WO 2006/057860 PCT/US2005/041367 2 POTENTIATORS OF GLUTAMATE RECEPTORS This application claims the benefit of U. S. provisional application Ser. No. 60/630,060 filed Nov. 22, 2004. The present invention provides a compound of formula I, pharmaceutical compositions thereof, and methods of using the same, as well as processes for preparing the same, and intermediates thereof. BACKGROUND OF THE INVENTION The excitatory amino acid L-glutamate (at times referred to herein simply as glutamate) through its many receptors mediates most of the excitatory neurotransmission within the mammalian central nervous system (CNS) and has been implicated in numerous peripheral nervous system (PNS) pathways. The excitatory amino acids, including glutamate, are of great physiological importance, playing a role in a variety of neurological, physiological and psychiatric processes, such as synaptic plasticity, motor control, respiration, cardiovascular regulation, sensory perception, and emotional responses. Glutamate acts via at least two distinct classes of receptors. One class is composed of the ionotropic glutamate (iGlu) receptors that act as ligand-gated ion channels. Via activation of the iGlu receptors, glutamate is thought to regulate fast neuronal transmission within the synapse of two connecting neurons in the CNS. The second general type of receptor is the G-protein or second messenger-linked "metabotropic" glutamate (mGlu) receptor. Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Previews, 15,41 (1990). The mGlu receptors belong to the Class C G-protein coupled receptor (GPCR) family. This family of GPCR's, mcluding the calcium-sensing receptors, GABAB receptors and sensory receptors, are unique in that effectors bind to the amino-terminus portion of the receptor protein translating a signal via the transmembrane segments to the intracellular matrix through receptor/G-protein interactions. Ozawa, Kamiya and Tsuzuski, Prog. Neurobio., 54, 581 (1998). It has been demonstrated that the receptors are localized either pre- and/or post-synapticly where they can regulate neurotransmitter WO 2006/057860 PCT/US2005/041367 3 release, either glutamate or other neurotransmitters, or modulate the post-synaptic response of neurotransmitters, respectively. At present, there are eight mGlu receptors that have been positively identified, cloned, and their sequences reported. These are further subdivided based on their amino acid sequence homology, their ability to effect certain signal transduction mechanisms, and their known pharmacological properties. Ozawa, Kamiya and Tsuzuski, Prog. Neurobio., 54, 581 (1998). For instance, the Group I mGlu receptors, which include the mGlul and mGlu5, are known to activate phospholipase C (PLC) via Gaq-proteins thereby resulting in the increased hydrolysis of phosphoinositides and intracellular calcium mobilization. There are several compounds that are reported to activate the Group I mGlu receptors including DHPG, (+/-)-3,5-dihydroxyphenylglycine. Schoepp, Goldworthy, Johnson, Salhoff and Baker, J. Neurochem., 63, 769 (1994); Ito, et al., Neurorep., 3,1013 (1992). The Group II mGlu receptors consist of the two distinct receptors, mGlu2 and mGlu3 receptors. Both receptors are negatively coupled to adenylate cyclase via activation of Gai-protein. These receptors can be activated by a group-selective compound such as (liS',25r,5i?,65J-2-aminobicyclo[3.1.0]hexane-2,6- dicarboxylate. Monn, et al., J. Med. Chem., 40, 528 (1997); Schoepp, et al., Neuropharmacol., 36, 1 (1997). Similarly, the Group III mGlu receptors, including mGlu4, mGlu6, mGlu7 and mGlu8, are negatively coupled to adenylate cyclase via God and are potently activated by L-AP4 (L-(+)-2-amino-4-phosphonobutyric acid). Schoepp, Neurochem. Int., 24,439 (1994). It should be noted that many of the available pharmacological tools are not ideal in that they cross react not only on the receptors within a group of mGlu receptors but also often have some activity between groups of mGlu receptors. For instance, compounds such as lS',3i?-ACPD, (lS,3i?)-l-aminocyclopentane-/ra/is-l,3-dicarboxylic acid, are believed to activate all of the Group I, II and III mGlu receptors depending upon the dose utilized while others, such as 1S,3S-ACPD, (lS,3S)-l-aminocyclopentane- trans-l,3-dicarboxylic acid, are more selective for the Group II receptors (mGlu2/3) than the Group I (mGlul/5) or Group III (mGlu4/6/7/8). Schoepp, Neurochem. Int., 24, 439 (1994). To date, there are very few examples of selective agents for the mGlu receptors. Schoepp, Jane, and Monn, Neuropharmacol., 38,1431 (1999). WO 2006/057860 PCT/US2005/041367 4 It has become increasingly clear that there is a link between modulation of excitatory amino acid receptors, including the glutamatergic system, through changes in glutamate release or alteration in postsynaptic receptor activation, and a variety of neurological, psychiatric and neuroinfiammatory disorders, e.g. Monaghan, Bridges