mg, 3.00 mmol) to give the title compound (557 mg). LC/MS: m/z 237.2 [M+H]+, Rt 3.03 min. Prepared according to the procedure used to prepare Intermediate 78 starting from ethyl (2£)-3-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-2-propenoate (130 mg, 0.52 mmol) to give the title compound (80 mg). LC/MS: m/z 255.1 [M+H]+, R,2.58 min. To a stirring solution of 4-hydroxy-2-methoxybenzaldehyde (1.02g, 6.70 mmol) and malonic acid (728 mg, 7.00 mmol) in pyridine (9.2 mL) at ambient temperature under nitrogen was added piperidine (0.20 mL, 2.02 mmol) drop-wise. The mixture was then heated to 80°C over 20 mins and then stirred at this temperature for 2 h. The reaction was then quenched with water (50 mL), acidified to pH 1 with concentrated HCI and then partitioned with EtOAc (50 mL) and the layers separated. The aqueous layer was re-extracted wit h EtOAc (50 mL) and the combined organic layer washed with brine (80 mL) and then concentrated under vacuum to give a bright yellow solid. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 25:1 to 0:1) afforded the title compound (674 mg). LC/MS: m/z 195.1 [M+H]+, Rt 2.48 min. Prepared according to the procedure used to prepare Intermediate 78 starting from (2£)-3- [4-hydroxy-2-(methyloxy)phenyl]-2-propenoic acid (335 mg, 1.73 mmol) to give the title compound (225 mg). LC/MS: m/z 197.2 [M+H]+, Rt 2.25 min. To a stirring solution of 3-[4-hydroxy-2-(methyloxy)phenyl]propanoic acid (229 mg, 1.17 mmol) in EtOH (14 mL) was added concentrated H2SO4 (0.031 mL, 0.58 mmol) and the reaction heated at reflux under nitrogen for 1 h. The mixture was then cooled to ambient temperature poured into ice (ca. 30 mL) and saturated aqueous Na2CO3 (60 mL) added. The mixture was then extracted with EtOAc (2 x 50 mL) and the combined organic layer washed with brine (70 mL) and concentrated under vacuum. The residue was then purified by SPE (silica, 5 g cartridge) eluting with cyclohexane:EtOAc (gradient 10:1 to 2:1) to afford the title compound (217 mg). LC/MS: m/z 225.2 [M+H]+, Rt 2.83 min. A stirred solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (62 mg, 0.20 mmol) and ethyl (2E)-3-(4-hydroxy-3,5-dimethy(phenyl)-2-propenoate (79 mg, 0.36 mmol) in THF (4 mL) at 0°C under nitrogen was added ADDP (101 mg, 0.40 mmol) followed by tri-N- butylphosphine (0.100 mL, 0.40 mmol). The resulting mixture was then allowed to warm slowly to ambient temperature overnight. After 66 h the solvent was removed under vacuum (Genevac) and the resulting solid partitioned between DCM (5 mL) and water (5 mL), the layers separated and the aqueous re-extracted with DCM (5 mL). The combined organic layer was then reduced under vacuum and purified by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 20:1 to 1:1) to give the title compound (35 mg). LC/MS: m/z 512.2 [M+H]+, Rt 4.53 min. Prepared according to the procedure used to prepare Intermediate 90 starting from ethyl (2E)-3-[4-hydroxy-3-(methyloxy)-5-(2-propen-1-yl)phenyl]-2-propenoate (94 mg, 0.36 mmol) to give the title compound (102 mg). LC/MS: m/z 554.2 [M+H]+, Rt 4.51 min. Prepared according to the procedure used to prepare Intermediate 90 starting from ethyl (2E)-3-[4-hydroxy-3-(2-propen-1-yl)phenyl]-2-propenoate (116 mg, 0.50 mmol) to give the title compound (103 mg). LC/MS: m/z 524.2 [M+Hf, R,4.60 min. Intermediate 93 Ethyl (2E)-3-{3-(ethyloxy)-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}-2-propenoate Prepared according to the procedure used to prepare Intermediate 90 starting from ethyl (2E)-3-[3-(ethyloxy)-4-hydroxyphenyl]-2-propenoate (557 mg, 2.36 mmol) to give the title compound (479 mg). LC/MS: m/z 528.2 [M+H]+, Rt 4.41 min. To a stirring solution of ethyl (2E)-3-{3,5-dimethyl-4-[(1-{6-[4-(trifluoromethyI)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}-2-propenoate (35 mg, 0.07 mmol) in THF (5 mL) and MeOH (5 mL) at ambient temperature was added NaOH (2N, 5 mL) and the mixture stirred for 2 h and then left to stand overnight. HCI (2N, 5 mL) was then added and the mixture reduced under vacuum. The residue was then purified by SPE (silica, 5 g cartridge) with a pad of celite on the top, eluting with cyclohexane:EtOAc (gradient 3:1 to 0:1) the EtOAc:MeOH (gradient 95:5 to 0:1) to give the title compound (28 mg). LC/MS: m/z 484.2 [M+H]+, Rt 4.40 min. Prepared according to the procedure used to prepare Intermediate 94 starting from ethyl (2E)-3-{3-(methyloxy)-5-(2-propen-1-yl)-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}-2-propenoate (102 mg, 0.18 mmol) to give the title compound (82 mg). LC/MS: m/z 526.2 [M+H]+, Rt 4.30 min. Prepared according to the procedure used to prepare Intermediate 94 starting from ethyl (2E)-3-{3-(2-propen-1-yl)-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}-2- propenoate (103 mg, 1.97 mmol) to give the title compound (39 mg). LC/MS: m/z 496.2 [M+H]+, Rt 4.45 min. Prepared according to the procedure used to prepare Intermediate 94 starting from ethyl (2E)-3-{3-(ethyloxy)-4-[(1-{6-t4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}-2- propenoate (479 mg, 0.91 mmol) to give the title compound (407 mg). LC/MS: m/z 500.2 [M+H]+, Rt 4.21 min. Intermediate 98 and Intermediate 99 (1 S)-1-{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol and (1 fl)-1-{6-[4- (Trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol Separation of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (2.50 g, 8.08 mmol) by preparative chiral HPLC (2" x 20 cm Chiralpak AD) eluting with 5% IPA in heptane, f = 60 mL/min, afforded (1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol as a pale yellow oil (1.03 g), Rt 15.5 min. Analytical ohiral HPLC (25 cm Chiralpak AD) eluting with 10% EtOH in heptane, f = 1.0 mL/min, wavelength 215 nm, Rt 8.7 min (95.2 %ee) and (1R)-1-{6-[4-(trifluoromethyl)phenyl]- 2-pyridinyl}-1 -pentanol as a pale yellow oil (0.94 g), Rt 23 min. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 10% EtOH in heptane, f = 1.0 mL/min, wavelength 215 nm, Rt 7.7 min (97.1 %ee). To a stirring solution of 3-chloro-4-hydroxy-5-methoxybenzaldehyde (599 mg, 3.21 mmol) in DMF (5 mL) under nitrogen was added CS2CO3 (1.10 g, 3.38 mmol) followed by benzyl chloride (0.40 mL, 3.48 mmol) and the mixture heated at reflux for 1 h. After allowing the mixture to cool to ambient temperature the reaction was quenched by the addition of aqueous NaOH (2N, 30 mL) and the mixture concentrated under vacuum. The residue was then partitioned between NaOH (2N, 30 mL) and EtOAc (50 mL) and the layers separated. The aqueous layer was then re- extracted with EtOAc (50 mL), the layers separated and the combined organic layer washed with brine and then concentrated under vacuum. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to 10:1) afforded the title compound (632 mg). LC/MS: m/z 277.1 [M+H]+, Rt 3.47 min. Intermediate 101 Ethyl (2E)-3-{3-chloro-5-(methyloxy)-4-[(phenylmethyl)oxy]phenyl}-2-propenoate To a stirring solution of triethylphosphonoacetate (530 µL, 2.67 mmol) in dry THF (12 mL) at ambient temperature under nitrogen was added NaH (60% dispersion in mineral oil, 107 mg, 2.68 mmol). After stirring for an additional few minutes 3-chloro-5-(methyloxy)-4- [(phenylmethyl)oxy]benzaldehyde (495 mg, 1.79 mmol) was added in THF (10 mL) and the resulting mixture heated at 80°C for 21 h. The mixture was then allowed to cool to ambient temperature and the reaction then quenched with saturated aqueous NH4CI (12 mL) and the product extracted with EtOAc (2 x 30 mL) and the combined organic layer washed with brine (50 mL) and then reduced under vacuum. Purification by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to 5:1) afforded a mixture of product and starting material (515 mg). This mixture was then subjected to the conditions described above to push the reaction further and was then worked-up as described. Purification by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to 1:1) afforded the title compound (535 mg). LC/MS: m/z 364.2 [M+NH4]+, Rt 3.84 min. To a stirring solution of ethyl (2E)-3-{3-chloro-5-(methyloxy)-4-[(phenylmethyl)oxy]phenyl}- 2-propenoate (441 mg, 1.27 mmol) in EtOAc (9 mL) under nitrogen at ambient temperature was added PtO2 (20 wt%, 88 mg) and the mixture stirred under an atmosphere of hydrogen for 18 h. The resulting mixture was then purified by SPE (silica, 5 g cartridge) with a pad of celite on the top, eluting with EtOAc. The filtrate was then reduced and purified further by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 20:1 to 3:1) to give the title compound (287 mg). LC/MS: m/z 276.1 [M+NH4]+, Rt 2.97 min. Intermediate 103 To a stirring solution of (1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (66 mg, 0.21 mmol) and ethyl 3-[3-chloro-4-hydroxy-5-(methyloxy)phenyl]propanoate (78 mg, 0.30 mmol) in THF (4 mL) at 0°C under nitrogen was added ADDP (100 mg, 0.40 mmol) followed by nBu3P (0.10 mL, 0.40 mmol). The resulting mixture was then stirred at 0°C with slow warming to ambient temperature over 19 h and then reduced under vacuum (Genevac). The residue was then purified by SPE (silica, 10 g cartridge) with a pad of celite on the top, eluting with cyclohexane:EtOAc (gradient 100:1 to 3:1) to afford the title compound (118 mg). LC/MS: m/z 550.1 [M+H]+, Rt 4.41 min. Prepared according to the procedure used to prepare Intermediate 103 starting from (1S)-1- {6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (208 mg, 0.67 mmol) and 2-chloro-4- hydroxybenzaldehyde (140,0.89 mmol) to afford the title compound (103 mg). LC/MS: m/z 448.0 [M+H]+, Rt 4.38 min. Prepared according to the procedure used to prepare Intermediate 103 starting from (1S)-1- {6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (196 mg, 0.63 mmol) and 3-chloro-4- hydroxybenzaldehyde (141,0.90 mmol) to afford the title compound (55 mg). LC/MS: m/z 448.0 [M+H]+, Rt 4.33 min. Prepared according to the procedure used to prepare Intermediate 103 starting from (1R)- 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (202 mg, 0.65 mmol) and 2-chloro-4- hydroxybenzaldehyde (140,0.89 mmol) to afford the title compound (102 mg). LC/MS: m/z 448.0 [M+H]\ R, 4.40 min. Prepared according to the procedure used to prepare Intermediate 103 from (1R)-1-{6-[4- (trifluoromethyl)phenyl]-2-pyridinyl}-1 -pentanol (208 mg, 0.67 mmol) and 3-chloro-4- hydroxybenzaldehyde (141, 0.90 mmol) to afford the title compound (59 mg). LC/MS: m/z 448.1 [M+H]+, Rt 4.33 min. Intermediate 108 Ethyl (2E)-3-{2-chloro-4-[((1 R)-1-{6-[4-(trif luoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}-2-propenoate To a stirring solution of triethylphosphonoacetate (64 u.L, 0.32 mmol) in dry THF (0.20 ml_) at ambient temperature under nitrogen was added NaH (60% dispersion in mineral oil, 13 mg, 0.33 mmol). After stirring for an additional few minutes 2-chloro-4-[((1R)-1 -{6-[4- (trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]benzaldehyde (103 mg, 0.23 mmol) was added in THF (0.8 mL) and the resulting mixture heated at 80°C for 17 h. The mixture was then allowed to cool to ambient temperature and the reaction then quenched with saturated aqueous NH4CI (3 mL) and the product extracted with EtOAc (2 x 20 mL) and the combined organic layer washed with brine (50 mL) and then reduced under vacuum. The crude reaction mixture was then subjected to the conditions described above to push the reaction further and was then worked-up as described. Purification by SPE (silica, 5 g cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to 15:1) afforded the title compound (103 mg). LC/MS: m/z 518.1 [M+H]+, Rt 4.58 min. Prepared according to the procedure used to prepare Intermediate 108 starting from 3- chloro-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]benzaldehyde (55 mg, 0.12 mmol) to afford the title compound (54 mg). LC/MS: m/z 518.2 [M+Hf, Ft, 4.54 min. Intermediate 110 Ethyl (2E)-3-{2-chloro-4-[((1 S)-1-{6-[4-(trifluoromethyI)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}-2-propenoate Prepared according to the procedure used to prepare Intermediate 108 starting from 2- chloro-4-[((1 S)-1 -{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]benzaldehyde (102 mg, 0.23 mmol) to afford the title compound (111 mg). LC/MS: m/z 518.1 [M+H]+, Rt 4.58 min. Prepared according to the procedure used to prepare Intermediate 108 starting from 3- chloro-4-[((1 S)-1 -{6-[4-(trif luoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]benzaldehyde (58 mg, 0.13 mmol) to afford the title compound (41 mg). LC/MS: m/z 518.1 [M+H]+, Rt 4.53 min. To a solution of 3-bromo-2-methyl benzoic acid (430 mg, 2.00 mmol) in anhydrous DCM, under nitrogen at ambient temperature was added N,O-dimethylhydroxylamine hydrochloride (215 mg, 2.20 mmol), pyridine (0.18 mL, 2.23 mmol) and CBr4 (662 mg, 2.00 mmol). Triphenyl phosphine (576 mg, 2.20 mmol) was added portion-wise over 10 min and the resulting mixture stirred at ambient temperature for 2.5 h. The reaction mixture then reduced under vacuum and purified by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 99:1 to 4:1) to afford the title compound as a colourless oil (310 mg). LC/MS: m/z 258.0/260.0 [M+H]+, Rt 2.73 min. To a solution of 3-bromo-N,2-dimethyl-N-(methyloxy)benzamide (2.55 g, 9.88 mmol) in anhydrous THF (28 mL) under nitrogen at -78°C was added a butylmagnesium chloride (20% wt in THF/toluene, 6.94 mL, 11.90 mmol) drop-wise over 15 min. The resulting solution was stirred at -78°C for 1 h, was allowed to warm to 0°C and then stirred with slow warming to ambient temperature over 20 h. The reaction was then quenched with water (50 mL) and extracted with EtOAc (2 x 60mL). Some saturated aqueous NH4CI was added to disperse the emulsion formed. The resulting organic layer was then washed with brine (100 mL}, dried (Na2SO4), filtered and reduced under vacuum. Purification by SPE (silica, 50 g cartridge), eluting with cyclohexane:EtOAc (gradient 49:1 to 9:1) afforded the title compound as a colourless oil (706 mg). LC/MS: m/z 272.1/274.0 [M+H]+, Rt 3.71 min. To a solution of 1-(3-bromo-2-methylphenyl)-1-pentanone (706 mg, 2.77 mmol) in anhydrous THF (12 mL) under nitrogen at 0°C was added sodium borohydride (209 mg, 5.53 mmol) in water (8 mL) and the resulting mixture stirred at 0°C for 2 h. Additional sodium borohydride (105 mg, 2.77 mmol) was then added, along with more THF (40 mL), and the resulting mixture stirred at 0oC for an additional 30 min. The reaction mixture was then partitioned between EtOAc (50 mL) and water (50 mL), the layers separated, and the aqueous re-extracted with EtOAc (50 mL). The combined organic solution was then dried (Na2SO4) filtered, and reduced under vacuum. Purification by SPE (silica, 20 g cartridge), eluted with cyclohexane: EtOAc (gradient 99:1 to 19:1) afforded the title compound as a colourless oil (495 mg). LC/MS: m/z 274.1/276.1 [M+H]+, Rt 3.55 min. Intermediate 115 Ethyl [(4-{[1-(3-bromo-2-methylphenyl)pentyl]oxy}-2-methylphenyl)oxy]acetate To a solution of 1-(3-bromo-2-methylphenyl)-1-pentanol (495 mg, 1.92 mmol) in anhydrous THF (40 mL) under nitrogen at 0°C was added portion-wise ethyl (4-hydroxy-2- methylphenoxy)acetate (405 mg, 1.93 mmol), followed by slow addition (over 25 min) of ADDP (971 mg, 3.85 mmol) and drop-wise addition of tributylphosphine (0.96 mL, 3.85 mmol). The resulting mixture was then stirred for 16 h with gradual warming to ambient temperature. The solvent was then removed under vacuum and the residue partitioned between EtOAc (100 mL) and water (150 mL), the layers separated, and the aqueous re-extracted with EtOAc (100 mL). The combined organic layer was then dried (Na2SO4), filtered and reduced under vacuum and the resulting residue purified by SPE (silica, 50 g cartridge), eluting with cyciohexane:EtOAc (gradient 99:1 to 4:1) to afford the title compound as a colourless oil (495 mg). LC/MS: m/z 466.0/468.1 [M+H]+, Rt 4.25 min. A solution of nBuLi (7.90 mL of a 1.6M solution in hexanes, 12.64 mmol) in THF (7.6 mL) was cooled to -78°C (dry-ice/acetone bath) under nitrogen and then treated with a solution of 2,6- dibromopyridine (3.00 g, 12.66 mmol) in THF (17.8 mL) drop-wise over 30 min. The resulting green solution was stirred at -78°C for 20 min and then treated with {[(1,1 - dimethylethyl)(dimethyl)silyl]oxy)acetaldehyde (3.00 mL, 15.75 mmol) over 1 min to give a deep purple/brown coloured solution which was stirred at this temperature for 15 min. The reaction was then quenched by the addition of a mixture of MeOH (12.5 mL) and AcOH (0.8 mL, 13.90 mmol) In one portion and the resulting clear, pale yellow solution allowed to warm slowly to ambient temperature over 1.25 h. The mixture was then partitioned between EtOAc (100 mL) and saturated aqueous NH4CI (100 mL), and the layers separated. Trie aqueous was re-extracted with EtOAc (100 mL) and the combined organic layer washed with brine (200 mL), dried (MgSO4), filtered and reduced to give the title compound as a clear, pale yellow oil which was used directly without lurther purification (4.61 g). LC/MS: m/z 332.0/334.0 [M+H]+, Rt 3.64 min. To a solution of Ph3P (1.10 g, 4.19 mmol) in dry THF (30 mL), was treated with ethyl [(4- hydroxy-2-methylphenyl)oxy]acetate (696 mg, 3.31 mmol) and 1-(6-bromo-2-pyridinyl)-2-{[(1,1- dimethylethyl)(dimethyl)silyl]oxy}ethanol (1.00 g, 3.01 mmol) and the resulting solution cooled to 0°C (ice/water bath) under nitrogen. DIAD (0.829 ml, 4.21 mmol) in THF (30 ml) was then added drop-wise over 2 h using a syringe pump. The resulting mixture was then allowed to warm to ambient temperature over 22.5 h and was then reduced under vacuum to give an orange oily residue. Purification by SPE (silica, 10 g cartridge) eluting with cyclohexane: EtOAc (gradient, 1:1 to 0:1) afforded the title compound (429 mg). LC/MS: m/z 524.1/526.1 [M+H]+, Rt 4.37 min. To a stirred solution of ethyl ({4-[(1-(6-bromo-2-pyridinyl)-2-{[(1,1 - dimethylethyl)(dimethyl)silyl]oxy}ethyl)oxy]-2-methylphenyl}oxy)acetate (273 mg, 0.52 mmol) in DME (2.3 mL) was added 4-(trifluoromethyl)benzeneboronic (129 mg, 0.68 mmol), Pd(PPh3)4 (60 mg, 0.052 mmol) and Na2CO3 (165 mg, 1.56 mmol) and water (1.13 mL) was heated at 45°C for 21 hours and then allowed to cool to ambient temperature. The resulting mixture was then reduced under vacuum, partitioned between water (90 mL) and EtOAc (100 mL)tand the layers separated. The organic layer was re-extracted with EtOAc (100 mL) and the combined organic layer washed with brine (100 mL), dried (MgSO4) filtered and reduced under vacuum. The residue was then purified by SPE (silica, 10g cartridge) eluting with cyclohexane: EtOAc (gradient, 30:1 to 3:1) to give the title compound (208 mg). LC/MS: m/z 590.6 [M+H]+, Rt 4.59 min. To a stirred solution of ethyl ({4-[(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-{6-[4- (trifluoromethyl)phenyl]-2-pyridinyI}ethyl)oxy]-2-methy!phenyl}oxy)acetate (208 mg, 0.352 mmol) in THF (3.5 mL) was added TBAF (1M in THF, 0.458 mL) dropwise over 1 min. The resulting solution was then stirred at ambient temperature for 18 h. The mixture was then reduced under vacuum and the residue purified by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 15:1 to 2:1) to afford the title compound (89 mg). LC/MS: m/z 476.1 [M+H]+, Rt 3.78 min. A solution of (ethyl [(4-mercapto-2-methylphenyI)oxy]acetate) (386 mg, 1.71 mmol), 1-(6- bromo-2-pyridinyl)-2-(ethyloxy)ethano! (352 mg, 1.43 mmol) and PPh3 (450 mg, 1.72 mmol) in DCM (17 mL) at 0°C under nitrogen was stirred for 10 mins and then treated drop-wise with DIAD (0.34 mL, 1.73 mmol). The resulting mixture was then stirred, with slow warming to ambient temperature over 18 h. The mixture was then reduced under vacuum and the resulting yellow oil purified by SPE (silica, 20 g cartridge), eluting with cyclohexane:EtOAc (gradient 15:1 to 5:1). Further purification using the OPTIX - SPE (C18 cartridge, 50 g) eluting with 60 - 80% MeCN (+0.05% HCOOH) in H2O (+0.01% HCOOH) over 56 mins afforded the title compound as an oil (232 mg). LC/MS: m/z 454.1/456.1 [M+H]+, Rt 3.64 min. To a mixture of palladium (II) acetate (6 mg, 0.027 mmol), 1,3-bis(2,4,6- trimethylphenyl)imidazoliumchloride (9 mg, 0.026 mmol) and Cs2CO3 (266 mg, 0.816 mmol) in 1,4-dioxane (1 mL) was added ethyl [(4-{[1-(6-bromo-2-pyridinyl)-2-(ethyloxy)ethyl]thio}-2- methylphenyl)oxy]acetate (125 mg, 0.275 mmol) in 1,4-dioxane (1.75 mL) and the resulting mixture stirred under nitrogen at ambient temperature for 10 min. 2-[4-(Trifluoromethyl)phenyl]- 1,3,2-dioxaborolane (69 mg, 0.300 mmol) was then added and the resulting mixture heated to 85CC and kept at this temperature for 16 h. The reaction mixture was then reduced and the residue partitioned between EtOAc (15 mL) and saturated aqueous NH4CI (15 mL) and the layers separated. The aqueous layer was then re-extracted with EtOAc (15 mL) and the combined organic layers washed with brine (50 mL) dried (MgSO4) and filtered. The mixture was then reduced under vacuum and the resulting residue purified by SPE (silica, 10 g cartridge), eluting with cyclohexane:EtOAc (gradient 50:1 to 3:1). Further purification by mass directed autoprep HPLC afforded the title compound as an oil (35 mg). LC/MS: m/z 520.2 [M+H]+, Rt 4.04 min. Separation of racemic material (35 mg, 0.067 mmol) by preparative chiral HPLC (1" x 25 cm Chiralcel OJ) eluting with 30% EtOH in heptane, f = 15 mL/min, afforded Enantiomer 1 as an oil (12 mg), Rt 9.0 min, analytical chiral HPLC (25 cm Chiralcel OJ) eluting with 30% IPA in heptane, f = 1.0 mL/min, wavelength 215 nm, Rt 8.4 min (>99.9 %ee) and Enantiomer 2 as an oil (13.7 mg) Rt 14.4 min, analytical chiral HPLC (25 cm Chiralcel OJ) eluting with 30% IPA in heptane, f = 1.0 mL/min, wavelength 215 nm, Rt 15.5 min (99.7 %ee). Intermediate 122 and Intermediate 123 (1R)-1-(6-Bromo-2-pyridinyl)-2-(ethyloxy)ethanol and (1 S)-1-(6-Bromo-2-pyridinyl)-2- (ethyloxy)ethanol Separation of 1-(6-bromo-2-pyridinyl)-2-(ethyloxy)ethanol (100g) by preparative chiral HPLC (2" x 20 cm Chiralcel OD) eluting with 2% EtOH in heptane, f = 60 mL/min, afforded (1 R)-1- (6-bromo-2-pyridinyl)-2-(ethyloxy)ethanol as a white solid (45.9g), Rt 11.5 min. Analytical chiral HPLC (25 cm Chiralcel OD-H) eluting with 5% EtOH in heptane, f = 1.0 mL/min, wavelength 215 nm, Rt 6.8 min (>99 %ee) and (1 S)-1-(6-bromo-2-pyridinyi)-2-(ethyloxy)ethanol as a white solid (46.8g), Rt 14.5 min. Analytical chiral HPLC (25 cm Chiralcel OD-H) eluting with 5% EtOH in heptane, f = 1.0 mL/min, wavelength 215 nm, Rt 8.3 min (96 %ee). Pd(PPh3)4 (187 mg, 0.162 mmol) and Na2CO3 (1.29 g, 12.2 mmol) was treated with DME (20 mL) and stirred under nitrogen for 2 min. Water (10 mL), (1 R)-1-(6-bromo-2-pyridinyl)-2- (ethyloxy)ethanol (1.0 g, 4.1 mmol) and (4-cyanophenyl)boronic acid (656 mg, 4.47 mmol) were added and the stirred reaction mixture heated at 80°C for 17 h. The mixture was then allowed to cool to ambient temperature and the residue partitioned between saturated NH4CI (100 mL) and EtOAc (100 mL). The aqueous phase was extracted with EtOAc (2 x 100 mL) and the combined organic extracts washed with brine (100 mL), dried (Na2SO4) and evaporated to give a yellow oil (1.43 g). Purification by Biotage™ chromatography (silica, 40 g cartridge) eluting with cyclohexane: EtOAc (4:1) afforded the title compound as a pale yellow oil (945 mg). LC/MS: m/z 269.2 [M+H]+, Rt 2.83 min. Intermediate 125 Ethyl [(4-{[(1S)-1 -[6-(4-cyanophenyl)-2-pyridEnyl]-2-(ethyloxy)ethyl]oxy}-2- methylphenyl)oxy]acetate A stirred mixture of ethyl [(4-hydroxy-2-methylphenyl)oxy]acetate (664 mg, 3.16 mmol), 4- {6-[(1R)-2-(ethyloxy)-1-hydroxyethyl]-2-pyridlnyl}benzonitrile (719 mg, 2.68 mmol) and triphenylphosphine (857 mg, 3.27 mmol) in dry DCM (35 mL) was cooled to 0°C under nitrogen. DIAD (633 µL, 3.21 mmol) was added dropwise over 10 min, and the reaction mixture stirred at 0°C for a further 2 h. DCM (120 mL) was added to the reaction mixture, washed with aq 1M NaOH (50 mL) and water (100 mL), dried (Na2SO4) and evaporated to give a yellow oil. Purification by Biotage™ chromatography (silica, 90 g cartridge) eluting with cyclohexane : EtOAc (8:1) afforded the title compound as a colourless oil (765 mg). LC/MS: m/z 461.2 [M+H]+, Rt 3.67 min. A solution of ethyl {[2-methyl-4-({[4'-(trifluoromethyl)-3- biphenylyl]methyl}thio)phenyl]oxy}acetate (209 mg) in THF (20 mL) and aqueous NaOH (2M, 20 mL) was stirred at rt overnight and then heated to 60°C for 2 hours. The mixture was then allowed to cool to rt and the THF removed under vacuum. The resulting aqueous mixture was then acidified and extracted with EtOAc (3 x) and the organic layer washed with brine dried (MgSO4), filtered and reduced. Purification by mass directed auto-prep HPLC afforded the title compound as a white solid (24mg). LC/MS: m/z 431.0 [M-H]+, Rt 4.80 min. 1H NMR (400MHz; CDCI3) d: 2.22 (3H, s), 4.06 (2H, s), 4.66 (2H, s), 6.63 (1H, d, J 8.5 Hz), 7.14 (1H, dd, J 8.5,2.5 Hz), 7.16, (1H, m), 7.24-7.28 (1H, m), 7.34-7.41 (2H, m), 7.46 (1H, m), 7.60 (2H, d, J 8.0 Hz), 7.67 (2H, d, J 8.0 Hz). Example 2 {[2-Methyl-4-({[4-methyl-4'-(trmuoromethyl)-3- biphenylyl]methyl}thio)phenyl]oxy)aceticacid A mixture of (5-bromo-2-methylphenyl)methanol (90 mg, 0.45 mmol), 4- (triflouromethyl)benzeneboronic (94 mg, 0.49 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol) and Na2CO3 (123 mg, 1.16 mmol) in a mixture of DME (20 mL) and water (10 mL) was heated at reflux for 7 hours and then allowed to cool to rt. The resulting mixture was then reduced under vacuum, partitioned between water and EtOAc and the layers separated. The organic layer was then washed with brine, reduced under vacuum and then purified by SPE (silica, 10g cartridge) eluting with cyclohexane : CHCI3 then cyclohexane: EtOAc to give a crude product containing a mixture of (5-bromo-2-methylphenyl)methano! and product. The mixture was then dissolved in DCM (10 mL) and then treated with thionyl chloride (200 uL, 2.74 mmol) and the mixture stirred for 5 hours. Additional thionyl chloride (200 µL, 2.74 mmol) was then added and after a further 2 hours, the reaction was quenched by the careful addition of aqueous K2CO3 (1N) and the resulting layers separated using a hydrophobe frit. The organic layer was reduced and the resulting crude mixture (98 mg) dissolved in MeCN (20 mL) was and treated ethyl (4-mercapto-2- methylphenoxy)acetate (92 mg, 0.41 mmol) and KaCO3 (55 mg, 0.40 mmol). The resulting mixture was then stirred under nitrogen over the 72 hours and the resulting mixture partitioned between water and EtOAc and the layers separated. The aqueous was re-extracted with EtOAc and the combined organic layers washed with brine, dried (MgSO4), filtered and reduced. Purification by SPE (silica) eluting with cyclohexane: CHCI3 (1:1) afforded the crude ester as a clear oil (125 mg). A solution of the ester in THF (10 mL) and aqueous NaOH (2M, 10 mL) was heated at 60°C for 1 hour and was then allowed to cool to rt overnight. The THF was then removed under vacuum and the resulting aqueous mixture was then acidified and extracted with EtOAc (2 x). The organic layer was then washed with brine, dried (MgSO4), filtered and reduced. Purification by mass directed auto-prep HPLC afforded the title compound as a white solid (41 mg). LC/MS: m/z 445.0 [M-H]+, Rt 4.32 min. 1H NMR (400MHz; DMSO-d6) d: 2.07 (3H, s), 2.35 (3H, s), 4.10 (2H, s), 4.64 (2H, s), 6.74 (1H, d, J 8.5 Hz), 7.09 (1H, m), 7.14 (1H, dd, J 8.0, 2.5 Hz), 7.24-7.30 (2H, m), 7.46 (1H, dd, J 8.0, 2.0 Hz), 7.64 (2H, d, J 8.5 Hz), 7.67 (2H, d, J 8.5 Hz). A solution of ethyl 3-[2-methyl-4-({[4'-(trifluoromethyl)-3- biphenylyl]methyl}oxy)phenyl]propanoate (135 mg, 0.31 mmol) in THF (4 mL) at rt was treated with aqueous NaOH (2M, 4 mL) and the resulting solution heated to 75°C for 7 hours and then allowed to cool to rt over 21 hours. The mixture was then reduced and the residue partitioned between CHCI3 and water and the aqueous phase separated and acidified to pH2 with aqueous HCI (2 N). The mixture was then extracted with CHCI3 (3 x) and the combined organic layer washed with brine, dried (Na2SO4), filtered and reduced to give the title compound as a white crystalline solid (123 mg). LC/MS: m/z 413.1 [M-H]+, Rt 4.21 min. 1H NMR (400MHz; CDCI3) d:2.31 (3H, s), 2.62 (2H, m), 2.91 (2H, m), 5.10 (2H, s), 6.79 (1H, dd, J 8.5,3.0 Hz), 6.83 (1H, d, 3.0 Hz), 7.08 (1H, d, J 8.5 Hz), 7.44-7.53 (2H, m), 7.56 (1H, m), 7.66 (1H,m), 7.70 (4H,s). A suspension of [(2-methyl-4-{2-[4I-(trifluoromethyl)-3-biphenylyl]ethenyl}phenyl)oxy]acetic acid (90 mg, 0.22 mmol) in EtOH (10 mL) was added to Pd/C (Degussa type E101 NE/N) (10 mg, 11wt%) and the resulting mixture stirred under an atmosphere of hydrogen for 6 hours. The mixture was then filtered through celite J2 washing with copious amounts of EtOH and the filtrate reduced under vacuum to give a sticky solid (100 mg) which was purified by mass directed auto- prep HPLC to give the title compound as a fluffy white solid (25mg). LC/MS: m/z 413.1 [M-H]+, Rt, 4.48 min. 1H NMR (400MHz; MeOD-d4) d: 2.21 (3H, s), 2.85 (2H, m), 2.95 (2H, m), 4.62 (2H, s), 6.70 (1H, d, J 8.0 Hz), 6.91-6.95 (2H, m), 7.22 (1H, dt, J 7.5,1.0 Hz), 7.35 (1H, m), 7.37 (1H, t, J 7.5 Hz), 7.46 (1H, ddd, J 7.5, 2.0,1.0 Hz), 7.72 (4H, s). A solution of ethyl ({2-methyl-4-[({6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}methyl)thio]phenyl}oxy)acetate (367 mg, 0.80 mmol) in THF (5 mL) was treated with aqueous NaOH (2M, 5 mL) and the resulting solution stirred at rt for 4 hours. The mixture was poured into a mixture of aqueous HCI (2M) and EtOAc and the layers separated. The organic layer was then washed with water and brine, dried MgSO4, filtered and then reduced under vacuum. Purification by mass-directed auto-prep HPLC afforded the title compound as an oil. LC/MS: m/z 434.2 [M+H]+, Rt 3.97 min. 1H NMR (400MHz; CDCI3) d: 2.22 (3H, s), 4.24 (2H, s), 4.63 (2H, s), 6.61 (1H, d, J 8.5 Hz), 7.16 (1H, dd, J 8.5, 2.0 Hz), 7.22-7.28 (2H, m), 7.60 (1H, d, J 8.5 Hz), 7.68-7.74 (3H, m), 8.02 (2H, d, J 8.0 Hz). A mixture of ethyl {[2-methyl-4-({1-[4'-(trifluoromethyl)-3- biphenylyl]ethyl}thio)phenyl]oxy}acetate (235 mg, 0.50 mmol) in dioxane (6 mL) was treated with aqueous NaOH (0.5N, 2.0 mL, 1.00 mmol) and the mixture heated at reflux for 1 hour. The resulting mixture was then cooled and treated with Dowex 50WX2 (pre-washed with dioxan), filtered and washed with more dioxan and reduced to give the title compound as a colourless gum (220 mg). LC/MS: m/z 445.2 [M-H]+, Rt 4.20 min. 1H NMR (400MHz; CDCI3) d:1.65 (3H, d, J 7.0 Hz), 2.18 (3H, s), 4.25 (1H, q, J 7.0 Hz), 4.64 (2H, s), 6.57 (1H, d, J 9.0 Hz), 7.08-7.13 (2H, m), 7.29 (1H, m), 7.33-7.41 (2H, m), 7.43 (1H, m), 7.59 (2H, d, J 8.5 Hz), 7.67 (2H, m, J 8.5 Hz). Example 7 {[2-Methyl-4-({1-[4'-(trifluoromethyl)-4-biphenylyl]ethyl}thio)phenyl]oxy}aceticacld Prepared from ethyl {[2-methyl-4-({1-[4'-(trifluoromethyl)-4- biphenylyl]ethyl}thio)phenyl]oxy}acetate (333 mg, 0.70 mmol) according to the procedure used for the preparation of Example 6 to give the title compound as a white solid (283 mg). LC/MS: m/z 445.2 [M-H]+, Rt 4.28 min. 1H NMR (400MHz; CDCI3) d:1.63 (3H, d, J 7.0 Hz), 2.19 (3H, s), 4.24 (1H, q, J 7.0 Hz), 4.65 (2H, s), 6.58 (1H, d, J 8.5 Hz), 7.08-7.14 (2H, m), 7.33 (2H, d, J 8.5 Hz), 7.50 (2H, d, J 8.5 Hz), 7.67 (4H, m). Ethyl 2-methyl-2-({2-methyl-4-[(1-{6-l4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyi)oxy]phenyl}oxy)propanoate (9 mg, 0.02 mmol) was dissolved in THF (0.75 mL), water (0.25 mL) and aqueous NaOH (2M, 35 µl, 0.07 mmol) and the mixture heated at 80°C for 16 hours. More aqueous NaOH (2M, 420 ul, 0.84 mmol) was then added and heating continued for an additional 24 hours. The mixture was then cooled, neutralised with aqueous HCI (2M), partitioned between EtOAc and water and the layers separated. The organic layer was then washed with brine, dried (Na2SO4) and reduced to give a pale yellow oil. Purification by SPE (aminopropyl, 1g cartridge) loading in CHCI3 and eluting with dioxane and then 10% aqueous ammonia in dioxane afforded the title compound as a colourless gum (4.5 mg). LC/MS: m/z 502.3 [M+H]+, Rt 4.49. 1H NMR (400MHz; CDCl3) d: 0.91 (3H, t, J 7.0 Hz), 1.50 (6H, s), 1.32-1.61 (4H, m), 2.00 (2H, m), 2.15 (3H, s), 5.23 (1H, t, J 6.0 Hz), 6.57 (1H, dd, J 8.5, 3.0 Hz), 6.69 (1H, d, J 8.5 Hz), 6.76 (1H, d, J 3.0 Hz), 7.37 (1H, dd, J 8.0,1.0 Hz), 7.62 (1H, dd, J 8.0,1.0 Hz), 7.73 (1H, t, J 8.0 Hz), 7.74 (2H, d, J 8.0 Hz), 8.12 (2H, d, J 8.0 Hz). Example 9 Ethyl {[2-methyl-4-({1 -[4'-(trifluoromethyl)-3-biphenylyl]pentyl}oxy)phenyl]oxy}acetate (138 mg, 0.28 mmo!) was dissolved in THF (1.5 mL), water (0.5 mL) and aqueous NaOH (2M, 0.52 mL, 1.04 mmol) and the mixture stirred at 70°C for 2 hours, cooled to rt and acidified to pH4 with aqueous hydrochloric acid (2M). The mixture was then partitioned between EtOAc and water, the layers separated and the organic layer washed with brine, dried (Na2SO4) and concentrated to give the title compound as a colourless gum (130 mg). LC/MS: m/z 471.2 [M-H]+. Rt 4.57 min. 1H NMR (400MHz; CDCI3) d: 0.90 (3H, t, J 7.0 Hz), 1.31-1.45 (3H, m), 1.45-1.60 (1H, m), 1.76-1.90 (1H, m), 1.93-2.07 (1H, m), 2.20 (3H, s), 4.55 (2H, s), 5.03 (2H, dd, J 8.0, 5.0 Hz), 6.55 (1H, d, J 9.0 Hz), 6.58 (1H, dd, J 9.0, 2.5 Hz), 6.75 (1H, 2.5 Hz), 7.36 (1H, m), 7.42 (1H, t, J 7.5 Hz), 7.48 (1H, dt, J 7.5,1.5 Hz), 7.5 (1H, m), 7.67 (4H, m). Prepared according to the procedure used for the preparation of Example 9 starting from ethyl [(4-{[1-(4'-chloro-3-biphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetate (137 mg, 0.29 mmol) to give the title compound (130 mg). LC/MS m/z 456.1 [M+NH4]+, Rt 4.55min. 1H NMR (400MHz; CDCI3) d: 0.90 (3H, t, J 7.0 Hz), 1.30-1.44 (3H, m), 1.44-1.59 (1H, m), 1.76-1.88 (1H, m), 1.94-2.06 (1H, m), 2.21 (3H, s), 4.51 (2H, s), 5.02 (2H, dd, J 6.0, 5.0 Hz), 6.53 (1H, d, J 9.0 Hz), 6.56 (1H, dd, J 9.0, 2.5 Hz), 6.74 (1H, 2.5 Hz), 7.32 (1H, dt, J 7.5,1.5 Hz), 7.36- 7.41 (3H,m), 7.43 (1H, dt, J 7.5,1.5 Hz), 7.47-7.53 (4H, m). Example 11 {[2-Methyl-4-({1-[4'-(trl(luoromethyl)-4-blphenylyl]pentyl}oxy)phenyl]oxy}acetic acld To a solution of ethyl {[2-methyl-4-({1-[4'-(trifluoromethyl)-4- blphenylyl]pentyl}oxy)phenyl]oxy}acetate (310 mg, 0.62 mmol) in dioxan (6 mL) and water (3 mL), was added aqueous NaOH (2M, 2.43 mL, 1.22 mmol), and the mixture stirred at rt for 1 hour. The dioxan was removed under vacuum and brine (5 mL) added to the residue. The precipitate was collected by filtration and dried under vacuum to give the title compound as a white solid (250 mg). LC/MS: m/z 471.3 [M-H]+, Rt 4.57 min. 1H NMR (400MHz; MeOD-d4) d: 0.91 (3H, t, J 7.0 Hz), 1.37 (2H, m), 1.39 (1H, m), 1.49 (1H, m), 1.80 (1H, m), 1.95 (1H, m), 2.17 (3H, s), 4.26 (2H, s), 5.11 (1H, dd, J 5.5, 5.5 Hz), 6.55 (1H, dd, J 8.5,2.0 Hz), 6.58 (1H, d, J 8.5 Hz), 6.68 (1H, d, J 2.0 Hz), 7.44 (2H, d, J 8.0 Hz), 7.61 (2H, d, J 8.0 Hz), 7.70 (2H, d, J 8.0 Hz), 7.77 (2H,d, J 8.0 Hz). Prepared from ethyl [(4-{[1-(4'-chloro-4-biphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetate (150 mg, 0.32 mmol) according to the procedure used for the preparation of Example 11, to give the title compound as a white solid (140 mg). LC/MS: m/z 437.2 [M-H]+, Rt 4.83 min. 'H NMR (400MHz; MeOD-d") d: 0.90 (3H, t, J 7.0 Hz), 1.36 (2H,m), 1.39 (1H, m), 1.49 (1H, m), 1.80 (1H, m), 1.95 (1H, m), 2.16 (3H, s), 4.26 (2H, s), 5.11 (1H, dd, J 7.5, 5.5 Hz), 6.54 (1H, dd, J 9.0,2.5 Hz), 6.58 (1H, d, J 9.0 Hz), 6.68 (1H, d, J 2.5 Hz), 7.39 (4H, d, J 8.5Hz), 7.53 (2H, d, J 8.5 Hz), 7.57(2H, d, J 8.5 Hz). To a solution of ethyl {[2-methyl-4-({(1R)-1 -[4'-(trif luoromethyl)-4- biphenylyl]pentyl}thio)phenyl]oxy}acetate (10 mg, 0.02 mmol) in THF (1 mL) and MeOH (1 mL) was added aqueous NaOH (2M, 1 mL) and the resulting mixture agitated for 1.5 hours at rt. The mixture was then reduced under vacuum, acidified with aqueous HCI (2M), extracted with DCM (2 mL) and reduced to afford the title compound as colourless oil (9 mg). LC/MS: m/z 487.3 [M-H]+, Rt 4.84 min. 1H NMR (400MHz; MeOD-d4) d: 0.85 (3H, t, J 7.0 Hz), 1.21-1.44 (4H, m), 1.84-2.02 (2H, m), 2.12 (3H, s), 4.06 (1H, dd, J 8.5, 6.5 Hz), 4.62 (2H, s), 6.64 (1H, d, J 8.5 Hz), 7.01 (1H, d, J 2.0 Hz), 7.04 (1H, dd, J 8.5, 2.0 Hz), 7.26 (2H, d, J 8.0 Hz), 7.55 (2H, d, J 8.0 Hz), 7.70 (2H, d, J 8.0 Hz), 7.77 (2H, d, J 8.0 Hz). i Prepared from ethyl {[2-methyl-4-({(1S)-1-[4'-(trifluoromethyl)-4- biphenyly!]pentyl}thio)phenyl]oxy}acetate (9 mg, 0.02 mmol) according to the procedure used for the preparation of Example 13 to give the title compound (8 mg). LC/MS: m/z 487.3 [M-H]+, Rt 4.84 min. 1H NMR (400MHz; MeOD-d4) d: 0.85 (3H, t, J 7.0 Hz), 1.21-1.44 (4H, m), 1.84-2.02 (2H, m), 2.12 (3H, s), 4.06 (1H, dd, J 8.5, 6.5 Hz), 4.62 (2H, s), 6.64 (1H, d, J 8.5 Hz), 7.01 (1H, d, J 2.0 Hz), 7.04 (1H, dd, J 8.5, 2.0 Hz), 7.26 (2H, d, J 8.0 Hz), 7.55 (2H, d, J 8.0 Hz), 7.70 (2H, d, J 8.0 Hz), 7.77 (2H, d, J 8.0 Hz). A solution of ethyl ({2-methyl-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}oxy)acetate (367 mg, 0.73 mmol) in THF (9 mL) and methanol (9 mL) was treated with aqueous NaOH (2M, 9 mL) drop-wise and the resulting solution stirred at rt for 3 h. The volatile solvents were then removed under vacuum and the resulting aqueous residue diluted with water (100 mL) and then acidified with aqueous HCI (2M, 11 mL). The product was extracted with DCM (2 x 50 mL). The combined organic layers were then washed with brine (150 mL), dried (MgSO4), filtered and then reduced under vacuum to give a pale yellow foam (341 mg). Purification by SPE (silica) eluting with heptane: EtOAc (gradient 10:1 to 0:1) afforded the title compound as a pale yellow foam (256 mg). LC/MS: m/z 473.9 [M+H]+, Rt 4.38 min. 1H NMR (400MHz; CDCI3) d: 0.91 (3H, t, J 7.0 Hz), 1.32-1.63 (4H, m), 2.00 (2H, m), 4.55 (2H, s), 5.22 (1H, m), 6.53-6.63 (2H, m), 6.79 (1H, d, J 2.0 Hz), 7.37 (1H, d, J 8.0 Hz), 7.62 (1H, d, J 8.0 Hz), 7.73 (3H, m), 8.13 (2H, d, J 8.0 Hz). Analytical chiral HPLC, 25cm chiralpak AD, 5% EtOH/heptane [0.1%TFA], 1.0 mL/min, wavelength 215 nm, Rt 9.53 min. Prepared from ethyl ({2-methyl-4-[((1 flH-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}oxy)acetate (360 mg, 0.72 mmol) according to the procedure used for the preparation of Example 15 to give the title compound as a pale yellow foam (269 mg). LC/MS: m/z 473.9 [M+H]+, Rt 4.38 min. 1H NMR (400MHz; CDCI3) d: 0.91 (3H, t, J 7.0 Hz), 1.32-1.63 (4H, m), 2.00 (2H, m), 4.55 (2H, s), 5.22 (1H, m), 6.53-6.53 (2H, m), 6.79 (1H, d, J 2.0 Hz), 7.37 (1H, d, J 8.0 Hz), 7.62 (1H, d, J 8.0 Hz), 7.73 (3H, m), 8.13 (2H, d, J 8.0 Hz). Analytical chiral HPLC 25cm chiralpak AD 5% EtOH/heptane [0.1%TFA], 1.0 mL/min, wavelength 215 nm, Rt 10.87 min To a solution of ethyl ({2-methyl-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)thio]phenyl}oxy)acetate (34 mg, 0.07 mmol) in THF (1 mL) and MeOH (1 mL) was added aqueous NaOH (2M, 1 mL) and the resulting mixture agitated for 1.5 hours at rt. The mixture was then reduced under vacuum, acidified with aqueous HCI (2M) and extracted with DCM (2 mL) and reduced to afford the title compound as a colourless oil (31 mg). LC/MS: m/z 490.0 [M+H]+, Rt 4.60 min. 1H NMR (400MHz; MeOD-d4) d: 0.86 (3H, t, 7.0 Hz), 1.23-1.48 (4H, m), 1.95-2.18 (2H, m), 2.08 (3H, s) 4.23 (1H, dd, J 8.5, 6.5 Hz), 4.54 (2H, s), 6.62 (1H, d, J 8.5 Hz), 6.97 (1H, d, J 1.5 Hz), 7.04 (1H, dd, J 8.5 Hz, 1.5 Hz), 7.26 (1H, d, J 8.0 Hz), 7.70 (1H, d, J 8.0 Hz), 7.73 (2H, d, J 8.0 Hz), 7.77 (1H, t, J 8.0 Hz), 8.04 (2H, d, J 8.0 Hz). Analytical chiral HPLC; 25cm chiralcel OJ-R, flow 0.5ml/min, wavelength 215nm, 50% acetonitrile/H3PO4-KH2PO4[0.2M] pH2, R, 27.25min. Prepared from ethyl ({2-methy!-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)thio]phenyl}oxy)acetate (29 mg, 0.06 mmol) according to the procedure used for the preparation of Example 17 to give the title compound (28 mg). LC/MS: m/z 490.0 [M+H]+, Rt 4.60 min. 1H NMR (400MHz; MeOD-d4) d: 0.86 (3H, t, 7.0 Hz), 1.23-1.48 (4H, m), 1.95-2.18 (2H, m), 2.08 (3H, s) 4.23 (1H, dd, J 8.5, 6.5 Hz), 4.54 (2H, s), 6.62 (1H, d, J 8.5 Hz), 6.97 (1H, d, J 1.5 Hz), 7.04 (1H, dd, J 8.5 Hz, 1.5 Hz), 7.26 (1H, d, J 8.0 Hz), 7.70 (1H, d, J 8.0 Hz), 7.73 (2H, d, J 8.0 Hz), 7.77 (1H, t, J 8.0 Hz), 8.04 (2H, d, J 8.0 Hz). Analytical chiral HPLC; 25cm chiralcel OJ-R, flow 0.5ml/min, wavelength 215nm, 50% acetonitrile/H3PO4-KH2PO4[0.2M] pH2, R, 30.34min. A stirred solution of ethyl ({2-methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)sulfinyl]phenyl)oxy)acetate (27 mg, 0.05 mmol) in THF (1 mL) and methanol (1 mL) was added, drop-wise, aqueous NaOH (2M, 1 mL). After 2 hours 50 minutes the mixture was concentrated producing a 'chalk-white' solid which was diluted with water (2 mL) and acidified with aqueous HCI (2M, 2 mL). The aqueous layer was extracted with DCM (2 x 2 mL then 1 mL) using a hydrophobic frit and the combined organic layer concentrated under vacuum yielding the title compound as a mixture of two diastereoisomers (24 mg). LC/MS: m/z 506.2 [M+H]+, Rt 4.24 min. 1H NMR (400MHz; CDCI3) d: isomer 1 (70%) 0.83 (3H, t, J 7.0 Hz), 1.17-1.41 (4H, m), 2.06 (3H, s), 1.97-2.42 (2H, m), 4.07 (1H, dd, J 11.0,4.0 Hz), 4.48 (1H, d, J 17.0 Hz), 4.53 (1H, d, J 17.0 Hz), 6.49 (1H, d, J 8.5 Hz), 6.86 (1H, d, J 2.0 Hz), 6.90 (1H, m), 7.11 (1H, dd, J 8.5, 2.0 Hz), 7.59-7.80 (4H, m), 7.94 (2H, d, 8.0 Hz); isomer 2 (30%) 0.83 (3H, t, J 7.0 Hz), 1.17-1.41 (4H, m), 2.16 (3H, s), 1.97-2.42 (2H, m), 4.14 (1H, m), 4.44 (1H, d, J 17.0 Hz), 4.53 (1H, d, J 17.0 Hz), 6.51 (1H, d, J 8.5 Hz), 7.03 (1H, d, J 2.0 Hz), 7.13 (1H, dd, J 8.5, 2.0 Hz), 7.32 (1H. d, J 8.0 Hz), 7.59-7.80 (6H, m). Prepared from ethyl ({2-methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl)-2- pyridinyl}pentyl)sulfonyl]phenyl}oxy)acetate (26 mg, 0.05 mmol) according to the procedure used for the preparation of Example 19 to give the title compound as a clear oil (22 mg). LC/MS: m/z 522.2 [M+H]+, Rt 4.23 min. 1H NMR (400MHz; CDCI3) d: 0.82 (3H, t, 7.0 Hz), 1.12-1.44 (4H, m), 2.11 (3H, s), 2.26-2.47 (2H,m), 4.40 (1H, dd, 11.5, 4.0 Hz), 4.57 (2H, s), 6.56 (1H, d, 8.5 Hz), 7.27 (1H, m), 7.34 (1H, dd, J 8.5 Hz, 2.0 Hz), 7.47 (1H, d, 7.0 Hz), 7.62 (2H, d, J 8.0 Hz), 7.67 (1H, d, 7.0 Hz), 7.73 (2H, d, J 8.0 Hz), 7.81 (1H, dd, J 7.0, 7.0 Hz). A solution of methyl {4-[(1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}acetate (329 mg, 0.72 mmol) in THF (9.5 mL) and methanol (9.5 mL) was treated with aqueous NaOH (2M, 9.5 mL) drop-wise and the resulting solution stirred at rt for 17 hours. The volatile solvents were then removed under vacuum and the resulting aqueous mixture acidified with aqueous HCI (2M, 15 mL), diluted with water (100 mL) and the product extracted with DCM (2 x 100 mL). The combined organic layers were then washed with brine (100 mL), dried (MgSO4), filtered and then reduced under vacuum to give the title compound as a pale yellow foam (314 mg). LC/MS: m/z 443.9 [M+H]+, Rt 4.15 min. 1H NMR (400MHz; CDCI3) d: 0.91 (3H, t, J 7.0 Hz), 1.32-1.63 (4H, m), 2.01 (2H, m), 3.52 (2H, s), 5.28 (1H, t, J 6.5 Hz), 6.84 (2H, d, J 9.0 Hz), 7.09 (2H, d, J 9.0 Hz), 7.36 (1H, d, J 7.5 Hz), 7.62 (1H, d, J 8.0 Hz), 7.72 (1H, dd, J 8.0, 7.5 Hz), 7.74 (2H, d, J 8.0 Hz), 8.14 (2H, d, J 8.0 Hz). A stirred solution of ethyl [(4-{[1-(6-bromo-2-pyridinyl)butyl]oxy}-2-methylphenyl)oxy]acetate (50 mg, 0.12 mmol) in DME (0.5 ml_) was treated with phenyl 4-(triflouromethyl)benzeneboronic acid (23 mg, 0.12 mmol) followed by Pd(PPh3)4 (14 mg, 0.01 mmol) and a solution of Na2CO3 (38 mg, 0.36 mmol) in water (0.5 mL), and the resulting mixture was heated at 70°C for 18 hours under nitrogen. The solvent was then removed under vacuum and the resulting mixture acidified with aqueous HCI (2M) and then partitioned between water and EtOAc, the layers separated and the organic layer reduced to an oil. Purification by mass directed auto-prep HPLC afforded the title compound (12 mg). LC/MS: m/z 459.9 [M+H]+, Rt 4.30 min. 1H NMR (400 MHz; CDCI3) d: 0.97 (3H, t, J 7.5 Hz), 1.56 (2H, m), 1.97 (2H, m), 2.19 (3H, s), 4.53 (2H, s), 5.23 (1H, dd, J 6.5, 6.5 Hz), 6.55 (1H, d, J 9.0 Hz), 6.59 (1H, dd, J 9.0, 3.0 Hz), 6.78 (1H, d, 3.0 Hz), 7.37 (1H, d, 7.5 Hz), 7.61 (1H, d, 7.5 Hz), 7.72 (3H, m), 8.13 (2H, d, 8.5 Hz). Prepared from ethyl ({4-[(1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}oxy)acetate (42 mg, 0.09 mmol) according to the procedure used for the preparation of Example 21 to give the title compound as a gum (40 mg). LC/MS: m/z 459.9 [M+H]+, Rt 4.31 mln. 1H NMR (400MHz; MeOD-d4) d: 0.92 (3H, t, J 7.5 Hz), 1.34-1.60 (4H, m), 2.00 (2H, m), 4.51 (2H, s), 5.25 (1H, dd, J 7.5, 5.5 Hz), 6.77 (2H, m), 6.82 (2H, m), 7.41 (1H, dd, J 7.5,1.5 Hz), 7.78 (2H, d, J 8.0Hz), 7.78-7.86 (2H, m), 8.13 (2H, d, J 8.0 Hz). Example 24 3-{4-t(1-{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid To a stirred solution of ethyl 3-{4-[(1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}propanoate (92 mg, 0.19 mmol) in THF (3 mL) and methanol (3 mL) was added, drop-wise, aqueous NaOH (2M, 3 mL). After 17 hours the mixture was concentrated under vacuum and the solid residue acidified with aqueous HCI (2M, 3.5 mL), diluted with water (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layer was washed with brine (20 mL), dried (MgSO4) and concentrated under vacuum. The acid was loaded onto a PE-AX isolute SPE cartridge (pre-conditioned with 1 column volume of methanol) in 9 mL of methanol and a few drops of Et3N. The cartridge was washed with 3 column volumes of methanol followed by 10% aqueous HCI (2M) in methanol (2x5 mL) and 20% aqueous HCI (2M) in methanol (2x5 mL), yielding the title compound (38 mg). LC/MS: m/z 458.0 [M+H]+, Rt 4.11 min. 1H NMR (400MHz; MeOD-d4) d: 0.90 (3H, t, 7.0 Hz), 1.32-1.59 (4H, m), 1.94-2.05 (2H, m), 2.47 (2H, t, 7.5 Hz), 2.76 (2H, t, 7.5 Hz), 5.29 (1H, dd, 6.5, 5.5 Hz), 6.78 (2H, d, 8.5 Hz), 7.01 (2H, d, 8.5 Hz), 7.39 (1H, d, 7.5 Hz), 7.78 (4H, m), 8.21 (2H, d, J 8.0 Hz). General procedure for the preparation of Examples 25-34 A stirred solution of ethyl [(4-{[1-(6-bromo-2-pyridinyl)pentyl]oxy}-2- methylphenyl)oxy]acetate (50 mg, 0.12 mmol) in DME (0.5 mL) was treated with the appropriate aryl boronic acid (0.12 mmol) followed by Pd(PPh3)4 (13 mg, 0.01 mmol) and a solution of Na2CO3 (37 mg, 0.34 mmol) in water (0.25 mL). The reaction mixture was heated at 70°C for 18 hours under nitrogen, allowed to cool to rt and then reduced under vacuum (Genevac). The residue was loaded in the minimum volume of methanol onto a SPE (C18 cartridge) (pre-conditioned with 1 column volume of methanol and then 1 column volume of 5% MeCN in water) eluting with 5% MeCN in water, then MeCN followed by methanol to give the crude product. Further purification by mass directed auto-prep HPLC afforded the title compounds. Example 25 {[4-({1-[6-(4-Chlorophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}aceticacid LC/MS: m/z 437.9 [M-H]+, Rt 4.45 min. 1H NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.5 Hz), 1.32-1.61 (4H, m), 1.90-2.05 (2H, m), 2.19 (3H, s), 4.53 (2H, s), 5.21 (1H, del, J 7.5, 5.5 Hz), 6.54 (1H, d, J 9.0 Hz), 6.58 (1H, dd, J 9.0, 3.0 Hz), 6.77 (1H, d, J 3.0 Hz), 7.32 (1H, d, J 8.0 Hz), 7.44 (2H, d, J 8.5 Hz), 7.54 (1H, d, J 8.0 Hz), 7.68 (1H, t, J 8.0 Hz), 7.95 (2H, d, J 8.5 Hz). LC/MS: m/z 436.0 [M+H]+, Rt 4.18 min. 1H NMR (400 MHz; CDCI3) d: 0.90 (3H, t, J 7.5 Hz), 1.31 -1.62 (4H, rn), 1.90-2.06 (2H, m), 2.19 (3H, s), 3.87 (3H, s), 4.53 (2H, s), 5.21 (1H, dd, J 8.0, 5.0 Hz), 6.55 (1H, d, J 9.0 Hz), 6.60 (1H, dd, J 9.0, 3.0 Hz), 6.78 (1H, d, J 3.0 Hz), 7.01 (2H, d, J 9.0 Hz), 7.26 (1H, d, J 7.5 Hz), 7.51 (1H, d, J 7.5 Hz), 7.66 (1H, t, J 7.5 Hz), 7.95 (2H, d, J 9.0 Hz). LC/MS: m/z 449.9 [M+H]+, Rt 4.32 min. 1H NMR (400 MHz; CDCI3) d: 0.90 (3H, t, J 7.5 Hz) 1.32-1.62 (4H, m), 1.45 (3H, t, J 7.0 Hz), 1.90-2.05 (2H, m), 2.17 (3H, s), 4.10 (2H, q, J 7.0 Hz), 4.50 (2H, s), 5.19 (1H, dd, J 8.0, 5.0 Hz), 6.54 (1H, d, J 9.0 Hz), 6.58 (1H, dd J 9.0, 3.0), 6.77 (1H, d, J 3.0), 6.99 (2H, d, J 9.0 Hz), 7.23 (1H, d, J 7.5 Hz), 7.49 (1H, d, J 7.5 Hz), 7.63 (1H, t, J 7.5 Hz), 7.94 (2H, d, J 9.0 Hz). LC/MS: m/z 419.9 [M+H]+, Rt 4.34 min. 1H NMR (400 MHz; CDCI3) d: 0.90 (3H, t, 7.0 Hz), 1.32-1.61 (4H, m), 1.90-2.06 (2H, m), 2.19 (3H, s), 2.41 (3H, s), 4.52 (2H, s), 5.21 (1H, dd, J 8.0, 5.0 Hz), 6.54 (1H, d, J 9.0 Hz), 6.59 (1H, dd, J 9.0, 3.0 Hz), 6.78 (1H, d, J 3.0 Hz), 7.27 (1H, dd, J 8.0,1.0 Hz), 7.28 (2H, d, J 8.0 Hz), 7.53 (1H, dd, J 8.0,1.0 Hz), 7.65 (1H, t, J 8.0 Hz), 7.89 (2H, d, J 8.0 Hz). LC/MS: m/z 473.8 [M+H]+, Rt 4.82 min. 1H NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.0 Hz), 1.33-1.61 (4H, m), 1.98 (2H, m), 2.20 (3H, s), 4.54 (2H, s), 5.20 (1H, dd, J 6.5, 6.5 Hz), 6.55 (1H, d, J 9.0 Hz), 6.58 (1H, d, J 9.0,2.5 Hz), 6.77 (1H, d, J 2.5 Hz), 7.34 (1H, d, J 8.0 Hz), 7.54 (2H, d, J 8.5 Hz), 7.69 (1H, t, J 8.0 Hz), 7.83 (1H, dd, J 8.5, 2.0 Hz), 8.14 (1H, d, J 2.0 Hz). LC/MS: m/z 473.9 [M+H]+, Rt 4.50 min. 1H NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.0 Hz), 1.34-1.62 (4H, m), 1.96-2.04 (2H, m), 2.19 (3H, s), 4.54 (2H, s), 5.22 (1H, m), 6.55 (1H, d, J 9.0 Hz), 6.60 (1H, dd, J 9.0, 3.0 Hz), 6.78 (1H, d, J 3.0 Hz), 7.36 (1H, d, J 7.5 Hz), 7.60 (1H, m), 7.61 (1H, d, J 8.0 Hz), 7.67 (1H, d, 8.0 Hz) 7.72 (1H, t, J 8.0 Hz), 8.20 (1H, d, J 8.0 Hz), 8.28 (1H, s). LC/MS: m/z 406.0 [M+H]+, Rt 4.20 min. 'H NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.0 Hz), 1.32-1.62 (4H, m), 1.92-2.06 (2H, m), 2.18 (3H, s), 4.49 (2H, s), 5.21 (1H, dd, J 7.5, 5.0 Hz), 6.53 (1H, d, J 9.0 Hz), 6.59 (1H, dd, J 9.0, 3.0 Hz), 6.77 (1H, d, 3.0 Hz), 7.30 (1H, d, 8.0 Hz), 7.41 (1H, m), 7.48 (2H, m), 7.56 (1H, dd, J 8.0, 1.0 Hz), 7.67 (1H, t, J 8.0 Hz), 8.00 (2H, m). LC/MS: m/z 448.1 [M+H]+, Rt 3.93 min. 1H NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.0 Hz), 1.32-1.63 (4H, m), 2.00 (2H, m), 2.19 (3H, s), 2.66 (3H, s), 4.53 (2H, s), 5.22 (1H, m), 6.55 (1H, d, J 9.0 Hz), 6.60 (1H, dd, J 9.0, 3.0 Hz), 6.78 (1H, d, J 3.0 Hz), 7.36 (1H, dd, J 7.5,1.0 Hz), 7.63 (1H, dd, J 7.5, 1.0 Hz), 7.72 (1H, t, J 7.5 Hz), 8.07 (2H, d, J 8.5 Hz), 8.12 (2H, d, J 8.5 Hz). 1H NMR (400 MHz; CDCI3) d:0.91 (3H, t, J 7.0 Hz), 1.32-1.61 (4H, m), 1.99 (2H, m), 2.18 (3H, s), 4.51 (2H, s), 5.19 (1H, dd, J 7.5, 5.5 Hz), 6.53 (1H, d, J 9.0 Hz), 6.58 (1H, dd, J 9.0, 3.0 Hz), 6.77 (1H, d, J 3.0 Hz), 7.16 (2H, m), 7.30 (1H, d, J 7.5 Hz), 7.52 (1H, d, J 7.5 Hz), 7.67 (1H, t, J 7.5 Hz), 7.98 (2H, m). LC/MS: m/z 431.1 [M+H]+, Rt 4.02 min. 1H NMR (400 MHz; CDCI3) 5:0.91 (3H, t, 7.0 Hz), 1.32-1.61 (4H, m), 1.99 (2H, m), 2.19 (3H, s), 4.53 (2H, s), 5.21 (1H, dd, J 6.5, 6.5 Hz), 6.54 (1H, d, J 9.0 Hz), 6.58 (1H, dd, J 9.0, 2.5 Hz), 6.77 (1H, d, J 2.5 Hz), 7.39 (1H, d, J 7.0 Hz), 7.62 (1H, d, J 8.0 Hz), 7.74 (1H, m), 7.77 (2H, d, J 8.5 Hz), 8.14 (2H, dd, J 8.5 Hz). To a solution of ethyl ({2-methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}hexyl)oxy]phenyl}oxy)acetate (80 mg, 0.16 mmol) in MeOH (2 mL) and THF (2 mL) at rt was added aqueous NaOH (2M, 1 mL, 2.0 mmol) and the resulting mixture stirred for 2.5 hours. The solvents were then removed under vacuum and the residue partitioned between DCM (20 mL) and aqueous HCI (2M, 20 mL), the layers separated and the aqueous re-extracted with DCM (20 mL). The combined organic solution was passed through a hydrophobic frit and then reduced affording the title compound as colourless oil (57 mg). LC/MS: m/z 488.3 [M+H]+, Rt 4.54 min. 1H NMR (400 MHz; CDCI3) d: 0.88 (3H, t, J 7.0 Hz), 1.27-1.40 (4H, m), 1.41-1.64 (2H, m), 1.99 (2H, m), 2.20 (3H, s), 4.55 (2H, s), 5.25 (1H, dd, J 6.5,6.5 Hz), 6.56 (1H, d, J 9.0 Hz), 6.60 (1H, dd, J 9.0 Hz, 3.0 Hz), 6.78 (1H, d, J 3 Hz), 7.38 (1H, d, J 7.5 Hz), 7.62 (1H, d, J 7.5 Hz), 7.74 (1H, t, J 7.5 Hz), 7.74 (2H, d, J 8.0 Hz), 8.13 (2H, d, J 8.0 Hz). Prepared from ethyl ({2-methyl-4-[(4-methyl-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}oxy)acetate (15 mg, 0.03 rnmol) according to the procedure used for the preparation of Example 35 to give the title compound as a colourless oil (10 mg). LC/MS: m/z 488.1 [M+H]+, Rt 4.49 min. nH NMR (400 MHz; CDCI3) d: 0.89 (3H, d, J 6.5 Hz), 0.90 (3H, d, J 6.5 Hz), 1.31-1.42 (1H, m), 1.43-1.54 (1H, m), 1.55-1.56 (1H, m), 2.00 (2H, m), 2.20 (3H, s), 4.55 (2H, s), 5.26 (1H, m), 6.56 (1H,d, J 9.0 Hz), 6.61 (1H, dd, J 9.0, 3.0 Hz), 6.79 (1H, d, J 3.0 Hz), 7.40 (1H, d, J 7.5 Hz), 7.63 (1H, d, J 7.5 Hz), 7.75 (2H, d, J 8.5 Hz), 7.76 (1H,m), 8.13 (2H, d, J 8.5 Hz). Prepared from ethyl ({2-methyl-4-[(3-methyl-1-{6-[4-(trifluoromethyl)phenylJ-2- pyridinyl}butyl)oxy]phenyl}oxy)acetate (132 mg, 0.26 mmol) according to the procedure used for the preparation of Example 35 to give the title compound as a pale orange solid (124 mg). LC/MS: m/z 474.1 [M+H]+, Rt 4.25 min. 1H NMR (400 MHz; CDCI3) d:1.03 (6H, m), 1.71-2.05 (3H, m), 2.20 (3H. s), 4.55 (2H, s), 5.57 (1H, m), 6.57 (1H, d, J 9.0 Hz), 6.66 (1H, dd, J 8.5 Hz, 3.0 Hz), 6.81 (1H, d, J 3.0 Hz), 7.47 (1H, d, J 8.0 Hz), 7.66 (1H, d, J 8.0 Hz), 7.77 (2H, d, J 8.0 Hz), 7.83 (1H, t, J 8.0 Hz), 8.16 (2H, d, J 8.0 Hz). General procedure for Examples 38 - 40 A stirred solution of ethyl [(4-{[1-(3-bromophenyl)pentyl]oxy}-2-methylphenyl)oxy]acetate (50 mg, 0.11 mmol) in DME (0.5 mL) was treated with the appropriate aryl boronic acid (0.11 mmol) followed by Pd(PPh3)4 (13 mg, 0.01 mmol) and a solution of Na2CO3 (37 mg, 0.33 mmol) in water (0.25 mL). The reaction mixture was heated at 70°C for 18 hours under nitrogen, allowed to cool to rt and then reduced under vacuum (Genevac). The residue was loaded in the minimum volume of methanol onto a SPE (C18 cartridges) (pre-conditioned with 1 column volume of methanol and then 1 column volume of 5% MeCN in water) eluting with 5% MeCN in water, then MeCN followed by methanol to give the crude product. Further purification by mass directed auto-prep HPLC afforded the title compounds. LC/MS: m/z 422.1 [M+H]+, Rt 4.24 min. 1H NMR (400 MHz; CDCI3) d: 0.89 (3H, t, J 7.0 Hz), 1.29-1.42 (3H, m), 1.44-1.57 (1H, m), 1.75-1.87 (1H, m), 1.93-2.05 (1H, m), 2.09 (3H, s), 4.35 (2H, s), 4.99 (1H, dd, J 8.0, 5.0 Hz), 6.46 (1H, d, J 9.0 Hz), 6.53 (1H, d, 9.0, 3.0 Hz), 6.69 (1H, d, 3.0 Hz), 7.24-7.46 (6H, m), 7.51-7.58 (3H, m). LC/MS: m/z 466.1 [M+NH4]+, Rt 4.29 min. 1H NMR (400 MHz; CDCI3) d: 0.89 (3H, t, J 7.0 Hz), 1.35 (3H, m), 1.42 (3H, t, J 7.0 Hz), 1.46-1.58 (1H, m), 1.75-1.86 (1H, m), 1.92-2.03 (1H, m), 2.10 (3H, s), 4.05 (2H, q, J 7.0 Hz), 4.38 (2H, s), 4.98 (1H, dd, J 8.0, 5.5 Hz), 6.47 (1H, d, J 9.0 Hz), 6.54 (1H, dd, J 9.0, 2.5 Hz), 6.70 (1H, d, J 2.5 Hz), 6.93 (2H, d, J 9.0 Hz), 7.23 (1H, d, J 7.5 Hz), 7.32 (1H, t, J 7.5 Hz), 7.40 (1H, d, J 7.5 Hz), 7.47 (2H, d, J 9.0 Hz), 7.49 (1H, m). LC/MS: m/z 447.3 [M+NH4]+, Rt 4.20 min. H NMR (400 MHz; CDC!3) d: 0.90 (3H, t, 7.0 Hz), 1.36 (3H, m), 1.45-1.57 (1H, m), 1.81 (1H, m), 1.98 (1H, m), 2.11 (3H, s), 4.39 (2H, s), 5.02 (1H, dd, J 8.0, 5.0 Hz), 6.48 (1H, d, J 9.0 Hz), 6.52 (1H, dd, J 9.0,2.5 Hz), 6.70 (1H, d, J 2.5 Hz), 7.34-7.47 (3H, m), 7.53 (1H, s), 7.62 (2H, d, J 8.0 Hz), 7.68 (2H, d, J 8.0 Hz). General procedure for Examples 41-45 A stirred solution of ethyl [(4-{[1 -(6-bromo-2-pyridinyl)pentyl]oxy}-2-ethylphenyl)oxy]acetate (50 mg, 0.11 mmol) in DME (0.5 mL) was treated with the appropriate aryl boronic acid (0.11 mmol) followed by Pd(PPh3)4 (13 mg, 0.01 mmol) and a solution of Na2CO3 (37 mg, 0.33 mmol) in water (0.25 mL). The reaction mixture was heated at 70°C for 18 hours under nitrogen, allowed to cool to rt and then reduced under vacuum (Genevac). The residue was loaded in the minimum volume of methano! onto a SPE (C18 cartridges) (pre-conditioned with 1 column volume of methanol and then 1 column volume of 5% MeCN in water) eluting with 5% MeCN in water, then MeCN followed by methanol to give the crude product. Further purification by mass directed auto-prep HPLC afforded the title compounds. LC/MS: m/z 420.2 [M+H]+, Rt 4.33 min. 1H NMR (400 MHz; CDCI3) d: 0.90 (3H, t, J 7.5 Hz), 1.07 (3H, t, J 7.5 Hz), 1.32-1.62 (4H, m), 1.99 (2H, m), 2.51 (2H, q, J 7.5 Hz), 4.37 (2H, s), 5.21 (1H, m), 6.48 (1H, d, J 9.0 Hz), 6.55 (1H, d, J 9.0 Hz), 6.76 (1H, dd, J 9.0, 3.0 Hz), 7.28 (1H, d, J 7.5 Hz), 7.40 (1H, m), 7.46 (2H, m), 7.53 (1H, d, J 7.5 Hz), 7.62 (1H, t, J 7.5 Hz), 7.99 (2H, m). LC/MS: m/z 454.1 [M+H]+, Rt 4.55 min. 1H NMR (400 MHz; CDCI3) d: 0.90 (3H, t, J 7.5 Hz), 1.10 (3H, t, J 7.5 Hz), 1.32-1.61 (4H, m), 1.99 (2H, m), 2.55 (2H, q, J 7.5 Hz), 4.45 (2H, s), 5.20 (1H, dd, J 6.5, 6.5 Hz), 6.51 (1H, d, J 9.0 Hz), 6.56 (1H, dd, J 9.0, 3.0 Hz), 6.78 (1H, d, J 3.0 Hz), 7.30 (1H, d, J 7.5 Hz), 7.44 (2H, d, J 8.5 Hz), 7.52 (1H, d, J 7.5 Hz), 7.65 (1H, t, J 7.5 Hz), 7.95 (2H, d, J 8.5 Hz). LC/MS: m/z 464.2 [M+H]+, Rt 4.39 min. 1H NMR (400 MHz; CDCI3) d: 0.90 (3H, t, J 7.0 Hz), 1.08 (3H, t, J 7.5 Hz), 1.44 (3H, t, J 7.0 Hz), 1.32-1.61 (4H, m), 1.98 (2H, m), 2.53 (2H, q, J 7.5 Hz), 4.09 (2H, q, J 7.0 Hz), 4.41 (2H, s), 5.19 (1H, dd, J 7.5, 5.0 Hz), 6.49 (1H, d, J 9.0 Hz), 6.56 (1H, dd, J 9.0, 3.0 Hz), 6.77 (1H, d, J 3.0 Hz), 6.98 (2H, d, J 9.0 Hz), 7.22 (1H, d J 7.5 Hz), 7.47 (1H, d, J 7.5 Hz), 7.59 (1H, t, J 7.5 Hz), 7.94 (2H, d, J 9.0 Hz). LC/MS: m/z 445.0 [M+H]+, Rt 4.09 min. 1H NMR (400 MHz; CDCI3) d: 0.90 (3H, t, J 7.0 Hz), 1.09 (3H, t, J 7.5 Hz), 1.32-1.62 (4H, m), 1.99 (2H, m), 2.54 (2H, q, J 7.5 Hz), 4.43 (2H, s), 5.21 (1H, dd, J 6.0 Hz), 6.50 (1H, d, J 9.0 Hz), 6.54 (1H, dd, J 9.0,2.5 Hz), 6.77 (1H, d, J 2.5 Hz), 7.38 (1H, d, J 8.0 Hz), 7.60 (1H, d, J 8.0 Hz), 7.71 (1H, t, J 8.0 Hz), 7.70 (2H, d, J 8.5 Hz), 8.13 (2H, d, J 8.5 Hz). LC/MS: m/z 488.1 [M+H]+, Rt 4.51 min. 1H NMR (400 MHz; GDCI3) d: 0.91 (3H, t, J 7.0 Hz), 1.13 (3H, t, J 7.5 Hz), 1.32-1.63 (4H, m), 2.00 (2H, m), 2.59 (2H, q, J 7.5 Hz), 4.52 (2H, s), 5.23 (1H, dd, J 6.5, 6.5 Hz), 6.54 (1H, d, J 9.0 Hz), 6.58 (1H, dd, J 9.0, 3.0 Hz), 6.80 (1H, d, J 3.0 Hz), 7.37 (1H, d, J 8.0 Hz), 7.61 (1H, d, J 8.0 Hz), 7.72 (1H, t, J 8.0 Hz), 7.73 (2H, d, J 8.0 Hz), 8.13 (2H, d, J 8.0 Hz). To a stirred solution of 2-(trimethylsilyl)ethyl 4-{4-[(1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}butanoate (42 mg, 0.07 mmol) in THF at rt was added, drop-wise, TBAF (70 u.L of a 1.0M solution in THF, 0.07 mmol) and the mixture stirred at rt for 1.5 hours. Additional TBAF (35 pL of a 1.0M solution in THF, 0.04 mmol) was then added and the mixture left to stir at rt for17.5 hours. The mixture was then concentrated under vacuum and the residue purified by SPE (silica, 1 g Cartridge) eluting with cyclohexane: EtOAc (gradient 25:1 to 0:1), then EtOAc: MeOH (gradient 10:1 to 0:1) to give a crude product which was purified further by mass directed auto-prep HPLC to give the title compound (6.4 mg). LC/MS: m/z 472.15 [M+H]+, Rt 4.21 min. 1H NMR (400MHz; MeOD-d4) d: 0.92 (3H, t, 7.0 Hz), 1.34-1.61 (4H, m), 1.80 (2H, m), 2.00 (2H, m), 2.22 (2H, t, 7.5 Hz), 2.51 (2H, t, 7.5 Hz), 5.29 (1H, dd, 7.0, 6.0 Hz), 6.79 (2H, d, 9.0 Hz), 7.00 (2H, d, 9.0 Hz), 7.40 (1H, dd, J 7.0,1.5 Hz), 7.75-7.85 (4H, m), 8.23 (2H, d, J 8.5 Hz). General procedures for Examples 47-50 Ethyl [(4-{[(1R)-1-(6-bromo-2-pyridinyl)pentyl]oxy}-2-methylphenyI)oxy]acetate (50 mg, 0.11 mmol) was dissolved in DME (0.50 mL) and then treated with the appropriate boronic acid (0.15 mmol) followed by Pd(PPh3)4 (13 mg, 0.01 mmol) and then a solution of Na2CO3 (36.5 mg, 0.34 mmol) in water (0.25 mL). The resulting mixture was then placed under nitrogen and heated at 70°C for 18 h. The solvents were the removed under vacuum (Genevac) and the residue purified using the OPTIX-SPE (C18 cartridge, 5g) eluting with 10-95% MeCN (+0.05% HCOOH) in H2O (+0.01% HCOOH) over 15 mins to afford the desired product which, if appropriate, were further purified by mass directed autoprep HPLC. LC/MS and 1H NMR as described for Example 25. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 15% IPA in heptane with 0.1%TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 6.6 min (>99 %ee). LC/MS and 1H NMR as described for Example 34. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 15% IPA in heptane with 0.1%TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 9-8 min (98.9 %ee). Example 49 ({2-Methyl-4-[((1fl)-1-{6-[4-(methyloxy)phenyl]-2- pyridjnyl}pentyl)oxy]phenyl}oxy)acetic acid LC/MS and 1H NMR as described for Example 26. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 15% IPA in heptane with 0.1 %TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 7.5 min (98.5 %ee). s LC/MS and 1H NMR as described for Example 32. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 15% IPA in heptane with 0.1%TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 9.5 min (99.3 %ee). Ethyl [(4-{[(1R)-1-(6-bromo-2-pyridinyl)pentyl]oxy}-2-m9thylphenyl)oxy]acetate (50 mg, 0.11 mmol) was dissolved in DME (0.76 ml_) and then treated with 1 -[2-(methyloxy)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone (41 mg, 0.15 mmol) followed by Pd(PPh3)4 (13 mg, 0.01 mmol) and then a solution of Na2CO3 (49 mg, 0.46 mmol) in water (0.42 mL). The resulting mixture was then placed under nitrogen and heated at 80°C for 18 h. The solvents were the removed under vacuum (Genevac) and the residue purified by mass directed autoprep HPLC) to give the title compound as an oil (39 mg,). LC/MS: m/z 478.1 [M+H]+, Rt 4.04 min. 1H NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.5 Hz), 1.33-1.44 (2H, m), 1.44-1.61 (2H, m), 1.95-2.05 (2H, m), 2.19 (3H, s), 2.66 (3H, s), 4.03 (3H, s), 4.53 (2H, s), 5.22 (1H, dd, J 6.5, 6.5 Hz), 6.55 (1H, d, J 9.0 Hz), 6.58 (1H, dd, J 9.0, 2.5 Hz), 6.78 (1H, d, J 2.5 Hz), 7.36 (1H, d, J 7.5 Hz), 7.55 (1H, dd J 8.0,1.5 Hz), 7.61 (1H, d, J 7.5 Hz), 7.71 (1H, t, J 7.5 Hz), 7.71 (1H, d, J 1.5 Hz),7.85(1H,d, J 8.0 Hz). General procedures for Examples 52-55 The following compounds were prepared as described for Examples 47-50 except starting from ethyl [(4-{[(1 S)-1-(6-bromo-2-pyridinyl)pentyl]oxy}-2-methylphenyl)oxy]acetate. LC/MS and 1H NMR as described for Example 25. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 15% IPA in heptane with 0.1%TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 8.0 min (92.9 %ee). Example 53 {[4-({(1S)-1-[6-(4-Cyanophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}acetic acid LC/MS and 'H NMR as described for Example 34. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 15% IPA in heptane with 0.1%TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 12.4 min (95.9 %ee). LC/MS and 1H NMR as described for Example 26. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 15% IPA in heptane with 0.1 %TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 8.6 min (95.1 %ee). LC/MS and 1H NMR as described for Example 32. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 15% IPA in heptane with 0.1 %TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 11.9 min (96.6 %ee). Example 56 ({4-[((1S)-1-{6-[4-Acetyl-3-(methyloxy)phenyl]-2-pyridinyl}pentyl)oxy]-2- methylphenyl}oxy)acetic acid Prepared according to the procedure used to prepare Example 51 starting from ethyl [(4- {[(1S)-1-(6-bromo-2-pyridinyl)pentyl]oxy}-2-methylphenyl)oxy]acetate (50 mg, 0.11 mmol) to give the title compound (27 mg). LC/MS and 1H NMR as described for Example 51. General procedure for Examples 57-58 A stirred solution of bromide ethyl [(4-{[(1 R)-1 -(6-bromo~2-pyridinyl)-3- (methyloxy)propyl]oxy}-2-rnethylphenyl)oxy]acetate (50 mg, 0.11 mmol) in DME (0.75 m!_) was treated with the appropriate aryl boronic acid (0.15 mmol) followed by Pd(PPh3)4 (13 mg, 0.01 mmol) and a solution of NaaCO3 (48 mg, 0.46 mmol) in water (0.42 mL). The reaction mixture was heated at 80°C for 17 h under nitrogen, allowed to cool to rt and then reduced under vacuum (Genevac). The residue was then purified using the OPTIX-SPE (C18 cartridge, 5g) eluting with 20 - 75% (or 20 - 60%) MeCN (+0.05% HCOOH) in H2O (+0.01% HCOOH) over 20 mins afforded the desired target molecules which, if appropriate, were purified further by mass directed autoprep HPLC. LC/MS: m/z 476.2 [M+H]+, Rt 3.83 min. 1H NMR (400 MHz; CDCI3) d: 2.19 (3H, s), 2.17-2.28 (1H, m), 2.28-2.40 (1H, m), 3.35 (3H, s), 3.58 (1H, m), 3.68 (1H, m), 4.51 (2H, br.s), 5.39 (1H, dd, J 9.0,4.0 Hz), 6.54 (1H, d, J 9.0 Hz), 6.60 (1H, dd, J 9.0, 3.0 Hz), 6.78 (1H, d, J 3.0 Hz), 7.37 (1H, d, J 7.5 Hz), 7.62 (1H, d, J 7.5 Hz), 7.72 (2H, d, J 8.0 Hz), 7.72 (1H, t, J 7.5 Hz), 8.14 (2H, d, J 8.0 Hz). LC/MS: m/z 442.2 [M+H]+, Rt 3.84 min. 1H NMR (400 MHz; CDCI3) d:2.18 (3H, s), 2.14-2.26 (1H, m), 2.27-2.39 (1H, m), 3.35 (3H, s), 3.57 (1H, m), 3.67 (1H, m), 4.51 (2H, br.s), 5.36 (1H, dd, J 9.0, 4.0 Hz), 6.53 (1H, d, J 9.0 Hz), 6.59 (1H, dd, J 9.0,2.5 Hz), 6.78 (1H, d, J 2.5 Hz), 7.32 (1H, d, J 8.0 Hz), 7.43 (2H, d, J 8.5 Hz), 7.55 (1H, d, J 8.0 Hz), 7.68 (1H, t, J 8.0 Hz), 7.96 (2H, d, J 8.5 Hz). General procedure for Examples 59-60 The following compounds were prepared as described for Examples 57-58 except starting from ethyl [(4-{[(1S)-1 -(6-bromo-2-pyridinyl)-3-(methyloxy)propyl]oxy}-2-methylphenyl)oxy]acetate. General procedure for Examples 61-65 A stirred solution of ethyl [(4-{[(1R)-1-(6-bromo-2-pyridinyl)-3-(methyloxy)propyl]oxy}-2- methylphenyl)oxy]acetate (50 mg, 0.11 mmol) in DME (0.50 mL) was treated with the appropriate aryl boronic acid (0.15 mmol) followed by Pd(PPh3)4 (13 mg, 0.01 mmol) and a solution of Na2CO3 (37 mg, 0.35 mmol) in water (0.25 mL). The reaction mixture was heated at 70°C for 16 h under nitrogen and then allowed to cool to rt and stirred at rt for 7 h. LC/MS analysis indicated a mixture of the desired acid and the ethyl ester, so MeOH (1 mL), THF (1 mL) and aqueous sodium hydroxide (2M, 1 mL) were added and the mixture stirred at rt for 18 h. The reaction was then quenched by the addition of aqueous HCI (2N, 2 mL) and the solvents then removed under vacuum (Genevac). The residue was then dissolved in MeCN:H2O (1:2,1.8 mL) and loaded onto an SPE (C18 cartridge, 5 g) which had been pre-conditioned with 2 column volumes of MeOH and then equilibrated with 20% MeCN (+0.05%HCOOH) in H2O (+0.01%HCOOH). Elution with 20 - 75% (or 20 - 60%) MeCN (+0.05%HCOOH) in H2O (+0.01%HC0OH) over 20 mins afforded the desired target molecules which, if appropriate, were purified further by mass directed autoprep HPLC. LC/MS: m/z 476.1 [M+H]+, Rt 4.01 min. 1H NMR (400 MHz; CDCI3) d: 1.20 (3H, t, J 7.0 Hz), 2.20 (3H, s), 3.62 (2H, m), 3.91 (1H, dd, J 11.0, 7.0 Hz), 3.98 (1H, dd, J 11.0, 3.0 Hz), 4.53 (2H, s), 5.45 (1H, dd, J 7.0, 3.0 Hz), 6.55 (1H, d, J 9.0 Hz), 6.64 (1H, dd, J 9.0,3.0 Hz), 6.83 (1H, d, J 3.0 Hz), 7.42 (1H, d, J 8.0 Hz), 7.65 (1H, d, J 8.0 Hz), 7.73 (2H, d, J 8.0 Hz), 7.74 (1H, t, J 8.0 Hz), 8.14 (2H, d, J 8.0 Hz). Analytical chiral HPLC (25 cm Chiralcel OJ) eluting with 20% EtOH in heptane with 0.1%TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 9.5 min (>99.9 %ee). Example 62 ({4-[((1R)-2-(Ethyloxy)-1-{6-[4-(methyloxy)phenyll-2-pyridinyl}ethyl)oxy]-2- methylphenyl}oxy)acetlc acid LC/MS: m/z 438.2 [M+H]+, Rt 3.70 min. 1H NMR (400 MHz; CDCI3) d: 1.19 (3H, t, J 7.0 Hz), 2.19 (3H, s), 3.62 (2H, m), 3.89 (1H, dd, J 11.0, 7.5 Hz), 3.97 (1H, dd, J 11.0, 3.0 Hz), 4.51 (2H, s), 5.43 (1H, dd, J 7.5, 3.0 Hz), 6.54 (1H, d, J 9.0 Hz), 6.63 (1H, dd, J 9.0, 3.0 Hz), 6.82 (1H, d, J 3.0 Hz), 7.00 (2H, d, J 9.0 Hz), 7.29 (1H, d, J 8.0 Hz), 7.54 (1H, d, J 8.0 Hz), 7.65 (1H, t, J 8.0 Hz), 7.97 (2H, d, J 9.0 Hz). Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 10% EtOH in heptane with 0.1%TFA, f = 1.0 mlVmin, wavelength 215 nm, Rt 13.9 min (>99.9 %ee). LC/MS: m/z 450.1 [M+H]+, Rt 3.45 min. 1H NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 2.19 (3H, s), 2,66 (3H, s), 3.62 (2H, m), 3.91 (1H, dd, J 11.0, 7.0 Hz), 3.99 (1H, dd, J 11.0, 3.0 Hz), 4.52 (2H, s), 5.45 (1H, dd, J 7.0, 3.0 Hz), 6.55 (1H, d, J 9.0 Hz), 6.64 (1H, dd, J 9.0, 3.0 Hz), 6.83 (1H, d, J 3.0 Hz), 7.41 (1H, d, J 7.5 Hz), 7.67 (1H, dd, J 7.5,1.0 Hz), 7.73 (1H, t, J 7.5 Hz), 8.07 (2H, d, J 8.5 Hz), 8.13 (2H, d, J 8.5 Hz 1H NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 2.19 (3H, s), 3.62 (2H, m), 3.90 (1H, dd, J 11.0, 7.0 Hz), 3.97 (1H, dd, J 11.0, 3.0 Hz), 4.51 (2H, s), 5.43 (1H, dd, J 7.0, 3.0 Hz), 6.55 (1H, d, J 9.0 Hz), 6.63 (1H, dd, J 9.0, 3.0 Hz), 6.82 (1H, d, J 3.0 Hz), 7.44 (1H, d, J 7.5 Hz), 7.65 (1H, d, J 7.5 Hz), 7.75 (1H, t, J 7.5 Hz), 7.77 (2H, d, J 8.5 Hz), 8.15 (2H, d, J 8.5 Hz). LC/MS: m/z 442.1 [M+H]+, Rt 3.95 min. 1H NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 2.19 (3H, s), 3.62 (2H, m), 3.90 (1H, dd, J 11.0, 7.0 Hz), 3.97 (1H, dd, J 11.0, 3.0 Hz), 4.52 (2H, s), 5.43 (1H, dd, J 7.0,3.0 Hz), 6.54 (1H, d, J 9.0 Hz), 6.63 (1H, dd, J 9.0, 3.0 Hz), 6.82 (1H, d, J 3.0 Hz), 7.37 (1H, d, J 7.5 Hz), 7.44 (2H, d, J 8.5 Hz), 7.57 (1H, d, J 7.5 Hz), 7.69 (1H, t, J 7.5 Hz), 7.96 (2H, d, J 8.5 Hz). General procedure for Examples 66-70 The following compounds were prepared as described for Examples 61-65 except starting from ethyl [(4-{[(1S)-1 -(6-bromo-2-pyridinyl)-3-(methyioxy)propyl]oxy}-2-methylphenyl)oxy]acetate. LC/MS and 1H NMR as described for Example 61. Analytical chiral HPLC (25 cm Chiralcel OJ) eluting with 20% EtOH in heptane with 0.1%TFA, f = 1.0 mL/min, wavelength 215 nm, R, 13.5 min (>99.9 %ee). LC/MS and 1H NMR as described for Example 62. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 10% EtOH in heptane with 0.1%TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 16.2 min (>99.9 %ee). LC/MS and 1H NMR as described for Example 63. r LC/MS and 1H NMR as described for Example 64. Example 70 [(4-{[(1S)-1-[6-(4-Chlorophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2- methylphenyl)oxy]acetic acid Ethyl [(4-{[(1S)-1 -[6-(4-cyanophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2- methylphenyl)oxy]acetate (0.886 g) was dissolved in THF (8.8 mL). Water (8.8 mL) and aq 2M NaOH (1.8 mL) were added and the mixture stirred at ambient temperature for 30 mins. The reaction mixture was acidified to pH 1 by the addition of aq 2M HCI and extracted with EtOAc (2 x 10 mL). The organic extracts were washed with brine (20 mL), dried (Na2SO4) and evaporated to give the title compound as a white foam (729 mg). LC/MS: m/z 433.2 [M+H]+, Rt 3.57 min. 1H NMR (400 MHz; CDCI3) d:1.20 (3H, t, J 7.0 Hz), 2.21 (3H, s), 3.63 (2H, m), 3.92 (1H, dd, J 11.0, 7.0 Hz), 3.99 (1H, dd, J 11.0, 3.0 Hz), 4.56 (2H, s), 5.45 (1H, dd, J 7.0, 3.0 Hz), 6.57 (1H, d, J 9.0 Hz), 6.65 (1H, dd, J 9.0,3.0 Hz), 6.84 (1H, d, J 3.0 Hz), 7.45 (1H, d, J 7.5 Hz), 7.67 (1H, d, J 7.5 Hz), 7.77 (1H, t, J 7.5 Hz), 7.78 (2H, d, J 8.5 Hz), 8.17 (2H, d, J 8.5 Hz). General procedure for Examples 71-84 A mixture of the boronic acid (or ester) (0.09 mmol) and Pd(PPh3)4 (7.5 mg, 0.006 mmol) in an 8 ml test tube within a greenhouse was purged with nitrogen and then treated with a solution of ethyl [(4-{[(1 ff)-1-(6-bromo-2-pyridinyl)-2-(ethyloxy)ethyl]oxy}-2-methylphenyl)oxy]acetate (30 mg, 0.068 mmol) in DME (1.5 mL) and then with aqueous Na2CO3 (1M, 1.0 mL). The resulting mixture was heated to 60°C with vigorous stirring for 2 h then at 80°C for a further 3 h. The mixture was then allowed to cool to ambient temperature then the solvent evaporated in a Genevac. The residue was treated cautiously with aqueous HCI (2M, 1.5 mL) and then the product extracted into DCM (2 x 3 mL). The combined organic solution was evaporated and the product purified either by mass directed autoprep HPLC or using the Optix (C18 SPE). LC/MS: m/z 440.3 [M+H]+, Rt 3.86 min. 1H NMR (400 MHz; CDCI3) d: 1.19 (3H, t, J 7.0 Hz), 2.19 (3H, s), 2.33 (3H, s), 3.62 (2H, m), 3.90 (1H, dd, J 11.0, 7.5 Hz), 3.98 (1H, dd, J 11.0, 3.0 Hz), 4.52 (2H, s), 5.43 (1H, dd, J 7.0, 3.0 Hz), 6.54 (1H, d, J 9.0 Hz), 6.63 (1H, dd, J 9.0, 3.0 Hz), 6.82 (1H, d, J 3.0 Hz), 7.27 (1H, dd, J 8.0, 8.0 Hz), 7.35 (1H, d, J 7.5 Hz), 7.56 (1H, d, J 7.5 Hz), 7.68 (1H, t, J 7.5 Hz), 7.67 (1H, dd, J 8.0, 1.5 Hz), 7.71 (1H, dd, J 11.0,1.5 Hz). LC/MS: m/z 422.4 [M+H]+, Rt 3.75 min. ^ NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 2.17 (3H, s), 2.41 (3H, s), 3.61 (2H, m), 3.90 (1H, dd, J 11.0, 7.5 Hz), 3.97 (1H, dd, J 11.0, 3.0 Hz), 4.47 (2H, s), 5.44 (1H, dd, J 7.0, 3.0 Hz). 6.52 (1H, d, J 9.0 Hz), 6.62 (1H, dd, J 9.0, 3.0 Hz), 6.81 (1H, d, J 3.0 Hz), 7.28 (2H, d, J 8.0 Hz), 7.32 (1H, d, J 7.5 Hz), 7.56 (1H, d, J 7.5 Hz), 7.65 (1H, t, J 7.5 Hz), 7.90 (2H, d, J 8.0 Hz). LC/MS: m/z 450.4 [M+H]+, Rt 4.04 min. 1H NMR (400 MHz; CDCI3) 8:1.19 (3H, t, J 7.0 Hz), 1.29 (6H, d, J 7.0 Hz), 2.18 (3H, s), 2.97 (1H, sept, J 7.0 Hz), 3.62 (2H, m), 3.90 (1H, del, J 11.0, 7.5 Hz), 3.98 (1H, dd, J 11.0,3.0 Hz), 4.50 (2H, s), 5.45 (1H, dd, J 7.5, 3.0 Hz), 6.53 (1H, d, J 9.0 Hz), 6.63 (1H, dd, J 9.0, 3.0 Hz), 6.81 (1H, d, J 3.0 Hz), 7.33 (3H,m), 7.57 (1H, d, J 7.5 Hz), 7.66 (1H, t, J 7.5 Hz), 7.93 (2H, d, J 8.5 Hz). LC/MS: m/z 451.3 [M+H]+, Rt 3.63 min. 1H NMR (400 MHz; CDCI3) d: 1.19 (3H, t, J 7.0 Hz), 2.18 (3H, s), 3.62 (2H, m), 3.91 (1H, dd, J 11.0, 7.0 Hz), 3.97 (1H, dd, J 11.0, 3.5 Hz), 4.50 (2H, s), 5.43 (1H, dd, J 7.0, 3.5 Hz), 6.53 (1H, d, J 9.0 Hz), 6.61 (1H, dd, J 9.0, 3.0 Hz), 6.80 (1H, d, J 3.0 Hz), 7.47 (1H, d, J 7.5 Hz), 7.65 (1H, d, J 7.5 Hz), 7.71 (1H, dd, J 8.0, 7.0 Hz), 7.76 (1H, t, J 7.5 Hz), 7.91 (1H, dd, J 8.0,1.5 Hz), 7.96 (1H,dd,J 10.5, 1.5 Hz). 1H NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 1.45 (3H, t, J 7.0 Hz), 2.18 (3H, s), 3.62 (2H, m), 3.89 (1H, dd, J 11.0, 7.5 Hz), 3.97 (1H, dd, J 11.0, 3.0 Hz), 4.09 (2H, q, J7.0 Hz), 4.49 (2H, s), 5.43 (1H, dd, J 7.0, 3.0 Hz), 6.53 (1H, d, J 9.0 Hz), 6.62 (1H, dd, J 9.0, 3.0 Hz), 6.81 (1H, d, J 3.0 Hz), 6.99 (2H, d, J 9.0 Hz), 7.29 (1H, d, J 7.5 Hz), 7.52 (1H, d, J 7.5 Hz), 7.64 (1H, t, J 7.5 Hz), 7.94 (2H, d, J 9.0 Hz). LC/MS: m/z 440.3 [M+H]+, Rt 3.80 min. 1H NMR (400 MHz; CDCI3) d: 1.19 (3H, t, J 7.0 Hz), 2.20 (3H, s), 2.40 (3H, s), 3.61 (2H, m), 3.89 (1H, dd, J 11.0, 7.0 Hz), 3.96 (1H, dd, J 11.0, 3.5 Hz), 4.53 (2H, s), 5.44 (1H, dd, J 7.0, 3.0 Hz), 6.56 (1H, d, J 9.0 Hz), 6.64 (1H, dd, J 9.0, 3.0 Hz), 6.83 (1H, d, J 3.0 Hz), 6.98 (1H, d, J 13.0 Hz), 7.08 (1H, d, J 8.0 Hz), 7.35 (1H, dd, J 7.0,1.5 Hz), 7.62 -7.71 (2H, m), 7.90 (1H, t, J 8.0 Hz). LC/MS: m/z 426.3 [M+H]+, Rt 3.67 min. 1H NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 2.18 (3H, s), 3.62 (2H, m), 3.90 (1H, dd, J 11.0, 7.0 Hz), 3.97 (1H, dd, J 11.0, 3.0 Hz), 4.49 (2H, s), 5.43 (1H, dd, J 7.0, 3.0 Hz), 6.52 (1H, d, J 9.0 Hz), 6.62 (1H, dd, J 9.0, 3.0 Hz), 6.81 (1H, d, J 3.0 Hz), 7.16 (2H, dd, J 8.5, 8.5 Hz), 7.35 (1H, d, J 8.0 Hz), 7.55 (1H, d, J 8.0 Hz), 7.68 (1H, t, J 8.0 Hz) 7.99 (2H, dd, J 8.5, 6.0 Hz). Example 78 [(4-{[(1R)-2-(Ethyloxy)-1-(6-{4-[(1-methylethyl)oxy]phenyl}-2-pyridinyl)ethyl]oxy}-2- methylphenyl)oxy]acetic acid LC/MS: m/z 466.4 [M+H]+, Rt, 3.86 min. 1H NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 1.37 (6H, d, J 6.0 Hz), 2.18 (3H, s), 3.61 (2H, m), 3.89 (1H, dd, J 11.0,7.5 Hz), 3.97 (1H, dd, J 11.0, 3.0 Hz), 4.49 (2H, s), 4.63 (1H, sept, J 6.0 Hz), 5.43 (1H, dd, J 7.0, 3.0 Hz), 6.53 (1H, d, J 9.0 Hz), 6.62 (1H, dd, J 9.0, 3.0 Hz), 6.81 (1H, d, J 3.0 Hz), 6.98 (2H, d, J 9.0 Hz), 7.28 (1H, d, J 8.0 Hz), 7.52 (1H, d, J 8.0 Hz), 7.64 (1H, t, J 8.0 Hz), 7.94 (2H, d, J 9.0 Hz). LC/MS: m/z 456.3 [M+H]+, Rt 4.06 min. 1H NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 2.19 (3H, s), 2.46 (3H, s), 3.62 (2H, m), 3.89 (1H, dd, J 11.0, 7.5 Hz), 3.97 (1H, dd, J 11.0,3.5 Hz), 4.51 (2H, s), 5.43 (1H, dd, J 7.5, 3.0 Hz), 6.54 (1H, d, J 9.0 Hz), 6.62 (1H, dd, J 9.0, 3.0 Hz), 6.82 (1H, d, J 3.0 Hz), 7.35 (1H, d, J 7.5 Hz), 7.43 (1H, d, J 8.5 Hz), 7.56 (1H, d, J 7.5 Hz), 7.68 (1H, t, J 7.5 Hz), 7.75 (1H, dd, J 8.5, 2.0 Hz),7.89(1H,d, J 2.0 Hz). 1H NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 2.18 (3H, s), 3.62 (2H, m), 3.90 (1H, dd, J 11.0, 7.0 Hz), 3.97 (1H, dd, J 11.0, 3.5 Hz), 4.51 (2H, s), 5.43 (1H, dd, J 7.0, 3.5 Hz), 6.53 (1H, d, J 9.0 Hz), 6.61 (1H, dd, J 9.0,3.0 Hz), 6.81 (1H, d, J 3.0 Hz), 7.47 (1H, d, J 7.5 Hz), 7.65 (1H, d, J 7.5 Hz), 7.76 (1H, t, J 7.5 Hz), 7.76 (1H, d, J 8.0 Hz), 8.01 (1H, dd, J 8.0,1.5 Hz), 8.23 (1H,d,J1.5Hz). LC/MS: m/z 447.3 [M+H]+, Rt 3.65 mln. 1H NMR (400 MHz; CDCI3) 5:1.19 (3H, t, J 7.0 Hz), 2.18 (3H, s), 2.64 (3H, s), 3.62 (2H, m), 3.90 (1H, dd, J 11.0, 7.0 Hz), 3.97 (1H, dd, J 11.0, 3.5 Hz), 4.50 (2H, s), 5.44 (1H, dd, J 7.0, 3.5 Hz), 6.54 (1H, d, J 9.0 Hz), 6.62 (1H, dd, J 9.0, 3.0 Hz), 6.81 (1H, d, J 3.0 Hz), 7.43 (1H, d, J 7.5 Hz), 7.63 (1H, d, J 7.5 Hz), 7.70 (1H, d, J 8.0 Hz), 7.73 (1H, t, J 7.5 Hz), 7.89 (1H, dd, J 8.0,1.0 Hz), 7.99(1H,d,J1.0Hz). LC/MS: m/z 456.3 [M+H]+, Rt 3.63 min. 1H NMR (400 MHz; CDCI3) d:1.20 (3H, t, J 7.0 Hz), 2.19 (3H, s), 3.62 (2H, m), 3.90 (1H, dd, J 11.0, 7.0 Hz), 3.95 (3H, s), 3.94-3.99 (1H, m), 4.52 (2H, s), 5.42 (1H, dd, J 7.5, 3.0 Hz), 6.54 (1H, d, J 9.0 Hz), 6.63 (1H, dd, J 9.0,3.0 Hz), 6.82 (1H, d, J 3.0 Hz), 7.04 (1H, dd, J 8.5, 8.5 Hz), 7.32 (1H, d, J 7.5 Hz), 7.53 (1H, d, J 7.5 Hz), 7.66 (1H, t, J 7.5 Hz), 7.74 (1H, bd, J 8.5 Hz) 7.82 (1H, dd,J13.0, 2.0 Hz). Example 83 LC/MS: m/z 451.3 [M+H]+, Rt 3.56 min. 1H NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 2.19 (3H, s), 3.61 (2H, m), 3.90 (1H, dd, J 11.0, 7.0 Hz), 3.96 (1H, dd, J 11.0, 3.5 Hz), 4.52 (2H, s), 5.43 (1H, dd, J 7.0, 3.5 Hz), 6.55 (1H, d, J 9.0 Hz), 6.62 (1H, dd, J 9.0, 3.0 Hz), 6.81 (1H, d, J 3.0 Hz), 7.44-7.51 (2H, m), 7.58 (1H, dd, J 8.0,1.5 Hz), 7.71-7.79 (2H, m), 8.21 (1H, t, J 8.0 Hz). LC/MS: m/z 447.3 [M+H]+, Rt 3.49 min. 1H NMR (400 MHz; CDCI3) d: 1.17 (3H, t, J 7.0 Hz), 2.18 (3H, s), 2.38 (3H, s), 3.59 (2H, m), 3.90 (2H, m), 4.52 (2H, s), 5.44 (1H, dd, J 5.0, 5.0 Hz), 6.55 (1H, d, J 9.0 Hz), 6.62 (1H, dd, J 9.0, 3.0 Hz), 6.79 (1H, d, J 3.0 Hz), 7.29 (1H, d, J 7.5 Hz), 7.47 (1H, d, J 7.5 Hz), 7.48 (1H, d, J 8.5 Hz), 7.54-7.62 (2H,m), 7.76 (1H, t, J 7.5 Hz). General procedure for Examples 85-98 The following compounds were prepared as described for Examples71-84 except starting from ethyl [(4-{[(1 S)-1-(6-bromo-2-pyridinyl)-2-(ethyloxy)ethyl]oxy}-2-methylphenyl)oxy]acetate bromide. Example 85 {[4-({(1S)-2-(Ethyloxy)-1-[6-(3-fluoro-4-methylphenyI)-2-pyridinyl]ethyl}oxy)-2- methylphenyl]oxy}acetic acid General procedure for Examples 99-103 A stirred solution of ethyl 3-(4-{[(1S)-1-(6-bromo-2-pyridinyl)pentyl]oxy}-2- methylphenyl)propanoate (76 mg, 0.17 mmol) in DME (1.2 mL) was treated with the appropriate aryl boronic acid (0.23 mmol) followed by and a solution of Na2CO3 (74 mg, 0.70 mmol) in water (0.7 mL). The reaction mixture was heated at 73°C for 21 h under nitrogen, allowed to cool to rt and then reduced under vacuum (Genevac). The residue was then treated with THF (2 mL), MeOH (2 mL) followed by aqueous NaOH (2N, 2 mL) and the resulting mixture stirred at ambient temperature for 4 h. The solvents were then removed under vacuum and the residue purified using the OPTIX-SPE (C18 cartridge, 5g) eluting with 25-100% MeCN (+0.05% HCOOH) in H2O (+0.01% HCOOH) over 18 mins to afford the desired product which, if appropriate, were further purified by mass directed autoprep HPLC. LC/MS: m/z 472.2 [M+H]+, Rt 4.26 min. nH NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.34-1.45 (2H, m), 1.45-1.64 (2H, m), 1.96-2.08 (2H, m), 2.23 (3H, s), 2.55 (2H, m), 2.83 (2H, m), 5.28 (1H, dd, J 7.5, 5.5 Hz), 6.64 (1H, dd, J 8.5, 2.5 Hz), 6.77 (1H, d, J 2.5 Hz), 6.95 (1H, d, J 8.5 Hz), 7.38 (1H, d, J 7.5 Hz), 7.62 (1H, d, J 7.5 Hz), 7.72 (1H, t, J 7.5 Hz), 7.75 (2H, d, J 8.5 Hz), 8.14 (2H, d, J 8.5 Hz). Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 20% IPA in heptane with 0.1 %TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 7.5 min (94 %ee). LC/MS: m/z 434.3 [M+H]+, Rt 4.05 min. 1H NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.33-1.44 (2H, m), 1.44-1.64 (2H, m), 1.94-2.09 (2H, m), 2.22 (3H, s), 2.54 (2H, m), 2.82 (2H, m), 3.88 (3H, s), 5.25 (1H, dd, J 8.0, 4.5 Hz), 6.65 (1H, dd, J 8.5,2.5 Hz), 6.77 (1H, d, J 2.5 Hz), 6.94 (1H, d, J 8.5 Hz), 7.02 (2H, d, J 9.0 Hz), 7.25 (1H, d, J 8.0 Hz), 7.51 (1H, d, J 8.0 Hz), 7.63 (1H, t, J 8.0 Hz), 7.98 (2H, d, J 0.0 Hz). Analytical chiral HPLC (25 cm Chiralcel OD) eluting with 2% EtOH in heptane with 0.1 %TFA, f = 1.0 mL/min, wavelength 254 nm, R, 22.2 min (97 %ee). LC/MS: m/z 446.3 [M+H]+, Rt 3.93 min. 1H NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.33-1.45 (2H, m), 1.45-1.65 (2H, m), 1.94-2.09 (2H, m), 2.23 (3H, s), 2.55 (2HP m), 2.66 (3H, s), 2.82 (2H, m), 5.29 (1H, dd, J 7.5, 5.5 Hz), 6.64 (1H, dd, J 8.5, 2.5 Hz), 6.77 (1H, d, J 2.5 Hz), 6.95 (1H, d, J 8.5 Hz), 7.37 (1H, d, J 7.5 Hz), 7.64 (1H, d, J 7.5 Hz), 7.71 (1H, t, J 7.5 Hz), 8.08 (2H, d, J 8.5 Hz), 8.14 (2H, d, J 8.5 Hz). LC/MS: m/z 429.3 [M+H]+, Rt 3.97 min. 1H NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.5 Hz), 1.33-1.43 (2H, m), 1.43-1.63 (2H, m), 1.94-2.07 (2H, m), 2.54 (2H, m), 2.82 (2H, m), 5.27 (1H, m), 6.62 (1H, d, J 8.5,2.5 Hz), 6.75 (1H, d, J 2.5 Hz), 7.94 (1H, d, J 8.5 Hz), 7.40 (1H, d, J 7.5 Hz), 7.62 (1H, d, J 7.5 Hz), 7.74 (1H, t, J 7.5 Hz), 7.78 (2H, d, J 8.5 Hz), 8.16 (2H, d, J 8.5 Hz). 