and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365-402 (1989); Schoepp and Sacann, Neurobio. Aging, 15,261-263 (1994); Meldrum and Garthwaite, Tr. Pharmacol. Sci., 11, 379-387 (1990). The medical consequences of such glutamate dysfunction make the abatement of these neurological processes an important therapeutic goal. Leukotrienes are potent local mediators, playing a major role in inflammatory and allergic responses including arthritis, asthma, psoriasis, and thrombotic disease. Leukotrienes are straight chain eicosanoids produced by the oxidation of arachidonic acid by lipoxygenases in several cell types including: eosinophils, neutrophils, mast cells, leukocytes, and macrophages. At the present time, there are two established Class A GPCR receptors for the cysteinyl-leukotrienes (CysLTl and CysLT2) which the leukotrienes LTC4, LTD4 and LTE4 activate, mediating their proinflarnmatory effects. Each of the CysLT receptors has distinct tissue distributions and associations with physiological responses. Also, the leukotriene LTD4 has a higher affinity for the CysLTl receptor than the other leukotrienes. Back, M. Life Sciences 71, 611-622, (2002). The leukotrienes, especially LTD4 and its receptor CysLTl, have been implicated in the pathogenesis of airway and allergic diseases such as asthma by contributing to bronchoconstriction, mucus secretion, and eosinophil migration. Thus, leukotrienes have been shown to play an important role in the pathology of asthma. Rigorous proof for the role of leukotrienes in asthma has been provided by several pivotal clinical trials in which orally administered LTD4 receptor antagonists produce clear therapeutic benefit in asthma patients. These benefits include reduction in the use of classic asthma therapies such as corticosteroids. Kemp, J.P., Amer. J. Resp. Medi. 2, 139-156, (2003). Numerous investigations confirm the importance of the leukotrienes in allergic disorders as well. Thus, after allergen provocation, a marked increase in the LT concentration in the nasal lavage fluid of patients with allergic rhinitis was detected both in the early phase and in the late phase. Creticos, P.S., S.P. Peters, N.F. Adkinson, R.M. Naclerio, E.C. Hayes, P.S. Norman, L.M. Lichtenstein, N. Eng. J. Med. 310:1626 (1984). In addition, treatment with clinically efficacious antihistamines, such as azelastine, has WO 2006/057860 PCT/US2005/041367 5 shown a reduction in the formation of the cysieinyl-leukotrines, establishing a correlative relationship of allergic reaction symptoms to the degree of leukotriene formation and, thus, CysLT receptor activation. Achterrath-Tuckermann, U., Th. Simmet, W. Luck, I. Szelenyi, B. A. Peskar, Agents and Actions 24:217, 1988; Shin, M. H., F. M. Baroody, D. Proud, A. Kagey-Sobotka, L. M. Lichtenstein, M. Naclerio, Clin. Exp. Allergy 22:289,1992. United States Patent No. 6,194,432 Bl discloses a method for using leukotriene antagonist drugs to prevent and treat recurrent primary headaches including migraine headaches. United States Patent No. 5,.977,177 discloses certain substituted phenyl derivative compounds are modulators of endothelin and, as such, are useful in treating many different conditions including asthma. United States Patent No. 4,853,398 discloses certain benzene derivative compounds are selective antagonists of leukotrienes and, as such, are useful in treating allergic disorders such as asthma. European Patent Application No. EP 28063 A1 and UK Patent Application No. GB 2058785 disclose certain phenol derivative compounds are antagonists of slow reacting substance of anaphylaxis and, as such, are useful in treating asthma, hay fever and skin afflictions. Brown, F. J. et al J. Med Chem. 32, p. 807-826 (1989) discloses certain hydroxyacetophenone derivative compounds are antagonists of leukotrienes and, as such, play a role in treating asthma. International Patent Application Publication No.WO 2001056990 A2 and United States Patent No. 6,800,651 B2 disclose certain pyridine derivative compounds are potentiators of metabotropic glutamatc receptor function, specifically; potentiators of mGlu2 receptor function and, as such, are useful in the treatment of many different conditions including anxiety and migraine headache. International Patent Application Publication No. WO 2004018386 and Pinkerton, A. B. et al Bioorg. Med. Chem. Lett., 14, p.5329-5332 (2004) disclose certain acetophenone derivative compounds are potentiators of glutamate receptor function, specifically; potentiators of mGlu2 receptor function and, as such, are useful in the WO 2006/057860 PCT/US2005/041367 6 treatment of many different conditions including anxiety, schizophrenia and migraine headache. Recently, Pinkerton, A. B. et al Bioorg. Med. Chem. Lett., 14, p. 5867-5872 (2004) disclose certain 4-thiopyridyl acetophenone derivative compounds are potentiators of glutamate receptor function, specifically; potentiators of mGlu2 receptor function and, as