1H NMR (400 MHz; CDC!3) d: 0.91 (3H, t, J 7.5 Hz), 1.32-1.44 (2H, m), 1.44-1.63 (2H, m), 1.92-2.07 (2H, m), 2.22 (3H, s), 2.54 (2H, m), 2.82 (2H, m), 5.25 (1H, dd, J 8.0, 5.0 Hz), 6.63 (1H, dd, J 8.5, 2.5 Hz), 6.75 (1H, d, J 2.5 Hz), 6.94 (1H, d, J 8.5 Hz), 7.32 (1H, d, J 7.5 Hz), 7.45 (2H, d, J 8.5 Hz), 7.54 (1H, d, J 7.5 Hz), 7.67 (1H, t, J 7.5 Hz), 7.97 (2H, d, J 8.5 Hz). General procedure for Examples 104-108 LC/MS and 1H NMR as described for Example 99. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 20% I PA in heptane with 0.1 %TFA, f = 1.0 rnL/min, wavelength 215 nm, Rt 4.2 min (99 %ee). LC/MS and 1H NMR as described for Example 100. Analytical chiral HPLC (25 cm Chiralcel OD) eluting with 2% EtOH in heptane with 0.1%TFA, f = 1.0 mL/min, wavelength 254 nm, Rt 17.2 min (>99 %ee). Example 106 3-[4-({(1R)-1-[6-(4-Acetylphenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]propanoic acid (28 mg, 0.06 mmol) to give, after further purification by mass directed autoprep HPLC, the title compound (15mg). LC/MS: m/z 486.3 [M+H]+, Rt 4.20 min. 1H NMR (400 MHz; CDCI3) d: 0.85 (3H, t, J 7.0 Hz), 1.18-1.39 (4H, m), 2.11 (6H, s), 2.14- 2.28 (2H, m), 2.62 (2H, m), 2.83 (2H, m), 4.96 (1H, dd, J 7.5, 6.0 Hz), 6.79 (2H, s), 7.40 (1H, d, J 7.5 Hz), 7.68 (1H, d, J 7.5 Hz), 7.71 (2H, d, J 8.5 Hz), 7.77 (1H, t, J 7.5 Hz), 8.10 (2H, d, J 8.5 Hz). Prepared according to the procedure used to prepare Intermediate 73 starting from (2£)-3- {3-(methyloxy)-5-(2-propen-1-yl)-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}- 2-propenoic acid (68 mg, 0.13 mmol) to give, after further purification by mass directed autoprep HPLC, the title compound (36 mg). LC/MS: m/z 430.2 [M+H]+, Rt 4.24 min. 1H NMR (400 MHz; CDCI3) 8:0.83 (3H, t, J 7.5 Hz), 0.87 (3H, m), 1.26-1.38 (4H, m), 1.38- 1.59 (2H, m), 2.03-2.14 (1H, m), 2.16-2.28 (1H, m), 2.43 (2H, t, J 8.0 Hz), 2.63 (2H, m), 2.85 (2H, m), 3.69 (3H, s), 4.96 (1H, dd, J 7.0, 5.5 Hz), 6.55 (2H, s), 7.46 (1H, d, J 7.5 Hz), 7.64 (1H, d, J 7.5 Hz), 7.70 (2H, d, J 8.0 Hz), 7.75 (1H, t, J 7.5 Hz), 8.10 (2H, d, J 8.0) Hz). Prepared according to the procedure used to prepare Intermediate 73 starting from (2E)-3- {3-(2-propen-1-yl)-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}-2-propenoic acid (39 mg, 0.08 mmol) to give, after further purification by mass directed autoprep HPLC, the title compound (25 mg). LC/MS: m/z 500.2 [M+H]+, Rt 4.37 min. 1H NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.02 (3H, t, J 7.5 Hz), 1.34-1.45 (2H, m), 1.46-1.59 (2H, m), 1.71 (2H, m), 2.04 (2H, m), 2.59 (2H, m), 2.71 (2H, t, J 8.0 Hz), 2.81 (2H, m), 5.30 (1H, dd, J 6.5, 6.5 Hz), 6.54 (1H, d, J 8.5 Hz), 6.78 (1H, dd, J 8.5, 2.5 Hz), 6.97 (1H, d, J 2.5 Hz), 7.31 (1H, d, J 7.5 Hz), 7.62 (1H, d, J 7.5 Hz), 7.71 (1H, t, J 7.5 Hz), 7.75 (2H, d, J 8.0 Hz), 8.15(2H,d,J8.0Hz). t Prepared according to the procedure used to prepare Intermediate 73 starting from (2£)-3- {3-(ethyloxy)-4-t(1-{6-[4-(trif!uoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}-2-propenoic acid (305 mg, 0.61 mmol) to give, after further purification by mass directed autoprep HPLC, the title compound (26 mg). LC/MS: m/z 502.2 [M+H]+, Rt 4.10 min. 1H NMR (400 MHz; MeOD-d4) d: 0.87 (3H, t, J 7.5 Hz), 1.30-1.58 (4H, m), 1.36 (3H, t, J 7.0 Hz), 1.90-2.09 (2H, m), 2.46 (2H, t, J 7.5 Hz), 2.72 (2H, t, J 7.5 Hz), 4.03 (2H, d, J 7.0 Hz), 5.23 (1H, dd, J 7.5, 5.0 Hz), 6.52 (1H, dd, J 8.5, 2.0 Hz), 6.64 (1H, d, J 8.5 Hz), 6.78 (1H, d, J 2.0Hz), 7.46 (1H, dd, J 7.5,1.0 Hz), 7.72 (2H, d, J 8.5 Hz), 7.73 (1H, dd, J 7.5,1.0 Hz), 7.78 (1H, t, J 7.5 Hz), 8.16 (2H, d, J 8.5 Hz). General procedure for Examples 113-117 A stirred solution of alcohol (1S)-1-{6-[4-(trifluoromethyi)phenyl]-2-pyridinyl}-1-pentanol (65 mg, 0.21 mmol) and the appropriate phenol (0.33 mmol) in THF (4 mL) at 0°C under nitrogen was added ADDP (106 mg, 0.42 mmol) followed by tri-N-butylphosphine (0.105 mL, 0.42 mmol). The resulting mixture was then allowed to warm slowly to ambient temperature overnight. After 21 h the solvent was removed under vacuum (Genevac) and the solid residue dissolved in THF (2 mL), MeOH (2 mL) and treated with aqueous NaOH (2N, 2 mL). The resulting mixture was then stirred at rt for 2-3 h and then treated with aqueous HCI (2N, 2 mL) and the solvents removed under vacuum (Genevac). The residue was then purified using the OPTIX-SPE (C18 cartridge, 5g) eluting with 50-100% MeCN (+0.05% HCOOH) in H2O (+0.01% HCOOH) over 15 minsto afford the crude productOPTIX. The suiting crude product containing un-reacted alcohol was further purified using an SPE (silica, 2 or 5 g cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 or 20:1 to 0:1) to give the desired product. LC/MS: m/z 458.2 [M+H]+, Rt 4.17 min. 1H NMR (400 MHz; CDCI3) d: 0.93 (3H, t, J 7.5 Hz), 1.36-1.46 (2H, m), 1.46-1.64 (2H, m), 2.03 (2H, m), 2.60 (2H, t, J 7.5 Hz), 2.84 (2H, t, J 7.5 Hz), 5.30 (1H, dd, J 6.5,6.5 Hz), 6.83 (2H, d, J 8.5 Hz), 7.04 (2H, d, J 8.5 Hz), 7.38 (1H, d, J 8.0 Hz), 7.62 (1H, d, J 8.0 Hz), 7.72 (1H, t, J 8.0 Hz), 7.75 (2H, d, J 8.0 Hz), 8.15 (2H, d, J 8.0 Hz), LC/MS: m/z 488.2 [M+H]+, R, 4.02 min. 1H NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.34-1.46 (2H, m), 1.45-1.55 (1H, m), 1.55-1.68 (1H, m), 2.01-2.20 (2H, m), 2.61 (2H, t, J 7.5 Hz), 2.84 (2H, t, J 7.5 Hz), 3.89 (3H. s), 5.29 (1H, dd, J 7.0, 6.0 Hz), 6.56 (1H, dd, J 8.0,1.5 Hz), 6.68 (1H, dd, J 8.0 Hz), 6.74 (1H, d, J 1.5 Hz), 7.48 (1H, d, J 7.5 Hz), 7.61 (1H, d, J 7.5 Hz), 7.70-7.77 (3H, m), 8.14 (2H, d, J 8.0 Hz). Example 115 {4-[((1R)-1-{6-[4-(Trlfluoromethyl)phenyl]-2-pyr!dinyl}pentyl)oxy]phenyl}acetic acid LC/MS: m/z 444.2 [M+H]+, Rt 4.09 min. 1H NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.34-1.45 (2H, m), 1.45-1.65 (2H, m), 2.03 (2H, m), 3.51 (2H, s), 5.30 (1H, dd, J 6.5, 6.5 Hz), 6.86 (2H, d, J 8.5 Hz), 7.10 (2H, d, J 8.5 Hz), 7.37 (1H, d, J 7.5 Hz), 7.62 (1H, d, J 7.5 Hz), 7.72 (1H, t, J 7.5 Hz), 7.75 (2H, d, J 8.0 Hz), 8.14 (2H, d, J 8.0 Hz), LC/MS: m/z 478.1 [M+H]+, Rt 4.23 min. 1H NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.34-1.46 (2H, m), 1.46-1.68 (2H, m), 2.01-2.16 (2H, m), 3.49 (2H, s), 5.36 (1H, dd, J 7.5,5.0 Hz), 6.74 (1H, d, J 8.5 Hz), 6.92 (1H, dd, J 8.5, 2.0 Hz), 7.30 (1H, d, J 2.0 Hz), 7.42 (1H, d, J 7.5 Hz), 7.64 (1H, d, J 7.5 Hz), 7.75 (1H, t, J 7.5 Hz), 7.75 (2H, d, J 8.0 Hz), 8.14 (2H, d, J 8.0 Hz). LC/MS: m/z 474.2 [M+H]+, Rt 3.96 min. nH NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.5 Hz), 1.34-1.44 (2H, m), 1.44-1.54 (1H, m), 1.54-1.67 (1H, m), 2.00-2.18 (2H, m), 3.51 (2H, s), 3.90 (3H, s), 5.29 (1H, dd, J 8.0, 5.0 Hz), 6.62 (1H, dd, J 8.0,1.5 Hz), 6.70 (1H, d, J 8.0 Hz), 6.81 (1H, d, J 1.5Hz), 7.46 (1H, d, J 7.5 Hz), 7.61 (1H, d, J 7.5 Hz), 7.69-7.77 (3H, m), 8.13 (2H, d, J 8.0 Hz). General procedure for Examples 118-121 The following compounds were prepared in a similar way to that described for Examples 113-117 except starting from alcohol (1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol. General procedure for Examples 123-126 The following compounds were prepared using a similar procedure to Examples 113-117 except the mixtures were not reduced after the Mitsunobu reaction but were treated directly with MeOH (2 mL) and aqueous NaOH (2 mL), stirred for 3 h and then quenched with aqueous HCI (2N, 2 mL) and reduced. The residue was then suspended in a DCM (ca. 1 mL) and filtered through a bond elut cartridge directly onto a SPE (silica, 5 g cartridge) washing with a more DCI (2 x 0.5 mL). The cartridge was left to dry and the compound purified using the OPTIX-SPE (Si cartridge, 5g) eluting with cyclohexane:EtOAc (gradient 85:15 to 0:1) over 15 mins to afford the desired products which were purified further by repeated SPE or mass directed autoprep HPLC as appropriate. Example 123 3-{3-Fluoro-4-[((1R)-1-{6-[4-(trif luoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}propanoicacid LC/MS: m/z 476.1 [M+H]+, Rt 4.14 min. 1H NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.33-1.45 (2H, m), 1.45-1.54 (1H, m), 1.54-1.66 (1H, m), 1.99-2.16 (2H, m), 2.58 (2H, t, J 7.5 Hz), 2.82 (2H, t, J 7.5 Hz), 5.31 (1H, dd, J 8.0, 5.0 Hz), 6.72 (1H, dd, J 8.5,2.0 Hz), 6.75 (1H, dd, J 16.0, 8.5 Hz), 6.93 (1H, dd, J 12.0, 2.0 Hz), 7.45 (1H, d, J 8.0 Hz), 7.64 (1H, d, J 8.0 Hz), 7.74 (2H, d, J 8.5 Hz), 7.76 (1H, t, J 8.5 Hz), 8.13(2H,d,J8.5Hz). LC/MS: m/z 472.2 [M+H]+, Rt 4.30 min. 1H NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.35-1.46 (2H, m), 1.46-1.65 (2H, m), 2.01-2.10 (2H, m), 2.35 (3H, s), 2.59 (2H, t, J 7.5 Hz), 2.81 (2H, t, J 7.5 Hz), 5.31 (1H, dd, J 6.5, 6.5 Hz), 6.56 (1H, d, J 8.5 Hz), 6.79 (1H, dd, J 8.5, 2.0 Hz), 7.00 (1H, d, J 2.0 Hz), 7.34 (1H, d, J 7.5 Hz), 7.62 (1H, d, J 7.5 Hz), 7.72 (1H, t, J 7.5 Hz), 7.75 (2H, d, J 8.5 Hz), 8.16(2H, d, J 8.5 Hz). 1H NMR (400 MHz; CDCI3) d: 0.89 (3H, t, J 7.5 Hz), 1.30-1.41 (2H, m), 1.41-1.52 (2H, m), 1.97-2.09 (1H, m), 2.09-2.22 (1H, m), 2.63 (2H, m), 2.85 (2H, m), 3.71 (6H, s), 5.28 (1H, dd, J 6.5, 6.5 Hz), 6.35 (2H, s), 7.60 (1H, del, J 7.5,1.5 Hz), 7.68 (2H, d, J 8.5 Hz), 7.71 (1H, dd, J 7.5,1.5 Hz), 7.76 (1H, t, J 7.5 Hz), 8.06 (2H, d, J 8.5 Hz). LC/MS: m/z 488.2 [M+H]+, Rt 4.15 min. 1H NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.34-1.46 (2H, m), 1.46-1.53 (1H, m), 1.53-1.65 (1H, m), 1.98-2.08 (2H, m), 2.56 (2H, m), 2.80 (2H, m), 3.72 (3H, s), 5.30 (1H, dd, J 6.5, 6.5 Hz), 6.32 (1H, dd, J 8.5, 2.5 Hz), 6.52 (1H, d, J 2.5 Hz), 6.90 (1H, d, J 8.5, Hz), 7.38 (1H, d, J 7.5 Hz), 7.62 (1H, d, J 7.5 Hz), 7.70-7.76 (3H, m), 8.15 (2H, d, J 8.5 Hz). General procedure for Examples 127-130 The following compounds were prepared in a similar way to that described for Examples 123-126 except starting from alcohol (1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol. LC/MS and 1H NMR as described for Example 123. Example 128 3-{3-Methyl-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2- pyrldinyl}pentyl)oxy]phenyl}propanoic acid To a stirring solution of ethyl 3-{3-chloro-5-(methyloxy)-4-[((1S)-1 -{6-[4- (trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}prapanoate (118 mg, 0.20 mmol) in THF (3 mL) and MeOH (3 mL) at ambient temperature was added NaOH (2N, 3 ml.) and the mixture stirred for 2 h and then left to stand overnight. HCI (2N, 3 mL) was then added and the mixture reduced under vacuum. The residue was then purified by SPE (silica, 5 g cartridge) with a pad of celite on the top, eluting with cyclohexane:EtOAc (gradient 20:1 to 0:1) to give the title compound (94 mg). LC/MS: m/z 522.1 [M+H]+, Rt 4.20 min. 1H NMR (400 MHz; CDCI3) d: 0.88 (3H, t, J 7.0 Hz), 1.29-1.47 (4H, m), 2.02-2.14 (1H, m), 2.16-2.29 (1H, m), 2.63 (2H, m), 2.84 (2H, m), 3.69 (3H, s), 5.42 (1H, dd, J 6,5, 6.5 Hz), 6.59 (1H, d, J 2.0 Hz), 6.77 (1H, d, J 2.0 Hz), 7.64 (1H, d, J 7.5 Hz), 7.65 (1H, d, J 7.5 Hz), 7.69 (2H, d, J 8.0 Hz), 7.78 (1H, t, J 7.5 Hz), 8.07 (2H, d, J 8.0 Hz). To a stirring solution of ethyl (2E)-3-{3-chloro-4-[((1 f?)-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}-2-propenoate (54 mg, 0.10 mmo!) in EtOAc (4 mL) under nitrogen at ambient temperature was added PtO2 (20 wt%, 11 mg) and the mixture stirred under an atmosphere of hydrogen for 5 h. The resulting mixture was then purified by SPE (silica, 5 g cartridge) with a pad of celite on the top, eluting with EtOAc. The filtrate was then reduced and purified further by SPE (silica, 5 g cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to 20:1) to give an inseparable mixture containing the desired material and some de-chlorinated compound (51 mg). This material was then dissolved in THF (2 mL) and MeOH (2 mL) at ambient temperature and treated with NaOH (2N, 2 mL). The resulting mixture was then stirred for 2 h and then left to stand overnight. HCI (2N, 2 mL) was then added and the mixture reduced under vacuum. The residue was then purified by SPE (silica, 5 g cartridge) with a pad of celite on the top, eluting with cyclohexane:EtOAc (gradient 20:1 to 0:1) to give a residue which was purified further by mass directed autoprep HPLC to give the title compound (30 mg). LC/MS: m/z 492.2 [M+H]+, Rt 4.28 min. 1H NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.5 Hz), 1.33-1.45 (2H, m), 1.46-1.65 (2H, m), 2.03-2.15 (2H, m), 2.58 (2H, t, J 7.5 Hz), 2.80 (2H, t, J 7.5 Hz), 5.38 (1H, dd, J 7.5, 5.0 Hz), 6.71 (1H, d, J 8.5 Hz), 6.86 (1H, dd, J 8.5, 2.0 Hz), 7.21 (1H, d, J 2.0 Hz), 7.45 (1H, d, J 7.5 Hz), 7.64 (1H, d, J 7.5 Hz), 7.74 (2H, d, J 8.0 Hz), 7.78 (1H, t, J 7.5 Hz), 8.12 (2H, d, J 8.0 Hz). Prepared according to the procedure used to prepare Example 132 starting from ethyl (2E)- 3-{2-chloro-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}-2-propenoate (53 mg, 0.10 mmol) to afford the title compound (29 mg). LC/MS: m/z 492.1 [M+H]+, Rt 4.35 min. 1H NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.5 Hz), 1.33-1.43 (2H, m), 1.43-1.62 (2H, m), 1.96-2.06 (2H, m), 2.61 (2H, m), 2.93 (2H, m), 5.26 (1H, dd, J 6.5, 6.5 Hz), 6.71 (1H, dd, J 8.5, 2.5 Hz), 6.97 (1H, d, J 2.5 Hz), 7.05 (1H, d, J 8.5 Hz), 7.35 (1H, d, J 8.0 Hz), 7.64 (1H, d, J 8.0 Hz), 7.74 (1H, t, J 8.0 Hz), 7.75 (2H, d, J 8.0 Hz), 8.14 (2H, d, J 8.0 Hz). Prepared according to the procedure used to prepare Example 132 starting from ethyl (2E)- 3-{3-chloro-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}-2-propenoate (41 mg, 0.08 mmol) to afford the title compound (12 mg). LC/MS and 'H NMR as described for Example 132. Example 135 3-{2-Chloro-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridlnyl}pentyl)oxy]phenyl}propanoic acid Prepared according to the procedure used to prepare Example 132 starting from ethyl (2E)- 3-{2-chloro-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}-2-propenoate (111 mg, 0.21 mmol) to afford the title compound (42 mg). LC/MS and 1H NMR as described for Example 133. General procedure for Examples 136-141 To a solution of ethyl [(4-{[1-(3-bromo-2-methylphenyl)pentyl]oxy}-2- methylphenyl)oxy]acetate (75 mg, 0.17 mmol) in DME (4 mL) under nitrogen at room temperature was added the appropriate boronic acid (0.20 mmol), water (2 mL) and sodium carbonate (46 mg, 0.43 mmol). The reaction vessel was flushed with nitrogen, Pd(PPh3)4 (4 mg, 0.003 mmol) added and the resulting mixture heated to 80°C and stirred for 18 h. The reaction mixture was allowed to cool and the solvents removed under vacuum (Genevac) and the residue purified by SPE (10g, Ci8 cartridge), eluting with MeCN:H2O gradient (1:19 to 9:1). The fractions containing UV active material collected and concentrated by Genevac. Further purification by SPE (1 Og, aminopropyl cartridge), eluting with DCM, CHCI3, Et2O, EtOAc, MeOH and then NH3:MeOH (1:9). The NH3/MeOH fraction was shaken with 2M HCI (4.5 mL) and DCM (10 mL) at room temperature for 2 h, passed through a hydrophoblc frit, combined with the MeOH fraction and concentrated under vacuum to afford the title compounds, with further purification by mass directed autoprep HPLC where appropriate. LC/MS: m/z 504.2 [M+NH4]+, Rt 4.32 min. 1H NMR (400 MHz; MeOD-d4) d: 0.93 (3H, t, J 7.5 Hz), 1.32-1.54 (3H, m), 1.54-1.66 (1H, m), 1.73-1.83 (1H, m), 1.83-1.96 (1H, m), 2.17 (3H, s), 2.23 (3H, s), 4.37 (2H, s), 5.30 (1H, dd, 8.5, 4.0 Hz), 6.47 (1H, dd, J 9.0, 3.0 Hz), 6.59 (1H, d, J 9.0 Hz), 6.65 (1H, d, J 3.0 Hz), 7.06 (1H, d, J 7.5 Hz), 7.19 (1H, t, J 7.5 Hz), 7.42 (1H, d, J 7.5 Hz), 7.46 (2H, d, J 8.0 Hz), 7.71 (2H, d, J 8.0 Hz). LC/MS: m/z 470.3 [M+NH4]+, Rt 4.41 min. 1H NMR (400 MHz; MeOD-d4) d: 0.92 (3H, t, J 7.5 Hz), 1.32-1.53 (3H, m), 1.53-1.66 (1H, m), 1.72-1.83 (1H, m), 1.83-1.96 (1H, m), 2.16 (3H, s), 2.23 (3H, s), 4.51 (2H, s), 5.29 (1H, dd, 8.5, 4.0 Hz), 6.47 (1H, dd, J 9.0,3.0 Hz), 6.60 (1H, d, J 9.0 Hz), 6.66 (1H, d, J 3.0 Hz), 7.04 (1H, d, J 7.5 Hz), 7.16 (1H, t, J 7.5 Hz), 7.24 (2H, d, J 8.5 Hz), 7.39 (3H, m). LC/MS: m/z 450.3 [M+NH4]+, Rt 4.34 min. 1H NMR (400 MHz; MeOD-d4) d: 0.92 (3H, t, J 7.5 Hz), 1.30-1.52 (3H. m), 1.52-1.65 (1H, m), 1.70-1.81 (1H, m), 1.81 -1.93 (1H, m), 2.16 (3H, s), 2.22 (3H, s), 2.37 (3H, s), 4.39 (2H, s), 5.27 (1H, dd, J 8.5, 4.0), 6.46 (1H, dd J 9.0, 3.0 Hz), 6.59 (1H, d, J 9.0 Hz), 6.64 (1H, d, J 3.0 Hz), 7.01 (1H, d, J 7.5,1.0 Hz), 7.12 (1H, t, J 7.5 Hz), 7.12 (2H, d, J 8.0 Hz), 7.20 (2H, d, J 8.0 Hz), 7.33 (1H,dd,J 7.5,1.0 Hz). Example 139 [(4-{[1-(4'-Cyano-2-methyl-3-biphenylyl)pentyl]oxy}-2-methyJphenyl)oxy]acetic acid LC/MS: m/z 461.3 [M+NH4]+, Rt 4.07 min. 1H NMR (400 MHz; MeOD-d4) d: 0.93 (3H, t, J 7.5 Hz), 1.34-1.53 (3H, m), 1.53-1.66 (1H, m), 1.74-1.84 (1H, m), 1.84-1.96 (1H, m), 2.16 (3H, s), 2.23 (3H, s), 4.53 (2H, s), 5.31 (1H, dd, J 8.5, 4.0 Hz), 6.48 (1H, dd, J 9.0 Hz, 3.0 Hz), 6.61 (1H, d, J 9,0 Hz), 6.67 (1H, d, J 3.0 Hz), 7.06 (1H, d, J 7.5 Hz), 7.21 (1H, t, J 7.5 Hz), 7.43 (1H, d, J 7.5 Hz), 7.47 (2H, d, J 8.5 Hz), 7.78 (2H, d, J 8.5 Hz). LC/MS: m/z 466.3 [M+NH4]+, Rt 4.18 min. 1H NMR (400 MHz; MeOD-d4) d: 0.92 (3H, t, J 7.5 Hz), 1.30-1.52 (3H,m), 1.52-1.65 (1H, m), 1.71-1.81 (1H, m), 1.81-1.93 (1H, m), 2.17 (3H, s), 2.22 (3H, s), 3.81 (3H, s), 4.34 (2H, s), 5.27 (1H, dd, J 8.5, 4.0 Hz), 6.45 (1H, dd, J 9.0, 3.0 Hz), 6.59 (1H, d, J 9.0 Hz), 6.64 (1H, d, J 3.0 Hz), 6.95 (2H, d, J 9.0 Hz), 7.02 (1H, dd, J 7.5, 1.0 Hz), 7.11 (1H, t, J 7.5 Hz), 7.16 (2H, d, J 9.0 Hz),7.33(1H,dd,J7.5,1.0 Hz). LC/MS: m/z 454.3 [M+NH4]+, Rt 4.22 min. 1H NMR (400 MHz; MeOD-d4) d: 0.92 (3H, t, J 7.5 Hz), 1.30-1.52 (3H, m), 1.52-1.65 (1H, m), 1.70-1.82 (1H, m), 1.82-1.95 (1H, m), 2.16 (3H, s), 2.22 (3H, s), 4.39 (2H, s), 5.28 (1H, dd, J 8.5, 4.0 Hz), 6.46 (1H, dd, J 9.0, 3.0 Hz), 6.59 (1H, d, J 9.0 Hz), 6.64 (1H, d, J 3.0 Hz), 7.03 (1H, dd, J 7.5,1.0 Hz), 7.09-7.17 (3H,m), 7.22-7.29 (2H,m), 7.37 (1H, d, J 7.5,1.0 Hz). NaH (60% dispersion in mineral oil, 9.6 mg, 0.241 mmol) was washed with cyclohexane (3 x 1 mL) under nitrogen and the resulting powdery residue treated with THF (1 mL) and the resulting mixture cooled to 0°C. Ethyl ({4-[(2-hydroxy-1-{6-[4-(trifluorornethyl)phenyl]-2- pyridinyl}ethyl)oxy]-2-methylphenyl}oxy)acetate (88 mg, 0.185 mmol) in THF (1.85 mL) was then added drop-wise over 2 min. 1 -lodopropane (0.024 mL, 0.241 mmol) was then added and the resulting mixture allowed to warm to ambient temperature over 18 h. The reaction had caused hydrolysis of the ester and not alkylation so the mixture was reduced and purified by SPE (silica, 5 g cartridge) eluting with cyclohexane:EtOAc (+1% HCOOH) (gradient 10:1 to 1:10) then EtOAciMeOH (1:1) to give the acid (66 mg, 0.148 mmol). This material was re-subjecting to the conditions described above using NaH (60% dispersion in mineral oil, 15.4 mg, 0.384 mmol) and 1-iodopropane (0.037 mL, 0.384 mmol) and the resulting solution reduced under vacuum. The residue was then partitioned between EtOAc (30 mL) and saturated aqueous NH4OH (50 mL) and the layers separated. The aqueous was re-extracted with EtOAc (30 mL) and the combined organic layer washed with brine (30 mL) and reduced to give an oil. Purification by SPE (silica, 5 g cartridge) eluting with cyclohexane:EtOAc (+1%HCOOH) (gradient 10:1 to 1:10) then EtOAc:MeOH (1:1) afforded an oil which was further purified by mass directed autoprep HPLC to afford the title compound (5 mg). LC/MS: m/z 490.1 [M+H]+, Rt 4.25 min. 1H NMR (400 MHz; CDCI3) d: 0.86 (3H, t, J 7.5 Hz), 1.58 (2H, m), 2.19 (3H, s), 3.51 (2H, m), 3.91 (1H, dd, J 11.0, 7.0 Hz), 3.98 (1H, dd, J 11.0, 3.0 Hz), 4.52 (2H, s), 5.44 (1H, d, J 7.0, 3.0 Hz), 6.56 (1H, d, J 9.0 Hz), 6.64 (1H, dd, J 9.0, 3.0 Hz), 6.83 (1H, d, J 3.0 Hz), 7.42 (1H, d, J 7.5 Hz), 7.65 (1H, d, J 7.5 Hz), 7.73 (1H, t, J 7.5 Hz), 7.73 (2H, d, J 8.0 Hz), 8.14 (2H, d, J 8.0 Hz). Example 143 A solution of the ethyl ({4-[(2-(ethyloxy)-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}ethyl)thio]-2-methylphenyl}oxy)acetate (Enantiomer 1) (12 mg, 0.023 mmol) in THF (1 mL) and MeOH (1 mL) was treated with aqueous NaOH (2N, 1 mL) and the resulting mixture agitated at ambient temperature for 15 h. Aqueous HCI (2N, 1 mL) was then added and the organic solvents removed under vacuum using a Genevac. The residue was the then made up to 2 mL by the addition of water and then extracted using DCM (3x3 mL) in an hydrophobic frit. The residue was reduced and then purified further by mass directed autoprep HPLC to afford the title compound as an oil (7 mg). LC/MS: m/z 492.2 [M+H]+, Rt 4.09 min. 1H NMR (400 MHz; CDCI3) d:1.12 (3H, t, J 7.0 Hz), 2.17 (3H, s), 3.50 (2H, m), 3.93 (1H, dd, J 10.0, 6.0 Hz), 4.11 (1H, dd, J 10.0, 8.0 Hz), 4.44 (1H, dd, J 8.0, 6.0 Hz), 4.60 (2H, s), 6.56 (1H, d, J 8.5 Hz), 7.15 (1H, dd, J 8.5,2.0 Hz), 7.18 (1H, d, J 2.0 Hz), 7.27 (1H, d, J 7.5 Hz), 7.61 (1H, d, J 7.5 Hz), 7.67-7.73 (3H, m), 8.04 (2H, d, J 8.0 Hz). Prepared according to the procedure used to prepare Example 143 (Enantiomer 1) starting from ethyl ({4-[(2-(ethyloxy)-1 -{6-[4-(trifluoromethyl)phenyI]-2-pyridinyl}ethyl)thio]-2- methylphenyl}oxy)acetate (Enantiomer 2) (13.7 mg, 0.026 mmol) to give, after further purification by mass directed autoprep HPLC, the title compound (9.1 mg). LC/MS and 1H NMR as described for Example 143 The following intermediates and ligands were prepared for the binding and transfection assays described below: (i) ({2-Methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)thio]phenyl}oxy)aceticacid. This compound was used as a PPARdelta reference in the transfection assays described below and was prepared according to the method reported in WO200100603-A1 (ii) 2-Methyl-2-t(4-{[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}carbonyl)amino]methyl}phenyl)oxy]propanoicacid. This compound was used as a PPAR alpha reference in the transfection assay described below and was prepared according to method reported in WO200140207-A1 (iii) 5-{[4-({2-[Methyl(2-pyridtnyl)amino]ethyl}oxy)phenyl]methyl}-1,3-thia2olidine-2,4-dione This compound was used as a PPAR gamma reference in the transfection assay described below and was prepared according to method reported in J.Med.Chem. 1994, 37(23), 3977 Binding Assav: Compounds were tested for their ability to bind to hPPAR gamma, hPPAR alpha, or hPPAR . delta using a Scintillation Proximity Assay (SPA). The PPAR ligand binding domain (LBD) was expressed in E. coli as polyHis tagged fusion proteins and purified. The LBD was then labelled with biotin and immobilised on streptavidin-modif ted scintillation proximity beads. The beads were then incubated with a constant amount of the appropriate radioligand (3H-BRL 49653 for PPAR gamma, and labelled GW 2433 (see Brown, P. J et al. Chem. Bio!., 4, 909-918 (1997) for the structure and synthesis of this ligand) for PPAR alpha and PPAR delta and variable concentrations of test compound, and after equilibration the radioactivity bound to the beads was measured by a scintillation counter. For each compound tested, plots of ligand concentration vs. CPM of radioligand bound were constructed and apparent Ki values were estimated from nonlinear least squares fit of the data assuming simple competitive binding. The details of this assay have been reported elsewhere (see, Blanchard, S. G. et. al. Development of a Scintillation Proximity Assay for Peroxisome Proliferator-Activated Receptor gamma Ligand Binding Domain. Anal. Biochem., 257,112-119 (1998)). Transfection assay: Compounds were screened for functional potency in transient transfection assays in CV-1 cells for their ability to activate the PPAR subtypes (transactivation assay). A previously established chimeric receptor system was utilized to allow comparison of the relative transcriptional activity of the receptor subtypes on the same target gene and to prevent endogenous receptor activation from complicating the interpretation of results. See, for example, lehmann, J. M.; Moore, L B.; Smith-Oliver, T. A.; Wilkison, W. O.; Willson, T. M.; Kliewer, S. A., An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPARgammaJ, J. Biol. Chem., 270, 12953-6 (1995). The ligand binding domains for murine and human PPAR alpha, PPAR gamma, and PPAR delta were each fused to the yeast transcription factor GAL4 DNA binding domain. CV-1 cells were transiently transfected with expression vectors for the respective PPAR chimera along with a reporter construct containing five copies of the GAL4 DNA binding site driving expression of secreted placenta! alkaline phosphatase (SPAP) and beta-galactosidase. After 16 h, the medium was exchanged to DME medium supplemented with 10% delipidated fetal calf serum and the test compound at the appropriate concentration. After an additional 24h, ceil extracts were prepared and assayed for alkaline phosphatase and beta-galactosidase activity. Alkaline phosphatase activity was corrected for transfection efficiency using the beta-galactosidase activity as an internal standard (see, for example, Kliewer, S. A., et. al. Cell 83, 813-819 (1995)). Rosiglitazone (BRL 49653) was used as a positive control in the hPPAR gamma assay. The positive control in the hPPAR alpha assays was 2-methyl-2-[(4-{[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}carbonyl)amino]methyl}phenyl)oxy]propanoic acid. The positive control for PPAR delta assays was ({2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thtazol-5- yl}methyl)thio]phenyl}oxy)aceticacid. All of the above acid Examples showed at least 50% activation of PPAR8 relative to the positive control at concentrations of 10-7 M or less. WE CLAIM: A coTioourc c*' 'cnula (I) whe'ein: .9 whereir: R1 arc R2 a-e independently H or C1-3alkyl; X represents aOcr (CH2)n where n is C1 or 2; R3and R4 lncependontly represent H1 C1-3 alkyl, -OCH3 -OCH3, -CF3, allyl. or halogen; X1 represents C, S, SO2. SO, or CH2. one of R5 amd R6 is hydrogen, the other is C1-6 alkyl (including branched alkyl nnd which is substituted or unsubstituted by C1-6alkoxy); R1 reprosents phenyl or a 6-mebence heterocycle selected from pyrimldine, pyrtdlne, Pyridazine and pyrazine each of which phenyl or heterocycle is substituted by phenyl or unsubstituted or substituted by one or more CFi, C1-3 alkyl,, halogen, CN) and optionally a further C1-3 alkyl substituent. 2. A compound as ciairncd in claim 1 wherein R1 and R2 are both H or both methyl. 3. A compound as claimed in claim 2 wherein R1 and R2 are both H 4.. A compound as claimed in clnims 1 - 3 whnro'r X is O. 5. A compound as claimed in claims 1 - 6 wherein R3 and R4 are independently H o- C1-3 aikyl. 5. A compound as claimed in claim 5 wherein one cf R3 and R4 is H and the other is not. 7. A compound as claimed in claim 7 wherein the substituents group which is not H is positioned to the X methyl. 8. A compound as claimed in 6 or 7 wherein one of R3 and R4 is methyl. 9. A compound as claimed in claims 1-8 whrrein X1 is C or S. 10 A compound as claimed In claim 1 wherein one of R5 and R6 is H and the other is butyl cr 11. A compound as claimed in claim 1 wherein R7 is a phenyi or pyridine ring which is substituted meta to the depicted X1 moiely by para -C6H4CF3, para -C6H4Me, para -C6H4CN or para -C6H4CI. 12. A compound as claimed in claim 1 selected from: {[2-Methyl-4-({1-[4'-(trifluoromethyl)-3-biphenylyl]ethyl}thio)phenyl]oxy}acetic acid {[2-Methyl-4-({1-[4'-(trifluoromethylH-biphenylyl]ethyl}thio)phenyl]oxy}acetiic acid 2-Methyl-2-({2-methyi-4-[(1-{6-[4-(trifluoromef:hyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}oxy)prop {[2-Methyl-4-({1-[4'-(trifIuoromethyl)-3-biphenylyl]pentyl}oxy)phenyl]oxy}acetic acid [(4-{[1-(4'-Ch!crc^3 biphcr;viv;)pcr;:ync:;v;-2-;Mcthyiphenyi)oxy]acetiGacicl {[2-Mettvyi-4-({1-[4'-(trifiucror;isihyi)-'i-i:)iph5nviyi]pentyl}oxy)phenyi]oxy}aceiic acid [(4-{[1-(4'-Chloro-4-bipher]yiy:)pentyljoxy;-2-inethylphenyl)oxy]acetic acid {[2-Methyl-4-({(1R)-1-[4'-(trif!uoromet.iyl)-4-biphenyIyl]pentyl}thio)phenyl]oxy}aceticacid {[2-Methyl-4-({(1S)-1-[4'-(trifluoromethyl)-4-biphenylyl]pentyl}thio)phenyl]oxy}acetic acid ({2-Mefhyl-4-[((1S)-1-{6-[4-(tr:fIuoromethyl)phonyl]-2- pyridinyl}pentyl)oxy]phenyl}oxy)acetiiD acid ({2-Methyf-4-[((1 R)-1 -{6-[4-(trifluororr othyi)phenyi]-2- pyridinyl}pentyl)oxy]phenyl}oxy)acetic acid ({2-Methyl-4-[((1 S)-1 -{6-[4-(trifluoramethyl)phenyl]-2- pyridinyl}pentyl)thio]phenyl}oxy)acetb acid ({2-Methyl-4-[((1f?)-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)thio]phenyl}oxy)acetic acid ({2-Methyi-4-[(1-{6-[4-(trifiuoromethyi)pheny!]~2-pyridinyi}pentyl)suifinyl]phenyl}oxy)acetic acid ({2-Methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]~2-pyridinyl}pentyl)sulfonyl]phenyl}oxy)acetic acid {4-[(1-{6-[4-(Trifluoromethyl)phenyl]-:'.-pyridinyl}pentyl)oxy]phenyl}aceticacid ({2-Methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyrldinyl}butyl)oxy]phenyl}oxy)acetic acid ({4-[(1-{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetic acid 3-{4-[(1-{6-[4-(Trifluorornethyl)phenyl]--2-pyridinyl}pentyl)oxy]phenyl}propanoic acid {[4-({1-[6-(4-Ch!oropheny!)-2-pyridinyl'jpenty!)oxy)-2-methylphenyl]oxy}acetic acid ({2-Methyl-4-[(1-{6-[4-(methy[oxy)phonyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetic acid ({4-[(1-{6-[4-(Ethyloxy)phenyl]-2-pyri(linyl}pentyl)oxy]-2-methylphenyl}oxy)ac6!ticacid {[2-Methyl-4-({1-[6-(4-methylphenyl)-?-pyriclinyl]pentyl}ory)pheny!]oxy}aceticacid {[4-({1-[6-(3,4-Dichlorophenyf)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}aceticacid ({2-Methyl-4-[(1-{6-[3-(trifluoromethyil)ph9nyi]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetic acid [(2-Methyl-4-{[1-(6-pheny!-2-pyridinyl)pentyl]oxy}phenyl)oxy]acetic acid {[4-({1-[6-(4-Acetylphenyl)-2-pyridinyl\|pentyl}oxy)-2-methylphenyl]oxy}acetlc acid {[4-({1-[6-(4-Fiuorophenyl)-2-pyridinyi]pentyl}oxy)-2-methyiphenyi]oxy}acetic acid {[4-({1-[6-(4-Cyanophenyl)-2-pyridiny]pentyl}oxy)-2-methylphenyl]oxy}aceticacid ({2-Methyl-4-[(1-{6-\|4-(trifluoromethyhphenyl]-2-pyridinyl}hexyl)oxy]phenyl}oxy)acetic aci ({2-Methyl-4-[(4-methyl-1-{6-[4-(trifluciromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}oxy)acefic. acid ({2-Methyl-4-[(3-methyl-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}butyl)oxy]phenyl}oxy)acetic acid [(4-{[1-(3-Biphenylyl)pentyl]oxy}-2-melhylphenyi)oxy]aceticacid [(4-{[1-(4'-Cyano-3-biphenylyl)penty[]oxy}-2-iTielhylphenyl)oxy]aceticacid [(2-Ethyl-4-{[1--(6~phenyl-2-pyrid!nyl)pentyl]oxy}pheny!)oxy]acetic acid {[4-({1-[8-(4-Cyanophenyl) 2 pyridinyi]psi;iyij-oxy)-2-ethylphenyl]oxy}aceiic acid ({2-Ethyl-4-[(1-{6-i4-(tririuuiorr!ethyi};jh3nylj-.i-pyridinyl}psntyl)oxy]phenyl}o: 4-{4-[(1-{6-[4-(Trifluoromethyl)phenyl\|-2-pyridinyl}pentyl)oxy]phenyl}butanoicacid {[4-({(1 R)-1 -[6-(4-Chlorophenyl)-2-py;idiny!]pentyl}oxy)-2-methylphenyl]oxy'»acetic acid {[4-({(1R)-1-[6-(4-Cyanophenyl)-2-pyiidiny!]penty1}oxy)-2-mothylphenyl]oxy}acetic acid {[4-({(1 S)-1 -[6-(4-Chlorophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy]acetic acid {[4-({(1 S)-1 -[6-(4-Cyanopheny!)-2-pyii:linyljpenfyl}oxy)-2-methylphenyl]oxy}acetic acid ({2-Methyl-4-[((1/?)-3-(methyloxy)-1-{5-r4-(frifluoromethyl)phenyn-2- pyridinyl}propyl)oxy]phenyl}oxy)aceU; acid [(4-{[{1R)-1-[6-(4-Chlorophenyl)-2-pyidinyl]-3-(mcthyloxy)propyl]oxy}-2- methylphenyi)oxy]acetic acid ({2-Methyl-4-[((1S)-3-(methyloxy)-1-{5-[4--(triftuoramethyl)phenyl]-2- pyridinyl}propyl)oxy]phenyl}oxy)aceti; acid [(4-{[(1S)-1-[6-(4-Chlorophenyl)-2-pyiidinyl]-3-(methyloxy)propyl]oxy}-2- methylphenyl)oxy]acetic acid ({4-[((1f?)-2-(Ethyloxy)-1-{6-[4-(trifluorome1hyl)phenyl]-2-pyridinyl}ethyl)oxy]-2- methylphenyl}oxy)acetic acid [(4-{[(1':?)-1-[6-(4-Cyanophenyl)-2-py-idinyi]-2-(ethyloxy)€!thyl]oxy}-2- methylphenyl)oxy]acetic acid [(4-{[(1R)-1-[6-(4-Chlorophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2- methyiphenyl)oxy]acetic acid ({4-[((1S)-2-(Ethyloxy)-1-{6-[4-(trifluo-omethyl)phenyl]-2-pyridinyl}ethyl)oxy]-2- methylphenyl}oxy)acetic acid [(4-{[(1S)-1-[6-(4-Cyanophenyl)-2-pyidinyl]-?-(ethyloxy)ethyl]oxvy}-2- methylphenyl)oxy]acetic acid [(4-{[(1S)-1-[6-(4-Chlorophenyl)-2-pyridinyi]-2-(ethyloxy)ethyl]oxy}-2- methylphenyl)oxy]acetic acid {[4-({(1/?)-2-(Ethyloxy)-1-[6-(3-fluoro-4-mafhy!pheny!)-2-pyridiny!]ethy!}oxy)-2- methy!phenyl]oxy}acetic acid {[4-({(1R)-2-{Ethyloxy)-1-[6-(4-methylphenyl)-2-pyridinyl]ethy!}oxy)-2- methylphenyl]oxy}acetic acid ({4-[((1/?)-2-(Ethyloxy)-1-{6-[4-(1-methylethy!)phenyl]-2-pyridinyl}ethyl)oxy]-2- methylphenyl}oxy)acetic acid [{4-{t(1R)-1-[6-(4-Cyano-3-fluorophenyl)-2-pyridinyn-2-(ethyloxy)ethyl1oxy}-2- methylphenyl)oxy]acetic acid {[4-({(1/?)-2-(Ethyloxy)-1-[6-(2-fluoro-4'm3thy!phenyl)-2-pyridinyl]ethy!}oxy)-2- methylphenyi]oxy}acetic acid {[4-({(1R)-2-(Efhy!oxy)-1-[6-(^-fluorof:h8nyl)-2-pyridiny!3ethy!}oxy)-2- methylphonyl]oxylacetic acid [(4-{[(1R)-1-[6-f4-Chloro-3-mathylphenyli-2-yridinyi]-2-(ethyioxy)e(hy!joxy}-2- rnethylpiienyi)oxy]gceiic ace: [(4-{[(1/?)-1-[6-(3-Chloro-4-cyanopheliy!)-2-pyridinyl]-2-(ethyloxy)ethy!]oxy}-2- methylphenyl)oxy]acetic acid [(4-{[(1/?)-1-[6-(4-Cyano-3-msthy!pher!y!)-2pyridiny!]-2-(ethyloxy)ethyl)oxy}-2- methylphenyl)oxy]acetic acid [(4-{[(1/?)-1-[6-(4-Cyano-2-fluorophenyl)-2-pyridinyl3-2-(ethyloxy)ethylloxy}-2- methylphenyl)oxylacetic acid [(4-{[(1/?)-1-[6-(4-Cyano-2-me(hy!pheriyl)-2-[)yridinyl]-2-(ethyioxy)ethyl]oxy}-2- methy!pheny!)oxyjscetic acid {[4-({(1S)-2-(Ethy[oxy)-1-[e-(3-fluoro-4-m8thylphenyl)-2-pyridinyl]ethyi}oxy)-2- methylphenyl]oxy}acetic acid {[4-({(1S)-2-(Ethyloxy)-1-[6-(4-rnethy!phenyi;-2-pyridinyl]ethyl}oxy}-2- methylphenyl]oxy}acetic acid ({4-[((1S)-2-(Ethyloxy)-1-{6-[4-(1-methylethyi)phenyl]-2-pyridinyl}ethy[)oxy]-2- methylphenyl}oxy)acetic acid [(4-{[(1S)-1-[6-(4-Cyano-3-fluorophenyl)-2-pyiidinyl]-2-(ethyloxy)ethy!loxy}-2- methylphenyl)oxy]acetic acid {[4-({(1S)-2-(Ethyloxy)-1-[6-(2-fluoro-4-methylphenyl)-2-pyridinyl]ethyl}oxy)-2- methylphenyl]oxy}acetic acid {[4-({(1S)-2-(Ethyloxy)-1-[6-(4-fluoropheny!)-2-pyridinyl]eihy!}oxy)-2- methylphenyl)oxy}acetic acid [(4-{[(1S)-1-[6-(4-Chloro-3-methylphenyl)-2-pyridinylI-2-(ethyloxv')ethyl]oxy}-2- methylphenyl)oxy]acetic acid [(4-{[(1S)-1-[6-(3-Chloro-4-cyanophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2- methylphenyl)oxy]acetic acid [(4-{[(1S)-1-[6-(4-Cyano-3-methyiphenyl)-2-pyridinyl]-2-(ethyloxy)ethyi]oxy}-2- methylphenyl)oxy]acefic acid [(4-{[(1S)-1-[6-(4-Cyano-2-fluoropheryi)-^-pyridinyl]-2-(ethyloxy)ethyl)oxy}-2- methyfphenyl)oxy]acetic acid 3-{2-Methyl-4-[((1S)-1-{6-[4-(trifiuoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}propanoic; acid 3-[4-({(1S)-1-[6-(4-Cyanophenyl)-2-pyridinylJpentyl}oxy)-2-methylphenyl]propanoic acid 3-[4-({(1S)-1-[6-(4-Chlorophenyl)-2-p-/ridinyl]pentyl}oxy)-2-methylphenyi]propanoic acid 3-{2-Methy!-4-[((1R)-1-{6-[4-(trif!uoromefhyl)phenyl3-2- pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-[4-({(1R)-1-[6-(4-Cyanophenyi)-2-pi/ridinyl]pentyl}oxy)-2-rnethylphenyl]propanoicacid 3-[4-({(1R)-1-[6-(4-Chlorophenyi)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]propanoic acid 3-{3,5-Dimethyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]pheny!}propanoin acid 3-{3-(Methyloxy)-5-propyl-4-[f1-{6-r4-[triflucormethyl)phenyl]-2- pyridinyl}penty!)oyy]ph«ny!}prof3rio 3-{3-Propyi-4-[(1-{6-[4-itrifiuoromethyi)phenvi]-2-pyridinyi}pentyi)oxy]phenyl}propanoic acid 3-{3-(Ethyloxy)-4-[(1-{6-[4-(trifluorome(.hyl)phenyi]-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{4-[((1R)-1-{6-[4-(Trif!uoromeihy!)phenyll-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{3-(Methyloxy)-4-[((1R)-1-{6-[4-(trifiuoramethyl)phenyl]-2- pyridinyl}penty!)oxyjphenyl}propanoii; acid {4-[((1/?)-1-{6-[4-(trifluoromethy!)phenj.'!]-2-pyridinyl}pentyl)oxy]phenyl}acetic acid {3-Chloro-4-[((1R)-1-{6-[4-(frifluorom3thyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}acetic acid {3-(Meihyloxy)-4-[((1R)-1-{6-[4-(trifluorometliyl}phenyl]-2- pyridiny!}pentyl)oxy]pheny!}aceticac:d 3-{4-[((1S)-1-{6-[4-(Trifluoromethy!)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoicacid 3-{3-(Methyloxy)-4-[((1S)-1-{6-[4-(trifiuoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}propanoi: acid {4-[((1S)-"l-{G-[4-(Trifluororneiiiyi}phe;!)yi]-2-pyridinyi}peniyi)oxy]phenyi}ace';!c acid {3-Chloro-4-[((1S)-1-{6-[4-(trifluorome(hyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}acetic acid {3-(Meihyloxy)-4-[({1S)-1-{6-[4-(triflu3romethyl)phenyl]-2- pyridinyl}pentyi)oxy]phenyl}acetic acid 3-{3-Fluoro-4-[((1R)-1-{6-[4-(trifluorome1hyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{3-Methyl-4-[((1f?)-1-{6-[4-(trifluorcrnethyl)pheny[]-2- pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{3,5-Bis(methyloxy)-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}propanoio acid 3-{2-(Methyloxy)-4-[((1 R)-1-{6-[4-(trifl Jorome1hyl)phenyl]-2- pyridinyl}pentyl)oxy\|phenyl}propanoic acid 3-{3-Fluoro-4-\|((1 S)-1 -{6-[4-(trif luoron ethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{3-Methyl-4-[((1S)-1-{6-[4-(trifluorornethyl)phenyl]-2- pyridinyl}penty!)oxy]phenyi}propanoic acid 3-{3,5-Bis(methyloxy)-4-[((1S)-1-{6-[4-('trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{2-(Methy!oxy)-4-i((1S)-1-{6-[4-(trif!jorornefhyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}propanoic acid 3-{3-Chloro-5-(methyloxy)-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2- pyridinyl}pentyl)oxylpheny!}propanok acid 3-{3-Chloro-4-[((1f?)-1-{6-r4-(frifluoromethy[)pheny!]-2- pyriciiny!)penfy!s!oxy]ph':'r!yi}p'op?ii'ioi'; r;cic' 3-{2-Chloro-4-[(( 1 R)-1 -{6-[4-( trif luoroi nethyl )ph enyi]-2- pyridinyl}pentyl)oxy]phenyi}propanoic acid 3-{3-Chloro-4-[((1S)-1-{6-[4-(trif!uorornethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}propanoic; acid 3-{2-Chloro-4-[((1S)-1-{6-[4-(lrifIuorornethyl)phenyl]-2- pyridinyl}pentyl)oxy]phenyl}propanoi<:. acid> {[2-Methyl-4-({1-[2-methyl-4'-(trifluorcrr]elhyl)-3-biphenylyi]pentyl}oxy)phenyl}oxy}acetic acid [(4-{[1-(4'-Chioro-2-methyl-3-biphenyyl)pentyl]oxy}-2-methylphenyl)oxy]aceticacid [(4-{[1-(2,4'-Dimethyl-3-biphenylyl)peTiyl\|oxy}-2-methylphenyl)oxy]acetic acid [(4-{[1-(4'-Cyano-2-methyl-3-biphenylyl)pentyl]oxy}-2-methylpheny\|)oxy]acetic acid [{4-{[1-(4'-Fluoro-2-methy!-3-biphenylyl)pcntv!]oxy}-2-melhylphenyl)oxy]acelic acid ({2-Methyl-4-[(2-(propyloxy)-1-{6-[4-(lrifluoromethyl)phenyl]-2- pyridinyi}ethyl)oxy]phenyl}oxy)acetic acio ({4-[(2-(Ethyloxy)-1-{6-[4-(trif!uorome'hyl)phenyl]-2-pyridinyi}ethyl)thio]-2- methyiphenyl}oxy)acetic acid 13. A compound as claimed in claims 1-12 for use in therapy. 14. A pharmaceutical composition comprising a compound as claimed in claims 1-12. 15. A pharmaceutical composition as claimed in claim 14 for the treatment of a hPPAR disease or condition. 16. A pharmaceutical composition as claimed in claim 15 for the treatment of dyslipidemia, syndrome X, heart failure, hypercholesterolemia, cardiovascular disease, obesity, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, obesity, anorexia bulimia and anorexia nervosa. The present invention provides a compound of formula (I):wherein.Rl and R2 are independently H or C1-3 alkyl;X represents a O or (CH2)n where n is 0, 1 or 2;R3and R4 independently represent H, C1-3 alkyl, -OCH3, -CF3, allyl, or halogen;Xl represents O, S, SO2, SO, or CH2;R5 and R6 independently represent hydrogen, C1-6 alkyl (including branched alkyl and optionally substituted by one or more halogens or Cl-6alkoxy), or together with the carbon atom to which they are bonded form a 3-6 membered cycloalkyl ring;R7 represents aphenyl or a 6 membered heteroaryl group containing 1, 2 or 3 nitrogen atoms wherein the phenyl or heteroaryl group is substituted by 1. 2 or 3 moieties selected from the group consisting of halogen, C1-6 alkoxy, C1-6 alkyl, CF3, hydroxy, or phenyl (which may be optionally substituted by one or more C1-3 alkyl, -OC1-3 alkyl, CN, acetyl, hydroxy, halogen or CF3).