such, may be useful in the treatment of CNS disorders including anxiety, schizophrenia and epilepsy. The present invention provides compounds of formula I that are potentiators of the mGlu2 receptor and antagonists of the CysLTl receptor. As such, compounds of formula I would provide a means to treat disorders associated with glutamate or leukotrienes. In addition, it is anticipated that in disorders with a glutamate and leukotriene component to the onset, propagation and/or symptoms, the compounds of formula I will provide an effective treatment for the patient. The medical consequences of such glutamate dysfunction make the abatement of these neurological processes an important therapeutic goal. SUMMARY OF THE INVENTION The present invention provides a compound of formula I: wherein R1 is selected from the group consisting of C1-C5 alkyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, phenyl and substituted phenyl; R2 is selected from the group consisting of hydrogen, C1-C5 alkyl, substituted C1-C5 alkyl, halo, phenyl, substituted phenyl, C1-C3 fluoroalkyl, CN, CO2R3, thiophenyl, substituted thiophenyl, thiazolyl, substituted thiazoyl, furanyl, substituted furanyl, pyridinyl, substituted pyridinyl, oxazolyl, substituted oxazloyl, isothiazolyl, substituted isothiazoyl, isoxazolyl, substituted isoxazolyl, 1,2,4-oxadiazolyl, substituted WO 2006/057860 PCT/US2005/041367 7 1,2,4-oxadiazolyl, pyrimidinyl, substituted pyrimidinyl, pyridazinyl, and substituted pyridazinyl; X is selected firom the group consisting of 0, S(O)m, and NR3; Y is selected from the group consisting of C1-C3 alkanediyl and substituted C1-C3 alkanediyl; Ar1 and Ar2 are independently selected from the group consisting of phenylene, substituted phenylene, thiophenediyl, substituted thiophenediyl, thiazolediyl, substituted thiazolediyl, furanediyl, substituted furanediyl, pyridinediyl, substituted pyridinediyl, oxazolediyl, substituted oxazolediyl, isothiazolediyl, substituted isothiazolediyl, isoxazolediyl, substituted isoxazolediyl, pyrimidinediyl, substituted pyrimidinediyl, pyridazinediyl, substituted pyridazinediyl and l,2,4-oxadiazole-3,5-diyl; L is selected from the group consisting of -G-O-J-, -G-S(O)p-J-, and -G-N(R4)-J-; G and J are independently selected from the group consisting of a bond and C1-C3 alkanediyl; R3 is independently hydrogen or C1-C5 alkyl; R4 is independently selected from the group consisting of hydrogen, C1-C5 alky], C(=O)R3, C(=O)NR3R3 and SO2R3; Z is selected from the group consisting of (CH2)nCOOH, m and p are independently 0,1, or 2; n and q are independently 0,1, 2 or 3; and pkarmaceutically acceptable salts thereof. The present invention also provides for novel pharmaceutical compositions, comprising a compound of the formula I and a pharmaceutically acceptable diluent. Because the compounds of formula I are potentiators of the mGlu2 receptor, the compounds of formula I are useful for the treatment of a variety of neurological and WO 2006/057860 PCT/US2005/041367 8 psychiatric disorders associated with glutamate dysfunction, including: acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS- induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, multiple sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), mood disorders (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, and conduct disorder. In another embodiment the present invention provides methods of treating neurological and psychiatric disorders associated with glutamate dysfunction, comprising administering to a patient in need thereof an effective amount of a compound of formula I. That is, the present invention provides for the use of a compound of formula I or pharmaceutical composition thereof for the treatment neurological and psychiatric disorders associated with glutamate dysfunction. Of the disorders above, the treatment of migraine, anxiety, schizophrenia, and epilepsy are of particular importance. In a preferred embodiment the present invention provides a method of treating migraine, comprising administering to a patient in need thereof an effective amount of a compound of formula I. In another preferred embodiment the present invention provides a method of treating anxiety, comprising administering to a patient in need thereof an effective amount of a compound of formula I. Particularly preferred anxiety disorders are generalized anxiety disorder, panic disorder, and obsessive compulsive disorder. WO 2006/057860 PCT/US2005/041367 9 In another preferred embodiment the present invention provides a method of treating schizophrenia, comprising administering to a patient in need thereof an effective amount of a compound of formula I. In yet another preferred embodiment the present invention provides the use of a compound of formula I for the manufacture of a medicament for the treatment of neurological and psychiatric disorders associated with glutamate dysfunction. In yet another preferred embodiment the present invention provides a compound of formula I for use as a medicament. In yet another preferred embodiment the present invention provides the use of a compound of formula I for the manufacture of a medicament for the treatment of migraine. In yet another preferred embodiment the present invention provides a pharmaceutical composition for the treatment of neurological and psychiatric disorders associated with glutamate dysfunction containing as an active ingredient a compound of formula I. In yet another preferred embodiment the present invention provides a method of treating epilepsy, comprising administering to a patient in need thereof an effective amount of a compound of formula I. Because such potentiators, including the compounds of formula I, positively modulate metabotropic glutamate receptor response to glutamate, it is an advantage that the present methods utilize endogenous glutamate. Because such potentiators positively modulate metabotropic glutamate receptor response to glutamate agonists it is understood that the present invention extends to the treatment of neurological and psychiatric disorders associated with glutamate dysfunction by administering an effective amount of a metabotropic glutamate potentiator, including the compounds of formula I, in combination with a potentiated amount of a metabotropic glutamate receptor agonist. Such a combination may be advantageous in that it may augment the activity and selectivity of an agonist of metabotropic glutamate receptors, in particular a potentiator of mGlu2 receptors. Because many the compounds of formula I are antagonists of the CysLTl receptor, many of the compounds of formula I are useful for the treatment of a variety of disorders mediated by one or more leukotrienes such as inflammatory and allergic WO 2006/057860 PCT/US2005/041367 10 disorders associated with leukotriene mediation including inflammatory bowel syndrome, inflammatory bowel disease, arthritis, asthma, psoriasis, and thrombotic disease. In another embodiment the present invention provides methods of treating a variety of disorders mediated by one or more leukotrienes, comprising administering to a patient in need thereof an effective amount of a compound of formula I. That is, the present invention provides for the use of a compound of formula I or pharmaceutical composition thereof for the treatment inflammatory and allergic disorders associated with leukotriene mediation. In a preferred embodiment the present invention provides a method of treating asthma, comprising administering to a patient in need thereof an effective amount of a compound of formula I. hi another embodiment the present invention provides a process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION This invention provides methods of potentiating metabotropic glutamate receptors, in particular mGlu2 receptors. In the present methods an effective amount of a potentiator of metabotropic glutamate 2 receptors, including a compound of formula I, is administered which positively modulates the effect of glutamate or glutamate agonists on the subject receptor. Before describing the present invention in greater detail, it is understood that the invention in its broadest sense is not limited to particular embodiments described herein, as variations of the particular embodiments described herein are within the scope of the claimed invention. Thus, compounds useful in the present invention are those which are potentiators of metabotropic glutamate receptors, particularly, those that potentiate the effects of glutamate and glutamate agonists at mGlu2 metabotropic glutamate receptors, and even more particularly, those that potentiate the effects of glutamate and glutamate agonists at mGlu2 receptors. Useful compounds are varied in structure, and so long as they embrace the above properties, they are suitable for use in the present invention. Preferred compounds include, but are not limited to, those described herein. The compounds of formula I potentiate the function of glutamate receptors. Specifically, the compounds of formula I are potentiators of the mGlu2 receptor. WO 2006/057860 PCT/US2005/041367 11 Compounds of in the present invention also include those which are modulators of leukotriene receptors, particularly, those tnat antagonize the CysLTl receptor. As used herein, the following terms have the meanings indicated: The term "C1-C5 alkyl" refers to a straight or branched alkyl chain having from one to five carbon atoms, and includes methyl, ethyl, propyl, iso-propyl, butyl, iso- bntyl, sec-butyl, t-butyl, pentyl and the like. Particular values of "C1-C5 alkyl" are methyl, ethyl, n-propyl and iso-propyl. The term "alkyl" refers to a monovalent aliphatic hydrocarbon. Within the meaning of "alkyl" is the term "C1-C3 alkyl". The term "C1-C3 alkyl" refers to a straight or branched alkyl chain having from one to three carbon atoms, and includes methyl, ethyl, propyl, iso-propyl, and the like. The term "substituted C1-C5 alkyl" refers to a straight or branched alkyl chain having from one to five carbon atoms, and includes methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, t-butyl and pentyl having from 1 to 3 substituents selected from the group consisting of hydroxy, halogen, azido, alkoxy, acyloxy, carboxy, alkoxycarbonyl, amido, substituted amido, amino, acylamino, sulfonylamido, sulfonamide, phenyl, substituted phenyl, pbenoxy, substituted phenoxy, benzyloxy, substituted benzyloxy, pyridyl, substituted pyridyl, thienyl, and substituted thienyl. The term "C1-C5 alkanediyl" refers to a straight or branched divalent alkyl chain having from one to five carbon atoms, and includes methylene and ethane- 1,1-diyl, The term "substituted C1-C5 alkanediyl" refers to a straight or branched divalent alkyl chain having from one to five carbon atoms, and includes methylene having a substituent selected from the group consisting of hydroxyl, fluoro, azido, methoxy, amino, acetylamino and methylsulfonamide. Particular values of "substituted C1-C5 alkanediyl" are CH(OH), CH(F), CHN3, CH(OCH3), CHNH2, CHNH(C=O)CH3, CHNH(SO2)CH3. The term "C1-C3 alkanediyl" refers to a straight or branched divalent alkyl chain having from one to three carbon atoms, and includes methylene. The term "substituted C1-C3 alkanediyl" refers to a straight or branched alkyl chain having from one to three carbon atoms, and includes methylene, having from 1 or 2 substituents selected from the group consisting of hydroxy, halogen, azido, alkoxy, acyloxy, carboxy. alkoxycarbonyl, amido, substituted amido, amino, acylamino, WO 2006/057860 PCT/US2005/041367 12 sulfonylamido, sulfonamide, phenyl, substituted phenyl, pyridyl, substituted pyridyl, thienyl, and substituted thienyl The term "halogen or halo" refers to chloro, fluoro, brorao or iodo. The term "C1-C3 fluoro alkyl" refers to an alkyl chain having from one to three carbon atoms substituted with one or more fluorine atoms, and includes fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and the like. A particular value of "C1-C3 fluoro alkyl" is trifluoromethyl. The term "alkoxy" refers to a straight or branched alkyl chain attached to an oxygen atom. Within the meaning of "alkoxy" is the term "Cl -C4 alkoxy". The term "C1-C4 alkoxy" refers to straight or branched alkyl chain having from one to four carbon atoms attached to an oxygen atom, and includes methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, sec-butoxy, t-butoxy, and the like. The term "substituted alkoxy" refers to a straight or branched alkyl chain attached to an oxygen atom having from 1 to 3 substituents. Within the meaning of "substitiuted alkoxy" is the term "substituted C1-C4 allcoxy". The term "substituted C1-C4 alkoxy" refers to straight or branched alkyl chain having from one to four carbon atoms attached to an oxygen atom, and includes methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, sec-butoxy, t-butoxy, and the like, having from 1 to 3 substituents selected from the group consisting of hydroxy, halogen, alkoxy, carboxy, amido, substituted amido, amino, acylamino, sulfonylamido, sulfonamide, phenyl, and substituted phenyl; and when one or more of the substituents is hydroxy, halogen, alkoxy, amino, acylamino, and sulfonamide, then those substituents are not attached to the same carbon as the alkoxy oxygen atom. The term "C3-C7 cycloalkyl" refers to saturated cyclic alkyl group having from three to seven carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "C4-C8 cycloalkylalkyl" refers to saturated cyclic alkyl group having from three to seven carbon atoms linked to the point of substitution by a divalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having at least 1 carbon atom and includes, cyclopropylmethyl, cyclopropyl-2-propyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl and the like. WO 2006/057860 PCT/US2005/041367 13 The terms "phenyl and substituted phenyl" or "phenylene and substituted phenylene" refer to a monovalent or divalent radical, repectively, of the formula wherein Ra is from 1 to 3 groups independently selected from the group consisting of hydrogen, hydroxy, alkyl, substituted alkyl, cycloallcyl, alkoxy, substituted alkoxy, halogen, carboxy, alkoxycarbonyl, amido, substituted amido, amino, acylamino, sulfonylamido, sulfonamide, cyano, nitro, phenyl, and substituted phenyl. Particular values of Ra are hydrogen, methoxy and fluoro. Particular values of Ra are hydrogen, methoxy, fluoro and trifluoromethyl. The terms "thiophenyl and substituted thiophenyl" or "thiophenediyl and substituted thiophenediyl" refer to a monovalent or divalent radical, repectively, of the formula wherein Rb is 1 or 2 groups independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, alkoxy, substituted alkoxy, halogen, carboxy, alkoxycarbonyl, amido, substituted amido, ammo, acylamino, sulfonylamido, sulfonamide, cyano, nitro, phenyl, and substituted phenyl. A particular value of