Full Text

PHENYLALKANOIC ACID AND PHENYLOXYALKANOIC ACID DERIVATIVES AS HPPAR ACTIVARORS
Chemical Compounds
The present invention relates to certain novel compounds. In particular, the present
invention relates to compounds that activate human peroxisome proliferator activated receptors
("hPPARs"). The present invention also relates to method for preparing the compounds, their use
in medicine, pharmaceutical compositions containing them and methods for the prevention or
treatment of PPAR mediated diseases or conditions.
Several independent risk factors have been associated with cardiovascular disease. These
include hypertension, increased fibrinogen levels, high levels of triglycerides, elevated LDL
cholesterol, elevated total cholesterol, and low levels of HDL cholesterol. HMG CoA reductase
inhibitors ("statins") are useful for treating conditions characterized by high LDL-c levels. It has
bean shown that lowering LDL-c is not sufficient for reducing the risk of cardiovascular disease in
some patients, particularly those with normal LDL-c levels. This population pool is identified by
the independent risk factor of low HDL-c. The increased risk of cardiovascular disease
associated with low HDL-c levels has not yet been totally successfully addressed by drug therapy
(Bisgaier, C. L.; Pape, M. E. Curr. Pharm. Des. 1998, 4, 53-70).
Syndrome X (including metabolic syndrome) is loosely defined as a collection of
abnormalities including hyperinsulemia, obesity, elevated levels of the following: triglycerides, uric
acid, fibrinogen, small dense LDL particles, and plasminogen activator inhibitor 1 (PAI-1), and
decreased levels of HDL-c.
NlDDK/I is described as insulin resistance, which in turn causes anomalous glucose output
and a decrease in glucose uptake, by skeletal muscle. These factors eventually lead to impaired
glucose tolerance (IGT) and hyperinsulinemia.
Peroxisome Proliferator Activated Receptors (PPARs) are orphan receptors belonging to
the steroid/retinoid receptor superfamily of ligand-activated transcription factors. See, for
example Willson T.M. and Wahli, W., Curr. Opin. Chem. B!ol., 1, pp235-241 (1997) and Willson
T.M. et. al., J. Med. Chem., 43, p527-549 (2000). The binding of agonist ligands to the receptor
results in changes in the expression level of mRNAs encoded by PPAR target genes.
Three mammalian Peroxisome Proliferator Activated Receptors have been isolated and
termed PPAR alpha, PPAR gamma, and PPAR delta (also known as NUC1 or PPAR beta).
These PPARs regulate expression of target genes by binding to DNA sequence elements, termed
PPAR response elements (PPRE). To date, PPREs have been identified in the enhancers of a
number of genes encoding proteins that regulate lipid metabolism suggesting that PPARs play a
pivotal role in the adipogenic signalling cascade and lipid homeostasis (H. Keller and W. Wahli,
Trends Endocrinol. Metab 291 -296, 4 (1993)).
It has now been reported that the thiazolidinedione class of drugs are potent and selective
activators of PPAR gamma and bind directly to the PPAR gamma receptor (J. M. Lehmann et. al.,
J. Biol. Chem. 12953-12956, 270 (1995)), providing evidence that PPAR gamma is a possible
target for the therapeutic actions of the thiazolidinediones.
Activators of the nuclear receptor PPAR?, for example rosiglitazone, have been shown in
the clinic to enhance insulin-action, reduce serum glucose and have small but significant effects
on reducing serum triglyceride levels in patients with Type 2 diabetes. See, for example, D. E.
Kelly et al., Curr. Opin. Endocrinol. Diabetes, 90-96, 5 (2), (1998); M. D. Johnson et al., Ann.
Pharmacother., 337-348,32 (3), (1997); and M. Leutenegger et al., Curr. Ther. Res., 403-416, 58
(7), (1997).
The mechanism for this triglyceride lowering effect appears to be predominantly increased
clearance of very low density lipoproteins (VLDL) through induction of lipoprotein lipase (LPL)
gene expression. See, for example, B. Staels et al., Arterioscler. Thromb., Vase. Biol., 1756-
1764,17 (9), (1997).
Fibrates are a class of drugs which may lower serum triglycerides 20-50%, lower LDLc 10-
15%, shift the LDL particle size from the more atherogenic small dense to normal dense LDL, and
increase HDLc 10-15%. Experimental evidence indicates that the effects of fibrates on serum
liplds are mediated through activation of PPARa. See, for example, B. Staels et al., Curr. Pharm.
Des., 1-14,3 (1), (1997). Activation of PPARa results in transcription of enzymes that increase
fatty acid catabolism and decrease de-novo fatty acid synthesis in the liver resulting in decreased
triglyceride synthesis and VLDL production/secretion. In addition, PPARa activation decreases
production of apoC-lll. Reduction in apoC-lll, an inhibitor of LPL activity, increases clearance of
VLDL. See, for example, J. Auwerx et al., Atherosclerosis, (Shannon, Ire!.), S29-S37,124
(Suppl), (1996).
Certain compounds that activate or otherwise interact with one or more of the PPARs have
been implicated in the regulation of triglyceride and cholesterol levels in animal models. See, for
example, U.S. Patents 5,847,008 (Doebber et al.) and 5,859,051 (Adams et al.) and PCT
publications WO 97/28149 (Leibowitz et al.), WO99/04815 (Shimokawa et al.) and WO 01/00603
(Glaxo Group Ltd.). Oliver et al, Proc Natl Acad Sci, 98, 5306-5311 (2001) reports raising of
HDLc and lowering of serum triglycerides in the obese rhesus monkey following administration of
a PPAR delta agonist.
Accordingly the invention provides a compound of formula 1 and pharmaceutically
acceptable salts and solvates and hydrolysable esters thereof.
wherein:
R1 and R2 are independently H or C1-3 alkyl;
X represents a O or (CH2)n where n is 0,1 or 2;
R3and R4 independently represent H, C1-6 alkyl, -OCH3, -CF3, allyl, or halogen;
XI represents O, S, SO2, SO, or CH2;
R5 and R6 independently represent hydrogen, C1-6alkyl (including branched alkyl and
optionally substituted by one or more halogens or C1-6alkoxy), or together with the carbon atom to
which they are bonded form a 3-6 membered cycloalkyl ring;
R7 represents a phenyl or a 6 membered heteroaryl group containing 1, 2 or 3 nitrogen
atoms wherein the phenyl or heteroaryl group is substituted by 1,2 or 3 moieties selected from
the group consisting of halogen, C1-6alkoxy, C1-6 alkyl, CF3, hydroxy, or phenyl (which may be
optionally substituted by one or more C1-3 alkyl, -OC1-3 alkyl, CN, acetyl, hydroxy, halogen or CF3).
In another aspect, the present invention discloses a method for prevention or treatment of a
disease or condition mediated by one or more human PPAR alpha, gamma or delta ("hPPARs")
comprising administration of a therapeutically effective amount of a compound of this Invention.
hPPAR mediated diseases or conditions include dyslipidemia including associated diabetic
dyslipidemia and mixed dyslipidemia, syndrome X (as defined in this application this embraces
metabolic syndrome), heart failure, hypercholesterolemia, cardiovascular disease including
atherosclerosis, arteriosclerosis, and hypertriglyceridemia, type II diabetes mellitus, type I
diabetes, insulin resistance, hyperlipidemia, Alzheimers disease and other cognitive disorders,
inflammation, epithelial hyperproliferative diseases including eczema and psoriasis and conditions
associated with the lung and gut and regulation of appetite and food intake in subjects suffering
from disorders such as obesity, anorexia bulimia, and anorexia nervosa. In particular, the
compounds of this invention are useful in the treatment and prevention of diabetes and
cardiovascular diseases and conditions including atherosclerosis, arteriosclerosis,
hypertriglyceridemia, and mixed dyslipidaemia.
In another aspect, the present invention provides pharmaceutical compositions comprising
a compound of the invention, preferably in association with a pharmaceutically acceptable diluent
or carrier.
In another aspect, the present invention provides a compound of the invention for use in
therapy, and in particular, in human medicine.
In another aspect, the present invention provides the use of a compound of the invention for
the manufacture of a medicament for the treatment of a hPPAR mediated disease or condition.
As used herein, "a compound of the invention" means a compound of formula (I) or a
pharmaceutically acceptable salt, or solvate, or hydrolysable ester thereof.
While hydrolyzable esters are included in the scope of this invention, the acids are
preferred because the data suggests that while the esters are useful compounds, it may actually
be the acids to which they hydrolyse that are the active compounds. Esters that hydrolyse readily
can produce the carboxylic acid in the assay conditions or in vivo. Generally the carboxylic acid is
active in both the binding and transient transfection assays, while the ester does not usually bind
well but is active in the transient transfection assay presumably due to hydrolysis. Preferred
hydrolysable esters are C1-6alkyl esters wherein the alkyl group may be straight chain or
branched chain. Methyl or ethyl esters are more preferred.
Preferably R1 and R2 are both H or both Me. More preferably both R1 and R2are H.
Preferably R3 and R4 are independently H or C1-3 alkyl. More preferably, at least one of R3
and R4 are hydrogen and when one of R4 and R3 is hydrogen and the other is not, then the
one that is not hydrogen is preferably ortho to the depicted moiety X. Most preferably the
one that is not hydrogen is methyl.
Preferably X is O.
Preferably X1 is O or S.
Preferably R5 and R8 are independently hydrogen or C1-6 alkyl (optionally substituted by
C1-6 alkoxy). More preferably one of R5 and R6 is H. Most preferably one of R5 and R6 is H
the other is butyl or ethyloxymethyl (CH3CH2OCH2).
Preferably R7 is phenyl or a 6 membered heterocycle selected from pyrimidine, pyridine,
pyridazine, pyrazine, each of which phenyl or heterocycle is substituted by phenyl
(optionally substituted by one or more C1-3 alkyl, CN, CF3, halogen). More preferably R7 is a
phenyl or pyridine ring which is substituted meta to the depicted moiety X1 by para
-C6H4CF3, para -C8H4Me, para -C6H4CN or para -C8H4CI.
Preferred compounds of formula (I) include:
{[2-Methyl-4-({[4'-(trifluoromBthyl)-3-biphenylyl]methyl}thio)phenyl]oxy}acetic acid
{[2-Methyl-4-({[4-methyl-4'-(trifluoromethyl)-3-biphenylyl]methyl}thio)phenyl]oxy}acetic acid
3-t2-Methyl-4-({[4'-(trifluoromethyl)-3-biphenylyl]methyl}oxy)phenyl]propanoic acid
[(2-Methyl-4-{2-[4'-(trifluoromethyl)-3-biphenylyl]ethyl}phenyl)oxy]acetic acid
({2-Methyl-4-[({6-[4-(trifluoromethyI)phenyl]-2-pyridinyl}methyl)thlo]phenyl}oxy)acetic acid
{[2-Methyl-4-({1-[4'-(trifluoromethyl)-3-biphenylyl]ethyl}thio)phenyl]oxy}acetic acid
{[2-Methyl-4-({1-[4'-(trifluoromethyl)-4-biphenylyl]ethyI}thio)phenyl]oxy}acetic acid
2-Methyl-2-({2-methyl-4-[(1-{6-[4-(trifluoromethyl)phenyi]-2-
pyridinyl}pentyl)oxy]phenyl}oxy)propanoic acid
{[2-Methyl-4-({1-[4'-(trifluoromethyl)-3-biphenylyl]pentyl}oxy)phenyl]oxy}acetic acid
[(4-{[1-(4'-Chloro-3-blphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetic acid
{[2-Methyl-4-({1-[4'-(trifluoromethyl)-4-biphenylyl]pentyl}oxy)phenyl]oxy}acetic acid
[(4-{[1-(4'-Chloro-4-biphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetic acid
{[2-Methyl-4-({(1 R)-1 -[4'-(trifluoromethyl)-4-biphenylyl]pentyl}thio)phenyl]oxy}acetic acid
{[2-Methyl-4-({(1 S)-1 -[4'-(trifluoromethyl)-4-biphenylyl]pentyl}thio)phenyl]oxy}acetic acid
({2-Methyl-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetic
acid
({2-Methyl-4-[((1/?)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetic
acid
({2-Methyl-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)thio]phenyl}oxy)acetic
acid
({2-Methyl-4-[((1fl)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)thio]phenyl}oxy)acetic
acid
({2-Methyl-4-[(1-{6-[4-{trifluoromethyl)phenyl]-2-pyridinyl}pentyl)sulfinyl]phenyl}oxy)acetic
acid
({2-Methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)sulfonyl]phenyl}oxy)acetic
acid
{4-[(1-{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}aceticacid
({2-Methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}butyl)oxy]phenyl}oxy)aceticacid
({4-[(1-{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)aceticacid
3-{4-[(1-{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoicacid
{[4-({1-[6-(4-Chlorophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}aceticacid
({2-Methyl-4-[(1-{6-[4-(methyloxy)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)aceticacid
({4-[(1-{6-[4-(Ethyloxy)phenyl]-2-pyridinyl}pentyl)oxy]-2-methylphenyl}oxy)aceticacid
{t2-Methyl-4-({1-[6-(4-methylphenyl)-2-pyridinyl]pentyl}oxy)phenyl]oxy}aceticacid
{[4-({1-l6-(3,4-Dichlorophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}aceticacid
({2-Methyl-4-[(1-{6-[3-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)aceticacid
[(2-Methyl-4-{[1-(6-phenyl-2-pyridinyl)pentyl]oxy}phenyl)oxy]aceticacid
{[4-({1-[6-(4-Acetylphenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}aceticacid
{[4-({1-l6-(4-Fluorophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyI]oxy}aceticacid
{[4-({1-[6-(4-Cyanophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}aceticacid
({2-Methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}hexyl)oxy]phenyl}oxy)aceticacid
({2-Methyl-4-[(4-methyl-1-{6-[4-(trifiuoromethyl)phenyl]-2-
pyridinyl}penlyl)oxy]phenyl}oxy)aceticacid
({2-Methyl-4-[(3-methyl-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}butyl)oxy]phenyl}oxy)aceticacid
[(4-{[1-(3-Biphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetic acid
{[4-({1-[4'-(Ethyloxy)-3-biphenylyl]pentyl}oxy)-2-methylphenyl]oxy}acetic acid
[(4-{[1-(4'-Cyano-3-biphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetic acid
[(2-Ethyl-4-{[1-(6-phenyl-2-pyridinyl)pentyl]oxy}pheny!)oxy]acetic acid
{[4-({1-t6-(4-Chlorophenyl)-2-pyridinyi]pentyl}oxy)-2-ethylphenyl]oxy}acetic acid
({2-Ethyl-4-[(1-{6-[4-(8thyloxy)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetic acid
{[4-({1-[6-(4-Cyanophenyl)-2-pyridinyl]pentyl}oxy)-2-ethylphenyl]oxy}acetic acid
({2-Ethyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetic acid
4-{4-[(1-{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}pen1yl)oxy]phenyl}butanoic acid
{[4-({(1R)-1-[6-(4-Chlorophenyl)-2-pyrldinyl]pentyl}oxy)-2-methylphenyl]oxy}acetic acid
{[4-({(1R)-1-[6-(4-Cyanophenyl)-2-pyridinyl]pentyl}oxy)-2-methy!phenyl]oxy}acetic acid
({2-Methyl-4-[((1 fl)-1 -{6-l4-(methyloxy)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetic acid
{[4-({(1R)-1 -[6-(4-Acetylphenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}acetic acid
({4-[((1R)-1-{6-[4-Acetyl-3-(msthyloxy)phenyl]-2-pyridinyl}pentyl)oxy]-2-
methylphenyl}oxy)acetic add
{[4-({(1S)-1 -[6-(4-Chlorophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}acetic acid
{[4-({(1S)-1 -[6-(4-Cyanophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}acetic acid
({2-Methyl-4-[((1 S)-1 -{6-[4-(methyloxy)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetic acid
{[4-({(1S)-1 -[6-(4-Acetylphenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}acetic acid
({4-[((1S)-1-{6-[4-Acetyl-3-(methyloxy)phenyl]-2-pyridinyl}pentyl)oxy]-2-
methylphenyl}oxy)acetic acid
({2-Methyl-4-[((1R)-3-(methyloxy)-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}propyl)oxy]phenyl}oxy)aceticacld
[(4-{[(1R)-1-[6-(4-Chlorophenyl)-2-pyridinyl]-3-(methytoxy)propyl]oxy}-2-
methylphenyl)oxy]acetic acid
({2-Methyl-4-[((1S)-3-(methyloxy)-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}propyl)oxy]pheny!}oxy)aceticacid
[(4-{[(1S)-1-[6-(4-Chlorophenyl)-2-pyridinyl]-3-(methyloxy)propyl]oxy}-2-
methylphenyl)oxy]acetic acid
({4-[((1R)-2-(Ethyloxy)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}ethyl)oxy]-2-
methylphenyl}oxy)acetic acid
({4-K(1R)-2-(Ethyloxy)-1-{6-[4-(methyloxy)phenyl]-2-pyridinyl}ethyl)oxy]-2-
methylphenyl}oxy)acetic acid
t(4-{[(1R)-1-[6-(4-Acetylphenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-methylphenyl)oxy]acetic
acid
[(4-{[(1R)-1-[6-(4-Cyanophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
[(4-{[(1R)-1-[6-(4-Chlorophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
({4-[((1S)-2-(Ethyloxy)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}ethyl)oxy]-2-
methylphenyl}oxy)acetic acid
({4-[((1S)-2-(Ethyloxy)-1-{6-[4-(methyloxy)phenyl]-2-pyridinyl}ethyl)oxy]-2-
methylpheny!}oxy)acetic acid
[(4-{[(1S)-1-[6-(4-Acetylphenyi)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-methylphenyl)oxy]acetic
acid
[(4-{[(1S)-1-[6-(4-Cyanophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
[(4-{[(1S)-1-[6-(4-Chlorophsnyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
{[4-({(1R)-2-(Ethyloxy)-1-[6-(3-fluoro-4-methylphenyl)-2-pyridinyl]ethyl}oxy)-2-
methylpheny]oxy)acetic acid
{[4-({(1R)-2-(Ethyloxy)-1-[6-(4-methylphenyl)-2-pyridinyl]ethyl}oxy)-2-
methylphenyl]oxy}acetic acid
({4-[((1R)-2-(Ethyioxy)-1-{6-[4-(1-methylethyl)phenyl]-2-pyridinyl}©thyl)oxy]-2-
methylphenyl}oxy)acetic acid
[(4-{[(1R)-1-[6-(4-Cyano-3-fluorophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
({4-[((1R)-2-(Ethyloxy)-1-{6-l4-(ethyloxy)pheny!]-2-pyridinyl}ethy!)oxy]-2-
methylphenyl}oxy)acetic acid
{[4-({(1R)-2-(Ethyloxy)-1-[6-(2-fluoro-4-methylphenyl)-2-pyridinyl]ethyl}oxy)-2-
methylphenyl]oxy}acetic acid
{[4-({{1R)-2-(Ethyloxy)-1-t6-(4-fluorophenyl)-2-pyrldinyl]ethyl}oxy)-2-methylphenyl]oxy}acetic
acid
[(4-{[(1R)-2-(Ethy!oxy)-1 -(6-{4-[(1 -methylethyl)oxy]phenyl}-2-pyridinyl)ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
[(4-{[(1R)-1-[6-(4-Chloro-3-methylphenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
[(4-{[(1R)-1-[6-(3-Chloro-4-cyanophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
[(4-{[(1ff)-1-[6-(4-Cyano-3-methylphenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
({4-[((1f5)-2-(Ethyloxy)-1-{6-[3-fIuoro-4-(methyloxy)phenyl]-2-pyridinyl}ethyl)oxy]-2-
methylphenyl}oxy)acetic acid
[(4-{[(1R)-1-[6-(4-Cyano-2-fluorophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
t(4-{[(1R)-1-[6-(4-Cyano-2-methylphenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-
methylphenyi)oxy]acetic acid
{[4-({(1S)-2-(Ethyloxy)-1-[6-(3-fluoro-4-methylphenyl)-2-pyridinyl]ethyl}oxy)-2-
methylphenyl]oxy}acGtic acid
{[4-({(1S)-2-(Ethyloxy)-1-[6-(4-me1hyiphenyl)-2-pyridinyl]ethyl}oxy)-2-
methylphenyl]oxy}acetic acid
({4-[((1S)-2-(Ethyloxy)-1 -{6-[4-(1 -methylethyl)phenyl]-2-pyridinyl}ethyl)oxy]-2-
methylphenyl}oxy)acetic acid
[(4-{[(1S)-1-[6-(4-Cyano-3-fluorophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-
mGthylphenyl)oxy]acetic acid
({4-[((1S)-2-(Ethyloxy)-1-{6-[4-(ethyloxy)phenyl]-2-pyridinyl}ethyl)oxy]-2-
methylphenyl}oxy)acetic acid
{[4-({(1S)-2-(Ethyloxy)-1-[6-(2-fluoro-4-methylphenyl)-2-pyridinyl]ethyl}oxy)-2-
methylphenyi]oxy}acetic acid
{[4-({(1S)-2-(Ethyloxy)-1-[6-(4-fluorophenyl)-2-pyridinyl]ethyl}oxy)-2-methylphenyl]oxy}acetic
acid
[(4-{[(1 S)-2-(Ethyloxy)-1 -(6-{4-[(1 -methylethyl)oxy]phenyl}-2-pyridinyl)ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
t(4-{[(1S)-1-[6-(4-Chloro-3-methylphenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
[(4-{[(1S)-1-[6-(3-Chloro-4-cyanophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
[(4-{[(1^-1-[6-(4-Cyano-3-methylphenyl)-2-pyridinyl]-2-(ethyloxy)ethylloxy}-2-
methylphenyl)oxy]acetic acid
({4-[((1S)-2-(Ethyloxy)-1-{6-[3-fluoro-4-(methyloxy)phenyl]-2-pyridinyl}ethyl)oxy]-2-
methylphenyl}oxy)acetic acid
[(4-{[(1S)-1-[6-(4-Cyano-2-fluorophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
[(4-{[(1S)-1-{6-[4-Cyano-3-(methyloxy)phenyl]-2-pyridinyl}-2-(ethyloxy)e1hyl]oxy}-2-
methylphenyl)oxy]acetic acid
3-{2-Methyl-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyi]-2-pyridinyl}pentyl)oxy]phenyl}propanoic
acid
3-{2-Methyl-4-[((1S)-1-{6-[4-(methyloxy)phenyl]-2-pyridinyl}pentyl)oxy]phenyi}propanoic
acid
3-[4-({(1 ^-1 -[6-(4-Acety|phenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]propanoic acid
3-[4-({(1S)-1 -[6-(4-Cyanophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]propanoic acid
3-[4-({(1S)-1 -[6-(4-ChIorophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]propanoic acid
3-{2-Methyl-4-[((1R)-1-{6-[4-(trifluoromethyl)ph6nyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic
acid
3-{2-Methyl-4-[((1R)-1-{6-[4-(methyloxy)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic
acid
3-[4-({(1R)-1 -[6-(4-Acetylphenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]propanoic acid
3-[4-({(1Rl)-1 -(6-(4-Cyanophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]propanoic acid
3-[4-({(1R)-1 -[6-(4-Chlorophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]propanoic acid
3-{3,5-Dimethyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic
acid
3-{3-(Methyloxy)-5-propyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}propanoicacid
3-{3-Propyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoicacid
3-{3-(Ethyloxy)-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic
acid
3-{4-[((1R)-1 -{6-[4-(Trif luoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid
3-{3-(Msthyloxy)-4-[((1R)-1 -{6-[4-(trif luoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}propanoic acid
{4-[((1R)-1 -{6-[4-(trif luoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}acetic acid
{3-Chloro-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]ph8nyl}aceticacid
{3-(Methyloxy)-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl)2-pyridinyl}pentyl)oxy]phenyl}acetic
acid
3-{4-[((1S)-1 -{6-[4-(Trif luoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid
3-{3-(Methyloxy)-4-[((1S)-1 -{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}propanoicacid
{4-[((1S)-1 -{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}acetic acid
{3-Chloro-4-[((1 S)-1 -{6-[4-(trifluoromethyi)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}acetic acid
{3-(Wlethyloxy)-4-l((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}acetic
acid
3-{3-Fluoro-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic
acid
3-{3-Methyl-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyI}propanoic
acid
3-{3,5-Bis(methyloxy)-4-[((1/:?)-1-{6-[4-(trifluoromethyl)phenyl3-2-
pyridinyl}pentyl)oxy]phenyl}propanoicacid
3-{2-(Methyloxy)-4-[((1 fl)-1 -{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}propanoic acid
3-{3-Fluoro-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic
acid
3-{3-Methyl-4-[((1S)-1-{6-[4-(trlfluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic
acid
3-{3,5-Bis(methyloxy)-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}propanoic acid
3-{2-(Methyloxy)-4-l((1S)-1 -{6-[4-(trif luoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}propanoic acid
3-{3-Chloro-5-(methyloxy)-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}propanoic acid
3-{3-Chloro-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic
acid
3-{2-Chloro-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic
acid
3-{3-Chloro-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyll-2-pyridinyl}pentyl)oxy]phenyl}propanoic
acid
3-{2-Chloro-4-t((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic
acid
{[2-Methyl-4-({1-[2-methyl-4'-(trifluoromethyl)-3-biphenylyl]pentyl}oxy)phenyl]oxy}acetic acid
[(4-{[1-(4'-Chloro-2-methyl-3-biphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetic acid
[(4-{[1-(2,4'-Dimethyl-3-biphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetic acid
[(4-{[1-(4'-Cyano-2-methyl-3-biphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetic acid
{[2-Methyl-4-({1-[2-methyl-4'-(methyloxy)-3-biphenylyl]pentyl}oxy)phenyl]oxy}acetic acid
[(4-{[1-(4'-Fluoro-2-methyl-3-biphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetic acid
({2-Methyl-4-[(2-(propyloxy)-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}ethyl)oxy]phenyl}oxy)aceticacid
({4-[(2-(Ethyloxy)-1-{6-[4-(trKluoromethyl)phenyl]-2-pyridinyl}ethyl)thio]-2-
methylphenyl)oxy)acetic acid
While the preferred groups for each variable have generally been listed above separately
for each variable, preferred compounds of this invention include those in which several or each
variable in Formula (I) Is selected from the preferred, more preferred, or most preferred groups for
each variable. Therefore, this invention is intended to include all combinations of preferred and
most preferred groups.
Those skilled in the art will recognize that stereocentres exist in compounds of formula (I).
Accordingly, the present invention includes all possible stereoisomers and geometric isomers of
formula (I) and includes not only racemic compounds but this invention is also intended to cover
each of these isomers in their racemic, enriched, or purified forms. When a compound of formula
(I) is desired as a single enantiomer, it may be obtained either by resolution of the final product or
by stereospecific synthesis using an optically active catalyst or a catalytic system with optically
active ligands or isomerically pure starting material or any convenient intermediate. Resolution of
the final product, an intermediate or a starting material may be effected by any suitable method
known in the art. See, for example, Stereochemistry of Carbon Compounds by E. L. Eliel
(Mcgraw Hill, 1962) and Tables of Resolving Agents by S. H. Wllen. Additionally, in situations
where tautomers of the compounds of formula (I) are possible, the present invention is intended
to include all tautomeric forms of the compounds. In particular, in many of the preferred
compounds of this invention the carbon atom to which R5 and R6 are bonded is chiral. In some of
these chiral compounds the activities at the various PPAR receptors varies between the S and R
isomers. Which of these isomers is preferred depends on the particular desired utility of the
compound. In other words, even with the same compound, it Is possible that the S isomer will be
preferred for some uses, while the R isomer will be preferred for others.
The hPPAR agonists of formula (I) may be agonists of only one type ("selective agonists"),
agonists for two PPAR subtypes ("dual agonists"), or agonists for ail three subtypes ("pan
agonists"). As used herein, by "agonist", or "activating compound", or "activator", or the like, is
meant those compounds which have a pKi of at least 6.0 preferably at least 7.0 to the relevant
PPAR, for example hPPARS in the binding assay described below, and which achieve at least
50% activation of the relevant PPAR relative to the appropriate indicated positive control in the
transfection assay described below at concentrations of 10-5 M or less. More preferably, the
agonists of this invention achieve 50% activation of at least one human PPAR in the relevant
transfection assay at concentrations of 10-6 M or less. Preferably the compounds are hPPARS
agonists. More preferably the compounds are selective hPPARS agonists.
It will also be appreciated by those skilled in the art that the compounds of the present
invention may also be utilised in the form of a pharmaceutically acceptable salt or solvate thereof.
The physiologically acceptable salts of the compounds of formula (I) include conventional salts
formed from pharmaceutically acceptable inorganic or organic acids or bases as well as
quaternary ammonium acid addition salts. More specific examples of suitable acid salts include
hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric; fumaric, acetic, proplonlc,
succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-
2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like.
Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in
the preparation of salts useful as intermediates in obtaining the compounds of the invention and
their pharmaceutically acceptable salts. More specific examples of suitable basic salts include
sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N.N'-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine salts.
Those skilled in the art of organic chemistry will appreciate that many organic compounds can
form complexes with solvents in which they are reacted or from which they are precipitated or
crystallized. These complexes are known as "solvents". For example, a complex with water is
known as a "hydrate". Solvates of the compound of formula (I) are within the scope of the
invention. References hereinafter to a compound according to the invention include both
compounds of formula (I) and their pharmaceutically acceptable salts and solvates.
The compounds of the invention and their pharmaceutically acceptable derivatives are
conveniently administered in the form of pharmaceutical compositions. Such compositions may
conveniently be presented for use in conventional manner in admixture with one or more
physiologically acceptable carriers or excipients.
While it is possible that compounds of the present invention may be therapeutically
administered as the raw chemical, it is preferable to present the active Ingredient as a
pharmaceutical formulation. The carriers) must be "acceptable" in the sense of being compatible
with the other ingredients of the formulation and not deleterious to the recipient thereof.
Accordingly, the present invention further provides for a pharmaceutical formulation
comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof
together with one or more pharmaceutically acceptable carriers therefore and, optionally, other
therapeutic and/or prophylactic ingredients.
The formulations include those suitable for oral, parenteral (including subcutaneous e.g. by
injection or by depot tablet, intradermal, intrathecal, Intramuscular e.g. by depot and intravenous),
rectal and topical (including dermal, buccal and sublingual) administration although the most
suitable route may depend upon for example the condition and disorder of the recipient. The
formulations may conveniently be presented in unit dosage form and may be prepared by any of
the methods well known in the art of pharmacy. All methods include the step of bringing into
association the compounds ("active ingredient") with the carrier, which constitutes one or more
accessory ingredients. In general the formulations are prepared by uniformly and intimately
bringing into association the active ingredient with liquid carriers or finely divided solid carriers or
both and then, if necessary, shaping the product into the desired formulation.
Formulations suitable for oral administration may be presented as discrete units such as
capsules, cachets or tablets (e.g. chewable tablets in particular for paediatric administration) each
containing a predetermined amount of the active ingredient; as a powder or granules; as a
solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid
emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a
bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory
ingredients. Compressed tablets may be prepared by compressing in a suitable machine the
active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a
other conventional excipients such as binding agents, (for example, syrup, acacia, gelatin,
sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, lactose,
sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for
example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for
example, potato starch or sodium starch glycollate) or wetting agents, such as sodium lauryl
sulfate. Moulded tablets may be made by moulding in a suitable machine a mixture of the
powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated
or scored and may be formulated so as to provide slow or controlled release of the active
ingredient therein. The tablets may be coated according to methods well-known in the art.
Alternatively, the compounds of the present invention may be incorporated into oral liquid
preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for
example. Moreover, formulations containing these compounds may be presented as a dry
product for constitution with water or other suitable vehicle before use. Such liquid preparations
may contain conventional additives such as suspending agents such as sorbitol syrup, methyl
cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum
stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan mono-
oleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil,
fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as
methyl or propyl p-hydroxybenzoates or sorbic acid. Such preparations may also be formulated
as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other
glycerides.
Formulations for parenteral administration include aqueous and non-aqueous sterile
injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended recipient; and aqueous and non-
aqueous sterile suspensions which may include suspending agents and thickening agents.
The formulations may be presented in unit-dose or multi-dose containers, for example
sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring
only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to
use. Extemporaneous injection solutions and suspensions may be prepared from sterile
powders, granules and tablets of the kind previously described.
Formulations for rectal administration may be presented as a suppository with the usual
carriers such as cocoa butter, hard fat or polyethylene glycol.
Formulations for topical administration in the mouth, for example buccally or sublingually,
include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia
or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and
glycerin or sucrose and acacia.
The compounds may also be formulated as depot preparations. Such long acting
formulations may be administered by implantation (for example subcutaneously or
intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be
formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an
acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a
sparingly soluble salt.
In addition to the ingredients particularly mentioned above, the formulations may include
other agents conventional in the art having regard to the type of formulation in question, for
example those suitable for oral administration may include flavouring agents.
It will be appreciated by those skilled in the art that reference herein to treatment extends to
prophylaxis as well as the treatment of established diseases or symptoms. Moreover, it will be
appreciated that the amount of a compound of the invention required for use in treatment will vary
with the nature of the condition being treated and the age and the condition of the patient and will
be ultimately at the discretion of the attendant physician or veterinarian. In general, however,
doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day,
preferably 1-1500 mg per day. The desired dose may conveniently be presented in a single dose
or as divided doses administered at appropriate intervals, for example as two, three, four or more
sub-doses per day. The formulations according to the invention may contain between 0.1-99% of
the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid
preparations.
The compound of formula (I) for use in the instant invention may be used in combination
with other therapeutic agents for example, statins and/or other lipid lowering drugs for example
MTP inhibitors and LDLR upregulators. The compounds of the invention may also be used in
combination with antidiabetic agents, e.g. metformln, sulfonylureas and/or PPAR gamma, PPAR
alpha or PPAR alpha/gamma agonists (for example thiazolidinediones such as e.g. pioglitazone
and rosiglitazone). The compounds may also be used in combination with antihypertensive
agents such as angiotensin antagonists e.g. telmisartan, calcium channel antagonists e.g.
lacidipine and ACE inhibitors e.g. enalapril. The invention thus provides in a further aspect the
use of a combination comprising a compound of formula (I) with a further therapeutic agent in the
treatment of a hPPAR mediated disease.
When the compounds of formula (I) are used in combination with other therapeutic agents,
the compounds may be administered either sequentially or simultaneously by any convenient
route.
The combinations referred to above may conveniently be presented for use in the form of a
pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as
defined above optimally together with a pharmaceutically acceptable carrier or excipient comprise
a further aspect of the invention. The individual components of such combinations may be
administered either sequentially or simultaneously in separate or combined pharmaceutical
formulations.
When combined in the same formulation it will be appreciated that the two compounds must
be stable and compatible with each other and the other components of the formulation and may
be formulated for administration. When formulated separately they may be provided in any
convenient formulation, conveniently in such a manner as are known for such compounds in the
art.
When a compound of formula (I) is used in combination with a second therapeutic agent
active against the same hPPAR mediated disease, the dose of each compound may differ from
that when the compound is used alone. Appropriate doses wilt be readily appreciated by those
skilled in the art.
Compounds of this invention may be conveniently prepared by a general process wherein a
moiety like (A) is coupled to an alcohol (B) using the Mitsunobu protocol (O. Mitsunobu, 1981,
Synthesis p1) or by alklylaton of (A) using a suitable non nucleophilic base such as K2CO3,
Cs2CO3 or NaH, with an alkyl halide (C).
Compounds of this invention may be conveniently prepared by a general process wherein a
moiety like (A) is coupled to an alcohol (B) using the Mitsunobu protocol (O. Mitsunobu, 1981,
Synthesis p1) or by alklylaton of (A) using a suitable non nucleophilic base such as K2CO3,
Cs2CO3 or NaH, with an alkyl halide (C).
Note this synthesis is preferably carried out with the acid group protected by R to give
intermediate (D). Preferably R is C1-6alky! which can be hydrolysed to give an acid of formula (1),
or if readily hydrolyzable, the resulting ester can be administered. The groups R1-R7 and X1 of
intermediate (D) can be further modified to provide further compounds of formula (1) by standard
chemistry.

Intermediates of formulae (A), (B), (C) and (D) are commercially available or may be
synthesised as outlined below. Alcohol (B) can be converted to alkyl halide (C) using standard
halogenation conditions.
For example, when X1 is O or S, the following synthetic schemes may be followed.
Scheme 1
Mitsunobu followed by hydrolysis
The following synthetic schemes may be followed to prepare intermediate (B) where R5 is H
and 'ring" represents a phenyl or a 6 membered heteroaryl group containing 1, 2 or 3 nitrogen
atoms:
Scheme 8
Alkylation, then Suzuki followed by reduction (or reduction followed by Suzuki) of a
carboxylic acid derivative (E).
Scheme 9
Oxidation, then Suzuki followed by alkylation (or alkylation followed by Suzuki) of an alcohol
derivative (F).
Other intermediates may be prepared as described in text below or in published literature
e.g. WO 01/00603 and their synthesis will be apparent to a person skilled in the art.
The following illustrates Intermediates and Examples of Formula 1 which should not be
construed as constituting a limitation thereto.
General purification and analytical methods
LC/MS refers to analysis by analytical HPLC which was conducted on a Supelcosil
LCABZ+PLUS column (3um, 3.3cm x 4.6mm ID) eluting with 0.1% HCO2H and 0.01 M
ammonium acetate in water (solvent A), and 95% acetonitrile and 0.05% HCO2H in water (solvent
B), using the following elution gradient 0-0.7 minutes 0%B, 0.7-4.2 minutes 0-*100%B, 4.2-5.3
minutes 100%B, 5.3-5.5 minutes 100?0%B at a flow rate of 3 ml/minute. The mass spectra (MS)
were recorded on a Fisons VG Platform mass spectrometer using electrospray positive ionisation
[(ES+veto give [M+H]+and [M+NH4]+molecular ions] or electrospray negative ionisation [(ES-ve
to give [M-H]- molecular ion] modes.
1H NMR spectra were recorded using a Bruker DPX 400MHz spectrometer.
Biotage™ chromatography refers to purification carried out using equipment sold by Dyax
Corporation (either the Flash 40i or Flash 150i) and cartridges pre-packed with KP-Sil™ silica.
OPTIX refers to purification using CombiFlash Optix 10 equipment provided by Isco Inc.
Mass directed auto-prep HPLC refers to the method where the material was purified by high
performance liquid chromatography on a HPLCABZ+ 5um column (5cm x 10mm i.d.) with 0.1%
HCO2H in water and 95% MeCN, 5% water (0.5% HCO2H) utilising the following gradient elution
conditions: 0-1.0 minutes 5%B, 1.0-8.0 minutes 5?30%B, 8.0-8.9 minutes 30%B, 8.9-9.0 minutes
30?95%B, 9.0-9.9 minutes 95%B, 9.9-10 minutes 95?0%B at a flow rate of 8ml/minute. The
Gilson 202-fraction collector was triggered by a VG Platform Mass Spectrometer on detecting the
mass of interest.
Hydrophobic frits refers to filtration tubes sold by Whatman.
SPE (solid phase extraction) refers to the use of cartridges sold by International Sorbent
Technology Ltd.
TLC (thin layer chromatography) refers to the use of TLC plates sold by Merck coated with
silica gel 60 F254.
Et2O: diethyl ether
EtOAc: ethyl acetate
MeCN: acetonitrile
MeOH: methanol
nBu3P: tributylphosphine
R1: retention time
TBAF: tetrabutylammonium fluoride
THF: tetrahydrofuran
br: broad
s: singlet
d: doublet
dd : doublet of doublets
t: triplet
q: quartet
m: multiplet
rt: room temperature
Intermediate 1
6-Bromo-N-methoxy-N-methylpyridine-2-carboxamlde
To a slurry of 6-bromopicolinic acid (5.44 g, 26.93 mmol) in DCM (100 mL) was added a
solution of CDI (5.67 g, 34.97 mmol) in DCM (70 mL) drop-wise over 15 minutes under nitrogen.
The solution cleared a little during the addition but remained cloudy and after 1 hour at rt the
mixture was treated drop-wise over 15 minutes with N,O-dimethylhydroxylamine [solution in DCM
prepared by treating N,O-dimethylhydroxylamine hydrochloride (5.35 g, 53.82 mmol) with
aqueous NaOH (2M, 100 mL) and extracting with DCM (2 x 100 mL)]. The mixture cleared during
the addition and the resulting clear pale yellow solution was left to stir under nitrogen for 20 hours.
The mixture was then reduced under vacuum and the residue partitioned between EtOAc (125
mL) and saturated aqueous NaHCO3 (125 mL). The layers were then separated and the organic
layer washed with brine (125 mL), dried (MgSO4), filtered and reduced to give the title compound
as a yellow oil (5.29 g).
LC/MS: m/z 245.0 [M+H]+, R, 2.27 min.
Intermediate 2
1-(6-Bromo-2-pyridinyl)-1-pentanone (Method A)
To a solution of 6-bromo-/V-methoxy-/V-methylpyridine-2-carboxamide (5.29 g, 21.58 mmol)
in dry THF (120 mL) at -78°C (dry ice/acetone bath) under nitrogen was added nBuMgCI (15.2
mL of a 20%wt solution in THF/toluene, 25.84 mmol) drop-wise over 15 minutes. The resulting
yellow mixture was stirred at this temperature for 1 hour and was then allowed to warm to 0°C
(ice/water bath) slowly over 1.5 hours and then to rt over 18 hours. The yellow cloudy mixture
was then added portion-wise to a stirred solution of aqueous HCI (2M, 200 mL) and the resulting
mixture partitioned with EtOAc (200 mL) and the layers separated. The aqueous was re-
extracted with EtOAc (200 mL) and the combined organic layer washed with brine (300 mL), dried
(MgSO4) filtered and reduced to give a yellow/orange oil. Purification by Biotage™
chromatography (silica) eluting with cyclohexane: EtOAc (gradient 20:1 to 1:2) afforded the title
compound (2.51 g).
LC/MS: m/z 242.0 [M+H]+, R1 3.57 min.
A solution of 1-(6-bromo-2-pyridinyl)-1-pentanone (2.51 g, 10.37 mmol) in DME (13 mL)
was treated with 4-(triflouromethyl)benzeneboronic acid (2.36 g, 12.43 mmol), Pd(PPh3)4 (1.19 g,
1.03 mmol) and then a slurry of Na2CO3 (3.29 g, 31.04 mmol) in water (13 mL). The resulting
mixture was then heated to reflux over 30 minutes and then stirred at this temperature for 17
hours. The mixture was then allowed to cool to rt and was reduced and the residue partitioned
between EtOAc (200 mL) and water (200 mL). The aqueous was re-extracted with EtOAc (100
mL) and the combined organic layer washed with saturated aqueous NaHCO3 (250 mL), brine
(250 mL), dried (MgS04), filtered and reduced to give a brown orange solid residue. Purification
by Biotage™ chromatography (silica) eluting with cyclohexane: EtOAc (gradient 1:0 to 10:1)
afforded the title compound as a white solid (3.02 g).
LC/MS: m/z 308.2 [M+Hf, R,4.14 min.
A mixture of 1 -{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1 -pentanone (2.80 g, 9.11 mmol) In
THF (61 mL) at 0°C (ice/water bath) was treated drop-wise with a mixture of sodium borohydride
(689 mg, 18.21 mmol) in water (11 mL) over 5-10 minutes. The resulting mixture was stirred at
this temperature for 2.5 hours and was then partitioned between EtOAc (200 mL) and water (200
mL) and the layers separated. The aqueous was re-extracted with EtOAc (200 mL) and the
combined organic layer washed with brine (250 mL), dried (MgSO4), filtered and reduced.
Purification by Biotage™ chromatography (silica) eluting with cyclohexane : EtOAc (gradient 20:1
to 5:1) afforded the title compound as a colourless oil (2.81 g).
LC/MS: m/z 310.2 [M+H]+, R1 3.87 min.
A solution of 6-bromo-2-pyridinecarboxaldehyde (512 mg, 2.75 mmol) and 4-
(triflouromethyl)benzeneboronic acid (522 mg, 2.75 mmol) in DME (46 mL) was treated a slurry of
Na2CO3 (875 mg, 8.26 mmol) in water (23 mL) followed by Pd(PPh3)4 (64 mg, 0.06 mmol). The
resulting mixture was then heated to reflux, under nitrogen over 30 minutes and then stirred at
this temperature for 17 hours. The mixture was then allowed to cool to rt, was reduced under
vacuum and the residue partitioned between EtOAc (50 mL) and water (50 mL) and the layers
separated. The aqueous was re-extracted with EtOAc (100 mL) and the combined organic layer
washed with brine (100 mL), dried (MgSO4), filtered and reduced to give a yellow solid residue.
Purification by SPE (silica) eluting with cyclohexane: EtOAc (gradient 1:0 to 10:1) afforded the
title compound as a yellow foam (565 mg).
LC/MS: m/z 251.9 [M+H]+, R1 3.57 min.
Intermediate 4
1 -{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (Method B)
A solution ot 6-|4-(trifiuorometnyi)pnenyl]-2-pynainecarbaicienyde (2.50 g, 9.95 mmol) in dry
THF (100 mL) was cooled to 0°C (ice/water bath) and treated with nBuLi (6.8 mL of a 1.6M
solution in hexanes, 10.88 mmol) under nitrogen drop-wise over 20 minutes. The resulting deep
red coloured solution was stirred at 0°C for 1.5 hours and then quenched by the addition of
aqueous HCI (2M, 10 mL) and allowed to warm to rt over about 20 minutes. The solvents were
then removed under vacuum and the residue partitioned between EtOAc (150 mL) and saturated
aqueous NaHCO3 (150 mL) and the layers separated. The aqueous was re-extracted with EtOAc
(100 mL) and the combined organic layer washed with water (200 mL), brine (200 mL), dried
(MgSO4), filtered and reduced to give a pale yellow foam. Purification by Biotage™
chromatography (silica) eluting with cyclohexane : EtOAc (gradient 100:1 to 0:1) afforded the title
compound as a pale yellow oil (1.99 g).
LC/MS: m/z 310.2 [M+Hf, R1 3.87 min.
A mixture 3-bromobenzyl alcohol (500 mg, 2.70 mmol), 4-(triflouromethyl)benzeneboronic
acid (1.01 g, 5.35 mmol), Pd(PPh3) 4 (68 mg, 0.06 mmol) and Na2CO3 (740 mg, 7.02 mmol) in a
mixture of DME (20 mL) and water (10 mL) was heated at reflux for 3 hours. The mixture was
allowed to cool to rt, and then partitioned between EtOAc and water. The layers were separated
and the aqueous re-extracted with EtOAc (2x) and the combined organic layer washed with water
and then brine, dried (Na2SO4), filtered and reduced to give an oil. Purification by flash
chromatography (silica) eluting with cyclohexane: EtOAc (5:2) afforded the title compound as a
clear oil which crystallised on standing (654 mg).
LC/MS: Ft, 3.58 min, no molecular ion observed.
A solution of [4'-(trifluoromethyl)-3-biphenylyl]nnethanol (177 mg, 0.70 mmol) in dry DCM
(10 mL) was cooled to 0°C (ice/water bath) under nitrogen and treated with CBr4 (256 mg, 0.77
mmol) in one portion. PPh3 (202 mg, 0.77 mmol) was then added portion-wise and the resulting
mixture stirred for 1 hour at this temperature and was then allowed to warm to rt. The resulting
mixture was then reduced and the residue purified directly by SPE (silica, 10 g cartridge) eluting
with cyclohexane : DCM afforded the title compound as a colourless oil (220 mg).
LC/MS: Rt 3.94 min, no molecular ion observed.
A mixture of 3-(bromornethyl)-4'-(trifluoromethyl)biphenyl (200 mg, 0.63 mmol), ethyl (4-
mercapto-2-methylphenoxy)acetate (144 mg, 0.63 mmol) and polymer supported
diisopropylethylamine (3mmol/g, 423 mg, 1.27 mmol) in DCM (20 mL) was stirred at rt overnight.
TLC (cyclohexane: DCM 1:1) indicated bromide still remaining so more thiol (100 mg, 0.44 mmol)
was added and after 3 hours no change was observed by TLC. The mixture was then filtered,
reduced and purified using SPE (silica, 10 g cartridge). The residue was dissolved in DCM (10
mL) and treated with polymer supported isocyante resin (1.43 mmol/g. 2 g, 2.46 mmol) and stirred
at rt overnight. The mixture was then filtered, washing with DCM and reduced to give the title
compound (209 mg).
1H NMR (400MHz; CDCI3) d:1.29 (3H, t, J 7 Hz), 2.25 (3H, s), 4.05 (2H, s), 4.26 (2H, q, J 7
Hz), 4.60 (2H, s), 7.59 (2H, d, J 8.5 Hz), 7.68 (2H, d, J 8.5 Hz).
Borane (10.80 mL of a 1M solution in THF, 10.80 mmol) was added to a cooled solution of
5-bromo-2-methyl-benzoic acid (116 mg, 0.54 mmol) in THF (15 mL), under nitrogen, at 0°C (ice
water bath) and the resulting mixture allowed to warm to rt overnight. The mixture was then
treated with MeOH (10 mL) followed by aqueous HCl (2M, 20 mL) and the mixture stirred for
about 15 minutes, concentrated under vacuum and then partitioned with EtOAc. The organic
layer was washed with aqueous HCl (2M), water and brine, dried (MgSO4), filtered and reduced to
give the title compound as a colourless oil (90 mg).
LC/MS: Rt 3.09 min, no molecular ion observed.

To a solution of [4'-(trifluoromethyl)-3-biphenylyl]methanol (121 mg, 0.48 mmol) in dry THF
(5 mL) under nitrogen at 0°C (ice/water bath) was added nBu3P (240 uL, 0.96 mmol) followed by
ethyl 3-(4-hydroxy-2-methylphenyl)propanoate (100 mg, 0.48 mmol) and then ADDM (246 mg,
0.96 mmol) portion-wise. The mixture was stirred at 0°C for 1 hour, allowed to warm to rt over 21
hours and then partitioned between water and EtOAc, and the layers separated. The aqueous
layer was then extracted with EtOAc and the combined organic extract washed with water and
then brine, dried (Na2SO4) and the solvent removed under vacuum. Purification by flash
chromatography (silica) eluting with cyclohexane: EtOAc (15:1) afforded the title compound as a
clear oil (141 mg).
LC/MS: R14.43 min, no molecular ion observed.

A suspension of [4-(2-ethoxy-2-oxoethoxy)-3-methylbenzyl](triphenyl)phosphonium chloride
(500 mg, 0.99 mmol) in dry THF (10 mL) was cooled to 0°C (ice/water bath) and treated with NaH
(44 mg of a 60% dispersion in mineral oil, 1.10 mmol) portion-wise over 5 minutes. The resulting
yellow suspension was stirred for 15 minutes and was then treated with 3-bromobenzaidehyde
(184 mg, 0.99 mmol) in dry THF (5 mL). The resulting white suspension was allowed to warm to
rt over 3.5 hours and was then heated at reflux for 1 hour. The reaction mixture was then allowed
to cool to rt, stirred overnight and was then reduced under vacuum. The residue was then
partitioned between CHCI3 (20 mL) and water (20 mL) and the layers separated. The cloudy
organic layer was dried through a hydrophobic frit and then concentrated to a cream coloured
gum (700 mg). Purification by SPE (silica) eluting with cyclohexane: EtOAc (9:1) afforded the
title compound (mixture of E:Zisomers) (258 mg).
LC/MS: Rt 4.23 min and 4.31 min, no molecular ions observed.

Ethyl ({4-[2-(3-bromophenyl)ethenyl]-2-methylphenyl}oxy)acetate (150 mg, 0.40 mmol),
Na2CO3 (106 mg, 1.00 mmol), 4-(triflouromethyl)benzeneboronic acid (83.5 mg, 0.44 mmol) and
Pd(PPh3)4 (23 mg, 0.02 mmol) was dissolved in DME and water (2:1,6 mL) and the mixture
heated at reflux for 4 hours. The mixture was allowed to cool to rt, was concentrated under
reduced pressure and the residue partitioned between EtOAc (15 mL) and water (15 mL). The
aqueous layer was then acidified with aqueous HCI (1N) and extracted with EtOAc and the
combined organic layers dried (MgSO4), filtered and reduced to give the title compound (94 mg).
LC/MS: m/z 411 [M-Hf, R1 4.45 min and 4.67 min.
I
A solution of the 2-(bromomethyl)-6-[4-(trifluoromethyl)phenyl]pyridine (238 mg, 0.75
mmol), ethyl (4-mercapto-2-methylphenoxy)acetate (84 mg, 0.37 mmol) and K2CO3 (57 mg, 0.41
mmol) in MeCN (5 mL) was stirred at rt, under nitrogen overnight. The mixture was then
partitioned between water and EtOAc and the layers separated. The organic layer was then
washed with water and brine, dried (MgSO4), filtered and reduced. Purification by SPE (silica, 2g
cartridge) eluting with CHCI3: cyclohexane (5:1) afforded the title compound (160 mg).
LC/MS: m/z 462.3 [M+H]+, R1 4.10 min.
A solution of 3-bromoacetophenone (661 µL, 5.00 mmol) and 4-
(triflouromethyl)benzeneboronic acid (950 mg, 5.00 mmol) in DME (50 mL) was added Na2CO3
(1.32 g, 12.50 mmoi) and Pd(PPh3)4 (283 mg, 0.24 mmol) and water (25 mL). The mixture was
then stirred at 100oC for 20 hours, diluted with water and extracted with EtOAc. The organic layer
was then washed with brine, dried (Na2SO4), filtered and reduced. Purification by flash
chromatography (silica) eluting with petrol: EtOAc (gradient 19:1 to 9:1) afforded the title
compound (1.01 g).
LC/MS: R1 3.62 min, no molecular ion observed.
A mixture of 1-[4'-(trifluoromethyl)-3-biphenylyl]ethanone (300 mg, 1.14 mmol) in water (1
mL) and EtOH (5 mL) was treated portion-wise with sodium borohydride (57 mg, 1.50 mmol) and
then stirred at rt for 1.5 hours. The reaction was then quenched by the addition of saturated
aqueous NH4CI, diluted with CHCI3 and the layers separated. The organic layer was then dried
(Na2SO4), filtered and reduced to give the title compound (274 mg).
LC/MS: Rt 3.50 min, no molecular ion observed.
Zinc (229 mg, 3.50 mmol) was added to EtOAc (10 mL) followed by AcOH (115 µM, 2.00
mmol) and ethyl [4-(chlorosulfonyl)-2-methylphenoxy]acetate (293 mg, 1.00 mmol). After 2 hours,
dichlorodimethylsilane (258 mg, 2.00 mmol) was added followed by 1 -[4'-(trifluoromethyl)-3-
biphenylyl]ethanol (266 mg, 1.00 mmol) and the mixture stirred for a further 1 hour and then
heated at 80°C for 5 hours. The mixture was then cooled, diluted with EtOAc and washed with
saturated aqueous NaHCO3, saturated aqueous NH4CI, water and brine, and then reduced.
Purification by Biotage™ chromatography (silica) eluting with petrol: EtOAc (9:1) afforded the title
compound as a colourless oil (238 mg).
LC/MS: m/z 492.2 [M+NH4]+, Rt 4.28 min.

Prepared according to the procedure used for the preparation of Intermediate 14, starting
from 4-bromoacetophenone (661 µL, 5.00 mmol), to give, after purification by Biotage™
chromatography (silica) eluting with petrol: EtOAc (8:1), the title compound (1.10 g).
LC/MS: Rt 3.63 min, no molecular ion observed.

Prepared from 1-[4'-(trifluoromethy!)-4-biphenylyl]ethanone (305 mg, 1.15 mmol) according
to the procedure used for the preparation of Intermediate 15 to give the title compound (324 mg).
LC/MS: Rt 3.54 min, no molecular ion observed.
Prepared from 1-[4'-(trifluoromethyl)-4-biphenylyl]ethanol (324 mg, 1.15 mmol) according to
the procedure used for the preparation of Intermediate 16, to give, after purification by Biotage™
chromatography (silica) eluting with petrol: EtOAc (8:1), the title compound as a colourless oil
(333 mg).
LC/MS: m/z 492.2 [M+NH4]+, Rt 4.31 min.