Rb is hydrogen. The terms "pyridinyl and substituted pyridinyl" or "pyridinediyl and substituted pyridinediyl" refer to a monovalent or divalent radical, repectively, of the formula wherein Rc is from 1 to 3 groups independently selected from the group consisting of hydrogen, hydroxy, alkyl, substituted alkyl, cycloalkyl, alkoxy, substituted alkoxy, halogen, carboxy, alkoxycarbonyl, amido, substituted amido, amino, acylamino, sulfonylamido, sulfonamide, cyano, nitro, phenyl, and substituted phenyl. A particular value of Rc is hydrogen. WO 2006/057860 PCT/US2005/041367 14 The terms "thiazolyl and substituted thiazolyl" or "thiazolediyl and substituted thiazolediyl" refer to a monovalent or divalent radical, repectively, of the formula wherein Rd is 1 or 2 groups independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, alkoxy, substituted alkoxy, halogen, carboxy, alkoxycarbonyl, amido, substituted amido, amino, acylamino, sulfonylamido, sulfonamide, cyano, nitro, phenyl, and substituted phenyl. A particular value of Rmol) in ethanol (75 mL) and cyclohexene (75 mL) and stir. Purge the reaction vessel with argon. Heat to reflux. After 18 hours, cool to ambient temperature, filter and concentrate under reduced pressure to yield the title compound as a grey solid (3.00 g, 91%): 1H NMR (CD3CN) 5 WO 2006/057860 PCT/US2005/041367 109 2.55 (s, 3H), 6.51 (d, 1H), 7.88 (d, IH), 13.91 (bs,,'lH). Example 50 Synthesis of l-(2-hydroxy-3-propyl-4-{3-[3-(2//-tetrazol-5-yl)-benzenesulfinyl]- benzyloxy}-phenyl)-ethanone sodium salt (phenol). Add sodium hydride (12.1 mg, 0.504 mmol, 95%, dry, 1.00 mrnol, Aldrich Chemical Co.) to a solution of l-(2-hydroxy-3-propyl-4-{3-[3-(2H-tetrazol-5-yl)- benzenesulfinyl]-benzyloxy}-phenyl)-ethanone (0.240 g, 0.504 mmol) in tetrahydrofuran (0.2 M). Evaporate solvent and triturate with diethyl ether. Filter to collect the title compound as the resulting precipitate (180 mg, 0.361 mmol, 72%): 'H NMR (400 MHz, DMSO-4;) 5 0.84 (t, J= 7.2 Hz, 3H), 1.33-1.39 (m, 2H), 2.45-2.47 (m, 2H), 2.50 (s, 3H), 5.07 (s, 2H), 5.77 (d, J= 9.4 Hz, 1H), 7.27 (d, J= 9.0 Hz, IH), 7.51-7.57 (m, 4H), 7.66 (d, J= 7.0 Hz, IH), 7.82 (s, IH), 8.07 (d, J= 7.0 Hz, IH), 8.26 (s, 1H). MS (m/z): 475 (M-l). Example 51 Synthesis of 1 -(2-hydroxy-3-propyl4-{3-[3-(2Na-tetrazol-5-yl)-benzenesulfinyl]- benzyloxy}-phenyl)-ethanone sodium salt (tetrazole). Add sodium methoxide (1.00 mmol, 0.5 M solution in methanol) to a solution of l-(2-hydroxy-3-propyl-4-{3-[3-(2//-tetrazol-5-yl);benzenesalfinyl]-benzyloxy}-phenyl)- ethanone (0.150 g, 0.315 mmol), and stir for 30 min. Evaporate solvent. Add 1:10 tetrahydrofuran/ether and soniccate the residue. Filter and collect the solid product. The title compound was obtained (0.150 g, 0.310 mmol, 96%): 'H NMR (400 MHz, DMSO-rf6) 5 0.86 (t, J= 7.4 Hz, 3H); 1.46 (q, J = 9.9 Hz, 2H), 2.55 (s, 3H), 2.57 (m, 2H), WO 2006/057860 PCT/US2005/041367 110 5.32 (s, 2H), 6.65 (d, J= 8.2 Hz, 1H), 7.53 (s, 1H), 7.56-7.61 (m, 4H), 7.71 (d, J= 7.4 Hz, 1H), 7.75 (d, J= 9.4 Hz, 1H), 7.84 (s, 1H), 8.06 (m, 1H), 8.24 (m, \H), 12.85 (s, 1H). MS (m/z): 475 (M-l). Example 52 Synthesis of 6-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenoxy]-nicotinic acid. Mix 6-[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenoxy]-nicotinonitrile (,0.14 g, 0.34 mmol), powdered potassium hydroxide (0.69 g, 12.20 mmol), isopropyl alcohol (1.5 mL) and water (1.5 mL). Heat to 130 °C for 8 hrs. Allow to cool to ambient temperature. Pour into water (20 mL) and acidify to pH 1 with hydrochloric acid (37% in water, 1 mL). Extract with ethyl acetate (3 x 30 mL). Combine the organic extracts, dry over magnesium sulfate, filter and concentrate under reduced pressure to obtain a residue. Purification using 5% isopropyl alcohol/chloroformchloroform to 10% isopropyl alcohol/chloroformchloroform as gradient eluent gives the title compound (0.02 g, 17%): MS (m/z): 420.1 (M-l). 'H NMR (acetone-tf6) 12.94 (s, 1H), 8.77 (s, 1H), 8.40 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.62 (d, J - 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 9.2 Hz, 1H), 5.34 (s, 2H), 2.73 (t, J = 7.5 Hz, 2H), 2.63 (s, 3H), 1.66-1.56 (m, 2.H), 0.96 (t, J = 7.5 Hz, 3H). Example 53 Synthesis of 6-[3-(3-hydroxy-2-methyl-4-propionyl-phenoxymethyl)-phenoxy]-nicotinic acid. Dissolve 6-[3-(3-hydroxy-2-methyl-4-propionyl-phenoxymethyl)-phenoxy]- nicotinic acid methyl ester ( 0.10 g, 0.24 mmol) in tetrahydrofuran (2 mL). Add lithium hydroxide (0.007 g, 0.29 imnol) and water (0.5 mL). Stir at ambient temperature for 2 WO 2006/057860 PCT/US2005/041367 111 hrs. Add 1 N hydrochloric acid (5 mL) and extract with ethyl acetate (3x10 mL). Combine the organic extracts, dry over magnesium sulfate, filter and concentrate under reduced pressure to obtain a residue. Purification using 5% isopropyl alcohol/chloroformchlorofonn to 10% isopropyl alcohol/chloroform as gradient eluent gives the title compound (0.06 g, 58%): MS (m/z): 406.1 (M-l). *H NMR (acetone-fife) 13.00 (s, 1H), 8.76 (s, 1H), 8.40 (dd, J = 1.7 Hz, 8.4 Hz, 1H), 7.86 (d, J = 9.2 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.38 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.76 (d, J = 9.2 Hz, 1H), 5.36 (s, 2H), 3.09 (q, J = 7.2 Hz, 2H), 2.14 (s,3H), 1.20 (t,J = 7.2 Hz, 3H). The following examples are prepared essentially as described for Example 52 or 53. WO 2006/057860 PCT/US2005/041367 112 WO 2006/057860 PCT/US2005/041367 113 WO 2006/057860 PCT/US2005/041367 114 Example 59 Synthesis of 2-[3-(4-acetyl-2-carboxy-3-hydroxy-phenoxymethyl)-phenoxy]-isonicotiiuc acid. The title compound is prepared essentially as described for 4-[4-(4-acetyl-3- hydroxy-2-propyl-benzyloxy)-benzenesulfinyl]-benzoic acid (Example 57) employing 2- [3-(4-acetyl-3-hydroxy-2-triiluoromethyl-phenoxymethyl)-phenoxy]-isonicotinonitrile. Heat in microwave reactor for 35 min. at 150 °C. (33%). LC-MS (m/e): 422 (M-l); 'H NMR (DMSO-d6) 8 8.34 (1 H, d), 8.00 (1 H, d), 7.57 (1 H, dd), 7.48 (1 H, dd), 7.39 (1 H, s), 7.31 (1 H, d), 7.25 (1 H, s), 7.15 (1 H, m), 6.80 (1 H, d), 5.35 (2 H, s), 2.52 (3 H, s) Preparation 106 Synthesis of dimethyl-thiocarbamic acid 5'-(4-acetyl-3-hydroxy-2-propyl-phenyl) ester. Stir a mixture of l-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (2 g, 10.3 rnmol), triethylamine (1.6 mL 11.3 mmol), and dichloromethane (40 mL) at room temperature. Add dimethylthiocarbamoyl chloride (1.27 g, 10.3 mmol) and stir at room temperature overnight. Wash the mixture with 1M hydrochloric acid (25 mL), dry over magnesium sulfate, filter and concentrate. Purify the residue via silica chromatography eluting with hexanes to 7:3 hexanes:ethyl acetate to afford dimethyl-thiocarbamic acid O-(4-acetyl-3- hydroxy-2-propyl-phenyl) ester (1.2 g, 41 %) as a light yellow solid. Stir the yellow solid in tetradecane (10 mL) at 250 °C for an hour and purify by silica chromatography eluting with hexanes to 6:4 hexanes:ethyl acetate to give the title compound (1.08 g, 90 %) as a white solid. LCMS (m/z) 280 m-l. Preparation 107 Synthesis of l-(2-hydroxy-4-mercapto-3-propyl-phenyl)~etlianone. Reflux a stirred mixture of dimethyl-thiocarbamic acid S-(4-acetyl-3-hydroxy-2- propyl-phenyl) ester (1.08 g, 3.84 mmol), potassium hydroxide (l.lg, 19.2 mmol), ethanol (25 mL), and water (10 mL) for 2 hours. Cool the reaction in an ice/water bath and adjust the pH to 2 with aqueous 5N hydrochloric acid. Extract the mixture with ethyl WO 2006/057860 PCT/US2005/041367 115 acetate (3 X 50 mL). Combine the extracts and wash with water (50 mL) and brine (50 mL) and dry over magnesium sulfate, filter, and concentrate to afford the title compound (0.76 g, 94 %) as a brown oil which solidifies on standing. LCMS (m/z) 211 m-1. Preparation 108 Synthesis of 2-fluoro-3-methoxy-phenol. A mixture of 2-fluoroanisole (1.8 ml, 15.85 mmol), pentamethyldiethyenetriamine (3.6 mL, 17.45 mmol) and tetrahydrofuran (10 mL) is stirred at -78 °C. A 2.5 M solution of n-butyllithium in hexanes (7 ml, 17.45 mmol) is added dropwise and the resulting solution is stirred at-78 °C 2 hr. Trimethylborate (2 mL, 17.45 mmol) is added and the reaction is wanned to room temperature and stirred 1 hr. Acetic acid (1.4 ml, 23.8 mmol) is added followed by an aqueous 30 % solution of hydrogen peroxide (1.8 mL, 17.45 mmol) and the resulting mixture is stirred rapidly 18 hr at room temperature. The reaction mixture is diluted with water and extracted with ethyl acetate (3 X 50 mL). The combined extracts are dried over magnesium sulfate, filtered and concetrated to about 10 mL volume. The resulting mixture is purified via silica chromatography eluting with hexanes to 8:1 hexanestethyl acetate to give the title compound (1.65 g, 73 %) as a colorless oil. MS ES 141 m-1. Preparation 109 Synthesis of l-(3-fluoro-2,4-dihydroxy-phenyl)-ethanone. A solution of 2-fluoro-3-methoxy-phenol (0.5 g, 3.53 mmol) and dichloromethane is stirred at -78 °C. A 1M solution of boron tribromide in dichloromethane (3.9 mL, 3.9 mmol) is added slowly and the mixture is stirred 10 min cold, then warmed to 0 °C and stirred 1 hr. The reaction is quenched with ice and stirred at room temperature overnight. The product is extracted with ethyl acetate (2 X 50 mL), dried over magnesium sulfate, filtered, and concentrated. The resulting residue is combined with boron trifluoride diethyl etherate (1.3 mL, 10.3 mmol) and acetic acid (0.2 mL, 3.28 mmol) and heated to reflux 8 hr. The mixture is cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3 X 50 mL). The combined extracts are dried over magnesium sulfate, filtered and concentrated to about 10 rnL volume. The resulting WO 2006/057860 PCT/US2005/041367 116 mixture is diluted with hexanes (50 rnL), cooled to 0 °C, and filtered to give the title compound (310 mg, 58 %) as a tan solid. MS ES 171 m+1. Preparation 110 Synthesis of l-(3-chloro-2,4-dihydroxy-phenyl)-ethanone. A solution of 2,4,-dihydroxyacetophenone (6 g, 39.4 mmol), aqueous 1M sodium