To a solution of nBu3P (47 uL, 0.19 mmol) in dry THF (2 mL), at 0°C (ice/water bath) under
nitrogen was added DIAD (37 mL, 0.19 mmol). After stirring for 10 minutes 1-{6-[4-
(trifluoromethyl)phenyl]-2-pyridinyl}-1 -pentanol (50 mg, 0.16 mmol) was added, followed after
another 20 minutes by ethyl 2-(4-hydroxy-2-methylphenoxy)-2-methylpropanoate (39 mg, 0.16
mmol). The mixture was then allowed to warm to rt over 16 hours and was then reduced under
vacuum and the residue partitioned between EtOAc and water. The layers were separated and
the organic layer washed with water (2 x) then brine, dried (Na2SO4) and reduced to give a brown
gum. Purification by Biotage™ chromatography (silica, 40 g cartridge) eluting with cyclohexane:
EtOAc (19:1) afforded the title compound as a colourless gum (9 mg).
LC/MS: m/z 530.3 [M+H]+, Rt 4.61 min.
To 3-bromobenzaldehyde (5.00 g, 27.02 mmol) in dry THF (100 mL), under nitrogen at -
78°C (dry ice/acetone bath) was added nBuMgCI (16.2 mL of a 2.0M solution in THF, 0.032 mol)
and the reaction stirred for 1 hour at -78°C and then allowed to warm to rt overnight. The
reaction was then quenched with water, extracted with EtOAc and the layers separated. The
organic layer was washed with water then brine, dried (Na2SO4) and reduced under vacuum to
give a colourless oil. Purification by Biotage™ chromatography (silica, 90 g cartridge) eluting with
cyclohexane : EtOAc 9:1 afforded the title compound as a colourless oil (4.07 g).
LC/MS: Rt 3.49 min, no molecular ion observed.

To a solution of 1 -(3-bromophenyl)-1 -pentanol (1.00 g, 4.11 mmol) in dry THF (40 mL) at
0°C was added ethyl (4-hydroxy-2-methylphenoxy)acetate (865 mg, 4.11 mmol), PPh3 (1.30 g,
4.94 mmol) and ADDP (1.25 g, 4.94 mmol) and the reaction stirred for 30 minutes and then
allowed to warm to rt overnight. The mixture was then reduced under vacuum and the residue
partitioned between EtOAc and water and the layers separated. The organic layer was washed
with water (2 x) then brine, dried (Na2SO4) and reduced under vacuum to give a brown oil.
Purification by Biotage™ chromatography (silica, 90 g cartridge) eluting with petroleum ether 40-
60oC: EtOAc (gradient 1:0 to 9:1) afforded the title compound as colourless oil (1.15 g).
LC/MS: 454.0/455.1 [M+NH4]+, R, 4.28 min.

Ethyl [(4-{[1-(3-bromophenyl)pentyl]oxy}-2-methylphenyl)oxy]acetate (200 mg, 0.46 mmol)
was dissolved in dry THF (3 mL), and treated with 4-(trifluoromethyl)benzeneboronic acid (104
mg, 0.55 mmol), Pd(PPh3)4 (53 mg, 0.046 mmol) and sodium carbonate (146 mg, 1.38 mmol) in
water (2 mL). The mixture was then heated at 70°C for 3 hours, cooled to rt and partitioned
between EtOAc and water. The layers were separated and the organic layer washed with brine,
dried (Na2SO4) and concentrated to give a brown oil. Purification by Biotage™ qhromatography
(silica, 40 g cartridge) eluting with petroleum ether 40-60°C : EtOAc (19:1) afforded the title
compound as a colourless gum (142 mg).
LC/MS: m/z 518.2 [M+NH4]+, R, 4.55 min.

Prepared according to the procedure used for the preparation of Intermediate 23, starting
from ethyl [(4-{[1-(3-bromophenyl)pentyl]oxy}-2-methylphenyl)oxy]acetate (200 mg, 0.46 mmol)
and 4-chlorobenzene boronic acid (86 mg, 0.55 mmol) to give, after purification by Biotage™
chromatography (silica, 40 g cartridge) eluting with petroleum ether 40-60°C: EtOAc (19:1), the
title compound (137 mg).
LC/MS: m/z 484.2 [M+NH4]+, Rt 4.55 min.

To a solution of 1-(4-methylphenyl)-1-pentanone (1.00 g, 4.15 mmol) in DME (20 mL) and
water (10 mL) was added 4-(trifluoromethyl)benzeneboronic acid (870 mg, 4.57 mmol) and
Na2CO3 (1.10 g, 10.38 mmol). After 10 minutes under nitrogen, Pd(PPh3)4 (480 mg, 0.42 mmol)
was added portion-wise, and the mixture heated to reflux and stirred under nitrogen for 2 hours.
The reaction mixture was then allowed to cool to rt and the solvents removed under vacuum. The
resulting residue was partitioned between water and EtOAc, the layers separated and the
aqueous re-extracted with EtOAc (3 x 30mL). The combined organic extract was separated and
dried (MgSO4), and the solvent removed under vacuum. Purification by flash chromatography
(silica), eluting with cyclohexane : EtOAc (19:1) afforded the title compound as a white solid (850
mg).
LC/MS: m/z 307.1 [M+H]+, Rt 4.16 min.
To a solution of 1-[4'-(trif!uoromethyl)-4-biphenylyl]-1-pentanone (500 mg, 1.63 mmol) in
THF (16 mL) and water (8 mL) under nitrogen at 0°C (ice/water bath) was added sodium
borohydride (74 mg, 1.96 mmol) portion-wise. After stirring the mixture for 1 hour at rt, the
reaction was diluted with water (30 mL) and extracted into EtOAc (3 x 30 mL). The combined
organic extract was separated, dried (MgSO4) and reduced under vacuum to afford the title
compound as a colourless gum (490 mg).
LC/MS: Rt 3.96 min, no molecular ion observed.
To a solution of 1 -[4'-(trifluoromethyl)-4-biphenyiyl]-1-pentanol (250 mg, 0.81 mmol) in dry
THF (20 mL) under nitrogen at 0°C (ice/water bath) was added nBu3P (0.41 mL, 1.64 mmol),
followed by ethyl (4-hydroxy-2-methylphenoxy)acetate (170 mg, 0.81 mmol) and ADDM (420 mg,
1.64 mmol) portion-wise. After stirring the mixture for 18 hours at rt under nitrogen the solvent
was removed under vacuum. The residue was partitioned between water and EtOAc and the
aqueous re-extracted with EtOAc (3 x 30 mL). The organic combined extract was dried (MgSO4)
and then reduced under vacuum. Purification by flash chromatography (silica), eluting with
cyclohexane : EtOAc (9:1) afforded the title compound as a colourless gum (310 mg).
LC/MS: m/z 518.2 [M+NH4]+, Rt 4.55 min.
To a solution of 4 -chloro-4-biphenylcarbaldehyde (200 mg, 0.92 mmol) in anhydrous THF
(10 mL) under nitrogen at -78°C (dry ice/acetone) was added nBuMgCI (550 uL of a 2M solution
in THF, 1.10 mmol). The reaction mixture was stirred at -78°C for 1 hour and then at rt for 18
hours. The reaction was quenched by cautious addition of water (15 mL) and extracted with
EtOAc (3 x 20 mL). The combined organic extract was then dried (MgSO4) and reduced under
vacuum. Purification by flash chromatography (silica), eluting with cyclohexane: EtOAc (9:1)
afforded the title compound as a colourless gum (140 mg).
LC/MS: Rt 3.98 min, no molecular ion observed.
To a solution of 1-(4'-chloro-4-biphenylyl)-1-pentanol (140 mg, 0.51 mmol) in dry THF (15
mL) under nitrogen at 0oC (ice/water bath) was added nBu3P (250 µL, 1.02 mmol), followed by
ethyl (4-hydroxy-2-methylphenoxy)acetate (110 mg, 0.52 mmol) and ADDP (260 mg, 1.03 mmol)
portion-wise. After stirring the mixture for 18 hours at rt under nitrogen the solvent was removed
under vacuum. The residue was partitioned between water and EtOAc and extracted with EtOAc
(3 x 30 mL). The organic extract was separated and dried (MgSO4) and the solvent removed
under vacuum. Purification by flash chromatography (silica) eluting with cyclohexane: EtOAc
(9:1) afforded the title compound as a colourless gum (150 mg).
LC/MS: m/z 484.2 [M+NH4]+, Rt 4.51 min.
To a solution of 1-[4-(trifluoromethyl)-4-biphenylyl]-1-pentanol (250 mg, 0.81 mmol) in dry
DCM (15 mL) under nitrogen at 0°C (ice/water bath) was added thionyl chloride (590 µL, 8.09
mmol) drop-wise. After stirring the mixture for 30 minutes at rt under nitrogen, the reaction was
quenched by cautious addition of saturated aqueous NaHCO3 (20 mL) and extracted with DCM (3
x 30 mL). The organic extract was separated, washed with brine, dried (MgSO4) and the solvents
removed under vacuum to afford the title compound as a yellow gum (251 mg).
LC/MS: Rt 4.42 min, no molecular ion observed.

To a solution of ethyl (4-mercapto-2-methylphenoxy)acetate (170 mg, 0.75 mmol) in
anhydrous MeCN (15 mL) under nitrogen was added 4-(1 -chloropentyl)-4'-
(trifluoromethyl)biphenyl (500 mg, 1.53 mmol) and caesium carbonate (500 mg, 1.53 mmol). After
18 hours stirring under nitrogen at room temperature, the reaction mixture was filtered and the
solvent removed under vacuum. Purification by flash chromatography (silica), eluting with
cyclohexane : EtOAc (9:1) afforded a colourless gum (230 mg).
LC/MS: m/z 517.1 [M+H]+, Rt 4.64 min.
Separation of a 20 mg sample by chiral HPLC (2 x 25cm chiralpak A) eluting with 5%
IPA/heptane, 15ml/min, wavelength 215nm afforded ethyl {[2-methyi-4-({(1R)-1-[4'-
(trifluoromethyl)-4-biphenylyl]pentyl}thio)phenyl]oxy}acetate as a colourless oil (10 mg, Rt 8.2 min)
and ethyl {[2-methyl-4-({(1S)-1-[4'-(trifluoromethyl)-4-biphenylyl]pentyl}thio)phenyl]oxy}acetate as
a colourless oil (9 mg, Rt 9.8 min).
To a solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (711 mg, 2.30 mmol)
in dry THF (46 ml_) at 0°C (ice/water bath) was added ethyl (4-hydroxy-2-methylphenoxy)acetate
(483 mg, 2.30 mmol) followed one minute later by ADDM (1.18 g, 4.60 mmol) in one portion. The
resulting slightly cloudy orange mixture was stirred at rt for 2-3 mins and the treated with nBu3P
(1.15 mL, 4.61 mmol) drop-wise over about 4 minutes to give a clear pale yellow solution. After 2
hours of slow warming, the solution had become slightly cloudy and was allowed to warm further
to rt over 20 hours. The resulting cloudy mixture was then reduced under vacuum and the
residue partitioned between EtOAc (150 mL) and water (150 mL) and the layers separated. The
aqueous was re-extracted with EtOAc (150 mL) and the combined organic layers washed with
brine (250 mL), dried (MgSO4), filtered and reduced to give an oil. Purification by SPE (silica)
eluting with cyclohexane: EtOAc (gradient 50:1 to 10:1) afforded a pale yellow foam (827 mg).
LC/MS: m/z 501.9 [M+H]+, Rt 4.45 min.
Separation by chiral HPLC (2' x 20 cm chiralpak) eluting with heptane : EtOH (98:2),
50mL/min, wavelength 230nM afforded ethyl ({2-methyl-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}oxy)acetate (367 mg, Rt 8.5 min) and ethyl ({2-methyl-4-[((1R)-1-{6-[4-
(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetate (360 mg, Rt 10.0 min).

To a solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (1.50 g, 4.85 mmol)
in dry DCM was added SOCI2 (3.53 mL, 48.50 mmol), and the resulting solution stirred under
nitrogen for 3 hours at rt. The mixture was then reduced under vacuum to afford the title
compound as an oily yellow solid (1.65 g).
To a solution of 2-(1-chloropentyl)-6-[4-(trifluoromethyl)phenyl]pyridine (522 mg, 1.59 mmol)
in dry THF (20 mL) was added caesium carbonate (621 mg, 1.91 mmol) and ethyl (4-mercapto-2-
methylphenoxy)acetate (361 mg, 1.59 mmol). The resulting mixture was stirred under nitrogen for
60 hours at rt, then at 66°C for 18 hours. The cooled reaction mixture was then diluted with water
(50 mL), extracted with EtOAc (100 mL), the layers separated and the organic layer washed with
brine (50 mL), dried (Na2SO4) and the solvents removed under vacuum. Purification by Biotage™
chromatography (silica, 40 g cartridge) eluting with cyclohexane: EtOAc (19:1) afforded a
colourless oil (376 mg).
LC/MS: m/z 518.4 [M+H]+, Rt 4.51 min.
Separation of a 100 mg sample by chiral HPLC (2cm x 25cm chiralcel OJ) eluting with 5%
EtOH/heptane, 15ml/min, wavelength 215nm afforded ethyl ({2-methyl-4-[((1S)-1-{6-[4-
(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)thio]phenyl}oxy)acetate as a colourless oil (34 mg, Rt
12.4 min) and ethyl ({2-methyl-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)thio]phenyl}oxy)acetate as a colourless oil (29 mg, Rt 14.7 min).
To a cooled (0°C, ice/water bath) solution of a racemic mixture of Intermediates 36 and 37
(130 mg, 0.25 mmol) in methanol (1 mL) was added Oxone (49.5% KHSO5,204 mg, 0.33 mmol)
in water (1 mL). After 15 minutes the reaction was quenched with Na2S2O5 (237 mg, 1.24 mmol)
and diluted with water (10mL). The aqueous layer was extracted with CHCI3 (3 x 10mL) and the
combined organic layer washed with brine (10mL), dried (Na2SO4) and concentrated under
vacuum. Purification by SPE (silica, 5 g cartridge) eluting with cyclohexane : EtOAc (gradient
elution 10:1 to 2:1), afforded the title compound as a mixture of isomers (60 mg).
LC/MS: m/z 534.4 [M+H], Rt 3.88 min.

To a cooled 0°C (ice/water bath) solution of a racemic mixture of Intermediates 36 and 37
(43 mg, 0.08 mmol) in methanol (1 mL) was added Oxone (49.5% KHSO6,153 mg, 0.25 mmol) in
water (1 mL). After 4 hours 10 minutes the reaction was quenched with Na2S2Os (80 mg, 0.42
mmol) and diluted with water (10 mL). The aqueous layer was extracted with CHCI3 (3 x 10mL)
and the combined organic layers washed with brine (30 mL), dried (Na2SO4) and concentrated
under vacuum. Purification by SPE (silica, 5 g cartridge), eluting with cyclohexane: EtOAc
(gradient 10:1 to 2:1) afforded the title compound (28 mg).
LC/MS: m/z 550.2 [M+H]+, Rt 4.09 min.

To a solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridlnyl}-1 -pentanol (349 mg, 1.13 mmol)
in dry THF (22.5 mL) at 0°C (ice/water bath) under nitrogen was added methyl-4-
hydroxyphenylacetate (187 mg, 1.13 mmol) followed after 1 minute by ADDM (578 mg, 2.25
mmol) in one portion. The resulting orange cloudy mixture was stirred for 3 minutes and then
treated with nBu3P (562 µL, 2.26 mmol) drop-wise over 1 minute. The resulting pale
yellow/orange mixture was then allowed to warm slowly to rt over 64 hours. The cloudy mixture
was then reduced under vacuum and the residue partitioned between EtOAc (50 mL) and water
(50 mL) and the layers separated. The aqueous was then re-extracted with EtOAc (50 mL) and
the combined organic layer washed with brine (100 mL) dried (MgSO4), filtered and reduced to
give an oil which was purified by SPE (silica) eluting with cyclohexane: EtOAc (gradient 100:1 to
5:1) to give the title compound (330 mg).
LC/MS: m/z 457.9 [M+H]+, Rt 4.32 min.

A solution of 2,6-dibromopyridine (1.00 g, 4.22 mmol) in THF (40 mL) was cooled to -78°C
(dry-ice/acetone bath) and treated with nBuLi (2.64 mL of a 1.6M solution in hexanes, 4.22 mmol)
drop-wise over 10 minutes under nitrogen. After 30 minutes at this temperature the pale
yellow/green solution was treated with butyraldehyde (400 uL, 4.44mmol) drop-wise over 5
minutes and the resulting orange/red solution stirred at this temperature for 1 hour. The solution
was then allowed to warm slowly to 0°C (ice/water bath) over 20 minutes and was then quenched
by the drop-wise addition of aqueous HCI (2M, 4 mL). The resulting pale yellow solution was
reduced to an oil, partitioned between EtOAc (100 mL) and aqueous HCI (2M, 100 mL), and the
layers separated. The aqueous was re-extracted with EtOAc (100 mL) and the combined organic
layer washed with water (150 mL), brine (150 mL), dried (MgSO4), filtered and reduced to an
orange/yellow oil. Purification by SPE (silica) eluting with cyclohexane : EtOAc (gradient 100:1 to
2:1) afforded the title compound (626 mg).

To a stirred solution of 1-(6-bromo-2-pyridinyl)-1-butanol (626 mg, 2.72 mmol) and ethyl (4-
hydroxy-2-methylphenoxy)acetate (539 mg, 2.56 mmol) in dry THF (51 mL) at 0°C (ice/water
bath) under nitrogen was added ADDM (1.32 g, 5.13 mmol) followed by nBu3P (1.28 mL, 4.95
mmol) drop-wise. The mixture was stirred with slow warming to rt over 18 hours and then
concentrated under vacuum, diluted with EtOAc (150 mL) and washed with water (3 x 75 mL),
dried (Na2SO4), filtered and reduced to give a yellow oil. Purification by SPE (silica, 20 g
cartridge) eluting with cyclohexane: EtOAc (gradient 20:1 to 10:1) afforded the title compound
(388 mg).
LC/MS: m/z 423.8 [M+H]+, Rt 3.92 min.

To a solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (99 mg, 0.32 mmol)
in dry THF (6.4 mL) at 0°C (ice/water bath) under nitrogen was added ethyl (4-
hydroxyphenoxy)acetate (63 mg, 0.32 mmol) followed after 1 minute by ADDM (164 mg, 0.64
mmol) in one portion. The resulting orange slurry was stirred for 2 minutes and then treated with
nBu3P (159 µL, 0.64 mmol) drop-wise over 1 minute. The resulting pale yellow/orange mixture
was then allowed to warm slowly to rt over 69 hours. The cloudy mixture was then reduced under
vacuum and the residue purified by SPE (silica) eluting with cyclohexane : EtOAc (gradient 100:1
to 1:1) to give the title compound (42 mg).
LC/MS: m/z 487.9 [M+H]+, Rt 4.33min.

To a stirred solution of the 1 -{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (50 mg,
0.16 mmol) and ethyl 3-(4-hydroxyphenyl)propanoate (31 mg, 0.16 mmol) in anhydrous THF (3.2
mL) under nitrogen at 0°C (ice/water bath) was added ADDM (83 mg, 0.32 mmol). After a few
minutes, nBu3P (81 µL, 0.32 mmol) was added (drop-wise) and the solution was stirred at 0°C
warming to rt overnight. After 17.5 hours the solvent was concentrated under vacuum and the
solid residue dissolved in DCM (5 mL) and washed with water (5 mL) using a hydrophobic frit.
The aqueous layer was re-extracted with DCM (5 mL) and the combined organic layers
concentrated under vacuum. The resulting solid residue was then purified by SPE (silica, 5 g
cartridge) eluting with cyclohexane : EtOAc (gradient 100:1 to 1:1) to afford the title compound (29
mg).
LC/MS: m/z 486.1 [M+H]+, Rt 4.33 min.
To a solution of nBuLi (26.40 mL of a 1.6M solution in hexanes, 42.24 mmol) in THF (25
mL) at -78°C (dry-ice/acetone bath) was added a solution 2,6-dibromopyridine (10.00 g, 42.21
mmol) in THF (60 mL) drop-wise over 45 minutes under nitrogen. The resulting dark green
coloured solution was stirred at -78°C for 15 minutes and then valeraldehyde (6.70 mL, 63.01
mmol) was added drop-wise over 1 minute. The resulting dark purple coloured solution was
stirred at -78CC for 15 minutes and was then treated in one portion with a mixture of methanol (42
mL) and AcOH (2.70 mL, 47.16 mmol). The resulting pale yellow coloured solution was then
allowed to warm to rt slowly over 1 hour. The mixture was then diluted with saturated aqueous
NH4CI (200 mL) and the product extracted with EtOAc (2 x 200 mL). The combined organic layer
was then washed with brine (250 mL), dried (MgSO4), filtered and reduced to an orange oil
(10.31g, 100%). Purification of 7.14 g of this material by Biotage™ chromatography (silica)
eluting with cyclohexane : EtOAc (gradient 100:1 to 1:1) afforded the title compound as a clear,
pale yellow oil (4.48 g).
LC/MS: m/z 246.0 [M+H]+, Rt 3.03 min.

To a stirred solution of 1-(6-bromo-2-pyridinyl)-1-pentanol (2.00 g, 8.19 mmol) and ethyl (4-
hydroxy-2-methylphenoxy)acetate (1.89 g, 8.99 mmol) in dry THF (160 mL) at 0°C (ice/water
bath) under nitrogen was added ADDP (4.13 g, 16.37 mmol) portion-wise over 5 min followed by
nBu3P (1.07 mL, 4.30 mmol) drop-wise over 1 -2 min. The mixture was stirred with slow warming
to rt over 21 h and then concentrated under vacuum, diluted with EtOAc (300 mL) and washed
with water (200 mL). The aqueous layer was then re-extracted with EtOAc (300 mL) and the
combined organic layer washed with brine (350 mL), dried (MgSO4), filtered and reduced to give a
orange solid residue. Purification by SPE (silica, 20 g Cartridge) eluting with cyclohexane: EtOAc
(gradient 1:0 to 1:1) afforded the title compound (2.31 g).
A solution of 6-[4-(trifluoromethyl)phenyl]-2-pyridinecarbaldehyde (300 mg, 1.19 mmol) in
dry toluene (12 mL) under nitrogen was cooled to 0°C (ice/water bath) and treated with n-
pentylmagnesium bromide (0.66 mL of a 2M solution in Et20,1.31 mmol) and the resulting
mixture was stirred at 0°C for 2 hours. The reaction was then quenched by the cautious addition
of aqueous HCI (2M, 2 mL) and the solvent was removed under vacuum and the residue
partitioned between EtOAc (2 x 50 mL) and aqueous HCI (2M, 50 mL). The organic solution was
washed with water (60 mL) then brine (60 mL), dried (MgSO4) and reduced. Purification by SPE
(silica, 20g cartridge) eluting with cyclohexane : EtOAc (gradient 99:1 to 19:1) afforded the title
compound as a colourless oil (131 mg).
LC/MS: m/z 324.1 [M+H]+, Rt, 3.88 min.

A solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-hexanol (131 mg, 0.41 mmol) in
dry THF (15 mL) under nitrogen was cooled to 0°C and treated with ethyl (4-hydroxy-2-
methylphenoxy)acetate (85 mg, 0.41 mmol), ADDM (210 mg, 0.82 mmol) and nBu3P (204 µL,
0.82 mmol). The reaction mixture was then allowed to warm to rt slowly over 22 hours. The
solvent was removed under vacuum and the residue partitioned between EtOAc (2 x 30 mL) and
water (30 mL). The layers were separated and the organic layer dried (Na2SO4) and reduced.
Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane: EtOAc (49:1 to 24:1)
afforded the title compound as a colourless oil (80 mg).
A solution of 6-[4-(trif luoromethyl)phenyl]-2-pyridinecarbaldehyde (350 mg, 1.39 mmol) In
Et2O (14 mL) was cooled to 0°C. To this was slowly added the freshly prepared Grignard reagent
(1.26 mL, 1.53 mmol), prepared from magnesium turnings (500 mg, 0.02 mol) and 1-bromo-3-
methyl butane (2.34 mL, 0.02 mol) in dry Et2O (16.5 mL). The resulting mixture was stirred under
nitrogen at 0°C. After 1.5 hours, more Grignard reagent (0.3 mL, 0.36 mmol) was added and the
resulting mixture stirred at 0oC for a further 1.5 hours. The reaction mixture was then quenched
by cautious addition of aqueous HCI (2M, 3 mL) and the solvent removed under vacuum. The
residue was partitioned between EtOAc (30 mL) and water (20 mL), the layers separated and the
aqueous re-extracted with EtOAc (30 mL). The combined organic layer was washed with brine
(50 mL), dried (MgSO4) and reduced under vacuum. Purification by SPE (silica, 20 g cartridge),
eluting with cyclohexane: EtOAc (gradient 99:1 to 1:1) followed by EtOAc then MeOH afforded
the title compound as a colourless oil (179 mg).
LC/MS: m/z 324.1 [M+H]+, Rt 3.8 mln.

Prepared from 4-methyl-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (80 mg, 0.25
mmol) according to the procedure used for the preparation of Intermediate 48 to give, after
purification by SPE (silica, 10 g cartridge) eluting with cyclohexane: EtOAc (gradient 99:1 to 1:1)
afforded the title compound as a colourless oil (13.2 mg).
LCMS: m/z 516.2 [M+H], Rt 4.42 min.
Prepared from 6-[4-(trifluoromethyl)phenyl]-2-pyridinecarbaldehyde (500 mg, 1.99 mmol) in
Et2O (20 mL) and isobutylmagnesium bromide (1.1 mL of a 2M solution in Et20,2.2 mmol)
according to the procedure used for the preparation of Intermediate 47 to give, after purification
by SPE (silica, 10 g cartridge) eluting with cyclohexane : EtOAc (gradient 99:1 to 4:1) the title
compound as a white crystalline solid (215 mg).
LC/MS: m/z 310.1 [M+H]+, R, 3.74 min.

A solution of 3-methyl-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-butanol (180 mg, 0.58
mmol) in dry THF (12 mL) under nitrogen was treated with ethyl (4-hydroxy-2-
methylphenoxy)acetate(122 mg, 0.58 mmol) and cooled to 0°C. This was treated portion-wise
with ADDP (0.3 g, 1.2 mmol), then drop-wise with nBu3P (0.29 mL, 1.2 mmol). The resulting pale
yellow suspension allowed to warm to rt slowly over 16 hours. The solvent was removed under
vacuum and the residue partitioned between EtOAc (60 mL) and water (60 mL) and the layers
separated. The aqueous was re-extracted with EtOAc (60 mL) and the combined organic layer
dried (Na2SO4) and reduced. Purification by SPE (silica, 10 g cartridge) eluting with cyclohexane
: EtOAc (gradient 99:1 to 49:1) gave the title compound as a colourless oil (137 mg).
LC/MS: m/z 502.1 [M+H]+, Rt 4.31 min.
To a stirred solution of 1 -(6-bromo-2-pyridinyl)-1 -pentanol (250 mg, 1.02 mmol) and ethyl
(4-hydroxy-2-ethylphenoxy)acetate (230 mg, 1.02 mmol) in dry THF (21 mlL at 0°C (ice/water
bath) under nitrogen was added ADDP (517 mg, 2.04 mmol) followed by nBu3P (510 µL, 2.04
mmol) drop-wise. The mixture was stirred with slow warming to rt over 18 hours and then
concentrated under vacuum, diluted with EtOAc (150 mL) and washed with water (3 x 75 mL),
dried (MgS04), filtered and reduced to give an oil. Purification by SPE (silica, 10 g Cartridge)
eluting with cyclohexane: EtOAc (gradient 20:1 to 5:1) afforded the title compound (307 mg).
LC/MS: m/z 452.0 [M+H]+, Rt 4.03 min.

To a stirred solution of 2-(trimethylsilyl) ethanol (0.56 mL, 3.91 mmol) in THF (1 mL) at rt
under nitrogen, was added 4-DMAP (113 mg, 0.92 mmol) followed by EDC (177 mg, 0.92 mmol).
After about 1 minute Et3N (170 µL, 1.22 mmol) was added, drop-wise followed by 4-(4-
hydroxyphenyl)butanoic acid (150 mg, 0.83 mmol) in THF (4 mL) and the mixture stirred at rt for
18 hours. The mixture was then partitioned between Et2O (25 mL) and aqueous HCI (2M, 30 mL)
and the layers separated. The aqueous layer was re-extracted with Et2O (20 mL) and the
combined organic layer washed with brine (50 mL), dried (MgSO4) and concentrated under
vacuum to give a 'chalk-white' milky oil. Purification by SPE (silica, 5 g Cartridge) eluting with
cyclohexane: EtOAc (gradient 25:1 to 1:2) afforded the title compound (55mg).
LC/MS: m/z 298.2 [M+NH4]+, Rt 3.63 min.
To a stirred solution of 1 -{6-[4-(trifiuoromethyl)phenyl]-2-pyridinyl}-1-pentanol (62 mg, 0.20
mmol) and 2-(trimethylsilyl)ethyl 4-(4-hydroxyphenyl)butanoate (55 mg, 0.20 mtnol) in dry THF (4
mL) at 0°C (ice/water bath), under nitrogen, was added ADDP (102 mg, 0.40 mmol) followed by
nBu3P (100 µL, 0.40 mmol), and the mixture stirred with slow warming to rt over 64.5 hours. The
mixture was then concentrated under vacuum and the solid residue partitioned between DCM (5
mL) and water (5 mL) using a hydrophobic frit. The layers were separated and the aqueous layer
re-extracted with DCM (5 mL) and the combined organic layer reduced. Purification by SPE
(silica, 5 g Cartridge) eluting with cyclohexane : EtOAc (gradient 50:1 to 7.5:1) afforded the title
compound (42 mg).
LC/MS: m/z 572.2 [M+H]+, Rt 4.75 min.

Separation of ethyl [(4-{[1-(6-bromo-2-pyridinyl)pentyl]oxy}-2-methylphenyl)oxy]acetate
(Intermediate 46; 2.31 g, 5.29 mmol) by preparative chiral HPLC (1" x 25 cm Chiralpak AD)
eluting with 2% IPA in heptane, f = 15 mL/min, afforded ethyl [(4-{[(1 f?)-1 -(6-bromo-2-
pyridinyl)pentyl]oxy}-2-methylphenyl)oxy]acetate as a pale yellow oil (962 mg), R, 10.0 min.
Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 10% IPA in heptane, f = 1.0 mL/min,
wavelength 215 nm, R, 5.3 min (96.3 %ee) and ethyl [(4-{[(1S)-1-(6-bromo-2-pyridinyl)pentyl]oxy}-
2-methylphenyl)oxy]acetate as a pale yellow oil (901 mg), Rt 14.5 min. Analytical chiral HPLC (25
cm Chiralpak AD) eluting with 10% IPA in heptane, f = 1.0 mL/min, wavelength 215 nm, Rt 6.0
min (96.2 %ee).
To a solution of 1-[4-bromo-2-(methy!oxy)phenyl]ethanone(205 mg, 0.89 mmol),
4,4I4'>4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (250 mg, 0.98 mmol), potassium acetate
(263 mg, 2.68 mmol) in DMF (5.3 mL) was added PdCI2(dppf) (73 mg, 0.09 mmol) and the
resulting mixture heated under nitrogen at 85°C, overnight. The mixture was then reduced under
vacuum and the residue purified by SPE (Si) possessing a layer of celite on the top, and eluting
with cyclohexane:EtOAc (gradient 50:1 to 1:2) to afford the title compound as a solid (146 mg).
LC/MS: m/z 277.1 [M+H]+, Rt 3.28 min.
A suspension of 1,1 '-carbonyldiimidazole (23.20 g, 0.14 mol) in dry DCM (240 mL) was
added portion-wise over 15 min to a solution of 3-methoxypropionic acid (10.00 mL, 0.11 mol) in
DCM (100 mL) under nitrogen at room temperature. The resulting solution was stirred under
nitrogen for 1 h and then treated with a solution of N-ethylbenzylamine (32.70 mL, 0.22 mol) in dry
DCM (140 mL) drop-wise over 50 min. The resultant pale brown solution was stirred under
nitrogen at room temperature for 16 h and then reduced in vacuo. The orange residue was
partitioned between EtOAc (500 mL) and saturated aqueous NaHCO3 (500 mL), the layers
separated and the organic layer washed with aqueous HCI (2M, 500 mL) and brine (350 mL).
Each of the aqueous washings was then re-extracted with EtOAC (250 mL) and the combined
organic layer dried (MgSO4), filtered and reduced In vacuo to give a yellow oil. Purification by
Biotage (silica, 5 x 90 g cartridges), eluting with cyclohexane:EtOAc 95:5 then 3:2 afforded the
title compound as a pale yellow oil (20.39 g).
LC/MS: m/z 222.2 [M+H]+, Rt 2.54 min.
To a solution of n-Butyllithium (1.6M in hexanes, 4.06 mL, 6.50 mmo!) in anhydrous THF
(4.0 mL) under nitrogen at -78°C was added a solution of 2,6-dibromopyridine (1.54 g, 6.50
mmol) in anhydrous THF (9.5 mL) drop-wise over 45 min. The resulting dark green solution was
stirred at -78°C for 15 min and then treated with N-ethyl-3-(methyloxy)-/v-
(phenylmethyl)propanamide (2.16 g, 9.76 mmol), washing in with anhydrous THF (3.0 mL). The
resulting green solution was stirred at -78°C for 15 min and was then treated with a solution of
AcOH (0.40 mL) in MeOH (6.60 mL) to give a pale brown solution. This mixture was removed
from the cooling bath and allowed to warm to room temperature, then stirred for 2 h. The mixture
was then treated with saturated aqueous. NH4CI (40 mL) and the products extracted with EtOAc
(2 x 50 mL). The combined organic layer was then washed with brine (60 mL), dried (MgSO4)
and the reduced in vacuo to give an orange oil. Purification by Biotage (silica, 90 g cartridge)
eluting with cyclohexane: EtOAc (10:1) afforded the title compound as a white solid (547 mg).
LC/MS: m/z 244.1/246.1 [M+H]+, Rt 2.65 min.
To a solution of 1-(6-bromo-2-pyridinyl)-3-(methyloxy)-1-propanone (547 mg, 2.24 mmol) in
anhydrous MeOH (15 mL) under nitrogen at 0°C was treated portion-wise with sodium
borohydride (127 mg, 3.36 mmol) over 10 min. The resulting solution was stirred under nitrogen
and gradually allowed to warm to room temperature over 2 h. The reaction mixture was then
diluted with aqueous HCI (0.5M, 20 mL) and the resulting mixture extracted with EtOAc (2 x 50
mL). The combined organic layer was dried (MgSO4) and reduced under vacuum to afford the
title compound as an off-white gum (551 mg).
LC/MS: m/z 246.0/248.0 [M+H]+, Rt 2.22 min.
A solution of diisopropylazodicarboxylate (1.44 mL,7.31 mmol) in dry THF (50 mg was
added drop-wise, under nitrogen, over 1.5 h (using a syringe pump) to a solution ethyl (4-hydroxy-
2-methylphenoxy)acetate (1.10 g, 5.21 mmol), 1-(6-bromo-z-pyridinyl)-3-(methyloxy)-1-propanol
(1.29 g, 5.24 mmol) and triphenylphosphine (1.92 g, 7.32 mmol) in dry THF (50 mL) at 0°C. The
resulting mixture was stirred under nitrogen and gradually allowed to warm to room temperature
over 19 h. The solvent was then removed in vacua and the residue purified by Biotage (silica, 90
g cartridge), elutlng with cyclohexane:EtOAc 85:15 to afford the title compound as a pale yellow
oil(1.32g).
LC/MS: m/z 438.1/440.1 [M+H]+, Rt 3.47 min.
Separation of ethyl [(4-{[1-(6-bromo-2-pyridinyl)-3-(methy!oxy)propyl]oxy}-2-
methylphenyl)oxy]acetate (1.32 g, 3.01 mmol) by preparative chiral HPLC (2" x 20 cm Chiralpak
AD) eluting with 5% EtOH in heptane, f = 40 mL/min, afforded ethyl [(4-{[(1R)-1-(6-bromo-2-
pyridinyl)-3-(methyloxy)propyl]oxy}-2-methylphenyl)oxy]acetate as a colourless oil (556 mg), Rt
10.0 min. Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 5% EtOH in heptane, f = 1.0
mL/min, wavelength 215 nm, R, 9.9 min (98.2 %ee) and ethyl [(4-{[(1S)-1-(6-bromo-2-pyridinyl)-3-
(methyloxy)propyl]oxy}-2-methylphenyl)oxy]acetate as a colourless oil (566 rng), Rt 12.5 min.
Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 5% EtOH in heptane, f = 1.0 mL/min,
wavelength 215 nm, Rt 11.7 min (94.9 %ee).

A suspension of 1,1'-carbonyldiimidazole (4.68 g, 28.86 mmol) in dry DCM (15 mL) was
added portion-wise over 15 min to a solution of ethoxyacetic acid (2.09 mL, 22.12 mmol) in DCM
(30 mL) under nitrogen at room temperature. The resulting solution was stirred under nitrogen for
1 h and then treated with a solution of N-ethylbenzylamine (6.60 mL, 44.37 mol) in dry
dichloromethane (30 mL) drop-wise over 15 min. The resultant solution was stirred under
nitrogen at room temperature for 18 h and then partitioned with aqueous HCI (2M, 2 X 75 mL) and
the combined organic layer dried (MgSO4), filtered and reduced in vacuo to give an oil.
Purification by SPE (silica, 2 x 50 g cartridges), eluting with cyclohexane:EtOAc gradient 15:1 to
1:1 afforded the title compound as a pale yellow oil (4.36 g).
LC/MS: m/z 222.2 [M+H], Rt 2.59 min.

To a solution of n-butyllithium (1.6M in hexanes, 4.19 mL, 6.70 mmol) in anhydrous THF
(4.0 mL) under nitrogen at -78°C was added a solution of 2,6-dibromopyridine (1.59 g, 6.71
mmol) in anhydrous THF (9.5 mL) drop-wise over 1 h. The resulting dark green solution was
stirred at -78CC for 15 min and then treated with N-ethyl-2-(ethyloxy)-N-(phenylmethyl)acetamide
(1.93 g, 8.70 mmol), washing in with anhydrous THF (1.0 mL). The resulting green solution was
stirred at -78°C for 15 min and was then treated with a solution of AcOH (0.42 mL) in MeOH (7.00
mL) to give a orange solution which was then treated with NaBH4 (0.38 g, 10.04 mmol). This
mixture was removed from the cooling bath and allowed to warm to room temperature over 2 h.
The mixture was then treated with saturated aqueous. NH4CI (50 mL) and the products extracted
with EtOAc (2 x 50 mL). The combined organic layer was then washed with brine (100 mL), driBd
(MgSO,t} and the reduced in vacua to give a yellow oil. Purification by SPE (silica, 20 g cartridge)
eluting with cyclohexane:EtOAc (gradient 50:1 to 1:1) afforded the title compound as a white solid
(612 mg).
LC/MS: m/z 246.0/248.0 [M+H]+, Rt 2.30 min.

A solution of diisopropylazodicarboxylate (0.96 mL, 4.89 mmol) in dry THF (35 mL) was
added drop-wise, under nitrogen, over 2 h (using a syringe pump) to a solution of ethyl (4-
hydroxy-2-methy!phenoxy)acetate (735 mg, 3.50 mmol), 1-(6-bromo-2-pyridinyl)-2-
(ethyloxy)ethanol (860 mg, 3.49 mmol) and triphenylphosphine (1.28 g, 4.88 mmol) in dry THF
(35 mL) at 0°C. The resulting mixture was stirred under nitrogen and gradually allowed to warm
to room temperature over 21 h. The solvent was then removed in vacuo and the residue purified
by SPE (silica, 2 x 50 g cartridge), eluting with cyclohexane:EtOAc (gradient 20:1 to1:1) to afford
the title compound as an oil (966 mg).
LC/MS: m/z 438.1/440.0 [M+H]+, Rt 3.67 min.

Intermediate 68 Intermediate 69
Separation of ethyl [(4-{[1-(6-bromo-2-pyridinyl)-2-(ethyloxy)ethyl]oxy}-2-
methylphenyl)oxy]acetate (966 mg, 2.20 mmol) by preparative chiral HPLC (2" x 20 cm Chiralcel
OD) eluting with 5% IPA in heptane, f = 50 mL/min, afforded ethyl [(4-{[(1R)-1-(6;bromo-2-
pyridiny!)-2-(ethyloxy)ethyl]oxy}-2-methylphenyl)oxy]acetate as a colourless oil (284 mg), Rt 14.0
min. Analytical chiral HPLC (25 cm Chiralcel ODH) eluting with 5% IPA in heptane, f = 1.0
mL/min, wavelength 215 nm, Rt 12.1 min (94.7 %ee) and ethyl [(4-{[(1 S)-1-(6-bromo-2-pyridinyl)-
2-(ethyloxy)ethyl]oxy}-2-methylphenyl)oxy]acetate as a colourless oil (273 mg), Rt 16.0 min.
Analytical chiral HPLC (25 cm Chiralcel ODH) eluting with 5% EtOH in heptane, f = 1.0 mL/min,
wavelength 215 nm, Rt 14.0 min (99.3 %ee).

To a stirring solution of 1-(6-bromo-2-pyridinyl)-1-pentanol (1.01g, 4.15 mmol) in chloroform
(27 mL) was added manganese oxide (14.24g, 0.16 mol) portion-wise over 4 h. The mixture was
then left to stir for an additional 3.5 h and was then filtered through celite placed directly on the
top of a SPE (silica, 20 g cartridge) eluting with chloroform. The filtrate was reduce under vacuum
and then purified further by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient
100:1 to 5:1) afforded the title compound as an oil (625 mg).
LC/MS: m/z 242.1/244.1 [M+H]\ R,3.50 min.

To a stirring solution of (S)-(-)-a,a-diphenyl-2-pyrrolidinemethanol (a,a-diphenyl-L-prolinol)
(840 mg, 3.32 mmol) in THF (3 mL) was added drop-wise trimethylborate (0.45 mL, 3.97 mmol) at
ambient temperature under nitrogen. After stirring for 1 h at this temperature, borane
dimethylsulfide (2M in THF, 2.5 mL, 5.00 mmol) drop-wise over 3-4 minutes. After the
effervescence had stopped, 1-(6-bromo-2-pyridinyl)-1-pentanone (797 mg, 3.29 mmol) in THF
(3.6 mL) was added over 1 h using a syringe pump. The mixture was stirred for an additional 5
minutes and the reaction was then quenched with aqueous HCI (2N, 5 mL) and the reaction
mixture stirred overnight at ambient temperature. The mixture was then reduced under vacuum
and the residue partitioned between EtOAc (30 mL) and water (30 mL) and the layers separated.
The aqueous was then re-extracted with EtOAc (30 mL) and the combined organic layer washed
with brine (50 mL) and then reduced under vacuum to give an oil. Purification by SPE (silica, 20 g
cartridge) eluting with cyclohexane:EtOAc (gradient 100:1 to 3:1) afforded the title compound as
an oil (712 mg).
LC/MS: m/z 244.1/246.1 [M+H]+, Rt 3.01 min.
Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 2% EtOH in heptane, f = 1.0
mL/min, wavelength 215 nm, Rt 11.7 min (97 %ee).

To a gently shaking solution of 1-(6-bromo-2-pyridinyl)-1-pentanol (1.00 g, 4.10 mmol) in
dry cyclohexane (100 mL) was added Lipase PS-C "Amano" {Pseudomonas cepacia) (9.97 g)
followed by vinyl acetate (1.5 mL, 16.27 mmol). Shaking was continued for 7.5 h with continual
monitoring by chiral HPLC. The mixture was then filtered and the filtrate reduced under vacuum
to give an oil which was purified by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc
(gradient 50:1 to 2:1) to afford (1 fl)-1-(6-bromo-2-pyridinyl)pentyl acetate as an oil (737 mg, 63%).
LC/MS: m/z 286.1/288.1 [M+H]+, Rt 3.38 min. Analytical chiral HPLC (25 cm Chiralpak AD)
eluting with 2% EtOH in heptane, f = 1.0 mL/min, wavelength 215 nm, (S-) R( 5.1 min and (R-) R,
5.4 min (43 %ee) and the title compound as an oil (349 mg).
LC/MS: m/z 244.1/246.1 [M+H]+, Rt 3.01 min.
Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 2% EtOH in heptane, f = 1.0
mL/min, wavelength 215 nm, Rt 12.7 min (95 %ee).

To a stirred solution of triethyl phosphonoacetate (1.40 mL, 7.06 mmol) in THF (40 mL) was
added portion-wise NaH (60% dispersion in mineral oil, 399 mg, 9.98 mmol) over 2-3 mins. After
effervescence had ceased, 2-methyl-4-benzyloxybenzaldehyde (1.50 g, 6.62 mmol) was added,
washing in with THF (4 mL), and the resulting mixture heated to reflux. After 4 h at this
temperature, the mixture was allowed to cool slowly to ambient temperature over night. Saturated
aqueous NH4CI (45 mL) was then added carefully and the organic solvent removed under
vacuum. The resulting aqueous mixture was then extracted with DCM (2 x 40 mL) and the
combined organic layer washed with brine (60 mL) and then concentrated under vacuum to give a
cream coloured solid. Purification by SPE (silica, 50 g cartridge) eluting with cyclohexane:EtOAc
(gradient 20:1 to 0:1) then EtOAc:MeOH (gradient 95:5 to 90:10) afforded the title compound as
an oil (1.22 g).
LC/MS: m/z 297.2 [M+H]+, Rt 3.80 min.

To a flask containing 10% Pd/C catalyst under nitrogen was added ethyl (2E)-3-{2-methyl-
4-[(phenylmethyl)oxy]phenyl}-2-propenoate (1.22 g, 4.12 mmol) in EtOH (15 mL) washing in with
more EtOH (2 x 4 mL). The reaction vessel was placed under an atmosphere of hydrogen and
stirred rapidly at ambient temperature for 19 h. The mixture was then filtered through a pad of
ceiite washing with EtOH and the filtrate reduced under vacuum. The residua was the purified by
SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 10:1 to 2:1) to afford the title
compound (548 mg).
LC/MS: m/z 436.2 [M+H]+, P., 4.07 min.

To a stirring solution of (1 R)-1 -(6-bromo-2-pyridinyl)-1 -pentanol (261 mg, 1.07 mmol) and
ethyl 3-(4-hydroxy-2-methylphenyl)propanoate (329 mg, 1.58 mmol) in THF (13 mL) at 0°C under
nitrogen was added ADDP (531 mg, 2.10mmol) followed by tri-N-butylphosphine (0.525 mL, 2.10
mmol) drop-wise. The resulting mixture was then stirred with slow warming to ambient
temperature over 15 h. The reaction mixture was then concentrated under vaccgm and the solid
residue purified directly by SPE (silica, 10 g cartridge) with a pad of celite on the top, eluting with
cyclohexane:EtOAc (gradient 100:1 to 20:1) to afford the title compound (350 mg).
LC/MS: m/z 434.1/436.1 [M+H]+, Rt 4.07 min.
Analytical chiral HPLC (25 cm Chiralcel OD-H) eluting with 2% IPA in heptane, f = 1.0
mL/min, wavelength 215 nm, Rt 5.7 min (96 %ee).

Prepared according to the procedure described for Intermediate 74, except starting from
(1 S)-1-(6-bromo-2-pyridlnyl)-1-pentanol (237 mg, 0.97 mmol) to give the title compound as an oil
(237 mg).
LC/MS: m/z 434.1/436.1 [M+H]+, Rt 4.07 min.
Analytical chiral HPLC (25 cm Chiralcel OD-H) eluting with 2% IPA in heptane, f = 1.0
mL/min, wavelength 215 nm, Rt 6.7 min (96 %ee).

To a stirring solution of 3-fluoro-4-hydroxybenzaldehyde (508 mg, 3.63 mmol) and CsCO3
(1.25 g, 3.84 mmol) in dry MeCN (5.6 mL) under nitrogen at ambient temperature was added
benzyl chloride (0.45 mL, 3.91 mmol) and the mixture heated at 40°C for 27 h. The mixture was
then allowed to cool to rt, was quenched by the addition of aqueous NaOH (2N, 30 mL) and the
product extracted with EtOAc (2 x 50 mL). The combined organic layer was then washed with
brine (80 mL) and reduced under vacuum. The residue was then purified by SPE (silica, 10 g
cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to 0:1) to afford the title compound as a
colourless solid (623 mg).
LC/MS: m/z 231.1 [M+H]+, Rt 3.26 min.
Prepared according to the procedure used to prepare Intermediate 72 starting from 3-
fluoro-4-[(phenylmethyl)oxy]benzaldehyde (620 mg, 2.69 mmol) except using 1.5 eq of triethyl
phosphonoacetate and heating for 18 h. The product was isolated and purified as described for
Intermediate 72, but contained some of the aldehyde starting material. Therefore, this crude
material was re-subjected to the reaction conditions described above and was isolated and
purified to give the title compound (605 mg).
LC/MS: m/z 301.2 [M+H]+, Rt 3.66 min.

A mixture of ethyl (2E)-3-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-2-propenoate (205 mg,
0.68 mmol) and 10% Pd/C catalyst (40 mg) in EtOH (4 mL) was stirred under an atmosphere of
hydrogen at ambient temperature for 16.5 h. The mixture was then filtered through celite placed
directly on the top of a SPE (silica, 5 g cartridge) eluting with EtOH. The filtrate was reduced
under vacuum and the residue purified further by SPE (silica, 5 g cartridge) eluting with
cyclohexane:EtOAc (gradient 25:1 to 3:1) to afford the title compound (140 mg).
LC/MS: m/z 213.1 [M+H]+, Rt 2.80 min.

Prepared according to the procedure used to prepare Intermediate 77 starting from 3-
methyl-4-[(phenylmethyl)oxy]benzaldehyde (1.00 g, 4.44 mmol) except that the reaction was re-
subjected to the reaction conditions twice before final purification. The title compound was
isolated as a cream coloured solid (1.10 g).
LC/MS: m/z 297.2 [M+H]+, Rt 3.86 min.

Prepared according to the procedure used to prepare Intermediate 78 starting from ethyl
(2E)-3-{3-methyI-4-[(phenylmethyl)oxy]phenyl}-2-propenoate (202 mg, 0.68 mmol) to give the title
compound (136 mg).
LC/MS: m/z 209.1 [M+H]+, Ft, 2.91 min.

To a stirred solution of triethyl phosphonoacetate (0.60 mL, 3.02 mmol) in THF (5 mL) was
added portion-wise NaH (60% dispersion in mineral oil, 360 mg, 9.00 mmol) over 2-3 mins. After
effervescence had ceased, 4-hydroxy-3,5-dimethoxybenzaldehyde (547 mg, 3.00 mmol) was
added portion-wise, washing in with THF (3 mL). More THF (2 x 2 mL) was added to the thick
slurry and the resulting mixture was then heated to reflux for 21 hours. The mixture was then
allowed to cool slowly to ambient temperature and the reaction quenched by the careful addition
of saturated aqueous NH4CI (20 mL). The organic solvent was then removed under vacuum and
the resulting aqueous mixture was then extracted with DCM (10 mL, 5 mL and then 2 mL) using
hydrophobic frits. The filtrate was then treated with Polymer Supported-TsNHNH2 resin (loading
3.22 mmol/g, 1.62 g, 5.23 mmol (3 eq wrt unreacted aldehyde)) and the mixture stirred for 16
hours to remove any unreacted aldehyde. The resin was then removed by filtration washing with
DCM (5 mL, 10 mL and then 5 mL) and the filtrate reduced under vacuum to give the title
compound (221 mg).
LC/MS: m/z 253.2 [M+H]+, Rt 2.76 min.
Intermediate 82
Prepared according to the procedure for Intermediate 81 starting from 3-ethoxy-4-
hydroxybenzaldehyde (500 mg, 3.00 mmol) to give the title compound (557 mg).
LC/MS: m/z 237.2 [M+H]+, Rt 3.03 min.

Prepared according to the procedure used to prepare Intermediate 78 starting from ethyl
(2£)-3-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-2-propenoate (130 mg, 0.52 mmol) to give the title
compound (80 mg).
LC/MS: m/z 255.1 [M+H]+, R,2.58 min.

To a stirring solution of 4-hydroxy-2-methoxybenzaldehyde (1.02g, 6.70 mmol) and malonic
acid (728 mg, 7.00 mmol) in pyridine (9.2 mL) at ambient temperature under nitrogen was added
piperidine (0.20 mL, 2.02 mmol) drop-wise. The mixture was then heated to 80°C over 20 mins
and then stirred at this temperature for 2 h. The reaction was then quenched with water (50 mL),
acidified to pH 1 with concentrated HCI and then partitioned with EtOAc (50 mL) and the layers
separated. The aqueous layer was re-extracted wit h EtOAc (50 mL) and the combined organic
layer washed with brine (80 mL) and then concentrated under vacuum to give a bright yellow
solid. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 25:1 to
0:1) afforded the title compound (674 mg).
LC/MS: m/z 195.1 [M+H]+, Rt 2.48 min.
Prepared according to the procedure used to prepare Intermediate 78 starting from (2£)-3-
[4-hydroxy-2-(methyloxy)phenyl]-2-propenoic acid (335 mg, 1.73 mmol) to give the title compound
(225 mg).
LC/MS: m/z 197.2 [M+H]+, Rt 2.25 min.

To a stirring solution of 3-[4-hydroxy-2-(methyloxy)phenyl]propanoic acid (229 mg, 1.17
mmol) in EtOH (14 mL) was added concentrated H2SO4 (0.031 mL, 0.58 mmol) and the reaction
heated at reflux under nitrogen for 1 h. The mixture was then cooled to ambient temperature
poured into ice (ca. 30 mL) and saturated aqueous Na2CO3 (60 mL) added. The mixture was
then extracted with EtOAc (2 x 50 mL) and the combined organic layer washed with brine (70 mL)
and concentrated under vacuum. The residue was then purified by SPE (silica, 5 g cartridge)
eluting with cyclohexane:EtOAc (gradient 10:1 to 2:1) to afford the title compound (217 mg).
LC/MS: m/z 225.2 [M+H]+, Rt 2.83 min.

A stirred solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (62 mg, 0.20
mmol) and ethyl (2E)-3-(4-hydroxy-3,5-dimethy(phenyl)-2-propenoate (79 mg, 0.36 mmol) in THF
(4 mL) at 0°C under nitrogen was added ADDP (101 mg, 0.40 mmol) followed by tri-N-
butylphosphine (0.100 mL, 0.40 mmol). The resulting mixture was then allowed to warm slowly to
ambient temperature overnight. After 66 h the solvent was removed under vacuum (Genevac)
and the resulting solid partitioned between DCM (5 mL) and water (5 mL), the layers separated
and the aqueous re-extracted with DCM (5 mL). The combined organic layer was then reduced
under vacuum and purified by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc
(gradient 20:1 to 1:1) to give the title compound (35 mg).
LC/MS: m/z 512.2 [M+H]+, Rt 4.53 min.

Prepared according to the procedure used to prepare Intermediate 90 starting from ethyl
(2E)-3-[4-hydroxy-3-(methyloxy)-5-(2-propen-1-yl)phenyl]-2-propenoate (94 mg, 0.36 mmol) to
give the title compound (102 mg).
LC/MS: m/z 554.2 [M+H]+, Rt 4.51 min.

Prepared according to the procedure used to prepare Intermediate 90 starting from ethyl
(2E)-3-[4-hydroxy-3-(2-propen-1-yl)phenyl]-2-propenoate (116 mg, 0.50 mmol) to give the title
compound (103 mg).
LC/MS: m/z 524.2 [M+Hf, R,4.60 min.
Intermediate 93
Ethyl (2E)-3-{3-(ethyloxy)-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}-2-propenoate
Prepared according to the procedure used to prepare Intermediate 90 starting from ethyl
(2E)-3-[3-(ethyloxy)-4-hydroxyphenyl]-2-propenoate (557 mg, 2.36 mmol) to give the title
compound (479 mg).
LC/MS: m/z 528.2 [M+H]+, Rt 4.41 min.

To a stirring solution of ethyl (2E)-3-{3,5-dimethyl-4-[(1-{6-[4-(trifluoromethyI)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}-2-propenoate (35 mg, 0.07 mmol) in THF (5 mL) and MeOH (5 mL) at
ambient temperature was added NaOH (2N, 5 mL) and the mixture stirred for 2 h and then left to
stand overnight. HCI (2N, 5 mL) was then added and the mixture reduced under vacuum. The
residue was then purified by SPE (silica, 5 g cartridge) with a pad of celite on the top, eluting with
cyclohexane:EtOAc (gradient 3:1 to 0:1) the EtOAc:MeOH (gradient 95:5 to 0:1) to give the title
compound (28 mg).
LC/MS: m/z 484.2 [M+H]+, Rt 4.40 min.

Prepared according to the procedure used to prepare Intermediate 94 starting from ethyl
(2E)-3-{3-(methyloxy)-5-(2-propen-1-yl)-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}-2-propenoate (102 mg, 0.18 mmol) to give the title compound (82
mg).
LC/MS: m/z 526.2 [M+H]+, Rt 4.30 min.

Prepared according to the procedure used to prepare Intermediate 94 starting from ethyl
(2E)-3-{3-(2-propen-1-yl)-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}-2-
propenoate (103 mg, 1.97 mmol) to give the title compound (39 mg).
LC/MS: m/z 496.2 [M+H]+, Rt 4.45 min.

Prepared according to the procedure used to prepare Intermediate 94 starting from ethyl
(2E)-3-{3-(ethyloxy)-4-[(1-{6-t4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}-2-
propenoate (479 mg, 0.91 mmol) to give the title compound (407 mg).
LC/MS: m/z 500.2 [M+H]+, Rt 4.21 min.
Intermediate 98 and Intermediate 99
(1 S)-1-{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol and (1 fl)-1-{6-[4-
(Trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol
Separation of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (2.50 g, 8.08 mmol) by
preparative chiral HPLC (2" x 20 cm Chiralpak AD) eluting with 5% IPA in heptane, f = 60 mL/min,
afforded (1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol as a pale yellow oil (1.03 g),
Rt 15.5 min. Analytical ohiral HPLC (25 cm Chiralpak AD) eluting with 10% EtOH in heptane, f =
1.0 mL/min, wavelength 215 nm, Rt 8.7 min (95.2 %ee) and (1R)-1-{6-[4-(trifluoromethyl)phenyl]-
2-pyridinyl}-1 -pentanol as a pale yellow oil (0.94 g), Rt 23 min. Analytical chiral HPLC (25 cm
Chiralpak AD) eluting with 10% EtOH in heptane, f = 1.0 mL/min, wavelength 215 nm, Rt 7.7 min
(97.1 %ee).

To a stirring solution of 3-chloro-4-hydroxy-5-methoxybenzaldehyde (599 mg, 3.21 mmol) in
DMF (5 mL) under nitrogen was added CS2CO3 (1.10 g, 3.38 mmol) followed by benzyl chloride
(0.40 mL, 3.48 mmol) and the mixture heated at reflux for 1 h. After allowing the mixture to cool
to ambient temperature the reaction was quenched by the addition of aqueous NaOH (2N, 30 mL)
and the mixture concentrated under vacuum. The residue was then partitioned between NaOH
(2N, 30 mL) and EtOAc (50 mL) and the layers separated. The aqueous layer was then re-
extracted with EtOAc (50 mL), the layers separated and the combined organic layer washed with
brine and then concentrated under vacuum. Purification by SPE (silica, 20 g cartridge) eluting
with cyclohexane:EtOAc (gradient 50:1 to 10:1) afforded the title compound (632 mg).
LC/MS: m/z 277.1 [M+H]+, Rt 3.47 min.
Intermediate 101
Ethyl (2E)-3-{3-chloro-5-(methyloxy)-4-[(phenylmethyl)oxy]phenyl}-2-propenoate
To a stirring solution of triethylphosphonoacetate (530 µL, 2.67 mmol) in dry THF (12 mL) at
ambient temperature under nitrogen was added NaH (60% dispersion in mineral oil, 107 mg, 2.68
mmol). After stirring for an additional few minutes 3-chloro-5-(methyloxy)-4-
[(phenylmethyl)oxy]benzaldehyde (495 mg, 1.79 mmol) was added in THF (10 mL) and the
resulting mixture heated at 80°C for 21 h. The mixture was then allowed to cool to ambient
temperature and the reaction then quenched with saturated aqueous NH4CI (12 mL) and the
product extracted with EtOAc (2 x 30 mL) and the combined organic layer washed with brine (50
mL) and then reduced under vacuum. Purification by SPE (silica, 10 g cartridge) eluting with
cyclohexane:EtOAc (gradient 50:1 to 5:1) afforded a mixture of product and starting material (515
mg). This mixture was then subjected to the conditions described above to push the reaction
further and was then worked-up as described. Purification by SPE (silica, 10 g cartridge) eluting
with cyclohexane:EtOAc (gradient 50:1 to 1:1) afforded the title compound (535 mg).
LC/MS: m/z 364.2 [M+NH4]+, Rt 3.84 min.

To a stirring solution of ethyl (2E)-3-{3-chloro-5-(methyloxy)-4-[(phenylmethyl)oxy]phenyl}-
2-propenoate (441 mg, 1.27 mmol) in EtOAc (9 mL) under nitrogen at ambient temperature was
added PtO2 (20 wt%, 88 mg) and the mixture stirred under an atmosphere of hydrogen for 18 h.
The resulting mixture was then purified by SPE (silica, 5 g cartridge) with a pad of celite on the
top, eluting with EtOAc. The filtrate was then reduced and purified further by SPE (silica, 10 g
cartridge) eluting with cyclohexane:EtOAc (gradient 20:1 to 3:1) to give the title compound (287
mg).
LC/MS: m/z 276.1 [M+NH4]+, Rt 2.97 min.
Intermediate 103
To a stirring solution of (1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (66 mg,
0.21 mmol) and ethyl 3-[3-chloro-4-hydroxy-5-(methyloxy)phenyl]propanoate (78 mg, 0.30 mmol)
in THF (4 mL) at 0°C under nitrogen was added ADDP (100 mg, 0.40 mmol) followed by nBu3P
(0.10 mL, 0.40 mmol). The resulting mixture was then stirred at 0°C with slow warming to
ambient temperature over 19 h and then reduced under vacuum (Genevac). The residue was
then purified by SPE (silica, 10 g cartridge) with a pad of celite on the top, eluting with
cyclohexane:EtOAc (gradient 100:1 to 3:1) to afford the title compound (118 mg).
LC/MS: m/z 550.1 [M+H]+, Rt 4.41 min.

Prepared according to the procedure used to prepare Intermediate 103 starting from (1S)-1-
{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (208 mg, 0.67 mmol) and 2-chloro-4-
hydroxybenzaldehyde (140,0.89 mmol) to afford the title compound (103 mg).
LC/MS: m/z 448.0 [M+H]+, Rt 4.38 min.
Prepared according to the procedure used to prepare Intermediate 103 starting from (1S)-1-
{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (196 mg, 0.63 mmol) and 3-chloro-4-
hydroxybenzaldehyde (141,0.90 mmol) to afford the title compound (55 mg).
LC/MS: m/z 448.0 [M+H]+, Rt 4.33 min.

Prepared according to the procedure used to prepare Intermediate 103 starting from (1R)-
1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (202 mg, 0.65 mmol) and 2-chloro-4-
hydroxybenzaldehyde (140,0.89 mmol) to afford the title compound (102 mg).
LC/MS: m/z 448.0 [M+H]\ R, 4.40 min.

Prepared according to the procedure used to prepare Intermediate 103 from (1R)-1-{6-[4-
(trifluoromethyl)phenyl]-2-pyridinyl}-1 -pentanol (208 mg, 0.67 mmol) and 3-chloro-4-
hydroxybenzaldehyde (141, 0.90 mmol) to afford the title compound (59 mg).
LC/MS: m/z 448.1 [M+H]+, Rt 4.33 min.
Intermediate 108
Ethyl (2E)-3-{2-chloro-4-[((1 R)-1-{6-[4-(trif luoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}-2-propenoate
To a stirring solution of triethylphosphonoacetate (64 u.L, 0.32 mmol) in dry THF (0.20 ml_)
at ambient temperature under nitrogen was added NaH (60% dispersion in mineral oil, 13 mg,
0.33 mmol). After stirring for an additional few minutes 2-chloro-4-[((1R)-1 -{6-[4-
(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]benzaldehyde (103 mg, 0.23 mmol) was added in
THF (0.8 mL) and the resulting mixture heated at 80°C for 17 h. The mixture was then allowed to
cool to ambient temperature and the reaction then quenched with saturated aqueous NH4CI (3
mL) and the product extracted with EtOAc (2 x 20 mL) and the combined organic layer washed
with brine (50 mL) and then reduced under vacuum. The crude reaction mixture was then
subjected to the conditions described above to push the reaction further and was then worked-up
as described. Purification by SPE (silica, 5 g cartridge) eluting with cyclohexane:EtOAc (gradient
50:1 to 15:1) afforded the title compound (103 mg).
LC/MS: m/z 518.1 [M+H]+, Rt 4.58 min.

Prepared according to the procedure used to prepare Intermediate 108 starting from 3-
chloro-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]benzaldehyde (55 mg, 0.12
mmol) to afford the title compound (54 mg).
LC/MS: m/z 518.2 [M+Hf, Ft, 4.54 min.
Intermediate 110
Ethyl (2E)-3-{2-chloro-4-[((1 S)-1-{6-[4-(trifluoromethyI)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}-2-propenoate
Prepared according to the procedure used to prepare Intermediate 108 starting from 2-
chloro-4-[((1 S)-1 -{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]benzaldehyde (102 mg, 0.23
mmol) to afford the title compound (111 mg).
LC/MS: m/z 518.1 [M+H]+, Rt 4.58 min.

Prepared according to the procedure used to prepare Intermediate 108 starting from 3-
chloro-4-[((1 S)-1 -{6-[4-(trif luoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]benzaldehyde (58 mg, 0.13
mmol) to afford the title compound (41 mg).
LC/MS: m/z 518.1 [M+H]+, Rt 4.53 min.

To a solution of 3-bromo-2-methyl benzoic acid (430 mg, 2.00 mmol) in anhydrous DCM,
under nitrogen at ambient temperature was added N,O-dimethylhydroxylamine hydrochloride (215
mg, 2.20 mmol), pyridine (0.18 mL, 2.23 mmol) and CBr4 (662 mg, 2.00 mmol). Triphenyl
phosphine (576 mg, 2.20 mmol) was added portion-wise over 10 min and the resulting mixture
stirred at ambient temperature for 2.5 h. The reaction mixture then reduced under vacuum and
purified by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 99:1 to 4:1) to
afford the title compound as a colourless oil (310 mg).
LC/MS: m/z 258.0/260.0 [M+H]+, Rt 2.73 min.
To a solution of 3-bromo-N,2-dimethyl-N-(methyloxy)benzamide (2.55 g, 9.88 mmol) in
anhydrous THF (28 mL) under nitrogen at -78°C was added a butylmagnesium chloride (20% wt
in THF/toluene, 6.94 mL, 11.90 mmol) drop-wise over 15 min. The resulting solution was stirred
at -78°C for 1 h, was allowed to warm to 0°C and then stirred with slow warming to ambient
temperature over 20 h. The reaction was then quenched with water (50 mL) and extracted with
EtOAc (2 x 60mL). Some saturated aqueous NH4CI was added to disperse the emulsion formed.
The resulting organic layer was then washed with brine (100 mL}, dried (Na2SO4), filtered and
reduced under vacuum. Purification by SPE (silica, 50 g cartridge), eluting with
cyclohexane:EtOAc (gradient 49:1 to 9:1) afforded the title compound as a colourless oil (706
mg).
LC/MS: m/z 272.1/274.0 [M+H]+, Rt 3.71 min.

To a solution of 1-(3-bromo-2-methylphenyl)-1-pentanone (706 mg, 2.77 mmol) in
anhydrous THF (12 mL) under nitrogen at 0°C was added sodium borohydride (209 mg, 5.53
mmol) in water (8 mL) and the resulting mixture stirred at 0°C for 2 h. Additional sodium
borohydride (105 mg, 2.77 mmol) was then added, along with more THF (40 mL), and the
resulting mixture stirred at 0oC for an additional 30 min. The reaction mixture was then partitioned
between EtOAc (50 mL) and water (50 mL), the layers separated, and the aqueous re-extracted
with EtOAc (50 mL). The combined organic solution was then dried (Na2SO4) filtered, and
reduced under vacuum. Purification by SPE (silica, 20 g cartridge), eluted with
cyclohexane: EtOAc (gradient 99:1 to 19:1) afforded the title compound as a colourless oil (495
mg).
LC/MS: m/z 274.1/276.1 [M+H]+, Rt 3.55 min.
Intermediate 115
Ethyl [(4-{[1-(3-bromo-2-methylphenyl)pentyl]oxy}-2-methylphenyl)oxy]acetate
To a solution of 1-(3-bromo-2-methylphenyl)-1-pentanol (495 mg, 1.92 mmol) in anhydrous
THF (40 mL) under nitrogen at 0°C was added portion-wise ethyl (4-hydroxy-2-
methylphenoxy)acetate (405 mg, 1.93 mmol), followed by slow addition (over 25 min) of ADDP
(971 mg, 3.85 mmol) and drop-wise addition of tributylphosphine (0.96 mL, 3.85 mmol). The
resulting mixture was then stirred for 16 h with gradual warming to ambient temperature. The
solvent was then removed under vacuum and the residue partitioned between EtOAc (100 mL)
and water (150 mL), the layers separated, and the aqueous re-extracted with EtOAc (100 mL).
The combined organic layer was then dried (Na2SO4), filtered and reduced under vacuum and the
resulting residue purified by SPE (silica, 50 g cartridge), eluting with cyciohexane:EtOAc (gradient
99:1 to 4:1) to afford the title compound as a colourless oil (495 mg).
LC/MS: m/z 466.0/468.1 [M+H]+, Rt 4.25 min.

A solution of nBuLi (7.90 mL of a 1.6M solution in hexanes, 12.64 mmol) in THF (7.6 mL)
was cooled to -78°C (dry-ice/acetone bath) under nitrogen and then treated with a solution of 2,6-
dibromopyridine (3.00 g, 12.66 mmol) in THF (17.8 mL) drop-wise over 30 min. The resulting
green solution was stirred at -78°C for 20 min and then treated with {[(1,1 -
dimethylethyl)(dimethyl)silyl]oxy)acetaldehyde (3.00 mL, 15.75 mmol) over 1 min to give a deep
purple/brown coloured solution which was stirred at this temperature for 15 min. The reaction
was then quenched by the addition of a mixture of MeOH (12.5 mL) and AcOH (0.8 mL, 13.90
mmol) In one portion and the resulting clear, pale yellow solution allowed to warm slowly to
ambient temperature over 1.25 h. The mixture was then partitioned between EtOAc (100 mL) and
saturated aqueous NH4CI (100 mL), and the layers separated. Trie aqueous was re-extracted
with EtOAc (100 mL) and the combined organic layer washed with brine (200 mL), dried (MgSO4),
filtered and reduced to give the title compound as a clear, pale yellow oil which was used directly
without lurther purification (4.61 g).
LC/MS: m/z 332.0/334.0 [M+H]+, Rt 3.64 min.

To a solution of Ph3P (1.10 g, 4.19 mmol) in dry THF (30 mL), was treated with ethyl [(4-
hydroxy-2-methylphenyl)oxy]acetate (696 mg, 3.31 mmol) and 1-(6-bromo-2-pyridinyl)-2-{[(1,1-
dimethylethyl)(dimethyl)silyl]oxy}ethanol (1.00 g, 3.01 mmol) and the resulting solution cooled to
0°C (ice/water bath) under nitrogen. DIAD (0.829 ml, 4.21 mmol) in THF (30 ml) was then added
drop-wise over 2 h using a syringe pump. The resulting mixture was then allowed to warm to
ambient temperature over 22.5 h and was then reduced under vacuum to give an orange oily
residue. Purification by SPE (silica, 10 g cartridge) eluting with cyclohexane: EtOAc (gradient,
1:1 to 0:1) afforded the title compound (429 mg).
LC/MS: m/z 524.1/526.1 [M+H]+, Rt 4.37 min.

To a stirred solution of ethyl ({4-[(1-(6-bromo-2-pyridinyl)-2-{[(1,1 -
dimethylethyl)(dimethyl)silyl]oxy}ethyl)oxy]-2-methylphenyl}oxy)acetate (273 mg, 0.52 mmol) in
DME (2.3 mL) was added 4-(trifluoromethyl)benzeneboronic (129 mg, 0.68 mmol), Pd(PPh3)4 (60
mg, 0.052 mmol) and Na2CO3 (165 mg, 1.56 mmol) and water (1.13 mL) was heated at 45°C for
21 hours and then allowed to cool to ambient temperature. The resulting mixture was then
reduced under vacuum, partitioned between water (90 mL) and EtOAc (100 mL)tand the layers
separated. The organic layer was re-extracted with EtOAc (100 mL) and the combined organic
layer washed with brine (100 mL), dried (MgSO4) filtered and reduced under vacuum. The
residue was then purified by SPE (silica, 10g cartridge) eluting with cyclohexane: EtOAc
(gradient, 30:1 to 3:1) to give the title compound (208 mg).
LC/MS: m/z 590.6 [M+H]+, Rt 4.59 min.

To a stirred solution of ethyl ({4-[(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-{6-[4-
(trifluoromethyl)phenyl]-2-pyridinyI}ethyl)oxy]-2-methy!phenyl}oxy)acetate (208 mg, 0.352 mmol)
in THF (3.5 mL) was added TBAF (1M in THF, 0.458 mL) dropwise over 1 min. The resulting
solution was then stirred at ambient temperature for 18 h. The mixture was then reduced under
vacuum and the residue purified by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc
(gradient 15:1 to 2:1) to afford the title compound (89 mg).
LC/MS: m/z 476.1 [M+H]+, Rt 3.78 min.

A solution of (ethyl [(4-mercapto-2-methylphenyI)oxy]acetate) (386 mg, 1.71 mmol), 1-(6-
bromo-2-pyridinyl)-2-(ethyloxy)ethano! (352 mg, 1.43 mmol) and PPh3 (450 mg, 1.72 mmol) in
DCM (17 mL) at 0°C under nitrogen was stirred for 10 mins and then treated drop-wise with DIAD
(0.34 mL, 1.73 mmol). The resulting mixture was then stirred, with slow warming to ambient
temperature over 18 h. The mixture was then reduced under vacuum and the resulting yellow oil
purified by SPE (silica, 20 g cartridge), eluting with cyclohexane:EtOAc (gradient 15:1 to 5:1).
Further purification using the OPTIX - SPE (C18 cartridge, 50 g) eluting with 60 - 80% MeCN
(+0.05% HCOOH) in H2O (+0.01% HCOOH) over 56 mins afforded the title compound as an oil
(232 mg).
LC/MS: m/z 454.1/456.1 [M+H]+, Rt 3.64 min.

To a mixture of palladium (II) acetate (6 mg, 0.027 mmol), 1,3-bis(2,4,6-
trimethylphenyl)imidazoliumchloride (9 mg, 0.026 mmol) and Cs2CO3 (266 mg, 0.816 mmol) in
1,4-dioxane (1 mL) was added ethyl [(4-{[1-(6-bromo-2-pyridinyl)-2-(ethyloxy)ethyl]thio}-2-
methylphenyl)oxy]acetate (125 mg, 0.275 mmol) in 1,4-dioxane (1.75 mL) and the resulting
mixture stirred under nitrogen at ambient temperature for 10 min. 2-[4-(Trifluoromethyl)phenyl]-
1,3,2-dioxaborolane (69 mg, 0.300 mmol) was then added and the resulting mixture heated to
85CC and kept at this temperature for 16 h. The reaction mixture was then reduced and the
residue partitioned between EtOAc (15 mL) and saturated aqueous NH4CI (15 mL) and the layers
separated. The aqueous layer was then re-extracted with EtOAc (15 mL) and the combined
organic layers washed with brine (50 mL) dried (MgSO4) and filtered. The mixture was then
reduced under vacuum and the resulting residue purified by SPE (silica, 10 g cartridge), eluting
with cyclohexane:EtOAc (gradient 50:1 to 3:1). Further purification by mass directed autoprep
HPLC afforded the title compound as an oil (35 mg).
LC/MS: m/z 520.2 [M+H]+, Rt 4.04 min.
Separation of racemic material (35 mg, 0.067 mmol) by preparative chiral HPLC (1" x 25 cm
Chiralcel OJ) eluting with 30% EtOH in heptane, f = 15 mL/min, afforded Enantiomer 1 as an oil
(12 mg), Rt 9.0 min, analytical chiral HPLC (25 cm Chiralcel OJ) eluting with 30% IPA in heptane,
f = 1.0 mL/min, wavelength 215 nm, Rt 8.4 min (>99.9 %ee) and Enantiomer 2 as an oil (13.7 mg)
Rt 14.4 min, analytical chiral HPLC (25 cm Chiralcel OJ) eluting with 30% IPA in heptane, f = 1.0
mL/min, wavelength 215 nm, Rt 15.5 min (99.7 %ee).
Intermediate 122 and Intermediate 123
(1R)-1-(6-Bromo-2-pyridinyl)-2-(ethyloxy)ethanol and (1 S)-1-(6-Bromo-2-pyridinyl)-2-
(ethyloxy)ethanol
Separation of 1-(6-bromo-2-pyridinyl)-2-(ethyloxy)ethanol (100g) by preparative chiral
HPLC (2" x 20 cm Chiralcel OD) eluting with 2% EtOH in heptane, f = 60 mL/min, afforded (1 R)-1-
(6-bromo-2-pyridinyl)-2-(ethyloxy)ethanol as a white solid (45.9g), Rt 11.5 min. Analytical chiral
HPLC (25 cm Chiralcel OD-H) eluting with 5% EtOH in heptane, f = 1.0 mL/min, wavelength 215
nm, Rt 6.8 min (>99 %ee) and (1 S)-1-(6-bromo-2-pyridinyi)-2-(ethyloxy)ethanol as a white solid
(46.8g), Rt 14.5 min. Analytical chiral HPLC (25 cm Chiralcel OD-H) eluting with 5% EtOH in
heptane, f = 1.0 mL/min, wavelength 215 nm, Rt 8.3 min (96 %ee).

Pd(PPh3)4 (187 mg, 0.162 mmol) and Na2CO3 (1.29 g, 12.2 mmol) was treated with DME
(20 mL) and stirred under nitrogen for 2 min. Water (10 mL), (1 R)-1-(6-bromo-2-pyridinyl)-2-
(ethyloxy)ethanol (1.0 g, 4.1 mmol) and (4-cyanophenyl)boronic acid (656 mg, 4.47 mmol) were
added and the stirred reaction mixture heated at 80°C for 17 h. The mixture was then allowed to
cool to ambient temperature and the residue partitioned between saturated NH4CI (100 mL) and
EtOAc (100 mL). The aqueous phase was extracted with EtOAc (2 x 100 mL) and the combined
organic extracts washed with brine (100 mL), dried (Na2SO4) and evaporated to give a yellow oil
(1.43 g). Purification by Biotage™ chromatography (silica, 40 g cartridge) eluting with
cyclohexane: EtOAc (4:1) afforded the title compound as a pale yellow oil (945 mg).
LC/MS: m/z 269.2 [M+H]+, Rt 2.83 min.
Intermediate 125
Ethyl [(4-{[(1S)-1 -[6-(4-cyanophenyl)-2-pyridEnyl]-2-(ethyloxy)ethyl]oxy}-2-
methylphenyl)oxy]acetate
A stirred mixture of ethyl [(4-hydroxy-2-methylphenyl)oxy]acetate (664 mg, 3.16 mmol), 4-
{6-[(1R)-2-(ethyloxy)-1-hydroxyethyl]-2-pyridlnyl}benzonitrile (719 mg, 2.68 mmol) and
triphenylphosphine (857 mg, 3.27 mmol) in dry DCM (35 mL) was cooled to 0°C under nitrogen.
DIAD (633 µL, 3.21 mmol) was added dropwise over 10 min, and the reaction mixture stirred at
0°C for a further 2 h. DCM (120 mL) was added to the reaction mixture, washed with aq 1M
NaOH (50 mL) and water (100 mL), dried (Na2SO4) and evaporated to give a yellow oil.
Purification by Biotage™ chromatography (silica, 90 g cartridge) eluting with cyclohexane : EtOAc
(8:1) afforded the title compound as a colourless oil (765 mg).
LC/MS: m/z 461.2 [M+H]+, Rt 3.67 min.

A solution of ethyl {[2-methyl-4-({[4'-(trifluoromethyl)-3-
biphenylyl]methyl}thio)phenyl]oxy}acetate (209 mg) in THF (20 mL) and aqueous NaOH (2M, 20
mL) was stirred at rt overnight and then heated to 60°C for 2 hours. The mixture was then
allowed to cool to rt and the THF removed under vacuum. The resulting aqueous mixture was
then acidified and extracted with EtOAc (3 x) and the organic layer washed with brine dried
(MgSO4), filtered and reduced. Purification by mass directed auto-prep HPLC afforded the title
compound as a white solid (24mg).
LC/MS: m/z 431.0 [M-H]+, Rt 4.80 min.
1H NMR (400MHz; CDCI3) d: 2.22 (3H, s), 4.06 (2H, s), 4.66 (2H, s), 6.63 (1H, d, J 8.5 Hz),
7.14 (1H, dd, J 8.5,2.5 Hz), 7.16, (1H, m), 7.24-7.28 (1H, m), 7.34-7.41 (2H, m), 7.46 (1H, m),
7.60 (2H, d, J 8.0 Hz), 7.67 (2H, d, J 8.0 Hz).
Example 2
{[2-Methyl-4-({[4-methyl-4'-(trmuoromethyl)-3-
biphenylyl]methyl}thio)phenyl]oxy)aceticacid
A mixture of (5-bromo-2-methylphenyl)methanol (90 mg, 0.45 mmol), 4-
(triflouromethyl)benzeneboronic (94 mg, 0.49 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol) and Na2CO3
(123 mg, 1.16 mmol) in a mixture of DME (20 mL) and water (10 mL) was heated at reflux for 7
hours and then allowed to cool to rt. The resulting mixture was then reduced under vacuum,
partitioned between water and EtOAc and the layers separated. The organic layer was then
washed with brine, reduced under vacuum and then purified by SPE (silica, 10g cartridge) eluting
with cyclohexane : CHCI3 then cyclohexane: EtOAc to give a crude product containing a mixture
of (5-bromo-2-methylphenyl)methano! and product. The mixture was then dissolved in DCM (10
mL) and then treated with thionyl chloride (200 uL, 2.74 mmol) and the mixture stirred for 5 hours.
Additional thionyl chloride (200 µL, 2.74 mmol) was then added and after a further 2 hours, the
reaction was quenched by the careful addition of aqueous K2CO3 (1N) and the resulting layers
separated using a hydrophobe frit. The organic layer was reduced and the resulting crude
mixture (98 mg) dissolved in MeCN (20 mL) was and treated ethyl (4-mercapto-2-
methylphenoxy)acetate (92 mg, 0.41 mmol) and KaCO3 (55 mg, 0.40 mmol). The resulting
mixture was then stirred under nitrogen over the 72 hours and the resulting mixture partitioned
between water and EtOAc and the layers separated. The aqueous was re-extracted with EtOAc
and the combined organic layers washed with brine, dried (MgSO4), filtered and reduced.
Purification by SPE (silica) eluting with cyclohexane: CHCI3 (1:1) afforded the crude ester as a
clear oil (125 mg). A solution of the ester in THF (10 mL) and aqueous NaOH (2M, 10 mL) was
heated at 60°C for 1 hour and was then allowed to cool to rt overnight. The THF was then
removed under vacuum and the resulting aqueous mixture was then acidified and extracted with
EtOAc (2 x). The organic layer was then washed with brine, dried (MgSO4), filtered and reduced.
Purification by mass directed auto-prep HPLC afforded the title compound as a white solid (41
mg).
LC/MS: m/z 445.0 [M-H]+, Rt 4.32 min.
1H NMR (400MHz; DMSO-d6) d: 2.07 (3H, s), 2.35 (3H, s), 4.10 (2H, s), 4.64 (2H, s), 6.74
(1H, d, J 8.5 Hz), 7.09 (1H, m), 7.14 (1H, dd, J 8.0, 2.5 Hz), 7.24-7.30 (2H, m), 7.46 (1H, dd, J
8.0, 2.0 Hz), 7.64 (2H, d, J 8.5 Hz), 7.67 (2H, d, J 8.5 Hz).
A solution of ethyl 3-[2-methyl-4-({[4'-(trifluoromethyl)-3-
biphenylyl]methyl}oxy)phenyl]propanoate (135 mg, 0.31 mmol) in THF (4 mL) at rt was treated
with aqueous NaOH (2M, 4 mL) and the resulting solution heated to 75°C for 7 hours and then
allowed to cool to rt over 21 hours. The mixture was then reduced and the residue partitioned
between CHCI3 and water and the aqueous phase separated and acidified to pH2 with aqueous
HCI (2 N). The mixture was then extracted with CHCI3 (3 x) and the combined organic layer
washed with brine, dried (Na2SO4), filtered and reduced to give the title compound as a white
crystalline solid (123 mg).
LC/MS: m/z 413.1 [M-H]+, Rt 4.21 min.
1H NMR (400MHz; CDCI3) d:2.31 (3H, s), 2.62 (2H, m), 2.91 (2H, m), 5.10 (2H, s), 6.79
(1H, dd, J 8.5,3.0 Hz), 6.83 (1H, d, 3.0 Hz), 7.08 (1H, d, J 8.5 Hz), 7.44-7.53 (2H, m), 7.56 (1H,
m), 7.66 (1H,m), 7.70 (4H,s).

A suspension of [(2-methyl-4-{2-[4I-(trifluoromethyl)-3-biphenylyl]ethenyl}phenyl)oxy]acetic
acid (90 mg, 0.22 mmol) in EtOH (10 mL) was added to Pd/C (Degussa type E101 NE/N) (10 mg,
11wt%) and the resulting mixture stirred under an atmosphere of hydrogen for 6 hours. The
mixture was then filtered through celite J2 washing with copious amounts of EtOH and the filtrate
reduced under vacuum to give a sticky solid (100 mg) which was purified by mass directed auto-
prep HPLC to give the title compound as a fluffy white solid (25mg).
LC/MS: m/z 413.1 [M-H]+, Rt, 4.48 min.
1H NMR (400MHz; MeOD-d4) d: 2.21 (3H, s), 2.85 (2H, m), 2.95 (2H, m), 4.62 (2H, s), 6.70
(1H, d, J 8.0 Hz), 6.91-6.95 (2H, m), 7.22 (1H, dt, J 7.5,1.0 Hz), 7.35 (1H, m), 7.37 (1H, t, J 7.5
Hz), 7.46 (1H, ddd, J 7.5, 2.0,1.0 Hz), 7.72 (4H, s).
A solution of ethyl ({2-methyl-4-[({6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}methyl)thio]phenyl}oxy)acetate (367 mg, 0.80 mmol) in THF (5 mL) was treated with
aqueous NaOH (2M, 5 mL) and the resulting solution stirred at rt for 4 hours. The mixture was
poured into a mixture of aqueous HCI (2M) and EtOAc and the layers separated. The organic
layer was then washed with water and brine, dried MgSO4, filtered and then reduced under
vacuum. Purification by mass-directed auto-prep HPLC afforded the title compound as an oil.
LC/MS: m/z 434.2 [M+H]+, Rt 3.97 min.
1H NMR (400MHz; CDCI3) d: 2.22 (3H, s), 4.24 (2H, s), 4.63 (2H, s), 6.61 (1H, d, J 8.5 Hz),
7.16 (1H, dd, J 8.5, 2.0 Hz), 7.22-7.28 (2H, m), 7.60 (1H, d, J 8.5 Hz), 7.68-7.74 (3H, m), 8.02
(2H, d, J 8.0 Hz).

A mixture of ethyl {[2-methyl-4-({1-[4'-(trifluoromethyl)-3-
biphenylyl]ethyl}thio)phenyl]oxy}acetate (235 mg, 0.50 mmol) in dioxane (6 mL) was treated with
aqueous NaOH (0.5N, 2.0 mL, 1.00 mmol) and the mixture heated at reflux for 1 hour. The
resulting mixture was then cooled and treated with Dowex 50WX2 (pre-washed with dioxan),
filtered and washed with more dioxan and reduced to give the title compound as a colourless gum
(220 mg).
LC/MS: m/z 445.2 [M-H]+, Rt 4.20 min.
1H NMR (400MHz; CDCI3) d:1.65 (3H, d, J 7.0 Hz), 2.18 (3H, s), 4.25 (1H, q, J 7.0 Hz),
4.64 (2H, s), 6.57 (1H, d, J 9.0 Hz), 7.08-7.13 (2H, m), 7.29 (1H, m), 7.33-7.41 (2H, m), 7.43 (1H,
m), 7.59 (2H, d, J 8.5 Hz), 7.67 (2H, m, J 8.5 Hz).
Example 7
{[2-Methyl-4-({1-[4'-(trifluoromethyl)-4-biphenylyl]ethyl}thio)phenyl]oxy}aceticacld
Prepared from ethyl {[2-methyl-4-({1-[4'-(trifluoromethyl)-4-
biphenylyl]ethyl}thio)phenyl]oxy}acetate (333 mg, 0.70 mmol) according to the procedure used for
the preparation of Example 6 to give the title compound as a white solid (283 mg).
LC/MS: m/z 445.2 [M-H]+, Rt 4.28 min.
1H NMR (400MHz; CDCI3) d:1.63 (3H, d, J 7.0 Hz), 2.19 (3H, s), 4.24 (1H, q, J 7.0 Hz),
4.65 (2H, s), 6.58 (1H, d, J 8.5 Hz), 7.08-7.14 (2H, m), 7.33 (2H, d, J 8.5 Hz), 7.50 (2H, d, J 8.5
Hz), 7.67 (4H, m).

Ethyl 2-methyl-2-({2-methyl-4-[(1-{6-l4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyi)oxy]phenyl}oxy)propanoate (9 mg, 0.02 mmol) was dissolved in THF (0.75 mL),
water (0.25 mL) and aqueous NaOH (2M, 35 µl, 0.07 mmol) and the mixture heated at 80°C for
16 hours. More aqueous NaOH (2M, 420 ul, 0.84 mmol) was then added and heating continued
for an additional 24 hours. The mixture was then cooled, neutralised with aqueous HCI (2M),
partitioned between EtOAc and water and the layers separated. The organic layer was then
washed with brine, dried (Na2SO4) and reduced to give a pale yellow oil. Purification by SPE
(aminopropyl, 1g cartridge) loading in CHCI3 and eluting with dioxane and then 10% aqueous
ammonia in dioxane afforded the title compound as a colourless gum (4.5 mg).
LC/MS: m/z 502.3 [M+H]+, Rt 4.49.
1H NMR (400MHz; CDCl3) d: 0.91 (3H, t, J 7.0 Hz), 1.50 (6H, s), 1.32-1.61 (4H, m), 2.00
(2H, m), 2.15 (3H, s), 5.23 (1H, t, J 6.0 Hz), 6.57 (1H, dd, J 8.5, 3.0 Hz), 6.69 (1H, d, J 8.5 Hz),
6.76 (1H, d, J 3.0 Hz), 7.37 (1H, dd, J 8.0,1.0 Hz), 7.62 (1H, dd, J 8.0,1.0 Hz), 7.73 (1H, t, J 8.0
Hz), 7.74 (2H, d, J 8.0 Hz), 8.12 (2H, d, J 8.0 Hz).
Example 9
Ethyl {[2-methyl-4-({1 -[4'-(trifluoromethyl)-3-biphenylyl]pentyl}oxy)phenyl]oxy}acetate (138
mg, 0.28 mmo!) was dissolved in THF (1.5 mL), water (0.5 mL) and aqueous NaOH (2M, 0.52 mL,
1.04 mmol) and the mixture stirred at 70°C for 2 hours, cooled to rt and acidified to pH4 with
aqueous hydrochloric acid (2M). The mixture was then partitioned between EtOAc and water, the
layers separated and the organic layer washed with brine, dried (Na2SO4) and concentrated to
give the title compound as a colourless gum (130 mg).
LC/MS: m/z 471.2 [M-H]+. Rt 4.57 min.
1H NMR (400MHz; CDCI3) d: 0.90 (3H, t, J 7.0 Hz), 1.31-1.45 (3H, m), 1.45-1.60 (1H, m),
1.76-1.90 (1H, m), 1.93-2.07 (1H, m), 2.20 (3H, s), 4.55 (2H, s), 5.03 (2H, dd, J 8.0, 5.0 Hz), 6.55
(1H, d, J 9.0 Hz), 6.58 (1H, dd, J 9.0, 2.5 Hz), 6.75 (1H, 2.5 Hz), 7.36 (1H, m), 7.42 (1H, t, J 7.5
Hz), 7.48 (1H, dt, J 7.5,1.5 Hz), 7.5 (1H, m), 7.67 (4H, m).

Prepared according to the procedure used for the preparation of Example 9 starting from
ethyl [(4-{[1-(4'-chloro-3-biphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetate (137 mg, 0.29 mmol)
to give the title compound (130 mg).
LC/MS m/z 456.1 [M+NH4]+, Rt 4.55min.
1H NMR (400MHz; CDCI3) d: 0.90 (3H, t, J 7.0 Hz), 1.30-1.44 (3H, m), 1.44-1.59 (1H, m),
1.76-1.88 (1H, m), 1.94-2.06 (1H, m), 2.21 (3H, s), 4.51 (2H, s), 5.02 (2H, dd, J 6.0, 5.0 Hz), 6.53
(1H, d, J 9.0 Hz), 6.56 (1H, dd, J 9.0, 2.5 Hz), 6.74 (1H, 2.5 Hz), 7.32 (1H, dt, J 7.5,1.5 Hz), 7.36-
7.41 (3H,m), 7.43 (1H, dt, J 7.5,1.5 Hz), 7.47-7.53 (4H, m).
Example 11
{[2-Methyl-4-({1-[4'-(trl(luoromethyl)-4-blphenylyl]pentyl}oxy)phenyl]oxy}acetic acld
To a solution of ethyl {[2-methyl-4-({1-[4'-(trifluoromethyl)-4-
blphenylyl]pentyl}oxy)phenyl]oxy}acetate (310 mg, 0.62 mmol) in dioxan (6 mL) and water (3 mL),
was added aqueous NaOH (2M, 2.43 mL, 1.22 mmol), and the mixture stirred at rt for 1 hour.
The dioxan was removed under vacuum and brine (5 mL) added to the residue. The precipitate
was collected by filtration and dried under vacuum to give the title compound as a white solid (250
mg).
LC/MS: m/z 471.3 [M-H]+, Rt 4.57 min.
1H NMR (400MHz; MeOD-d4) d: 0.91 (3H, t, J 7.0 Hz), 1.37 (2H, m), 1.39 (1H, m), 1.49 (1H,
m), 1.80 (1H, m), 1.95 (1H, m), 2.17 (3H, s), 4.26 (2H, s), 5.11 (1H, dd, J 5.5, 5.5 Hz), 6.55 (1H,
dd, J 8.5,2.0 Hz), 6.58 (1H, d, J 8.5 Hz), 6.68 (1H, d, J 2.0 Hz), 7.44 (2H, d, J 8.0 Hz), 7.61 (2H,
d, J 8.0 Hz), 7.70 (2H, d, J 8.0 Hz), 7.77 (2H,d, J 8.0 Hz).

Prepared from ethyl [(4-{[1-(4'-chloro-4-biphenylyl)pentyl]oxy}-2-methylphenyl)oxy]acetate
(150 mg, 0.32 mmol) according to the procedure used for the preparation of Example 11, to give
the title compound as a white solid (140 mg).
LC/MS: m/z 437.2 [M-H]+, Rt 4.83 min.
'H NMR (400MHz; MeOD-d") d: 0.90 (3H, t, J 7.0 Hz), 1.36 (2H,m), 1.39 (1H, m), 1.49 (1H,
m), 1.80 (1H, m), 1.95 (1H, m), 2.16 (3H, s), 4.26 (2H, s), 5.11 (1H, dd, J 7.5, 5.5 Hz), 6.54 (1H,
dd, J 9.0,2.5 Hz), 6.58 (1H, d, J 9.0 Hz), 6.68 (1H, d, J 2.5 Hz), 7.39 (4H, d, J 8.5Hz), 7.53 (2H, d,
J 8.5 Hz), 7.57(2H, d, J 8.5 Hz).
To a solution of ethyl {[2-methyl-4-({(1R)-1 -[4'-(trif luoromethyl)-4-
biphenylyl]pentyl}thio)phenyl]oxy}acetate (10 mg, 0.02 mmol) in THF (1 mL) and MeOH (1 mL)
was added aqueous NaOH (2M, 1 mL) and the resulting mixture agitated for 1.5 hours at rt. The
mixture was then reduced under vacuum, acidified with aqueous HCI (2M), extracted with DCM (2
mL) and reduced to afford the title compound as colourless oil (9 mg).
LC/MS: m/z 487.3 [M-H]+, Rt 4.84 min.
1H NMR (400MHz; MeOD-d4) d: 0.85 (3H, t, J 7.0 Hz), 1.21-1.44 (4H, m), 1.84-2.02 (2H,
m), 2.12 (3H, s), 4.06 (1H, dd, J 8.5, 6.5 Hz), 4.62 (2H, s), 6.64 (1H, d, J 8.5 Hz), 7.01 (1H, d, J
2.0 Hz), 7.04 (1H, dd, J 8.5, 2.0 Hz), 7.26 (2H, d, J 8.0 Hz), 7.55 (2H, d, J 8.0 Hz), 7.70 (2H, d, J
8.0 Hz), 7.77 (2H, d, J 8.0 Hz).
i
Prepared from ethyl {[2-methyl-4-({(1S)-1-[4'-(trifluoromethyl)-4-
biphenyly!]pentyl}thio)phenyl]oxy}acetate (9 mg, 0.02 mmol) according to the procedure used for
the preparation of Example 13 to give the title compound (8 mg).
LC/MS: m/z 487.3 [M-H]+, Rt 4.84 min.
1H NMR (400MHz; MeOD-d4) d: 0.85 (3H, t, J 7.0 Hz), 1.21-1.44 (4H, m), 1.84-2.02 (2H,
m), 2.12 (3H, s), 4.06 (1H, dd, J 8.5, 6.5 Hz), 4.62 (2H, s), 6.64 (1H, d, J 8.5 Hz), 7.01 (1H, d, J
2.0 Hz), 7.04 (1H, dd, J 8.5, 2.0 Hz), 7.26 (2H, d, J 8.0 Hz), 7.55 (2H, d, J 8.0 Hz), 7.70 (2H, d, J
8.0 Hz), 7.77 (2H, d, J 8.0 Hz).
A solution of ethyl ({2-methyl-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}oxy)acetate (367 mg, 0.73 mmol) in THF (9 mL) and methanol (9 mL)
was treated with aqueous NaOH (2M, 9 mL) drop-wise and the resulting solution stirred at rt for 3
h. The volatile solvents were then removed under vacuum and the resulting aqueous residue
diluted with water (100 mL) and then acidified with aqueous HCI (2M, 11 mL). The product was
extracted with DCM (2 x 50 mL). The combined organic layers were then washed with brine (150
mL), dried (MgSO4), filtered and then reduced under vacuum to give a pale yellow foam (341 mg).
Purification by SPE (silica) eluting with heptane: EtOAc (gradient 10:1 to 0:1) afforded the title
compound as a pale yellow foam (256 mg).
LC/MS: m/z 473.9 [M+H]+, Rt 4.38 min.
1H NMR (400MHz; CDCI3) d: 0.91 (3H, t, J 7.0 Hz), 1.32-1.63 (4H, m), 2.00 (2H, m), 4.55
(2H, s), 5.22 (1H, m), 6.53-6.63 (2H, m), 6.79 (1H, d, J 2.0 Hz), 7.37 (1H, d, J 8.0 Hz), 7.62 (1H,
d, J 8.0 Hz), 7.73 (3H, m), 8.13 (2H, d, J 8.0 Hz).
Analytical chiral HPLC, 25cm chiralpak AD, 5% EtOH/heptane [0.1%TFA], 1.0 mL/min,
wavelength 215 nm, Rt 9.53 min.

Prepared from ethyl ({2-methyl-4-[((1 flH-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}oxy)acetate (360 mg, 0.72 mmol) according to the procedure used for
the preparation of Example 15 to give the title compound as a pale yellow foam (269 mg).
LC/MS: m/z 473.9 [M+H]+, Rt 4.38 min.
1H NMR (400MHz; CDCI3) d: 0.91 (3H, t, J 7.0 Hz), 1.32-1.63 (4H, m), 2.00 (2H, m), 4.55
(2H, s), 5.22 (1H, m), 6.53-6.53 (2H, m), 6.79 (1H, d, J 2.0 Hz), 7.37 (1H, d, J 8.0 Hz), 7.62 (1H,
d, J 8.0 Hz), 7.73 (3H, m), 8.13 (2H, d, J 8.0 Hz).
Analytical chiral HPLC 25cm chiralpak AD 5% EtOH/heptane [0.1%TFA], 1.0 mL/min,
wavelength 215 nm, Rt 10.87 min

To a solution of ethyl ({2-methyl-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)thio]phenyl}oxy)acetate (34 mg, 0.07 mmol) in THF (1 mL) and MeOH (1 mL) was
added aqueous NaOH (2M, 1 mL) and the resulting mixture agitated for 1.5 hours at rt. The
mixture was then reduced under vacuum, acidified with aqueous HCI (2M) and extracted with
DCM (2 mL) and reduced to afford the title compound as a colourless oil (31 mg).
LC/MS: m/z 490.0 [M+H]+, Rt 4.60 min.
1H NMR (400MHz; MeOD-d4) d: 0.86 (3H, t, 7.0 Hz), 1.23-1.48 (4H, m), 1.95-2.18 (2H, m),
2.08 (3H, s) 4.23 (1H, dd, J 8.5, 6.5 Hz), 4.54 (2H, s), 6.62 (1H, d, J 8.5 Hz), 6.97 (1H, d, J 1.5
Hz), 7.04 (1H, dd, J 8.5 Hz, 1.5 Hz), 7.26 (1H, d, J 8.0 Hz), 7.70 (1H, d, J 8.0 Hz), 7.73 (2H, d, J
8.0 Hz), 7.77 (1H, t, J 8.0 Hz), 8.04 (2H, d, J 8.0 Hz).
Analytical chiral HPLC; 25cm chiralcel OJ-R, flow 0.5ml/min, wavelength 215nm, 50%
acetonitrile/H3PO4-KH2PO4[0.2M] pH2, R, 27.25min.

Prepared from ethyl ({2-methy!-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)thio]phenyl}oxy)acetate (29 mg, 0.06 mmol) according to the procedure used for
the preparation of Example 17 to give the title compound (28 mg).
LC/MS: m/z 490.0 [M+H]+, Rt 4.60 min.
1H NMR (400MHz; MeOD-d4) d: 0.86 (3H, t, 7.0 Hz), 1.23-1.48 (4H, m), 1.95-2.18 (2H, m),
2.08 (3H, s) 4.23 (1H, dd, J 8.5, 6.5 Hz), 4.54 (2H, s), 6.62 (1H, d, J 8.5 Hz), 6.97 (1H, d, J 1.5
Hz), 7.04 (1H, dd, J 8.5 Hz, 1.5 Hz), 7.26 (1H, d, J 8.0 Hz), 7.70 (1H, d, J 8.0 Hz), 7.73 (2H, d, J
8.0 Hz), 7.77 (1H, t, J 8.0 Hz), 8.04 (2H, d, J 8.0 Hz).
Analytical chiral HPLC; 25cm chiralcel OJ-R, flow 0.5ml/min, wavelength 215nm, 50%
acetonitrile/H3PO4-KH2PO4[0.2M] pH2, R, 30.34min.

A stirred solution of ethyl ({2-methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)sulfinyl]phenyl)oxy)acetate (27 mg, 0.05 mmol) in THF (1 mL) and methanol (1
mL) was added, drop-wise, aqueous NaOH (2M, 1 mL). After 2 hours 50 minutes the mixture was
concentrated producing a 'chalk-white' solid which was diluted with water (2 mL) and acidified
with aqueous HCI (2M, 2 mL). The aqueous layer was extracted with DCM (2 x 2 mL then 1 mL)
using a hydrophobic frit and the combined organic layer concentrated under vacuum yielding the
title compound as a mixture of two diastereoisomers (24 mg).
LC/MS: m/z 506.2 [M+H]+, Rt 4.24 min.
1H NMR (400MHz; CDCI3) d: isomer 1 (70%) 0.83 (3H, t, J 7.0 Hz), 1.17-1.41 (4H, m), 2.06
(3H, s), 1.97-2.42 (2H, m), 4.07 (1H, dd, J 11.0,4.0 Hz), 4.48 (1H, d, J 17.0 Hz), 4.53 (1H, d, J
17.0 Hz), 6.49 (1H, d, J 8.5 Hz), 6.86 (1H, d, J 2.0 Hz), 6.90 (1H, m), 7.11 (1H, dd, J 8.5, 2.0 Hz),
7.59-7.80 (4H, m), 7.94 (2H, d, 8.0 Hz); isomer 2 (30%) 0.83 (3H, t, J 7.0 Hz), 1.17-1.41 (4H, m),
2.16 (3H, s), 1.97-2.42 (2H, m), 4.14 (1H, m), 4.44 (1H, d, J 17.0 Hz), 4.53 (1H, d, J 17.0 Hz),
6.51 (1H, d, J 8.5 Hz), 7.03 (1H, d, J 2.0 Hz), 7.13 (1H, dd, J 8.5, 2.0 Hz), 7.32 (1H. d, J 8.0 Hz),
7.59-7.80 (6H, m).
Prepared from ethyl ({2-methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl)-2-
pyridinyl}pentyl)sulfonyl]phenyl}oxy)acetate (26 mg, 0.05 mmol) according to the procedure used
for the preparation of Example 19 to give the title compound as a clear oil (22 mg).
LC/MS: m/z 522.2 [M+H]+, Rt 4.23 min.
1H NMR (400MHz; CDCI3) d: 0.82 (3H, t, 7.0 Hz), 1.12-1.44 (4H, m), 2.11 (3H, s), 2.26-2.47
(2H,m), 4.40 (1H, dd, 11.5, 4.0 Hz), 4.57 (2H, s), 6.56 (1H, d, 8.5 Hz), 7.27 (1H, m), 7.34 (1H, dd,
J 8.5 Hz, 2.0 Hz), 7.47 (1H, d, 7.0 Hz), 7.62 (2H, d, J 8.0 Hz), 7.67 (1H, d, 7.0 Hz), 7.73 (2H, d, J
8.0 Hz), 7.81 (1H, dd, J 7.0, 7.0 Hz).

A solution of methyl {4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}acetate (329 mg, 0.72 mmol) in THF (9.5 mL) and methanol (9.5 mL)
was treated with aqueous NaOH (2M, 9.5 mL) drop-wise and the resulting solution stirred at rt for
17 hours. The volatile solvents were then removed under vacuum and the resulting aqueous
mixture acidified with aqueous HCI (2M, 15 mL), diluted with water (100 mL) and the product
extracted with DCM (2 x 100 mL). The combined organic layers were then washed with brine
(100 mL), dried (MgSO4), filtered and then reduced under vacuum to give the title compound as a
pale yellow foam (314 mg).
LC/MS: m/z 443.9 [M+H]+, Rt 4.15 min.
1H NMR (400MHz; CDCI3) d: 0.91 (3H, t, J 7.0 Hz), 1.32-1.63 (4H, m), 2.01 (2H, m), 3.52
(2H, s), 5.28 (1H, t, J 6.5 Hz), 6.84 (2H, d, J 9.0 Hz), 7.09 (2H, d, J 9.0 Hz), 7.36 (1H, d, J 7.5 Hz),
7.62 (1H, d, J 8.0 Hz), 7.72 (1H, dd, J 8.0, 7.5 Hz), 7.74 (2H, d, J 8.0 Hz), 8.14 (2H, d, J 8.0 Hz).
A stirred solution of ethyl [(4-{[1-(6-bromo-2-pyridinyl)butyl]oxy}-2-methylphenyl)oxy]acetate
(50 mg, 0.12 mmol) in DME (0.5 ml_) was treated with phenyl 4-(triflouromethyl)benzeneboronic
acid (23 mg, 0.12 mmol) followed by Pd(PPh3)4 (14 mg, 0.01 mmol) and a solution of Na2CO3 (38
mg, 0.36 mmol) in water (0.5 mL), and the resulting mixture was heated at 70°C for 18 hours
under nitrogen. The solvent was then removed under vacuum and the resulting mixture acidified
with aqueous HCI (2M) and then partitioned between water and EtOAc, the layers separated and
the organic layer reduced to an oil. Purification by mass directed auto-prep HPLC afforded the
title compound (12 mg).
LC/MS: m/z 459.9 [M+H]+, Rt 4.30 min.
1H NMR (400 MHz; CDCI3) d: 0.97 (3H, t, J 7.5 Hz), 1.56 (2H, m), 1.97 (2H, m), 2.19 (3H,
s), 4.53 (2H, s), 5.23 (1H, dd, J 6.5, 6.5 Hz), 6.55 (1H, d, J 9.0 Hz), 6.59 (1H, dd, J 9.0, 3.0 Hz),
6.78 (1H, d, 3.0 Hz), 7.37 (1H, d, 7.5 Hz), 7.61 (1H, d, 7.5 Hz), 7.72 (3H, m), 8.13 (2H, d, 8.5 Hz).

Prepared from ethyl ({4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}oxy)acetate (42 mg, 0.09 mmol) according to the procedure used for
the preparation of Example 21 to give the title compound as a gum (40 mg).
LC/MS: m/z 459.9 [M+H]+, Rt 4.31 mln.
1H NMR (400MHz; MeOD-d4) d: 0.92 (3H, t, J 7.5 Hz), 1.34-1.60 (4H, m), 2.00 (2H, m), 4.51
(2H, s), 5.25 (1H, dd, J 7.5, 5.5 Hz), 6.77 (2H, m), 6.82 (2H, m), 7.41 (1H, dd, J 7.5,1.5 Hz), 7.78
(2H, d, J 8.0Hz), 7.78-7.86 (2H, m), 8.13 (2H, d, J 8.0 Hz).
Example 24
3-{4-t(1-{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid
To a stirred solution of ethyl 3-{4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}propanoate (92 mg, 0.19 mmol) in THF (3 mL) and methanol (3 mL)
was added, drop-wise, aqueous NaOH (2M, 3 mL). After 17 hours the mixture was concentrated
under vacuum and the solid residue acidified with aqueous HCI (2M, 3.5 mL), diluted with water
(10 mL) and extracted with DCM (2 x 10 mL). The combined organic layer was washed with brine
(20 mL), dried (MgSO4) and concentrated under vacuum. The acid was loaded onto a PE-AX
isolute SPE cartridge (pre-conditioned with 1 column volume of methanol) in 9 mL of methanol
and a few drops of Et3N. The cartridge was washed with 3 column volumes of methanol followed
by 10% aqueous HCI (2M) in methanol (2x5 mL) and 20% aqueous HCI (2M) in methanol (2x5
mL), yielding the title compound (38 mg).
LC/MS: m/z 458.0 [M+H]+, Rt 4.11 min.
1H NMR (400MHz; MeOD-d4) d: 0.90 (3H, t, 7.0 Hz), 1.32-1.59 (4H, m), 1.94-2.05 (2H, m),
2.47 (2H, t, 7.5 Hz), 2.76 (2H, t, 7.5 Hz), 5.29 (1H, dd, 6.5, 5.5 Hz), 6.78 (2H, d, 8.5 Hz), 7.01 (2H,
d, 8.5 Hz), 7.39 (1H, d, 7.5 Hz), 7.78 (4H, m), 8.21 (2H, d, J 8.0 Hz).
General procedure for the preparation of Examples 25-34
A stirred solution of ethyl [(4-{[1-(6-bromo-2-pyridinyl)pentyl]oxy}-2-
methylphenyl)oxy]acetate (50 mg, 0.12 mmol) in DME (0.5 mL) was treated with the appropriate
aryl boronic acid (0.12 mmol) followed by Pd(PPh3)4 (13 mg, 0.01 mmol) and a solution of Na2CO3
(37 mg, 0.34 mmol) in water (0.25 mL). The reaction mixture was heated at 70°C for 18 hours
under nitrogen, allowed to cool to rt and then reduced under vacuum (Genevac). The residue
was loaded in the minimum volume of methanol onto a SPE (C18 cartridge) (pre-conditioned with
1 column volume of methanol and then 1 column volume of 5% MeCN in water) eluting with 5%
MeCN in water, then MeCN followed by methanol to give the crude product. Further purification
by mass directed auto-prep HPLC afforded the title compounds.
Example 25
{[4-({1-[6-(4-Chlorophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}aceticacid
LC/MS: m/z 437.9 [M-H]+, Rt 4.45 min.
1H NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.5 Hz), 1.32-1.61 (4H, m), 1.90-2.05 (2H, m),
2.19 (3H, s), 4.53 (2H, s), 5.21 (1H, del, J 7.5, 5.5 Hz), 6.54 (1H, d, J 9.0 Hz), 6.58 (1H, dd, J 9.0,
3.0 Hz), 6.77 (1H, d, J 3.0 Hz), 7.32 (1H, d, J 8.0 Hz), 7.44 (2H, d, J 8.5 Hz), 7.54 (1H, d, J 8.0
Hz), 7.68 (1H, t, J 8.0 Hz), 7.95 (2H, d, J 8.5 Hz).

LC/MS: m/z 436.0 [M+H]+, Rt 4.18 min.
1H NMR (400 MHz; CDCI3) d: 0.90 (3H, t, J 7.5 Hz), 1.31 -1.62 (4H, rn), 1.90-2.06 (2H, m),
2.19 (3H, s), 3.87 (3H, s), 4.53 (2H, s), 5.21 (1H, dd, J 8.0, 5.0 Hz), 6.55 (1H, d, J 9.0 Hz), 6.60
(1H, dd, J 9.0, 3.0 Hz), 6.78 (1H, d, J 3.0 Hz), 7.01 (2H, d, J 9.0 Hz), 7.26 (1H, d, J 7.5 Hz), 7.51
(1H, d, J 7.5 Hz), 7.66 (1H, t, J 7.5 Hz), 7.95 (2H, d, J 9.0 Hz).

LC/MS: m/z 449.9 [M+H]+, Rt 4.32 min.
1H NMR (400 MHz; CDCI3) d: 0.90 (3H, t, J 7.5 Hz) 1.32-1.62 (4H, m), 1.45 (3H, t, J 7.0
Hz), 1.90-2.05 (2H, m), 2.17 (3H, s), 4.10 (2H, q, J 7.0 Hz), 4.50 (2H, s), 5.19 (1H, dd, J 8.0, 5.0
Hz), 6.54 (1H, d, J 9.0 Hz), 6.58 (1H, dd J 9.0, 3.0), 6.77 (1H, d, J 3.0), 6.99 (2H, d, J 9.0 Hz),
7.23 (1H, d, J 7.5 Hz), 7.49 (1H, d, J 7.5 Hz), 7.63 (1H, t, J 7.5 Hz), 7.94 (2H, d, J 9.0 Hz).
LC/MS: m/z 419.9 [M+H]+, Rt 4.34 min.
1H NMR (400 MHz; CDCI3) d: 0.90 (3H, t, 7.0 Hz), 1.32-1.61 (4H, m), 1.90-2.06 (2H, m),
2.19 (3H, s), 2.41 (3H, s), 4.52 (2H, s), 5.21 (1H, dd, J 8.0, 5.0 Hz), 6.54 (1H, d, J 9.0 Hz), 6.59
(1H, dd, J 9.0, 3.0 Hz), 6.78 (1H, d, J 3.0 Hz), 7.27 (1H, dd, J 8.0,1.0 Hz), 7.28 (2H, d, J 8.0 Hz),
7.53 (1H, dd, J 8.0,1.0 Hz), 7.65 (1H, t, J 8.0 Hz), 7.89 (2H, d, J 8.0 Hz).

LC/MS: m/z 473.8 [M+H]+, Rt 4.82 min.
1H NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.0 Hz), 1.33-1.61 (4H, m), 1.98 (2H, m), 2.20
(3H, s), 4.54 (2H, s), 5.20 (1H, dd, J 6.5, 6.5 Hz), 6.55 (1H, d, J 9.0 Hz), 6.58 (1H, d, J 9.0,2.5
Hz), 6.77 (1H, d, J 2.5 Hz), 7.34 (1H, d, J 8.0 Hz), 7.54 (2H, d, J 8.5 Hz), 7.69 (1H, t, J 8.0 Hz),
7.83 (1H, dd, J 8.5, 2.0 Hz), 8.14 (1H, d, J 2.0 Hz).

LC/MS: m/z 473.9 [M+H]+, Rt 4.50 min.
1H NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.0 Hz), 1.34-1.62 (4H, m), 1.96-2.04 (2H, m),
2.19 (3H, s), 4.54 (2H, s), 5.22 (1H, m), 6.55 (1H, d, J 9.0 Hz), 6.60 (1H, dd, J 9.0, 3.0 Hz), 6.78
(1H, d, J 3.0 Hz), 7.36 (1H, d, J 7.5 Hz), 7.60 (1H, m), 7.61 (1H, d, J 8.0 Hz), 7.67 (1H, d, 8.0 Hz)
7.72 (1H, t, J 8.0 Hz), 8.20 (1H, d, J 8.0 Hz), 8.28 (1H, s).

LC/MS: m/z 406.0 [M+H]+, Rt 4.20 min.
'H NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.0 Hz), 1.32-1.62 (4H, m), 1.92-2.06 (2H, m),
2.18 (3H, s), 4.49 (2H, s), 5.21 (1H, dd, J 7.5, 5.0 Hz), 6.53 (1H, d, J 9.0 Hz), 6.59 (1H, dd, J 9.0,
3.0 Hz), 6.77 (1H, d, 3.0 Hz), 7.30 (1H, d, 8.0 Hz), 7.41 (1H, m), 7.48 (2H, m), 7.56 (1H, dd, J 8.0,
1.0 Hz), 7.67 (1H, t, J 8.0 Hz), 8.00 (2H, m).

LC/MS: m/z 448.1 [M+H]+, Rt 3.93 min.
1H NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.0 Hz), 1.32-1.63 (4H, m), 2.00 (2H, m), 2.19
(3H, s), 2.66 (3H, s), 4.53 (2H, s), 5.22 (1H, m), 6.55 (1H, d, J 9.0 Hz), 6.60 (1H, dd, J 9.0, 3.0
Hz), 6.78 (1H, d, J 3.0 Hz), 7.36 (1H, dd, J 7.5,1.0 Hz), 7.63 (1H, dd, J 7.5, 1.0 Hz), 7.72 (1H, t, J
7.5 Hz), 8.07 (2H, d, J 8.5 Hz), 8.12 (2H, d, J 8.5 Hz).
1H NMR (400 MHz; CDCI3) d:0.91 (3H, t, J 7.0 Hz), 1.32-1.61 (4H, m), 1.99 (2H, m), 2.18
(3H, s), 4.51 (2H, s), 5.19 (1H, dd, J 7.5, 5.5 Hz), 6.53 (1H, d, J 9.0 Hz), 6.58 (1H, dd, J 9.0, 3.0
Hz), 6.77 (1H, d, J 3.0 Hz), 7.16 (2H, m), 7.30 (1H, d, J 7.5 Hz), 7.52 (1H, d, J 7.5 Hz), 7.67 (1H,
t, J 7.5 Hz), 7.98 (2H, m).

LC/MS: m/z 431.1 [M+H]+, Rt 4.02 min.
1H NMR (400 MHz; CDCI3) 5:0.91 (3H, t, 7.0 Hz), 1.32-1.61 (4H, m), 1.99 (2H, m), 2.19
(3H, s), 4.53 (2H, s), 5.21 (1H, dd, J 6.5, 6.5 Hz), 6.54 (1H, d, J 9.0 Hz), 6.58 (1H, dd, J 9.0, 2.5
Hz), 6.77 (1H, d, J 2.5 Hz), 7.39 (1H, d, J 7.0 Hz), 7.62 (1H, d, J 8.0 Hz), 7.74 (1H, m), 7.77 (2H,
d, J 8.5 Hz), 8.14 (2H, dd, J 8.5 Hz).

To a solution of ethyl ({2-methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}hexyl)oxy]phenyl}oxy)acetate (80 mg, 0.16 mmol) in MeOH (2 mL) and THF (2 mL) at rt
was added aqueous NaOH (2M, 1 mL, 2.0 mmol) and the resulting mixture stirred for 2.5 hours.
The solvents were then removed under vacuum and the residue partitioned between DCM (20
mL) and aqueous HCI (2M, 20 mL), the layers separated and the aqueous re-extracted with DCM
(20 mL). The combined organic solution was passed through a hydrophobic frit and then reduced
affording the title compound as colourless oil (57 mg).
LC/MS: m/z 488.3 [M+H]+, Rt 4.54 min.
1H NMR (400 MHz; CDCI3) d: 0.88 (3H, t, J 7.0 Hz), 1.27-1.40 (4H, m), 1.41-1.64 (2H, m),
1.99 (2H, m), 2.20 (3H, s), 4.55 (2H, s), 5.25 (1H, dd, J 6.5,6.5 Hz), 6.56 (1H, d, J 9.0 Hz), 6.60
(1H, dd, J 9.0 Hz, 3.0 Hz), 6.78 (1H, d, J 3 Hz), 7.38 (1H, d, J 7.5 Hz), 7.62 (1H, d, J 7.5 Hz), 7.74
(1H, t, J 7.5 Hz), 7.74 (2H, d, J 8.0 Hz), 8.13 (2H, d, J 8.0 Hz).

Prepared from ethyl ({2-methyl-4-[(4-methyl-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}oxy)acetate (15 mg, 0.03 rnmol) according to the procedure used for
the preparation of Example 35 to give the title compound as a colourless oil (10 mg).
LC/MS: m/z 488.1 [M+H]+, Rt 4.49 min.
nH NMR (400 MHz; CDCI3) d: 0.89 (3H, d, J 6.5 Hz), 0.90 (3H, d, J 6.5 Hz), 1.31-1.42 (1H,
m), 1.43-1.54 (1H, m), 1.55-1.56 (1H, m), 2.00 (2H, m), 2.20 (3H, s), 4.55 (2H, s), 5.26 (1H, m),
6.56 (1H,d, J 9.0 Hz), 6.61 (1H, dd, J 9.0, 3.0 Hz), 6.79 (1H, d, J 3.0 Hz), 7.40 (1H, d, J 7.5 Hz),
7.63 (1H, d, J 7.5 Hz), 7.75 (2H, d, J 8.5 Hz), 7.76 (1H,m), 8.13 (2H, d, J 8.5 Hz).

Prepared from ethyl ({2-methyl-4-[(3-methyl-1-{6-[4-(trifluoromethyl)phenylJ-2-
pyridinyl}butyl)oxy]phenyl}oxy)acetate (132 mg, 0.26 mmol) according to the procedure used for
the preparation of Example 35 to give the title compound as a pale orange solid (124 mg).
LC/MS: m/z 474.1 [M+H]+, Rt 4.25 min.
1H NMR (400 MHz; CDCI3) d:1.03 (6H, m), 1.71-2.05 (3H, m), 2.20 (3H. s), 4.55 (2H, s),
5.57 (1H, m), 6.57 (1H, d, J 9.0 Hz), 6.66 (1H, dd, J 8.5 Hz, 3.0 Hz), 6.81 (1H, d, J 3.0 Hz), 7.47
(1H, d, J 8.0 Hz), 7.66 (1H, d, J 8.0 Hz), 7.77 (2H, d, J 8.0 Hz), 7.83 (1H, t, J 8.0 Hz), 8.16 (2H, d,
J 8.0 Hz).
General procedure for Examples 38 - 40
A stirred solution of ethyl [(4-{[1-(3-bromophenyl)pentyl]oxy}-2-methylphenyl)oxy]acetate
(50 mg, 0.11 mmol) in DME (0.5 mL) was treated with the appropriate aryl boronic acid (0.11
mmol) followed by Pd(PPh3)4 (13 mg, 0.01 mmol) and a solution of Na2CO3 (37 mg, 0.33 mmol) in
water (0.25 mL). The reaction mixture was heated at 70°C for 18 hours under nitrogen, allowed to
cool to rt and then reduced under vacuum (Genevac). The residue was loaded in the minimum
volume of methanol onto a SPE (C18 cartridges) (pre-conditioned with 1 column volume of
methanol and then 1 column volume of 5% MeCN in water) eluting with 5% MeCN in water, then
MeCN followed by methanol to give the crude product. Further purification by mass directed
auto-prep HPLC afforded the title compounds.

LC/MS: m/z 422.1 [M+H]+, Rt 4.24 min.
1H NMR (400 MHz; CDCI3) d: 0.89 (3H, t, J 7.0 Hz), 1.29-1.42 (3H, m), 1.44-1.57 (1H, m),
1.75-1.87 (1H, m), 1.93-2.05 (1H, m), 2.09 (3H, s), 4.35 (2H, s), 4.99 (1H, dd, J 8.0, 5.0 Hz), 6.46
(1H, d, J 9.0 Hz), 6.53 (1H, d, 9.0, 3.0 Hz), 6.69 (1H, d, 3.0 Hz), 7.24-7.46 (6H, m), 7.51-7.58 (3H,
m).

LC/MS: m/z 466.1 [M+NH4]+, Rt 4.29 min.
1H NMR (400 MHz; CDCI3) d: 0.89 (3H, t, J 7.0 Hz), 1.35 (3H, m), 1.42 (3H, t, J 7.0 Hz),
1.46-1.58 (1H, m), 1.75-1.86 (1H, m), 1.92-2.03 (1H, m), 2.10 (3H, s), 4.05 (2H, q, J 7.0 Hz), 4.38
(2H, s), 4.98 (1H, dd, J 8.0, 5.5 Hz), 6.47 (1H, d, J 9.0 Hz), 6.54 (1H, dd, J 9.0, 2.5 Hz), 6.70 (1H,
d, J 2.5 Hz), 6.93 (2H, d, J 9.0 Hz), 7.23 (1H, d, J 7.5 Hz), 7.32 (1H, t, J 7.5 Hz), 7.40 (1H, d, J 7.5
Hz), 7.47 (2H, d, J 9.0 Hz), 7.49 (1H, m).
LC/MS: m/z 447.3 [M+NH4]+, Rt 4.20 min.
*H NMR (400 MHz; CDC!3) d: 0.90 (3H, t, 7.0 Hz), 1.36 (3H, m), 1.45-1.57 (1H, m), 1.81
(1H, m), 1.98 (1H, m), 2.11 (3H, s), 4.39 (2H, s), 5.02 (1H, dd, J 8.0, 5.0 Hz), 6.48 (1H, d, J 9.0
Hz), 6.52 (1H, dd, J 9.0,2.5 Hz), 6.70 (1H, d, J 2.5 Hz), 7.34-7.47 (3H, m), 7.53 (1H, s), 7.62 (2H,
d, J 8.0 Hz), 7.68 (2H, d, J 8.0 Hz).
General procedure for Examples 41-45
A stirred solution of ethyl [(4-{[1 -(6-bromo-2-pyridinyl)pentyl]oxy}-2-ethylphenyl)oxy]acetate
(50 mg, 0.11 mmol) in DME (0.5 mL) was treated with the appropriate aryl boronic acid (0.11
mmol) followed by Pd(PPh3)4 (13 mg, 0.01 mmol) and a solution of Na2CO3 (37 mg, 0.33 mmol) in
water (0.25 mL). The reaction mixture was heated at 70°C for 18 hours under nitrogen, allowed to
cool to rt and then reduced under vacuum (Genevac). The residue was loaded in the minimum
volume of methano! onto a SPE (C18 cartridges) (pre-conditioned with 1 column volume of
methanol and then 1 column volume of 5% MeCN in water) eluting with 5% MeCN in water, then
MeCN followed by methanol to give the crude product. Further purification by mass directed
auto-prep HPLC afforded the title compounds.

LC/MS: m/z 420.2 [M+H]+, Rt 4.33 min.
1H NMR (400 MHz; CDCI3) d: 0.90 (3H, t, J 7.5 Hz), 1.07 (3H, t, J 7.5 Hz), 1.32-1.62 (4H,
m), 1.99 (2H, m), 2.51 (2H, q, J 7.5 Hz), 4.37 (2H, s), 5.21 (1H, m), 6.48 (1H, d, J 9.0 Hz), 6.55
(1H, d, J 9.0 Hz), 6.76 (1H, dd, J 9.0, 3.0 Hz), 7.28 (1H, d, J 7.5 Hz), 7.40 (1H, m), 7.46 (2H, m),
7.53 (1H, d, J 7.5 Hz), 7.62 (1H, t, J 7.5 Hz), 7.99 (2H, m).
LC/MS: m/z 454.1 [M+H]+, Rt 4.55 min.
1H NMR (400 MHz; CDCI3) d: 0.90 (3H, t, J 7.5 Hz), 1.10 (3H, t, J 7.5 Hz), 1.32-1.61 (4H,
m), 1.99 (2H, m), 2.55 (2H, q, J 7.5 Hz), 4.45 (2H, s), 5.20 (1H, dd, J 6.5, 6.5 Hz), 6.51 (1H, d, J
9.0 Hz), 6.56 (1H, dd, J 9.0, 3.0 Hz), 6.78 (1H, d, J 3.0 Hz), 7.30 (1H, d, J 7.5 Hz), 7.44 (2H, d, J
8.5 Hz), 7.52 (1H, d, J 7.5 Hz), 7.65 (1H, t, J 7.5 Hz), 7.95 (2H, d, J 8.5 Hz).

LC/MS: m/z 464.2 [M+H]+, Rt 4.39 min.
1H NMR (400 MHz; CDCI3) d: 0.90 (3H, t, J 7.0 Hz), 1.08 (3H, t, J 7.5 Hz), 1.44 (3H, t, J 7.0
Hz), 1.32-1.61 (4H, m), 1.98 (2H, m), 2.53 (2H, q, J 7.5 Hz), 4.09 (2H, q, J 7.0 Hz), 4.41 (2H, s),
5.19 (1H, dd, J 7.5, 5.0 Hz), 6.49 (1H, d, J 9.0 Hz), 6.56 (1H, dd, J 9.0, 3.0 Hz), 6.77 (1H, d, J 3.0
Hz), 6.98 (2H, d, J 9.0 Hz), 7.22 (1H, d J 7.5 Hz), 7.47 (1H, d, J 7.5 Hz), 7.59 (1H, t, J 7.5 Hz),
7.94 (2H, d, J 9.0 Hz).

LC/MS: m/z 445.0 [M+H]+, Rt 4.09 min.
1H NMR (400 MHz; CDCI3) d: 0.90 (3H, t, J 7.0 Hz), 1.09 (3H, t, J 7.5 Hz), 1.32-1.62 (4H,
m), 1.99 (2H, m), 2.54 (2H, q, J 7.5 Hz), 4.43 (2H, s), 5.21 (1H, dd, J 6.0 Hz), 6.50 (1H, d, J 9.0
Hz), 6.54 (1H, dd, J 9.0,2.5 Hz), 6.77 (1H, d, J 2.5 Hz), 7.38 (1H, d, J 8.0 Hz), 7.60 (1H, d, J 8.0
Hz), 7.71 (1H, t, J 8.0 Hz), 7.70 (2H, d, J 8.5 Hz), 8.13 (2H, d, J 8.5 Hz).

LC/MS: m/z 488.1 [M+H]+, Rt 4.51 min.
1H NMR (400 MHz; GDCI3) d: 0.91 (3H, t, J 7.0 Hz), 1.13 (3H, t, J 7.5 Hz), 1.32-1.63 (4H,
m), 2.00 (2H, m), 2.59 (2H, q, J 7.5 Hz), 4.52 (2H, s), 5.23 (1H, dd, J 6.5, 6.5 Hz), 6.54 (1H, d, J
9.0 Hz), 6.58 (1H, dd, J 9.0, 3.0 Hz), 6.80 (1H, d, J 3.0 Hz), 7.37 (1H, d, J 8.0 Hz), 7.61 (1H, d, J
8.0 Hz), 7.72 (1H, t, J 8.0 Hz), 7.73 (2H, d, J 8.0 Hz), 8.13 (2H, d, J 8.0 Hz).

To a stirred solution of 2-(trimethylsilyl)ethyl 4-{4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}butanoate (42 mg, 0.07 mmol) in THF at rt was added, drop-wise,
TBAF (70 u.L of a 1.0M solution in THF, 0.07 mmol) and the mixture stirred at rt for 1.5 hours.
Additional TBAF (35 pL of a 1.0M solution in THF, 0.04 mmol) was then added and the mixture
left to stir at rt for17.5 hours. The mixture was then concentrated under vacuum and the residue
purified by SPE (silica, 1 g Cartridge) eluting with cyclohexane: EtOAc (gradient 25:1 to 0:1), then
EtOAc: MeOH (gradient 10:1 to 0:1) to give a crude product which was purified further by mass
directed auto-prep HPLC to give the title compound (6.4 mg).
LC/MS: m/z 472.15 [M+H]+, Rt 4.21 min.
1H NMR (400MHz; MeOD-d4) d: 0.92 (3H, t, 7.0 Hz), 1.34-1.61 (4H, m), 1.80 (2H, m), 2.00
(2H, m), 2.22 (2H, t, 7.5 Hz), 2.51 (2H, t, 7.5 Hz), 5.29 (1H, dd, 7.0, 6.0 Hz), 6.79 (2H, d, 9.0 Hz),
7.00 (2H, d, 9.0 Hz), 7.40 (1H, dd, J 7.0,1.5 Hz), 7.75-7.85 (4H, m), 8.23 (2H, d, J 8.5 Hz).
General procedures for Examples 47-50
Ethyl [(4-{[(1R)-1-(6-bromo-2-pyridinyl)pentyl]oxy}-2-methylphenyI)oxy]acetate (50 mg, 0.11
mmol) was dissolved in DME (0.50 mL) and then treated with the appropriate boronic acid (0.15
mmol) followed by Pd(PPh3)4 (13 mg, 0.01 mmol) and then a solution of Na2CO3 (36.5 mg, 0.34
mmol) in water (0.25 mL). The resulting mixture was then placed under nitrogen and heated at
70°C for 18 h. The solvents were the removed under vacuum (Genevac) and the residue purified
using the OPTIX-SPE (C18 cartridge, 5g) eluting with 10-95% MeCN (+0.05% HCOOH) in H2O
(+0.01% HCOOH) over 15 mins to afford the desired product which, if appropriate, were further
purified by mass directed autoprep HPLC.

LC/MS and 1H NMR as described for Example 25.
Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 15% IPA in heptane with
0.1%TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 6.6 min (>99 %ee).

LC/MS and 1H NMR as described for Example 34.
Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 15% IPA in heptane with
0.1%TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 9-8 min (98.9 %ee).
Example 49
({2-Methyl-4-[((1fl)-1-{6-[4-(methyloxy)phenyl]-2-
pyridjnyl}pentyl)oxy]phenyl}oxy)acetic acid
LC/MS and 1H NMR as described for Example 26.
Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 15% IPA in heptane with
0.1 %TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 7.5 min (98.5 %ee).
s
LC/MS and 1H NMR as described for Example 32.
Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 15% IPA in heptane with
0.1%TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 9.5 min (99.3 %ee).
Ethyl [(4-{[(1R)-1-(6-bromo-2-pyridinyl)pentyl]oxy}-2-m9thylphenyl)oxy]acetate (50 mg, 0.11
mmol) was dissolved in DME (0.76 ml_) and then treated with 1 -[2-(methyloxy)-4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone (41 mg, 0.15 mmol) followed by Pd(PPh3)4
(13 mg, 0.01 mmol) and then a solution of Na2CO3 (49 mg, 0.46 mmol) in water (0.42 mL). The
resulting mixture was then placed under nitrogen and heated at 80°C for 18 h. The solvents were
the removed under vacuum (Genevac) and the residue purified by mass directed autoprep HPLC)
to give the title compound as an oil (39 mg,).
LC/MS: m/z 478.1 [M+H]+, Rt 4.04 min.
1H NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.5 Hz), 1.33-1.44 (2H, m), 1.44-1.61 (2H, m),
1.95-2.05 (2H, m), 2.19 (3H, s), 2.66 (3H, s), 4.03 (3H, s), 4.53 (2H, s), 5.22 (1H, dd, J 6.5, 6.5
Hz), 6.55 (1H, d, J 9.0 Hz), 6.58 (1H, dd, J 9.0, 2.5 Hz), 6.78 (1H, d, J 2.5 Hz), 7.36 (1H, d, J 7.5
Hz), 7.55 (1H, dd J 8.0,1.5 Hz), 7.61 (1H, d, J 7.5 Hz), 7.71 (1H, t, J 7.5 Hz), 7.71 (1H, d, J 1.5
Hz),7.85(1H,d, J 8.0 Hz).
General procedures for Examples 52-55
The following compounds were prepared as described for Examples 47-50 except starting
from ethyl [(4-{[(1 S)-1-(6-bromo-2-pyridinyl)pentyl]oxy}-2-methylphenyl)oxy]acetate.

LC/MS and 1H NMR as described for Example 25.
Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 15% IPA in heptane with
0.1%TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 8.0 min (92.9 %ee).
Example 53
{[4-({(1S)-1-[6-(4-Cyanophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}acetic
acid
LC/MS and 'H NMR as described for Example 34.
Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 15% IPA in heptane with
0.1%TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 12.4 min (95.9 %ee).

LC/MS and 1H NMR as described for Example 26.
Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 15% IPA in heptane with
0.1 %TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 8.6 min (95.1 %ee).

LC/MS and 1H NMR as described for Example 32.
Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 15% IPA in heptane with
0.1 %TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 11.9 min (96.6 %ee).
Example 56
({4-[((1S)-1-{6-[4-Acetyl-3-(methyloxy)phenyl]-2-pyridinyl}pentyl)oxy]-2-
methylphenyl}oxy)acetic acid
Prepared according to the procedure used to prepare Example 51 starting from ethyl [(4-
{[(1S)-1-(6-bromo-2-pyridinyl)pentyl]oxy}-2-methylphenyl)oxy]acetate (50 mg, 0.11 mmol) to give
the title compound (27 mg).
LC/MS and 1H NMR as described for Example 51.
General procedure for Examples 57-58
A stirred solution of bromide ethyl [(4-{[(1 R)-1 -(6-bromo~2-pyridinyl)-3-
(methyloxy)propyl]oxy}-2-rnethylphenyl)oxy]acetate (50 mg, 0.11 mmol) in DME (0.75 m!_) was
treated with the appropriate aryl boronic acid (0.15 mmol) followed by Pd(PPh3)4 (13 mg, 0.01
mmol) and a solution of NaaCO3 (48 mg, 0.46 mmol) in water (0.42 mL). The reaction mixture
was heated at 80°C for 17 h under nitrogen, allowed to cool to rt and then reduced under vacuum
(Genevac). The residue was then purified using the OPTIX-SPE (C18 cartridge, 5g) eluting with
20 - 75% (or 20 - 60%) MeCN (+0.05% HCOOH) in H2O (+0.01% HCOOH) over 20 mins afforded
the desired target molecules which, if appropriate, were purified further by mass directed autoprep
HPLC.

LC/MS: m/z 476.2 [M+H]+, Rt 3.83 min.
1H NMR (400 MHz; CDCI3) d: 2.19 (3H, s), 2.17-2.28 (1H, m), 2.28-2.40 (1H, m), 3.35 (3H,
s), 3.58 (1H, m), 3.68 (1H, m), 4.51 (2H, br.s), 5.39 (1H, dd, J 9.0,4.0 Hz), 6.54 (1H, d, J 9.0 Hz),
6.60 (1H, dd, J 9.0, 3.0 Hz), 6.78 (1H, d, J 3.0 Hz), 7.37 (1H, d, J 7.5 Hz), 7.62 (1H, d, J 7.5 Hz),
7.72 (2H, d, J 8.0 Hz), 7.72 (1H, t, J 7.5 Hz), 8.14 (2H, d, J 8.0 Hz).
LC/MS: m/z 442.2 [M+H]+, Rt 3.84 min.
1H NMR (400 MHz; CDCI3) d:2.18 (3H, s), 2.14-2.26 (1H, m), 2.27-2.39 (1H, m), 3.35 (3H,
s), 3.57 (1H, m), 3.67 (1H, m), 4.51 (2H, br.s), 5.36 (1H, dd, J 9.0, 4.0 Hz), 6.53 (1H, d, J 9.0 Hz),
6.59 (1H, dd, J 9.0,2.5 Hz), 6.78 (1H, d, J 2.5 Hz), 7.32 (1H, d, J 8.0 Hz), 7.43 (2H, d, J 8.5 Hz),
7.55 (1H, d, J 8.0 Hz), 7.68 (1H, t, J 8.0 Hz), 7.96 (2H, d, J 8.5 Hz).
General procedure for Examples 59-60
The following compounds were prepared as described for Examples 57-58 except starting
from ethyl [(4-{[(1S)-1 -(6-bromo-2-pyridinyl)-3-(methyloxy)propyl]oxy}-2-methylphenyl)oxy]acetate.
General procedure for Examples 61-65
A stirred solution of ethyl [(4-{[(1R)-1-(6-bromo-2-pyridinyl)-3-(methyloxy)propyl]oxy}-2-
methylphenyl)oxy]acetate (50 mg, 0.11 mmol) in DME (0.50 mL) was treated with the appropriate
aryl boronic acid (0.15 mmol) followed by Pd(PPh3)4 (13 mg, 0.01 mmol) and a solution of Na2CO3
(37 mg, 0.35 mmol) in water (0.25 mL). The reaction mixture was heated at 70°C for 16 h under
nitrogen and then allowed to cool to rt and stirred at rt for 7 h. LC/MS analysis indicated a mixture
of the desired acid and the ethyl ester, so MeOH (1 mL), THF (1 mL) and aqueous sodium
hydroxide (2M, 1 mL) were added and the mixture stirred at rt for 18 h. The reaction was then
quenched by the addition of aqueous HCI (2N, 2 mL) and the solvents then removed under
vacuum (Genevac). The residue was then dissolved in MeCN:H2O (1:2,1.8 mL) and loaded onto
an SPE (C18 cartridge, 5 g) which had been pre-conditioned with 2 column volumes of MeOH
and then equilibrated with 20% MeCN (+0.05%HCOOH) in H2O (+0.01%HCOOH). Elution with
20 - 75% (or 20 - 60%) MeCN (+0.05%HCOOH) in H2O (+0.01%HC0OH) over 20 mins afforded
the desired target molecules which, if appropriate, were purified further by mass directed autoprep
HPLC.

LC/MS: m/z 476.1 [M+H]+, Rt 4.01 min.
1H NMR (400 MHz; CDCI3) d: 1.20 (3H, t, J 7.0 Hz), 2.20 (3H, s), 3.62 (2H, m), 3.91 (1H,
dd, J 11.0, 7.0 Hz), 3.98 (1H, dd, J 11.0, 3.0 Hz), 4.53 (2H, s), 5.45 (1H, dd, J 7.0, 3.0 Hz), 6.55
(1H, d, J 9.0 Hz), 6.64 (1H, dd, J 9.0,3.0 Hz), 6.83 (1H, d, J 3.0 Hz), 7.42 (1H, d, J 8.0 Hz), 7.65
(1H, d, J 8.0 Hz), 7.73 (2H, d, J 8.0 Hz), 7.74 (1H, t, J 8.0 Hz), 8.14 (2H, d, J 8.0 Hz).
Analytical chiral HPLC (25 cm Chiralcel OJ) eluting with 20% EtOH in heptane with
0.1%TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 9.5 min (>99.9 %ee).
Example 62
({4-[((1R)-2-(Ethyloxy)-1-{6-[4-(methyloxy)phenyll-2-pyridinyl}ethyl)oxy]-2-
methylphenyl}oxy)acetlc acid
LC/MS: m/z 438.2 [M+H]+, Rt 3.70 min.
1H NMR (400 MHz; CDCI3) d: 1.19 (3H, t, J 7.0 Hz), 2.19 (3H, s), 3.62 (2H, m), 3.89 (1H,
dd, J 11.0, 7.5 Hz), 3.97 (1H, dd, J 11.0, 3.0 Hz), 4.51 (2H, s), 5.43 (1H, dd, J 7.5, 3.0 Hz), 6.54
(1H, d, J 9.0 Hz), 6.63 (1H, dd, J 9.0, 3.0 Hz), 6.82 (1H, d, J 3.0 Hz), 7.00 (2H, d, J 9.0 Hz), 7.29
(1H, d, J 8.0 Hz), 7.54 (1H, d, J 8.0 Hz), 7.65 (1H, t, J 8.0 Hz), 7.97 (2H, d, J 9.0 Hz).
Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 10% EtOH in heptane with
0.1%TFA, f = 1.0 mlVmin, wavelength 215 nm, Rt 13.9 min (>99.9 %ee).

LC/MS: m/z 450.1 [M+H]+, Rt 3.45 min.
1H NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 2.19 (3H, s), 2,66 (3H, s), 3.62 (2H, m),
3.91 (1H, dd, J 11.0, 7.0 Hz), 3.99 (1H, dd, J 11.0, 3.0 Hz), 4.52 (2H, s), 5.45 (1H, dd, J 7.0, 3.0
Hz), 6.55 (1H, d, J 9.0 Hz), 6.64 (1H, dd, J 9.0, 3.0 Hz), 6.83 (1H, d, J 3.0 Hz), 7.41 (1H, d, J 7.5
Hz), 7.67 (1H, dd, J 7.5,1.0 Hz), 7.73 (1H, t, J 7.5 Hz), 8.07 (2H, d, J 8.5 Hz), 8.13 (2H, d, J 8.5
Hz
1H NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 2.19 (3H, s), 3.62 (2H, m), 3.90 (1H,
dd, J 11.0, 7.0 Hz), 3.97 (1H, dd, J 11.0, 3.0 Hz), 4.51 (2H, s), 5.43 (1H, dd, J 7.0, 3.0 Hz), 6.55
(1H, d, J 9.0 Hz), 6.63 (1H, dd, J 9.0, 3.0 Hz), 6.82 (1H, d, J 3.0 Hz), 7.44 (1H, d, J 7.5 Hz), 7.65
(1H, d, J 7.5 Hz), 7.75 (1H, t, J 7.5 Hz), 7.77 (2H, d, J 8.5 Hz), 8.15 (2H, d, J 8.5 Hz).

LC/MS: m/z 442.1 [M+H]+, Rt 3.95 min.
1H NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 2.19 (3H, s), 3.62 (2H, m), 3.90 (1H,
dd, J 11.0, 7.0 Hz), 3.97 (1H, dd, J 11.0, 3.0 Hz), 4.52 (2H, s), 5.43 (1H, dd, J 7.0,3.0 Hz), 6.54
(1H, d, J 9.0 Hz), 6.63 (1H, dd, J 9.0, 3.0 Hz), 6.82 (1H, d, J 3.0 Hz), 7.37 (1H, d, J 7.5 Hz), 7.44
(2H, d, J 8.5 Hz), 7.57 (1H, d, J 7.5 Hz), 7.69 (1H, t, J 7.5 Hz), 7.96 (2H, d, J 8.5 Hz).
General procedure for Examples 66-70
The following compounds were prepared as described for Examples 61-65 except starting
from ethyl [(4-{[(1S)-1 -(6-bromo-2-pyridinyl)-3-(methyioxy)propyl]oxy}-2-methylphenyl)oxy]acetate.

LC/MS and 1H NMR as described for Example 61.
Analytical chiral HPLC (25 cm Chiralcel OJ) eluting with 20% EtOH in heptane with
0.1%TFA, f = 1.0 mL/min, wavelength 215 nm, R, 13.5 min (>99.9 %ee).
LC/MS and 1H NMR as described for Example 62.
Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 10% EtOH in heptane with
0.1%TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 16.2 min (>99.9 %ee).

LC/MS and 1H NMR as described for Example 63.
r
LC/MS and 1H NMR as described for Example 64.
Example 70
[(4-{[(1S)-1-[6-(4-Chlorophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
Ethyl [(4-{[(1S)-1 -[6-(4-cyanophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-
methylphenyl)oxy]acetate (0.886 g) was dissolved in THF (8.8 mL). Water (8.8 mL) and aq 2M
NaOH (1.8 mL) were added and the mixture stirred at ambient temperature for 30 mins. The
reaction mixture was acidified to pH 1 by the addition of aq 2M HCI and extracted with EtOAc (2 x
10 mL). The organic extracts were washed with brine (20 mL), dried (Na2SO4) and evaporated to
give the title compound as a white foam (729 mg).
LC/MS: m/z 433.2 [M+H]+, Rt 3.57 min.
1H NMR (400 MHz; CDCI3) d:1.20 (3H, t, J 7.0 Hz), 2.21 (3H, s), 3.63 (2H, m), 3.92 (1H,
dd, J 11.0, 7.0 Hz), 3.99 (1H, dd, J 11.0, 3.0 Hz), 4.56 (2H, s), 5.45 (1H, dd, J 7.0, 3.0 Hz), 6.57
(1H, d, J 9.0 Hz), 6.65 (1H, dd, J 9.0,3.0 Hz), 6.84 (1H, d, J 3.0 Hz), 7.45 (1H, d, J 7.5 Hz), 7.67
(1H, d, J 7.5 Hz), 7.77 (1H, t, J 7.5 Hz), 7.78 (2H, d, J 8.5 Hz), 8.17 (2H, d, J 8.5 Hz).
General procedure for Examples 71-84
A mixture of the boronic acid (or ester) (0.09 mmol) and Pd(PPh3)4 (7.5 mg, 0.006 mmol) in
an 8 ml test tube within a greenhouse was purged with nitrogen and then treated with a solution of
ethyl [(4-{[(1 ff)-1-(6-bromo-2-pyridinyl)-2-(ethyloxy)ethyl]oxy}-2-methylphenyl)oxy]acetate (30 mg,
0.068 mmol) in DME (1.5 mL) and then with aqueous Na2CO3 (1M, 1.0 mL). The resulting mixture
was heated to 60°C with vigorous stirring for 2 h then at 80°C for a further 3 h. The mixture was
then allowed to cool to ambient temperature then the solvent evaporated in a Genevac. The
residue was treated cautiously with aqueous HCI (2M, 1.5 mL) and then the product extracted into
DCM (2 x 3 mL). The combined organic solution was evaporated and the product purified either
by mass directed autoprep HPLC or using the Optix (C18 SPE).

LC/MS: m/z 440.3 [M+H]+, Rt 3.86 min.
1H NMR (400 MHz; CDCI3) d: 1.19 (3H, t, J 7.0 Hz), 2.19 (3H, s), 2.33 (3H, s), 3.62 (2H, m),
3.90 (1H, dd, J 11.0, 7.5 Hz), 3.98 (1H, dd, J 11.0, 3.0 Hz), 4.52 (2H, s), 5.43 (1H, dd, J 7.0, 3.0
Hz), 6.54 (1H, d, J 9.0 Hz), 6.63 (1H, dd, J 9.0, 3.0 Hz), 6.82 (1H, d, J 3.0 Hz), 7.27 (1H, dd, J 8.0,
8.0 Hz), 7.35 (1H, d, J 7.5 Hz), 7.56 (1H, d, J 7.5 Hz), 7.68 (1H, t, J 7.5 Hz), 7.67 (1H, dd, J 8.0,
1.5 Hz), 7.71 (1H, dd, J 11.0,1.5 Hz).

LC/MS: m/z 422.4 [M+H]+, Rt 3.75 min.
^ NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 2.17 (3H, s), 2.41 (3H, s), 3.61 (2H, m),
3.90 (1H, dd, J 11.0, 7.5 Hz), 3.97 (1H, dd, J 11.0, 3.0 Hz), 4.47 (2H, s), 5.44 (1H, dd, J 7.0, 3.0
Hz). 6.52 (1H, d, J 9.0 Hz), 6.62 (1H, dd, J 9.0, 3.0 Hz), 6.81 (1H, d, J 3.0 Hz), 7.28 (2H, d, J 8.0
Hz), 7.32 (1H, d, J 7.5 Hz), 7.56 (1H, d, J 7.5 Hz), 7.65 (1H, t, J 7.5 Hz), 7.90 (2H, d, J 8.0 Hz).
LC/MS: m/z 450.4 [M+H]+, Rt 4.04 min.
1H NMR (400 MHz; CDCI3) 8:1.19 (3H, t, J 7.0 Hz), 1.29 (6H, d, J 7.0 Hz), 2.18 (3H, s),
2.97 (1H, sept, J 7.0 Hz), 3.62 (2H, m), 3.90 (1H, del, J 11.0, 7.5 Hz), 3.98 (1H, dd, J 11.0,3.0
Hz), 4.50 (2H, s), 5.45 (1H, dd, J 7.5, 3.0 Hz), 6.53 (1H, d, J 9.0 Hz), 6.63 (1H, dd, J 9.0, 3.0 Hz),
6.81 (1H, d, J 3.0 Hz), 7.33 (3H,m), 7.57 (1H, d, J 7.5 Hz), 7.66 (1H, t, J 7.5 Hz), 7.93 (2H, d, J
8.5 Hz).

LC/MS: m/z 451.3 [M+H]+, Rt 3.63 min.
1H NMR (400 MHz; CDCI3) d: 1.19 (3H, t, J 7.0 Hz), 2.18 (3H, s), 3.62 (2H, m), 3.91 (1H,
dd, J 11.0, 7.0 Hz), 3.97 (1H, dd, J 11.0, 3.5 Hz), 4.50 (2H, s), 5.43 (1H, dd, J 7.0, 3.5 Hz), 6.53
(1H, d, J 9.0 Hz), 6.61 (1H, dd, J 9.0, 3.0 Hz), 6.80 (1H, d, J 3.0 Hz), 7.47 (1H, d, J 7.5 Hz), 7.65
(1H, d, J 7.5 Hz), 7.71 (1H, dd, J 8.0, 7.0 Hz), 7.76 (1H, t, J 7.5 Hz), 7.91 (1H, dd, J 8.0,1.5 Hz),
7.96 (1H,dd,J 10.5, 1.5 Hz).
1H NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 1.45 (3H, t, J 7.0 Hz), 2.18 (3H, s), 3.62
(2H, m), 3.89 (1H, dd, J 11.0, 7.5 Hz), 3.97 (1H, dd, J 11.0, 3.0 Hz), 4.09 (2H, q, J7.0 Hz), 4.49
(2H, s), 5.43 (1H, dd, J 7.0, 3.0 Hz), 6.53 (1H, d, J 9.0 Hz), 6.62 (1H, dd, J 9.0, 3.0 Hz), 6.81 (1H,
d, J 3.0 Hz), 6.99 (2H, d, J 9.0 Hz), 7.29 (1H, d, J 7.5 Hz), 7.52 (1H, d, J 7.5 Hz), 7.64 (1H, t, J 7.5
Hz), 7.94 (2H, d, J 9.0 Hz).

LC/MS: m/z 440.3 [M+H]+, Rt 3.80 min.
1H NMR (400 MHz; CDCI3) d: 1.19 (3H, t, J 7.0 Hz), 2.20 (3H, s), 2.40 (3H, s), 3.61 (2H, m),
3.89 (1H, dd, J 11.0, 7.0 Hz), 3.96 (1H, dd, J 11.0, 3.5 Hz), 4.53 (2H, s), 5.44 (1H, dd, J 7.0, 3.0
Hz), 6.56 (1H, d, J 9.0 Hz), 6.64 (1H, dd, J 9.0, 3.0 Hz), 6.83 (1H, d, J 3.0 Hz), 6.98 (1H, d, J 13.0
Hz), 7.08 (1H, d, J 8.0 Hz), 7.35 (1H, dd, J 7.0,1.5 Hz), 7.62 -7.71 (2H, m), 7.90 (1H, t, J 8.0 Hz).

LC/MS: m/z 426.3 [M+H]+, Rt 3.67 min.
1H NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 2.18 (3H, s), 3.62 (2H, m), 3.90 (1H,
dd, J 11.0, 7.0 Hz), 3.97 (1H, dd, J 11.0, 3.0 Hz), 4.49 (2H, s), 5.43 (1H, dd, J 7.0, 3.0 Hz), 6.52
(1H, d, J 9.0 Hz), 6.62 (1H, dd, J 9.0, 3.0 Hz), 6.81 (1H, d, J 3.0 Hz), 7.16 (2H, dd, J 8.5, 8.5 Hz),
7.35 (1H, d, J 8.0 Hz), 7.55 (1H, d, J 8.0 Hz), 7.68 (1H, t, J 8.0 Hz) 7.99 (2H, dd, J 8.5, 6.0 Hz).
Example 78
[(4-{[(1R)-2-(Ethyloxy)-1-(6-{4-[(1-methylethyl)oxy]phenyl}-2-pyridinyl)ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
LC/MS: m/z 466.4 [M+H]+, Rt, 3.86 min.
1H NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 1.37 (6H, d, J 6.0 Hz), 2.18 (3H, s),
3.61 (2H, m), 3.89 (1H, dd, J 11.0,7.5 Hz), 3.97 (1H, dd, J 11.0, 3.0 Hz), 4.49 (2H, s), 4.63 (1H,
sept, J 6.0 Hz), 5.43 (1H, dd, J 7.0, 3.0 Hz), 6.53 (1H, d, J 9.0 Hz), 6.62 (1H, dd, J 9.0, 3.0 Hz),
6.81 (1H, d, J 3.0 Hz), 6.98 (2H, d, J 9.0 Hz), 7.28 (1H, d, J 8.0 Hz), 7.52 (1H, d, J 8.0 Hz), 7.64
(1H, t, J 8.0 Hz), 7.94 (2H, d, J 9.0 Hz).

LC/MS: m/z 456.3 [M+H]+, Rt 4.06 min.
1H NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 2.19 (3H, s), 2.46 (3H, s), 3.62 (2H, m),
3.89 (1H, dd, J 11.0, 7.5 Hz), 3.97 (1H, dd, J 11.0,3.5 Hz), 4.51 (2H, s), 5.43 (1H, dd, J 7.5, 3.0
Hz), 6.54 (1H, d, J 9.0 Hz), 6.62 (1H, dd, J 9.0, 3.0 Hz), 6.82 (1H, d, J 3.0 Hz), 7.35 (1H, d, J 7.5
Hz), 7.43 (1H, d, J 8.5 Hz), 7.56 (1H, d, J 7.5 Hz), 7.68 (1H, t, J 7.5 Hz), 7.75 (1H, dd, J 8.5, 2.0
Hz),7.89(1H,d, J 2.0 Hz).
1H NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 2.18 (3H, s), 3.62 (2H, m), 3.90 (1H,
dd, J 11.0, 7.0 Hz), 3.97 (1H, dd, J 11.0, 3.5 Hz), 4.51 (2H, s), 5.43 (1H, dd, J 7.0, 3.5 Hz), 6.53
(1H, d, J 9.0 Hz), 6.61 (1H, dd, J 9.0,3.0 Hz), 6.81 (1H, d, J 3.0 Hz), 7.47 (1H, d, J 7.5 Hz), 7.65
(1H, d, J 7.5 Hz), 7.76 (1H, t, J 7.5 Hz), 7.76 (1H, d, J 8.0 Hz), 8.01 (1H, dd, J 8.0,1.5 Hz), 8.23
(1H,d,J1.5Hz).

LC/MS: m/z 447.3 [M+H]+, Rt 3.65 mln.
1H NMR (400 MHz; CDCI3) 5:1.19 (3H, t, J 7.0 Hz), 2.18 (3H, s), 2.64 (3H, s), 3.62 (2H, m),
3.90 (1H, dd, J 11.0, 7.0 Hz), 3.97 (1H, dd, J 11.0, 3.5 Hz), 4.50 (2H, s), 5.44 (1H, dd, J 7.0, 3.5
Hz), 6.54 (1H, d, J 9.0 Hz), 6.62 (1H, dd, J 9.0, 3.0 Hz), 6.81 (1H, d, J 3.0 Hz), 7.43 (1H, d, J 7.5
Hz), 7.63 (1H, d, J 7.5 Hz), 7.70 (1H, d, J 8.0 Hz), 7.73 (1H, t, J 7.5 Hz), 7.89 (1H, dd, J 8.0,1.0
Hz), 7.99(1H,d,J1.0Hz).

LC/MS: m/z 456.3 [M+H]+, Rt 3.63 min.
1H NMR (400 MHz; CDCI3) d:1.20 (3H, t, J 7.0 Hz), 2.19 (3H, s), 3.62 (2H, m), 3.90 (1H,
dd, J 11.0, 7.0 Hz), 3.95 (3H, s), 3.94-3.99 (1H, m), 4.52 (2H, s), 5.42 (1H, dd, J 7.5, 3.0 Hz), 6.54
(1H, d, J 9.0 Hz), 6.63 (1H, dd, J 9.0,3.0 Hz), 6.82 (1H, d, J 3.0 Hz), 7.04 (1H, dd, J 8.5, 8.5 Hz),
7.32 (1H, d, J 7.5 Hz), 7.53 (1H, d, J 7.5 Hz), 7.66 (1H, t, J 7.5 Hz), 7.74 (1H, bd, J 8.5 Hz) 7.82
(1H, dd,J13.0, 2.0 Hz).
Example 83
LC/MS: m/z 451.3 [M+H]+, Rt 3.56 min.
1H NMR (400 MHz; CDCI3) d:1.19 (3H, t, J 7.0 Hz), 2.19 (3H, s), 3.61 (2H, m), 3.90 (1H,
dd, J 11.0, 7.0 Hz), 3.96 (1H, dd, J 11.0, 3.5 Hz), 4.52 (2H, s), 5.43 (1H, dd, J 7.0, 3.5 Hz), 6.55
(1H, d, J 9.0 Hz), 6.62 (1H, dd, J 9.0, 3.0 Hz), 6.81 (1H, d, J 3.0 Hz), 7.44-7.51 (2H, m), 7.58 (1H,
dd, J 8.0,1.5 Hz), 7.71-7.79 (2H, m), 8.21 (1H, t, J 8.0 Hz).

LC/MS: m/z 447.3 [M+H]+, Rt 3.49 min.
1H NMR (400 MHz; CDCI3) d: 1.17 (3H, t, J 7.0 Hz), 2.18 (3H, s), 2.38 (3H, s), 3.59 (2H, m),
3.90 (2H, m), 4.52 (2H, s), 5.44 (1H, dd, J 5.0, 5.0 Hz), 6.55 (1H, d, J 9.0 Hz), 6.62 (1H, dd, J 9.0,
3.0 Hz), 6.79 (1H, d, J 3.0 Hz), 7.29 (1H, d, J 7.5 Hz), 7.47 (1H, d, J 7.5 Hz), 7.48 (1H, d, J 8.5
Hz), 7.54-7.62 (2H,m), 7.76 (1H, t, J 7.5 Hz).
General procedure for Examples 85-98
The following compounds were prepared as described for Examples71-84 except starting
from ethyl [(4-{[(1 S)-1-(6-bromo-2-pyridinyl)-2-(ethyloxy)ethyl]oxy}-2-methylphenyl)oxy]acetate
bromide.
Example 85
{[4-({(1S)-2-(Ethyloxy)-1-[6-(3-fluoro-4-methylphenyI)-2-pyridinyl]ethyl}oxy)-2-
methylphenyl]oxy}acetic acid
General procedure for Examples 99-103
A stirred solution of ethyl 3-(4-{[(1S)-1-(6-bromo-2-pyridinyl)pentyl]oxy}-2-
methylphenyl)propanoate (76 mg, 0.17 mmol) in DME (1.2 mL) was treated with the appropriate
aryl boronic acid (0.23 mmol) followed by and a solution of Na2CO3 (74 mg, 0.70 mmol) in water
(0.7 mL). The reaction mixture was heated at 73°C for 21 h under nitrogen, allowed to cool to rt
and then reduced under vacuum (Genevac). The residue was then treated with THF (2 mL),
MeOH (2 mL) followed by aqueous NaOH (2N, 2 mL) and the resulting mixture stirred at ambient
temperature for 4 h. The solvents were then removed under vacuum and the residue purified
using the OPTIX-SPE (C18 cartridge, 5g) eluting with 25-100% MeCN (+0.05% HCOOH) in H2O
(+0.01% HCOOH) over 18 mins to afford the desired product which, if appropriate, were further
purified by mass directed autoprep HPLC.

LC/MS: m/z 472.2 [M+H]+, Rt 4.26 min.
nH NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.34-1.45 (2H, m), 1.45-1.64 (2H, m),
1.96-2.08 (2H, m), 2.23 (3H, s), 2.55 (2H, m), 2.83 (2H, m), 5.28 (1H, dd, J 7.5, 5.5 Hz), 6.64 (1H,
dd, J 8.5, 2.5 Hz), 6.77 (1H, d, J 2.5 Hz), 6.95 (1H, d, J 8.5 Hz), 7.38 (1H, d, J 7.5 Hz), 7.62 (1H,
d, J 7.5 Hz), 7.72 (1H, t, J 7.5 Hz), 7.75 (2H, d, J 8.5 Hz), 8.14 (2H, d, J 8.5 Hz).
Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 20% IPA in heptane with
0.1 %TFA, f = 1.0 mL/min, wavelength 215 nm, Rt 7.5 min (94 %ee).

LC/MS: m/z 434.3 [M+H]+, Rt 4.05 min.
1H NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.33-1.44 (2H, m), 1.44-1.64 (2H, m),
1.94-2.09 (2H, m), 2.22 (3H, s), 2.54 (2H, m), 2.82 (2H, m), 3.88 (3H, s), 5.25 (1H, dd, J 8.0, 4.5
Hz), 6.65 (1H, dd, J 8.5,2.5 Hz), 6.77 (1H, d, J 2.5 Hz), 6.94 (1H, d, J 8.5 Hz), 7.02 (2H, d, J 9.0
Hz), 7.25 (1H, d, J 8.0 Hz), 7.51 (1H, d, J 8.0 Hz), 7.63 (1H, t, J 8.0 Hz), 7.98 (2H, d, J 0.0 Hz).
Analytical chiral HPLC (25 cm Chiralcel OD) eluting with 2% EtOH in heptane with
0.1 %TFA, f = 1.0 mL/min, wavelength 254 nm, R, 22.2 min (97 %ee).
LC/MS: m/z 446.3 [M+H]+, Rt 3.93 min.
1H NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.33-1.45 (2H, m), 1.45-1.65 (2H, m),
1.94-2.09 (2H, m), 2.23 (3H, s), 2.55 (2HP m), 2.66 (3H, s), 2.82 (2H, m), 5.29 (1H, dd, J 7.5, 5.5
Hz), 6.64 (1H, dd, J 8.5, 2.5 Hz), 6.77 (1H, d, J 2.5 Hz), 6.95 (1H, d, J 8.5 Hz), 7.37 (1H, d, J 7.5
Hz), 7.64 (1H, d, J 7.5 Hz), 7.71 (1H, t, J 7.5 Hz), 8.08 (2H, d, J 8.5 Hz), 8.14 (2H, d, J 8.5 Hz).

LC/MS: m/z 429.3 [M+H]+, Rt 3.97 min.
1H NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.5 Hz), 1.33-1.43 (2H, m), 1.43-1.63 (2H, m),
1.94-2.07 (2H, m), 2.54 (2H, m), 2.82 (2H, m), 5.27 (1H, m), 6.62 (1H, d, J 8.5,2.5 Hz), 6.75 (1H,
d, J 2.5 Hz), 7.94 (1H, d, J 8.5 Hz), 7.40 (1H, d, J 7.5 Hz), 7.62 (1H, d, J 7.5 Hz), 7.74 (1H, t, J 7.5
Hz), 7.78 (2H, d, J 8.5 Hz), 8.16 (2H, d, J 8.5 Hz).
1H NMR (400 MHz; CDC!3) d: 0.91 (3H, t, J 7.5 Hz), 1.32-1.44 (2H, m), 1.44-1.63 (2H, m),
1.92-2.07 (2H, m), 2.22 (3H, s), 2.54 (2H, m), 2.82 (2H, m), 5.25 (1H, dd, J 8.0, 5.0 Hz), 6.63 (1H,
dd, J 8.5, 2.5 Hz), 6.75 (1H, d, J 2.5 Hz), 6.94 (1H, d, J 8.5 Hz), 7.32 (1H, d, J 7.5 Hz), 7.45 (2H,
d, J 8.5 Hz), 7.54 (1H, d, J 7.5 Hz), 7.67 (1H, t, J 7.5 Hz), 7.97 (2H, d, J 8.5 Hz).
General procedure for Examples 104-108

LC/MS and 1H NMR as described for Example 99.
Analytical chiral HPLC (25 cm Chiralpak AD) eluting with 20% I PA in heptane with
0.1 %TFA, f = 1.0 rnL/min, wavelength 215 nm, Rt 4.2 min (99 %ee).

LC/MS and 1H NMR as described for Example 100.
Analytical chiral HPLC (25 cm Chiralcel OD) eluting with 2% EtOH in heptane with
0.1%TFA, f = 1.0 mL/min, wavelength 254 nm, Rt 17.2 min (>99 %ee).
Example 106
3-[4-({(1R)-1-[6-(4-Acetylphenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]propanoic
acid
(28 mg, 0.06 mmol) to give, after further purification by mass directed autoprep HPLC, the title
compound (15mg).
LC/MS: m/z 486.3 [M+H]+, Rt 4.20 min.
1H NMR (400 MHz; CDCI3) d: 0.85 (3H, t, J 7.0 Hz), 1.18-1.39 (4H, m), 2.11 (6H, s), 2.14-
2.28 (2H, m), 2.62 (2H, m), 2.83 (2H, m), 4.96 (1H, dd, J 7.5, 6.0 Hz), 6.79 (2H, s), 7.40 (1H, d, J
7.5 Hz), 7.68 (1H, d, J 7.5 Hz), 7.71 (2H, d, J 8.5 Hz), 7.77 (1H, t, J 7.5 Hz), 8.10 (2H, d, J 8.5
Hz).

Prepared according to the procedure used to prepare Intermediate 73 starting from (2£)-3-
{3-(methyloxy)-5-(2-propen-1-yl)-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}-
2-propenoic acid (68 mg, 0.13 mmol) to give, after further purification by mass directed autoprep
HPLC, the title compound (36 mg).
LC/MS: m/z 430.2 [M+H]+, Rt 4.24 min.
1H NMR (400 MHz; CDCI3) 8:0.83 (3H, t, J 7.5 Hz), 0.87 (3H, m), 1.26-1.38 (4H, m), 1.38-
1.59 (2H, m), 2.03-2.14 (1H, m), 2.16-2.28 (1H, m), 2.43 (2H, t, J 8.0 Hz), 2.63 (2H, m), 2.85 (2H,
m), 3.69 (3H, s), 4.96 (1H, dd, J 7.0, 5.5 Hz), 6.55 (2H, s), 7.46 (1H, d, J 7.5 Hz), 7.64 (1H, d, J
7.5 Hz), 7.70 (2H, d, J 8.0 Hz), 7.75 (1H, t, J 7.5 Hz), 8.10 (2H, d, J 8.0) Hz).

Prepared according to the procedure used to prepare Intermediate 73 starting from (2E)-3-
{3-(2-propen-1-yl)-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}-2-propenoic
acid (39 mg, 0.08 mmol) to give, after further purification by mass directed autoprep HPLC, the
title compound (25 mg).
LC/MS: m/z 500.2 [M+H]+, Rt 4.37 min.
1H NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.02 (3H, t, J 7.5 Hz), 1.34-1.45 (2H,
m), 1.46-1.59 (2H, m), 1.71 (2H, m), 2.04 (2H, m), 2.59 (2H, m), 2.71 (2H, t, J 8.0 Hz), 2.81 (2H,
m), 5.30 (1H, dd, J 6.5, 6.5 Hz), 6.54 (1H, d, J 8.5 Hz), 6.78 (1H, dd, J 8.5, 2.5 Hz), 6.97 (1H, d, J
2.5 Hz), 7.31 (1H, d, J 7.5 Hz), 7.62 (1H, d, J 7.5 Hz), 7.71 (1H, t, J 7.5 Hz), 7.75 (2H, d, J 8.0
Hz), 8.15(2H,d,J8.0Hz).
t
Prepared according to the procedure used to prepare Intermediate 73 starting from (2£)-3-
{3-(ethyloxy)-4-t(1-{6-[4-(trif!uoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}-2-propenoic acid
(305 mg, 0.61 mmol) to give, after further purification by mass directed autoprep HPLC, the title
compound (26 mg).
LC/MS: m/z 502.2 [M+H]+, Rt 4.10 min.
1H NMR (400 MHz; MeOD-d4) d: 0.87 (3H, t, J 7.5 Hz), 1.30-1.58 (4H, m), 1.36 (3H, t, J 7.0
Hz), 1.90-2.09 (2H, m), 2.46 (2H, t, J 7.5 Hz), 2.72 (2H, t, J 7.5 Hz), 4.03 (2H, d, J 7.0 Hz), 5.23
(1H, dd, J 7.5, 5.0 Hz), 6.52 (1H, dd, J 8.5, 2.0 Hz), 6.64 (1H, d, J 8.5 Hz), 6.78 (1H, d, J 2.0Hz),
7.46 (1H, dd, J 7.5,1.0 Hz), 7.72 (2H, d, J 8.5 Hz), 7.73 (1H, dd, J 7.5,1.0 Hz), 7.78 (1H, t, J 7.5
Hz), 8.16 (2H, d, J 8.5 Hz).
General procedure for Examples 113-117
A stirred solution of alcohol (1S)-1-{6-[4-(trifluoromethyi)phenyl]-2-pyridinyl}-1-pentanol (65
mg, 0.21 mmol) and the appropriate phenol (0.33 mmol) in THF (4 mL) at 0°C under nitrogen was
added ADDP (106 mg, 0.42 mmol) followed by tri-N-butylphosphine (0.105 mL, 0.42 mmol). The
resulting mixture was then allowed to warm slowly to ambient temperature overnight. After 21 h
the solvent was removed under vacuum (Genevac) and the solid residue dissolved in THF (2 mL),
MeOH (2 mL) and treated with aqueous NaOH (2N, 2 mL). The resulting mixture was then stirred
at rt for 2-3 h and then treated with aqueous HCI (2N, 2 mL) and the solvents removed under
vacuum (Genevac). The residue was then purified using the OPTIX-SPE (C18 cartridge, 5g)
eluting with 50-100% MeCN (+0.05% HCOOH) in H2O (+0.01% HCOOH) over 15 minsto afford
the crude productOPTIX. The suiting crude product containing un-reacted alcohol was further
purified using an SPE (silica, 2 or 5 g cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 or
20:1 to 0:1) to give the desired product.

LC/MS: m/z 458.2 [M+H]+, Rt 4.17 min.
1H NMR (400 MHz; CDCI3) d: 0.93 (3H, t, J 7.5 Hz), 1.36-1.46 (2H, m), 1.46-1.64 (2H, m),
2.03 (2H, m), 2.60 (2H, t, J 7.5 Hz), 2.84 (2H, t, J 7.5 Hz), 5.30 (1H, dd, J 6.5,6.5 Hz), 6.83 (2H,
d, J 8.5 Hz), 7.04 (2H, d, J 8.5 Hz), 7.38 (1H, d, J 8.0 Hz), 7.62 (1H, d, J 8.0 Hz), 7.72 (1H, t, J 8.0
Hz), 7.75 (2H, d, J 8.0 Hz), 8.15 (2H, d, J 8.0 Hz),

LC/MS: m/z 488.2 [M+H]+, R, 4.02 min.
1H NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.34-1.46 (2H, m), 1.45-1.55 (1H, m),
1.55-1.68 (1H, m), 2.01-2.20 (2H, m), 2.61 (2H, t, J 7.5 Hz), 2.84 (2H, t, J 7.5 Hz), 3.89 (3H. s),
5.29 (1H, dd, J 7.0, 6.0 Hz), 6.56 (1H, dd, J 8.0,1.5 Hz), 6.68 (1H, dd, J 8.0 Hz), 6.74 (1H, d, J
1.5 Hz), 7.48 (1H, d, J 7.5 Hz), 7.61 (1H, d, J 7.5 Hz), 7.70-7.77 (3H, m), 8.14 (2H, d, J 8.0 Hz).
Example 115
{4-[((1R)-1-{6-[4-(Trlfluoromethyl)phenyl]-2-pyr!dinyl}pentyl)oxy]phenyl}acetic acid
LC/MS: m/z 444.2 [M+H]+, Rt 4.09 min.
1H NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.34-1.45 (2H, m), 1.45-1.65 (2H, m),
2.03 (2H, m), 3.51 (2H, s), 5.30 (1H, dd, J 6.5, 6.5 Hz), 6.86 (2H, d, J 8.5 Hz), 7.10 (2H, d, J 8.5
Hz), 7.37 (1H, d, J 7.5 Hz), 7.62 (1H, d, J 7.5 Hz), 7.72 (1H, t, J 7.5 Hz), 7.75 (2H, d, J 8.0 Hz),
8.14 (2H, d, J 8.0 Hz),

LC/MS: m/z 478.1 [M+H]+, Rt 4.23 min.
1H NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.34-1.46 (2H, m), 1.46-1.68 (2H, m),
2.01-2.16 (2H, m), 3.49 (2H, s), 5.36 (1H, dd, J 7.5,5.0 Hz), 6.74 (1H, d, J 8.5 Hz), 6.92 (1H, dd,
J 8.5, 2.0 Hz), 7.30 (1H, d, J 2.0 Hz), 7.42 (1H, d, J 7.5 Hz), 7.64 (1H, d, J 7.5 Hz), 7.75 (1H, t, J
7.5 Hz), 7.75 (2H, d, J 8.0 Hz), 8.14 (2H, d, J 8.0 Hz).

LC/MS: m/z 474.2 [M+H]+, Rt 3.96 min.
nH NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.5 Hz), 1.34-1.44 (2H, m), 1.44-1.54 (1H, m),
1.54-1.67 (1H, m), 2.00-2.18 (2H, m), 3.51 (2H, s), 3.90 (3H, s), 5.29 (1H, dd, J 8.0, 5.0 Hz), 6.62
(1H, dd, J 8.0,1.5 Hz), 6.70 (1H, d, J 8.0 Hz), 6.81 (1H, d, J 1.5Hz), 7.46 (1H, d, J 7.5 Hz), 7.61
(1H, d, J 7.5 Hz), 7.69-7.77 (3H, m), 8.13 (2H, d, J 8.0 Hz).
General procedure for Examples 118-121
The following compounds were prepared in a similar way to that described for Examples
113-117 except starting from alcohol (1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol.
General procedure for Examples 123-126
The following compounds were prepared using a similar procedure to Examples 113-117
except the mixtures were not reduced after the Mitsunobu reaction but were treated directly with
MeOH (2 mL) and aqueous NaOH (2 mL), stirred for 3 h and then quenched with aqueous HCI
(2N, 2 mL) and reduced. The residue was then suspended in a DCM (ca. 1 mL) and filtered
through a bond elut cartridge directly onto a SPE (silica, 5 g cartridge) washing with a more DCI
(2 x 0.5 mL). The cartridge was left to dry and the compound purified using the OPTIX-SPE (Si
cartridge, 5g) eluting with cyclohexane:EtOAc (gradient 85:15 to 0:1) over 15 mins to afford the
desired products which were purified further by repeated SPE or mass directed autoprep HPLC
as appropriate.
Example 123
3-{3-Fluoro-4-[((1R)-1-{6-[4-(trif luoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}propanoicacid
LC/MS: m/z 476.1 [M+H]+, Rt 4.14 min.
1H NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.33-1.45 (2H, m), 1.45-1.54 (1H, m),
1.54-1.66 (1H, m), 1.99-2.16 (2H, m), 2.58 (2H, t, J 7.5 Hz), 2.82 (2H, t, J 7.5 Hz), 5.31 (1H, dd, J
8.0, 5.0 Hz), 6.72 (1H, dd, J 8.5,2.0 Hz), 6.75 (1H, dd, J 16.0, 8.5 Hz), 6.93 (1H, dd, J 12.0, 2.0
Hz), 7.45 (1H, d, J 8.0 Hz), 7.64 (1H, d, J 8.0 Hz), 7.74 (2H, d, J 8.5 Hz), 7.76 (1H, t, J 8.5 Hz),
8.13(2H,d,J8.5Hz).

LC/MS: m/z 472.2 [M+H]+, Rt 4.30 min.
1H NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.35-1.46 (2H, m), 1.46-1.65 (2H, m),
2.01-2.10 (2H, m), 2.35 (3H, s), 2.59 (2H, t, J 7.5 Hz), 2.81 (2H, t, J 7.5 Hz), 5.31 (1H, dd, J 6.5,
6.5 Hz), 6.56 (1H, d, J 8.5 Hz), 6.79 (1H, dd, J 8.5, 2.0 Hz), 7.00 (1H, d, J 2.0 Hz), 7.34 (1H, d, J
7.5 Hz), 7.62 (1H, d, J 7.5 Hz), 7.72 (1H, t, J 7.5 Hz), 7.75 (2H, d, J 8.5 Hz), 8.16(2H, d, J 8.5
Hz).
1H NMR (400 MHz; CDCI3) d: 0.89 (3H, t, J 7.5 Hz), 1.30-1.41 (2H, m), 1.41-1.52 (2H, m),
1.97-2.09 (1H, m), 2.09-2.22 (1H, m), 2.63 (2H, m), 2.85 (2H, m), 3.71 (6H, s), 5.28 (1H, dd, J 6.5,
6.5 Hz), 6.35 (2H, s), 7.60 (1H, del, J 7.5,1.5 Hz), 7.68 (2H, d, J 8.5 Hz), 7.71 (1H, dd, J 7.5,1.5
Hz), 7.76 (1H, t, J 7.5 Hz), 8.06 (2H, d, J 8.5 Hz).

LC/MS: m/z 488.2 [M+H]+, Rt 4.15 min.
1H NMR (400 MHz; CDCI3) d: 0.92 (3H, t, J 7.5 Hz), 1.34-1.46 (2H, m), 1.46-1.53 (1H, m),
1.53-1.65 (1H, m), 1.98-2.08 (2H, m), 2.56 (2H, m), 2.80 (2H, m), 3.72 (3H, s), 5.30 (1H, dd, J 6.5,
6.5 Hz), 6.32 (1H, dd, J 8.5, 2.5 Hz), 6.52 (1H, d, J 2.5 Hz), 6.90 (1H, d, J 8.5, Hz), 7.38 (1H, d, J
7.5 Hz), 7.62 (1H, d, J 7.5 Hz), 7.70-7.76 (3H, m), 8.15 (2H, d, J 8.5 Hz).
General procedure for Examples 127-130
The following compounds were prepared in a similar way to that described for Examples
123-126 except starting from alcohol (1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol.

LC/MS and 1H NMR as described for Example 123.
Example 128
3-{3-Methyl-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyrldinyl}pentyl)oxy]phenyl}propanoic acid
To a stirring solution of ethyl 3-{3-chloro-5-(methyloxy)-4-[((1S)-1 -{6-[4-
(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}prapanoate (118 mg, 0.20 mmol) in THF (3
mL) and MeOH (3 mL) at ambient temperature was added NaOH (2N, 3 ml.) and the mixture
stirred for 2 h and then left to stand overnight. HCI (2N, 3 mL) was then added and the mixture
reduced under vacuum. The residue was then purified by SPE (silica, 5 g cartridge) with a pad of
celite on the top, eluting with cyclohexane:EtOAc (gradient 20:1 to 0:1) to give the title compound
(94 mg).
LC/MS: m/z 522.1 [M+H]+, Rt 4.20 min.
1H NMR (400 MHz; CDCI3) d: 0.88 (3H, t, J 7.0 Hz), 1.29-1.47 (4H, m), 2.02-2.14 (1H, m),
2.16-2.29 (1H, m), 2.63 (2H, m), 2.84 (2H, m), 3.69 (3H, s), 5.42 (1H, dd, J 6,5, 6.5 Hz), 6.59 (1H,
d, J 2.0 Hz), 6.77 (1H, d, J 2.0 Hz), 7.64 (1H, d, J 7.5 Hz), 7.65 (1H, d, J 7.5 Hz), 7.69 (2H, d, J
8.0 Hz), 7.78 (1H, t, J 7.5 Hz), 8.07 (2H, d, J 8.0 Hz).

To a stirring solution of ethyl (2E)-3-{3-chloro-4-[((1 f?)-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}-2-propenoate (54 mg, 0.10 mmo!) in EtOAc (4 mL) under nitrogen at
ambient temperature was added PtO2 (20 wt%, 11 mg) and the mixture stirred under an
atmosphere of hydrogen for 5 h. The resulting mixture was then purified by SPE (silica, 5 g
cartridge) with a pad of celite on the top, eluting with EtOAc. The filtrate was then reduced and
purified further by SPE (silica, 5 g cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to
20:1) to give an inseparable mixture containing the desired material and some de-chlorinated
compound (51 mg). This material was then dissolved in THF (2 mL) and MeOH (2 mL) at
ambient temperature and treated with NaOH (2N, 2 mL). The resulting mixture was then stirred
for 2 h and then left to stand overnight. HCI (2N, 2 mL) was then added and the mixture reduced
under vacuum. The residue was then purified by SPE (silica, 5 g cartridge) with a pad of celite on
the top, eluting with cyclohexane:EtOAc (gradient 20:1 to 0:1) to give a residue which was purified
further by mass directed autoprep HPLC to give the title compound (30 mg).
LC/MS: m/z 492.2 [M+H]+, Rt 4.28 min.
1H NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.5 Hz), 1.33-1.45 (2H, m), 1.46-1.65 (2H, m),
2.03-2.15 (2H, m), 2.58 (2H, t, J 7.5 Hz), 2.80 (2H, t, J 7.5 Hz), 5.38 (1H, dd, J 7.5, 5.0 Hz), 6.71
(1H, d, J 8.5 Hz), 6.86 (1H, dd, J 8.5, 2.0 Hz), 7.21 (1H, d, J 2.0 Hz), 7.45 (1H, d, J 7.5 Hz), 7.64
(1H, d, J 7.5 Hz), 7.74 (2H, d, J 8.0 Hz), 7.78 (1H, t, J 7.5 Hz), 8.12 (2H, d, J 8.0 Hz).
Prepared according to the procedure used to prepare Example 132 starting from ethyl (2E)-
3-{2-chloro-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}-2-propenoate
(53 mg, 0.10 mmol) to afford the title compound (29 mg).
LC/MS: m/z 492.1 [M+H]+, Rt 4.35 min.
1H NMR (400 MHz; CDCI3) d: 0.91 (3H, t, J 7.5 Hz), 1.33-1.43 (2H, m), 1.43-1.62 (2H, m),
1.96-2.06 (2H, m), 2.61 (2H, m), 2.93 (2H, m), 5.26 (1H, dd, J 6.5, 6.5 Hz), 6.71 (1H, dd, J 8.5,
2.5 Hz), 6.97 (1H, d, J 2.5 Hz), 7.05 (1H, d, J 8.5 Hz), 7.35 (1H, d, J 8.0 Hz), 7.64 (1H, d, J 8.0
Hz), 7.74 (1H, t, J 8.0 Hz), 7.75 (2H, d, J 8.0 Hz), 8.14 (2H, d, J 8.0 Hz).

Prepared according to the procedure used to prepare Example 132 starting from ethyl (2E)-
3-{3-chloro-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}-2-propenoate
(41 mg, 0.08 mmol) to afford the title compound (12 mg).
LC/MS and 'H NMR as described for Example 132.
Example 135
3-{2-Chloro-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridlnyl}pentyl)oxy]phenyl}propanoic acid
Prepared according to the procedure used to prepare Example 132 starting from ethyl (2E)-
3-{2-chloro-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}-2-propenoate
(111 mg, 0.21 mmol) to afford the title compound (42 mg).
LC/MS and 1H NMR as described for Example 133.
General procedure for Examples 136-141
To a solution of ethyl [(4-{[1-(3-bromo-2-methylphenyl)pentyl]oxy}-2-
methylphenyl)oxy]acetate (75 mg, 0.17 mmol) in DME (4 mL) under nitrogen at room temperature
was added the appropriate boronic acid (0.20 mmol), water (2 mL) and sodium carbonate (46 mg,
0.43 mmol). The reaction vessel was flushed with nitrogen, Pd(PPh3)4 (4 mg, 0.003 mmol) added
and the resulting mixture heated to 80°C and stirred for 18 h. The reaction mixture was allowed to
cool and the solvents removed under vacuum (Genevac) and the residue purified by SPE (10g,
Ci8 cartridge), eluting with MeCN:H2O gradient (1:19 to 9:1). The fractions containing UV active
material collected and concentrated by Genevac. Further purification by SPE (1 Og, aminopropyl
cartridge), eluting with DCM, CHCI3, Et2O, EtOAc, MeOH and then NH3:MeOH (1:9). The
NH3/MeOH fraction was shaken with 2M HCI (4.5 mL) and DCM (10 mL) at room temperature for
2 h, passed through a hydrophoblc frit, combined with the MeOH fraction and concentrated under
vacuum to afford the title compounds, with further purification by mass directed autoprep HPLC
where appropriate.

LC/MS: m/z 504.2 [M+NH4]+, Rt 4.32 min.
1H NMR (400 MHz; MeOD-d4) d: 0.93 (3H, t, J 7.5 Hz), 1.32-1.54 (3H, m), 1.54-1.66 (1H,
m), 1.73-1.83 (1H, m), 1.83-1.96 (1H, m), 2.17 (3H, s), 2.23 (3H, s), 4.37 (2H, s), 5.30 (1H, dd,
8.5, 4.0 Hz), 6.47 (1H, dd, J 9.0, 3.0 Hz), 6.59 (1H, d, J 9.0 Hz), 6.65 (1H, d, J 3.0 Hz), 7.06 (1H,
d, J 7.5 Hz), 7.19 (1H, t, J 7.5 Hz), 7.42 (1H, d, J 7.5 Hz), 7.46 (2H, d, J 8.0 Hz), 7.71 (2H, d, J 8.0
Hz).

LC/MS: m/z 470.3 [M+NH4]+, Rt 4.41 min.
1H NMR (400 MHz; MeOD-d4) d: 0.92 (3H, t, J 7.5 Hz), 1.32-1.53 (3H, m), 1.53-1.66 (1H,
m), 1.72-1.83 (1H, m), 1.83-1.96 (1H, m), 2.16 (3H, s), 2.23 (3H, s), 4.51 (2H, s), 5.29 (1H, dd,
8.5, 4.0 Hz), 6.47 (1H, dd, J 9.0,3.0 Hz), 6.60 (1H, d, J 9.0 Hz), 6.66 (1H, d, J 3.0 Hz), 7.04 (1H,
d, J 7.5 Hz), 7.16 (1H, t, J 7.5 Hz), 7.24 (2H, d, J 8.5 Hz), 7.39 (3H, m).

LC/MS: m/z 450.3 [M+NH4]+, Rt 4.34 min.
1H NMR (400 MHz; MeOD-d4) d: 0.92 (3H, t, J 7.5 Hz), 1.30-1.52 (3H. m), 1.52-1.65 (1H,
m), 1.70-1.81 (1H, m), 1.81 -1.93 (1H, m), 2.16 (3H, s), 2.22 (3H, s), 2.37 (3H, s), 4.39 (2H, s),
5.27 (1H, dd, J 8.5, 4.0), 6.46 (1H, dd J 9.0, 3.0 Hz), 6.59 (1H, d, J 9.0 Hz), 6.64 (1H, d, J 3.0 Hz),
7.01 (1H, d, J 7.5,1.0 Hz), 7.12 (1H, t, J 7.5 Hz), 7.12 (2H, d, J 8.0 Hz), 7.20 (2H, d, J 8.0 Hz),
7.33 (1H,dd,J 7.5,1.0 Hz).
Example 139
[(4-{[1-(4'-Cyano-2-methyl-3-biphenylyl)pentyl]oxy}-2-methyJphenyl)oxy]acetic acid
LC/MS: m/z 461.3 [M+NH4]+, Rt 4.07 min.
1H NMR (400 MHz; MeOD-d4) d: 0.93 (3H, t, J 7.5 Hz), 1.34-1.53 (3H, m), 1.53-1.66 (1H,
m), 1.74-1.84 (1H, m), 1.84-1.96 (1H, m), 2.16 (3H, s), 2.23 (3H, s), 4.53 (2H, s), 5.31 (1H, dd, J
8.5, 4.0 Hz), 6.48 (1H, dd, J 9.0 Hz, 3.0 Hz), 6.61 (1H, d, J 9,0 Hz), 6.67 (1H, d, J 3.0 Hz), 7.06
(1H, d, J 7.5 Hz), 7.21 (1H, t, J 7.5 Hz), 7.43 (1H, d, J 7.5 Hz), 7.47 (2H, d, J 8.5 Hz), 7.78 (2H, d,
J 8.5 Hz).

LC/MS: m/z 466.3 [M+NH4]+, Rt 4.18 min.
1H NMR (400 MHz; MeOD-d4) d: 0.92 (3H, t, J 7.5 Hz), 1.30-1.52 (3H,m), 1.52-1.65 (1H,
m), 1.71-1.81 (1H, m), 1.81-1.93 (1H, m), 2.17 (3H, s), 2.22 (3H, s), 3.81 (3H, s), 4.34 (2H, s),
5.27 (1H, dd, J 8.5, 4.0 Hz), 6.45 (1H, dd, J 9.0, 3.0 Hz), 6.59 (1H, d, J 9.0 Hz), 6.64 (1H, d, J 3.0
Hz), 6.95 (2H, d, J 9.0 Hz), 7.02 (1H, dd, J 7.5, 1.0 Hz), 7.11 (1H, t, J 7.5 Hz), 7.16 (2H, d, J 9.0
Hz),7.33(1H,dd,J7.5,1.0 Hz).

LC/MS: m/z 454.3 [M+NH4]+, Rt 4.22 min.
1H NMR (400 MHz; MeOD-d4) d: 0.92 (3H, t, J 7.5 Hz), 1.30-1.52 (3H, m), 1.52-1.65 (1H,
m), 1.70-1.82 (1H, m), 1.82-1.95 (1H, m), 2.16 (3H, s), 2.22 (3H, s), 4.39 (2H, s), 5.28 (1H, dd, J
8.5, 4.0 Hz), 6.46 (1H, dd, J 9.0, 3.0 Hz), 6.59 (1H, d, J 9.0 Hz), 6.64 (1H, d, J 3.0 Hz), 7.03 (1H,
dd, J 7.5,1.0 Hz), 7.09-7.17 (3H,m), 7.22-7.29 (2H,m), 7.37 (1H, d, J 7.5,1.0 Hz).

NaH (60% dispersion in mineral oil, 9.6 mg, 0.241 mmol) was washed with cyclohexane (3
x 1 mL) under nitrogen and the resulting powdery residue treated with THF (1 mL) and the
resulting mixture cooled to 0°C. Ethyl ({4-[(2-hydroxy-1-{6-[4-(trifluorornethyl)phenyl]-2-
pyridinyl}ethyl)oxy]-2-methylphenyl}oxy)acetate (88 mg, 0.185 mmol) in THF (1.85 mL) was then
added drop-wise over 2 min. 1 -lodopropane (0.024 mL, 0.241 mmol) was then added and the
resulting mixture allowed to warm to ambient temperature over 18 h. The reaction had caused
hydrolysis of the ester and not alkylation so the mixture was reduced and purified by SPE (silica,
5 g cartridge) eluting with cyclohexane:EtOAc (+1% HCOOH) (gradient 10:1 to 1:10) then
EtOAciMeOH (1:1) to give the acid (66 mg, 0.148 mmol). This material was re-subjecting to the
conditions described above using NaH (60% dispersion in mineral oil, 15.4 mg, 0.384 mmol) and
1-iodopropane (0.037 mL, 0.384 mmol) and the resulting solution reduced under vacuum. The
residue was then partitioned between EtOAc (30 mL) and saturated aqueous NH4OH (50 mL) and
the layers separated. The aqueous was re-extracted with EtOAc (30 mL) and the combined
organic layer washed with brine (30 mL) and reduced to give an oil. Purification by SPE (silica, 5
g cartridge) eluting with cyclohexane:EtOAc (+1%HCOOH) (gradient 10:1 to 1:10) then
EtOAc:MeOH (1:1) afforded an oil which was further purified by mass directed autoprep HPLC to
afford the title compound (5 mg).
LC/MS: m/z 490.1 [M+H]+, Rt 4.25 min.
1H NMR (400 MHz; CDCI3) d: 0.86 (3H, t, J 7.5 Hz), 1.58 (2H, m), 2.19 (3H, s), 3.51 (2H,
m), 3.91 (1H, dd, J 11.0, 7.0 Hz), 3.98 (1H, dd, J 11.0, 3.0 Hz), 4.52 (2H, s), 5.44 (1H, d, J 7.0,
3.0 Hz), 6.56 (1H, d, J 9.0 Hz), 6.64 (1H, dd, J 9.0, 3.0 Hz), 6.83 (1H, d, J 3.0 Hz), 7.42 (1H, d, J
7.5 Hz), 7.65 (1H, d, J 7.5 Hz), 7.73 (1H, t, J 7.5 Hz), 7.73 (2H, d, J 8.0 Hz), 8.14 (2H, d, J 8.0
Hz).
Example 143
A solution of the ethyl ({4-[(2-(ethyloxy)-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}ethyl)thio]-2-methylphenyl}oxy)acetate (Enantiomer 1) (12 mg, 0.023 mmol) in THF (1
mL) and MeOH (1 mL) was treated with aqueous NaOH (2N, 1 mL) and the resulting mixture
agitated at ambient temperature for 15 h. Aqueous HCI (2N, 1 mL) was then added and the
organic solvents removed under vacuum using a Genevac. The residue was the then made up to
2 mL by the addition of water and then extracted using DCM (3x3 mL) in an hydrophobic frit.
The residue was reduced and then purified further by mass directed autoprep HPLC to afford the
title compound as an oil (7 mg).
LC/MS: m/z 492.2 [M+H]+, Rt 4.09 min.
1H NMR (400 MHz; CDCI3) d:1.12 (3H, t, J 7.0 Hz), 2.17 (3H, s), 3.50 (2H, m), 3.93 (1H,
dd, J 10.0, 6.0 Hz), 4.11 (1H, dd, J 10.0, 8.0 Hz), 4.44 (1H, dd, J 8.0, 6.0 Hz), 4.60 (2H, s), 6.56
(1H, d, J 8.5 Hz), 7.15 (1H, dd, J 8.5,2.0 Hz), 7.18 (1H, d, J 2.0 Hz), 7.27 (1H, d, J 7.5 Hz), 7.61
(1H, d, J 7.5 Hz), 7.67-7.73 (3H, m), 8.04 (2H, d, J 8.0 Hz).

Prepared according to the procedure used to prepare Example 143 (Enantiomer 1) starting
from ethyl ({4-[(2-(ethyloxy)-1 -{6-[4-(trifluoromethyl)phenyI]-2-pyridinyl}ethyl)thio]-2-
methylphenyl}oxy)acetate (Enantiomer 2) (13.7 mg, 0.026 mmol) to give, after further purification
by mass directed autoprep HPLC, the title compound (9.1 mg).
LC/MS and 1H NMR as described for Example 143
The following intermediates and ligands were prepared for the binding and transfection
assays described below:
(i) ({2-Methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-
yl}methyl)thio]phenyl}oxy)aceticacid.
This compound was used as a PPARdelta reference in the transfection assays described
below and was prepared according to the method reported in WO200100603-A1
(ii) 2-Methyl-2-t(4-{[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-
yl}carbonyl)amino]methyl}phenyl)oxy]propanoicacid.
This compound was used as a PPAR alpha reference in the transfection assay described
below and was prepared according to method reported in WO200140207-A1
(iii) 5-{[4-({2-[Methyl(2-pyridtnyl)amino]ethyl}oxy)phenyl]methyl}-1,3-thia2olidine-2,4-dione
This compound was used as a PPAR gamma reference in the transfection assay described
below and was prepared according to method reported in J.Med.Chem. 1994, 37(23), 3977
Binding Assav:
Compounds were tested for their ability to bind to hPPAR gamma, hPPAR alpha, or hPPAR
. delta using a Scintillation Proximity Assay (SPA). The PPAR ligand binding domain (LBD) was
expressed in E. coli as polyHis tagged fusion proteins and purified. The LBD was then labelled
with biotin and immobilised on streptavidin-modif ted scintillation proximity beads. The beads were
then incubated with a constant amount of the appropriate radioligand (3H-BRL 49653 for PPAR
gamma, and labelled GW 2433 (see Brown, P. J et al. Chem. Bio!., 4, 909-918 (1997) for the
structure and synthesis of this ligand) for PPAR alpha and PPAR delta and variable
concentrations of test compound, and after equilibration the radioactivity bound to the beads was
measured by a scintillation counter. For each compound tested, plots of ligand concentration vs.
CPM of radioligand bound were constructed and apparent Ki values were estimated from
nonlinear least squares fit of the data assuming simple competitive binding. The details of this
assay have been reported elsewhere (see, Blanchard, S. G. et. al. Development of a Scintillation
Proximity Assay for Peroxisome Proliferator-Activated Receptor gamma Ligand Binding Domain.
Anal. Biochem., 257,112-119 (1998)).
Transfection assay:
Compounds were screened for functional potency in transient transfection assays in CV-1
cells for their ability to activate the PPAR subtypes (transactivation assay). A previously
established chimeric receptor system was utilized to allow comparison of the relative
transcriptional activity of the receptor subtypes on the same target gene and to prevent
endogenous receptor activation from complicating the interpretation of results. See, for example,
lehmann, J. M.; Moore, L B.; Smith-Oliver, T. A.; Wilkison, W. O.; Willson, T. M.; Kliewer, S. A.,
An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated
receptor gamma (PPARgammaJ, J. Biol. Chem., 270, 12953-6 (1995). The ligand binding
domains for murine and human PPAR alpha, PPAR gamma, and PPAR delta were each fused to
the yeast transcription factor GAL4 DNA binding domain. CV-1 cells were transiently transfected
with expression vectors for the respective PPAR chimera along with a reporter construct
containing five copies of the GAL4 DNA binding site driving expression of secreted placenta!
alkaline phosphatase (SPAP) and beta-galactosidase. After 16 h, the medium was exchanged to
DME medium supplemented with 10% delipidated fetal calf serum and the test compound at the
appropriate concentration. After an additional 24h, ceil extracts were prepared and assayed for
alkaline phosphatase and beta-galactosidase activity. Alkaline phosphatase activity was
corrected for transfection efficiency using the beta-galactosidase activity as an internal standard
(see, for example, Kliewer, S. A., et. al. Cell 83, 813-819 (1995)). Rosiglitazone (BRL 49653) was
used as a positive control in the hPPAR gamma assay. The positive control in the hPPAR alpha
assays was 2-methyl-2-[(4-{[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-
yl}carbonyl)amino]methyl}phenyl)oxy]propanoic acid. The positive control for PPAR delta assays
was ({2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thtazol-5-
yl}methyl)thio]phenyl}oxy)aceticacid.
All of the above acid Examples showed at least 50% activation of PPAR8 relative to the
positive control at concentrations of 10-7 M or less.
WE CLAIM:
A coTioourc c*' 'cnula (I) whe'ein:
.9
whereir:
R1 arc R2 a-e independently H or C1-3alkyl;
X represents aOcr (CH2)n where n is C1 or 2;
R3and R4 lncependontly represent H1 C1-3 alkyl, -OCH3 -OCH3, -CF3, allyl. or halogen;
X1 represents C, S, SO2. SO, or CH2.
one of R5 amd R6 is hydrogen, the other is C1-6 alkyl (including branched alkyl nnd
which is substituted or unsubstituted by C1-6alkoxy);
R1 reprosents phenyl or a 6-mebence heterocycle selected from pyrimldine, pyrtdlne,
Pyridazine and pyrazine each of which phenyl or heterocycle is substituted by phenyl
or unsubstituted or substituted by one or more CFi, C1-3 alkyl,,
halogen, CN) and optionally a further C1-3 alkyl substituent.
2. A compound as ciairncd in claim 1 wherein R1 and R2 are both H or both methyl.
3. A compound as claimed in claim 2 wherein R1 and R2 are both H
4.. A compound as claimed in clnims 1 - 3 whnro'r X is O.
5. A compound as claimed in claims 1 - 6 wherein R3 and R4 are independently H o- C1-3
aikyl.
5. A compound as claimed in claim 5 wherein one cf R3 and R4 is H and the other is not.
7. A compound as claimed in claim 7 wherein the substituents group which is not H is
positioned to the X methyl.
8. A compound as claimed in 6 or 7 wherein one of R3 and R4 is methyl.
9. A compound as claimed in claims 1-8 whrrein X1 is C or S.
10 A compound as claimed In claim 1 wherein one of R5 and R6 is H and the other is butyl cr
11. A compound as claimed in claim 1 wherein R7 is a phenyi or pyridine ring which is
substituted meta to the depicted X1 moiely by
para -C6H4CF3, para -C6H4Me, para -C6H4CN or para -C6H4CI.
12. A compound as claimed in claim 1 selected from:
{[2-Methyl-4-({1-[4'-(trifluoromethyl)-3-biphenylyl]ethyl}thio)phenyl]oxy}acetic acid
{[2-Methyl-4-({1-[4'-(trifluoromethylH-biphenylyl]ethyl}thio)phenyl]oxy}acetiic acid
2-Methyl-2-({2-methyi-4-[(1-{6-[4-(trifluoromef:hyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}oxy)prop {[2-Methyl-4-({1-[4'-(trifIuoromethyl)-3-biphenylyl]pentyl}oxy)phenyl]oxy}acetic acid
[(4-{[1-(4'-Ch!crc^3 biphcr;viv;)pcr;:ync:;v;-2-;Mcthyiphenyi)oxy]acetiGacicl
{[2-Mettvyi-4-({1-[4'-(trifiucror;isihyi)-'i-i:)iph5nviyi]pentyl}oxy)phenyi]oxy}aceiic acid
[(4-{[1-(4'-Chloro-4-bipher]yiy:)pentyljoxy;-2-inethylphenyl)oxy]acetic acid
{[2-Methyl-4-({(1R)-1-[4'-(trif!uoromet.iyl)-4-biphenyIyl]pentyl}thio)phenyl]oxy}aceticacid
{[2-Methyl-4-({(1S)-1-[4'-(trifluoromethyl)-4-biphenylyl]pentyl}thio)phenyl]oxy}acetic acid
({2-Mefhyl-4-[((1S)-1-{6-[4-(tr:fIuoromethyl)phonyl]-2-
pyridinyl}pentyl)oxy]phenyl}oxy)acetiiD acid
({2-Methyf-4-[((1 R)-1 -{6-[4-(trifluororr othyi)phenyi]-2-
pyridinyl}pentyl)oxy]phenyl}oxy)acetic acid
({2-Methyl-4-[((1 S)-1 -{6-[4-(trifluoramethyl)phenyl]-2-
pyridinyl}pentyl)thio]phenyl}oxy)acetb acid
({2-Methyl-4-[((1f?)-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)thio]phenyl}oxy)acetic acid
({2-Methyi-4-[(1-{6-[4-(trifiuoromethyi)pheny!]~2-pyridinyi}pentyl)suifinyl]phenyl}oxy)acetic
acid
({2-Methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]~2-pyridinyl}pentyl)sulfonyl]phenyl}oxy)acetic
acid
{4-[(1-{6-[4-(Trifluoromethyl)phenyl]-:'.-pyridinyl}pentyl)oxy]phenyl}aceticacid
({2-Methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyrldinyl}butyl)oxy]phenyl}oxy)acetic acid
({4-[(1-{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetic acid
3-{4-[(1-{6-[4-(Trifluorornethyl)phenyl]--2-pyridinyl}pentyl)oxy]phenyl}propanoic acid
{[4-({1-[6-(4-Ch!oropheny!)-2-pyridinyl'jpenty!)oxy)-2-methylphenyl]oxy}acetic acid
({2-Methyl-4-[(1-{6-[4-(methy[oxy)phonyl]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetic acid
({4-[(1-{6-[4-(Ethyloxy)phenyl]-2-pyri(linyl}pentyl)oxy]-2-methylphenyl}oxy)ac6!ticacid
{[2-Methyl-4-({1-[6-(4-methylphenyl)-?-pyriclinyl]pentyl}ory)pheny!]oxy}aceticacid
{[4-({1-[6-(3,4-Dichlorophenyf)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy}aceticacid
({2-Methyl-4-[(1-{6-[3-(trifluoromethyil)ph9nyi]-2-pyridinyl}pentyl)oxy]phenyl}oxy)acetic
acid
[(2-Methyl-4-{[1-(6-pheny!-2-pyridinyl)pentyl]oxy}phenyl)oxy]acetic acid
{[4-({1-[6-(4-Acetylphenyl)-2-pyridinyl|pentyl}oxy)-2-methylphenyl]oxy}acetlc acid
{[4-({1-[6-(4-Fiuorophenyl)-2-pyridinyi]pentyl}oxy)-2-methyiphenyi]oxy}acetic acid
{[4-({1-[6-(4-Cyanophenyl)-2-pyridiny]pentyl}oxy)-2-methylphenyl]oxy}aceticacid
({2-Methyl-4-[(1-{6-|4-(trifluoromethyhphenyl]-2-pyridinyl}hexyl)oxy]phenyl}oxy)acetic aci
({2-Methyl-4-[(4-methyl-1-{6-[4-(trifluciromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}oxy)acefic. acid
({2-Methyl-4-[(3-methyl-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}butyl)oxy]phenyl}oxy)acetic acid
[(4-{[1-(3-Biphenylyl)pentyl]oxy}-2-melhylphenyi)oxy]aceticacid
[(4-{[1-(4'-Cyano-3-biphenylyl)penty[]oxy}-2-iTielhylphenyl)oxy]aceticacid
[(2-Ethyl-4-{[1--(6~phenyl-2-pyrid!nyl)pentyl]oxy}pheny!)oxy]acetic acid
{[4-({1-[8-(4-Cyanophenyl) 2 pyridinyi]psi;iyij-oxy)-2-ethylphenyl]oxy}aceiic acid
({2-Ethyl-4-[(1-{6-i4-(tririuuiorr!ethyi};jh3nylj-.i-pyridinyl}psntyl)oxy]phenyl}o: 4-{4-[(1-{6-[4-(Trifluoromethyl)phenyl|-2-pyridinyl}pentyl)oxy]phenyl}butanoicacid
{[4-({(1 R)-1 -[6-(4-Chlorophenyl)-2-py;idiny!]pentyl}oxy)-2-methylphenyl]oxy'»acetic acid
{[4-({(1R)-1-[6-(4-Cyanophenyl)-2-pyiidiny!]penty1}oxy)-2-mothylphenyl]oxy}acetic acid
{[4-({(1 S)-1 -[6-(4-Chlorophenyl)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]oxy]acetic acid
{[4-({(1 S)-1 -[6-(4-Cyanopheny!)-2-pyii:linyljpenfyl}oxy)-2-methylphenyl]oxy}acetic acid
({2-Methyl-4-[((1/?)-3-(methyloxy)-1-{5-r4-(frifluoromethyl)phenyn-2-
pyridinyl}propyl)oxy]phenyl}oxy)aceU; acid
[(4-{[{1R)-1-[6-(4-Chlorophenyl)-2-pyidinyl]-3-(mcthyloxy)propyl]oxy}-2-
methylphenyi)oxy]acetic acid
({2-Methyl-4-[((1S)-3-(methyloxy)-1-{5-[4--(triftuoramethyl)phenyl]-2-
pyridinyl}propyl)oxy]phenyl}oxy)aceti; acid
[(4-{[(1S)-1-[6-(4-Chlorophenyl)-2-pyiidinyl]-3-(methyloxy)propyl]oxy}-2-
methylphenyl)oxy]acetic acid
({4-[((1f?)-2-(Ethyloxy)-1-{6-[4-(trifluorome1hyl)phenyl]-2-pyridinyl}ethyl)oxy]-2-
methylphenyl}oxy)acetic acid
[(4-{[(1':?)-1-[6-(4-Cyanophenyl)-2-py-idinyi]-2-(ethyloxy)€!thyl]oxy}-2-
methylphenyl)oxy]acetic acid
[(4-{[(1R)-1-[6-(4-Chlorophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-
methyiphenyl)oxy]acetic acid
({4-[((1S)-2-(Ethyloxy)-1-{6-[4-(trifluo-omethyl)phenyl]-2-pyridinyl}ethyl)oxy]-2-
methylphenyl}oxy)acetic acid
[(4-{[(1S)-1-[6-(4-Cyanophenyl)-2-pyidinyl]-?-(ethyloxy)ethyl]oxvy}-2-
methylphenyl)oxy]acetic acid
[(4-{[(1S)-1-[6-(4-Chlorophenyl)-2-pyridinyi]-2-(ethyloxy)ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
{[4-({(1/?)-2-(Ethyloxy)-1-[6-(3-fluoro-4-mafhy!pheny!)-2-pyridiny!]ethy!}oxy)-2-
methy!phenyl]oxy}acetic acid
{[4-({(1R)-2-{Ethyloxy)-1-[6-(4-methylphenyl)-2-pyridinyl]ethy!}oxy)-2-
methylphenyl]oxy}acetic acid
({4-[((1/?)-2-(Ethyloxy)-1-{6-[4-(1-methylethy!)phenyl]-2-pyridinyl}ethyl)oxy]-2-
methylphenyl}oxy)acetic acid
[{4-{t(1R)-1-[6-(4-Cyano-3-fluorophenyl)-2-pyridinyn-2-(ethyloxy)ethyl1oxy}-2-
methylphenyl)oxy]acetic acid
{[4-({(1/?)-2-(Ethyloxy)-1-[6-(2-fluoro-4'm3thy!phenyl)-2-pyridinyl]ethy!}oxy)-2-
methylphenyi]oxy}acetic acid
{[4-({(1R)-2-(Efhy!oxy)-1-[6-(^-fluorof:h8nyl)-2-pyridiny!3ethy!}oxy)-2-
methylphonyl]oxylacetic acid
[(4-{[(1R)-1-[6-f4-Chloro-3-mathylphenyli-2-yridinyi]-2-(ethyioxy)e(hy!joxy}-2-
rnethylpiienyi)oxy]gceiic ace:
[(4-{[(1/?)-1-[6-(3-Chloro-4-cyanopheliy!)-2-pyridinyl]-2-(ethyloxy)ethy!]oxy}-2-
methylphenyl)oxy]acetic acid
[(4-{[(1/?)-1-[6-(4-Cyano-3-msthy!pher!y!)-2pyridiny!]-2-(ethyloxy)ethyl)oxy}-2-
methylphenyl)oxy]acetic acid
[(4-{[(1/?)-1-[6-(4-Cyano-2-fluorophenyl)-2-pyridinyl3-2-(ethyloxy)ethylloxy}-2-
methylphenyl)oxylacetic acid
[(4-{[(1/?)-1-[6-(4-Cyano-2-me(hy!pheriyl)-2-[)yridinyl]-2-(ethyioxy)ethyl]oxy}-2-
methy!pheny!)oxyjscetic acid
{[4-({(1S)-2-(Ethy[oxy)-1-[e-(3-fluoro-4-m8thylphenyl)-2-pyridinyl]ethyi}oxy)-2-
methylphenyl]oxy}acetic acid
{[4-({(1S)-2-(Ethyloxy)-1-[6-(4-rnethy!phenyi;-2-pyridinyl]ethyl}oxy}-2-
methylphenyl]oxy}acetic acid
({4-[((1S)-2-(Ethyloxy)-1-{6-[4-(1-methylethyi)phenyl]-2-pyridinyl}ethy[)oxy]-2-
methylphenyl}oxy)acetic acid
[(4-{[(1S)-1-[6-(4-Cyano-3-fluorophenyl)-2-pyiidinyl]-2-(ethyloxy)ethy!loxy}-2-
methylphenyl)oxy]acetic acid
{[4-({(1S)-2-(Ethyloxy)-1-[6-(2-fluoro-4-methylphenyl)-2-pyridinyl]ethyl}oxy)-2-
methylphenyl]oxy}acetic acid
{[4-({(1S)-2-(Ethyloxy)-1-[6-(4-fluoropheny!)-2-pyridinyl]eihy!}oxy)-2-
methylphenyl)oxy}acetic acid
[(4-{[(1S)-1-[6-(4-Chloro-3-methylphenyl)-2-pyridinylI-2-(ethyloxv')ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
[(4-{[(1S)-1-[6-(3-Chloro-4-cyanophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-
methylphenyl)oxy]acetic acid
[(4-{[(1S)-1-[6-(4-Cyano-3-methyiphenyl)-2-pyridinyl]-2-(ethyloxy)ethyi]oxy}-2-
methylphenyl)oxy]acefic acid
[(4-{[(1S)-1-[6-(4-Cyano-2-fluoropheryi)-^-pyridinyl]-2-(ethyloxy)ethyl)oxy}-2-
methyfphenyl)oxy]acetic acid
3-{2-Methyl-4-[((1S)-1-{6-[4-(trifiuoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}propanoic; acid
3-[4-({(1S)-1-[6-(4-Cyanophenyl)-2-pyridinylJpentyl}oxy)-2-methylphenyl]propanoic acid
3-[4-({(1S)-1-[6-(4-Chlorophenyl)-2-p-/ridinyl]pentyl}oxy)-2-methylphenyi]propanoic acid
3-{2-Methy!-4-[((1R)-1-{6-[4-(trif!uoromefhyl)phenyl3-2-
pyridinyl}pentyl)oxy]phenyl}propanoic acid
3-[4-({(1R)-1-[6-(4-Cyanophenyi)-2-pi/ridinyl]pentyl}oxy)-2-rnethylphenyl]propanoicacid
3-[4-({(1R)-1-[6-(4-Chlorophenyi)-2-pyridinyl]pentyl}oxy)-2-methylphenyl]propanoic acid
3-{3,5-Dimethyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]pheny!}propanoin acid
3-{3-(Methyloxy)-5-propyl-4-[f1-{6-r4-[triflucormethyl)phenyl]-2-
pyridinyl}penty!)oyy]ph«ny!}prof3rio
3-{3-Propyi-4-[(1-{6-[4-itrifiuoromethyi)phenvi]-2-pyridinyi}pentyi)oxy]phenyl}propanoic
acid
3-{3-(Ethyloxy)-4-[(1-{6-[4-(trifluorome(.hyl)phenyi]-2-pyridinyl}pentyl)oxy]phenyl}propanoic
acid
3-{4-[((1R)-1-{6-[4-(Trif!uoromeihy!)phenyll-2-pyridinyl}pentyl)oxy]phenyl}propanoic acid
3-{3-(Methyloxy)-4-[((1R)-1-{6-[4-(trifiuoramethyl)phenyl]-2-
pyridinyl}penty!)oxyjphenyl}propanoii; acid
{4-[((1/?)-1-{6-[4-(trifluoromethy!)phenj.'!]-2-pyridinyl}pentyl)oxy]phenyl}acetic acid
{3-Chloro-4-[((1R)-1-{6-[4-(frifluorom3thyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}acetic
acid
{3-(Meihyloxy)-4-[((1R)-1-{6-[4-(trifluorometliyl}phenyl]-2-
pyridiny!}pentyl)oxy]pheny!}aceticac:d
3-{4-[((1S)-1-{6-[4-(Trifluoromethy!)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoicacid
3-{3-(Methyloxy)-4-[((1S)-1-{6-[4-(trifiuoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}propanoi: acid
{4-[((1S)-"l-{G-[4-(Trifluororneiiiyi}phe;!)yi]-2-pyridinyi}peniyi)oxy]phenyi}ace';!c acid
{3-Chloro-4-[((1S)-1-{6-[4-(trifluorome(hyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}acetic
acid
{3-(Meihyloxy)-4-[({1S)-1-{6-[4-(triflu3romethyl)phenyl]-2-
pyridinyl}pentyi)oxy]phenyl}acetic acid
3-{3-Fluoro-4-[((1R)-1-{6-[4-(trifluorome1hyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}propanoic acid
3-{3-Methyl-4-[((1f?)-1-{6-[4-(trifluorcrnethyl)pheny[]-2-
pyridinyl}pentyl)oxy]phenyl}propanoic acid
3-{3,5-Bis(methyloxy)-4-[((1R)-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}propanoio acid
3-{2-(Methyloxy)-4-[((1 R)-1-{6-[4-(trifl Jorome1hyl)phenyl]-2-
pyridinyl}pentyl)oxy|phenyl}propanoic acid
3-{3-Fluoro-4-|((1 S)-1 -{6-[4-(trif luoron ethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}propanoic acid
3-{3-Methyl-4-[((1S)-1-{6-[4-(trifluorornethyl)phenyl]-2-
pyridinyl}penty!)oxy]phenyi}propanoic acid
3-{3,5-Bis(methyloxy)-4-[((1S)-1-{6-[4-('trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}propanoic acid
3-{2-(Methy!oxy)-4-i((1S)-1-{6-[4-(trif!jorornefhyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}propanoic acid
3-{3-Chloro-5-(methyloxy)-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-
pyridinyl}pentyl)oxylpheny!}propanok acid
3-{3-Chloro-4-[((1f?)-1-{6-r4-(frifluoromethy[)pheny!]-2-
pyriciiny!)penfy!s!oxy]ph':'r!yi}p'op?ii'ioi'; r;cic'
3-{2-Chloro-4-[(( 1 R)-1 -{6-[4-( trif luoroi nethyl )ph enyi]-2-
pyridinyl}pentyl)oxy]phenyi}propanoic acid
3-{3-Chloro-4-[((1S)-1-{6-[4-(trif!uorornethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}propanoic; acid
3-{2-Chloro-4-[((1S)-1-{6-[4-(lrifIuorornethyl)phenyl]-2-
pyridinyl}pentyl)oxy]phenyl}propanoi<:. acid> {[2-Methyl-4-({1-[2-methyl-4'-(trifluorcrr]elhyl)-3-biphenylyi]pentyl}oxy)phenyl}oxy}acetic
acid
[(4-{[1-(4'-Chioro-2-methyl-3-biphenyyl)pentyl]oxy}-2-methylphenyl)oxy]aceticacid
[(4-{[1-(2,4'-Dimethyl-3-biphenylyl)peTiyl|oxy}-2-methylphenyl)oxy]acetic acid
[(4-{[1-(4'-Cyano-2-methyl-3-biphenylyl)pentyl]oxy}-2-methylpheny|)oxy]acetic acid
[{4-{[1-(4'-Fluoro-2-methy!-3-biphenylyl)pcntv!]oxy}-2-melhylphenyl)oxy]acelic acid
({2-Methyl-4-[(2-(propyloxy)-1-{6-[4-(lrifluoromethyl)phenyl]-2-
pyridinyi}ethyl)oxy]phenyl}oxy)acetic acio
({4-[(2-(Ethyloxy)-1-{6-[4-(trif!uorome'hyl)phenyl]-2-pyridinyi}ethyl)thio]-2-
methyiphenyl}oxy)acetic acid
13. A compound as claimed in claims 1-12 for use in therapy.
14. A pharmaceutical composition comprising a compound as claimed in claims 1-12.
15. A pharmaceutical composition as claimed in claim 14 for the treatment of a hPPAR
disease or condition.
16. A pharmaceutical composition as claimed in claim 15 for the treatment of dyslipidemia,
syndrome X, heart failure, hypercholesterolemia, cardiovascular disease, obesity, type II
diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, obesity, anorexia
bulimia and anorexia nervosa.
The present invention provides a compound of formula (I):wherein.Rl
and R2 are independently H or C1-3 alkyl;X represents a O or (CH2)n where n is 0, 1 or
2;R3and R4 independently represent H, C1-3 alkyl, -OCH3, -CF3, allyl, or halogen;Xl
represents O, S, SO2, SO, or CH2;R5 and R6 independently represent hydrogen, C1-6
alkyl (including branched alkyl and optionally substituted by one or more halogens or
Cl-6alkoxy), or together with the carbon atom to which they are bonded form a 3-6 membered
cycloalkyl ring;R7 represents aphenyl or a 6 membered heteroaryl group containing
1, 2 or 3 nitrogen atoms wherein the phenyl or heteroaryl group is substituted by 1. 2 or 3
moieties selected from the group consisting of halogen, C1-6 alkoxy, C1-6 alkyl, CF3, hydroxy, or phenyl (which may be optionally
substituted by one or more C1-3 alkyl, -OC1-3 alkyl, CN, acetyl, hydroxy, halogen or CF3).

Documents:

1889-kolnp-2004-granted-abstract.pdf

1889-kolnp-2004-granted-assignment.pdf

1889-kolnp-2004-granted-claims.pdf

1889-kolnp-2004-granted-correspondence.pdf

1889-kolnp-2004-granted-description (complete).pdf

1889-kolnp-2004-granted-examination report.pdf

1889-kolnp-2004-granted-form 1.pdf

1889-kolnp-2004-granted-form 18.pdf

1889-kolnp-2004-granted-form 3.pdf

1889-kolnp-2004-granted-form 5.pdf

1889-kolnp-2004-granted-gpa.pdf

1889-kolnp-2004-granted-reply to examination report.pdf

1889-kolnp-2004-granted-specification.pdf

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Patent Number

224751

Indian Patent Application Number

1889/KOLNP/2004

PG Journal Number

43/2008

Publication Date

24-Oct-2008

Grant Date

22-Oct-2008

Date of Filing

09-Dec-2004

Name of Patentee

SMITHKLINE BEECHAM CORPORATION

Applicant Address

ONE FRANKLIN PLAZA, P.O BOX 7929, PHILADELPHIA, PA

Inventors:

#	Inventor's Name	Inventor's Address
1	BELL RICHARD	GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HEATFORDSHIRE SG1 2NY
2	BESWICK PAUL JOHN	GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HEATFORDSHIRE SG1 2NY
3	PATEL VIPULKUMAR KANTIBHAI	GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HEARTFORDSHIRE SG1 2NY
4	GRIMES RICHARD MARTIN	GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HEARTFORDSHIRE SG1 2NY
5	HAMLETT CHRISTOPHER CHARLES FREDRICK	GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE, HEATFORDSHIRE SG1 2NY
6	GOSMINI ROMAIN LUC MARIE	LABORATOIRE GLAXO-SMITHKLINE, CENTER DE RECHERCHES, Z.A. DE COURTABOEUF, 25, AVENUE DU QUEBEC
7	KING NIGEL PAUL	GLAZOSMITHKLINE, NEW FRONTIERS SCIENCE PARK, THIRD AVENUE, HARLOW, ESSEX CM19 5AW

PCT International Classification Number

A61K 31/44

PCT International Application Number

PCT/EP2003/006415

PCT International Filing date

2003-06-18

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0214149.7	2002-06-19	U.K.