hydroxide (41.4 mL. 41.4 mmol) and water (200 mL) is stirred at room temperature. An aqueous 1.6M solution of sodium hypochlorite (32 mL) is added over a 1 hr period. The resulting dark brown solution is stirred 18 hr at room temperature. The reaction mixture is adjusted to a pH of 2-3 with concentrated aqueous hydrochloric acid. The resulting suspension is filtered and washed with water (4 X 100 mL). The filtered solid was dried under vacuum at 45 °C for 2.5 days to give the title compound (4.8 g, 65 %) as a brown solid. LCMS 1 187 m+. Preparation 111 Synthesis of l-(3-chloro-2,4-dihydroxy-phenyl)-propan-l-one. The title compound was prepared in a similar manner to l-(3-chloro-2,4- dihydroxy-phenyl)-ethanone (Preparation 111) employing 2,4-dihydroxypropiophenone to give 4.5 g, 37 % of an off-white solid. LCMS 1 201 m+. Preparation 112 Synthesis of l-[2-hydroxy-4-(4-ritro-benzyloxy)-3-propyl-phenyl]-ethanone. To 2',4'-dihydroxy-3'-propyl acetophenone (3.0 g, 15.4 mmol) and 4-nitrobenzyl bromide (3.6 g, 17 mmol) in acetone (62 mL) is added K2CO3 (3.2 g, 23 mmol). The reaction mixture is refluxed for lh and cooled to room temperature. The precipitate is filtered, washed with water (5 x 70 mL), and dried to give the title compound (4.8 g, 94%). LC-MS (m/z): 328 (M-l). Preparation 113 Synthesis of l-[4-(4-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone. To l-[2-Hydroxy-4-(4-nitro-benzyloxy)-3-propyl-phenyl]-ethanone (1.0 g, 3.0 mmol) in tetrahydrofuran (13 mL) is added concentrated hydrochloric acid (2.7 mL) and stannous chloride dihydrate (2.2 g, 9.9 mmol). The reaction mixture is stirred at room WO 2006/057860 PCT/US2005/041367 117 temperature overnight. The reaction mixture is quenched into saturated aqueous NH4CI (100 mL). The resulting emulsion is filtered and the filtrate extracted with ethyl acetate (3 x 100 mL). The combined organic layers are washed with brine, dried over sodium sulfatesodium sulfate, and concentrated to provide! the title compound in crude form (980 mg,). LC-MS (m/z): 298 (M-l). Preparation 114 Synthesis of l-(2,6-dihydroxy-biphenyl-3-yl)-ethanone. To a solution of l-(2,4-dihydroxy-3-iodo-phenyl)-ethanone (1.0 g, 3.59 mmol; 581938, may be prepared as described in G. Batu and R. Stevenson, J. Org. Chem. 1979, 44, 3948) in tetrahydrofuran/water (15 mL/ 3 mL) at room temperature is added phenvl boronic acid (0.877 g, 7.19 mmol), Pd(dppfhCl2 (0.088 g, 0.107 mmol), and cesium hydroxide monohydrate (1.81 g, 10.8 mmol). After stirring for 15 hours, the mixture is filtered through a pad of Celite®, washing with ethyl acetate. The residue is diluted with 30 mL of IN hydrochloric acid and extracted with,ethyl acetate. The combined organic phases are washed with brine; dried over magnesium sulfate; filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography, eluting with 30% ethyl acetate/hexanes to give the title compound as a colorless solid: MS (m/z) 228(M+); 'H NMR (DMSO-d6) 5 13.1 (s, 1H), 10.6 (bs, 1H), 7.81 (d, J= 8.8 Hz, 1H), 7.41-7.28 (m, 5H), 6.61 (d, J= 8.8 Hz, 1H), 2.58 (s, 3H); Rf = 0.58 in 40% ethyl acetate/hexanes. Preparation 115 Synthesis of l-(4'-fluoro-2,6-dihydroxy-biphenyl-3-yl)-ethanone. The title compound is prepared essentially as described in Preparation 119 using 4-fluorophenylboronic acid: mass spectrum (m/e); 245(M-1); 'H NMR (acetone-^) 8 13.2 (s, 1H), 7.82 (d, J<= 8.4 Hz, 1H), 7.44-7.40 (m, 2H), 7.18-7.13 (m, 2H), 6.61 (d J = 8.8 Hz, 1H), 2.60 (s, 3H); Rf = 0.40 in 40% ethyl acetate/hexanes. Preparation 116 Synthesis of (6-bromo-pyridin-2-yl)-methanol. Add n-butyl lithium (16.2 mL, 2.5 M in hexanes, 40.5 mmol) dropwise to a solution of 2,6-dibromopyridine (8.00 g, 33.8 mmol) in tetrahydrofuran (100 mL) at - 78°C. Stir 30 minutes then add dimethylformamide (12.3 g, 169 mmol) via syringe. WO 2006/057860 PCT/US2005/041367 118 Allow solution to warm to ambient temperature then pour it into a solution of sodium borohydride (17.85 g, 338 mmol) in ethanol (50 mL) at -10°C. After 10 minutes, remove the cooling bath. After 1 hour at ambient temperature, add water and IN hydrochloric acid (gas evolution), then add saturated sodium bicarbonate solution until the mixture is neutralized. Extract the aqueous phase with ethyl acetate, dry over sodium sulfate, filter and concentrate under reduced pressure. Dissolve the residue in diethyl ether and add an excess of hydrogen chloride (2N in diethyl ether). Decant the organic phase and add saturated sodium bicarbonate solution to the residue. Extract with ethyl acetate (3 x), dry over sodium sulfate, filter and concentrate under reduced pressure to afford the title compound as a brown oil (2.73 g, 14.5 mmol): MS (m/z): 189 (M+l). Preparation 117 Synthesis of 1 -[4-(6-bromo-pyridin-2-ylmethoxy)-2-hydrox}'-3-propyl-phenyl]-ethanone. Combine (6-bromo-pyridin-2-yl)-methanol (1.00 g, 5.32 mmol), l-(2,4- dihydroxy-3-propyl-phenyl)-ethanone (1.033 g, 5.32 mmol) and tri-«-butylphosphine (1.46 mL, 5.85 mmol, Aldrich Chemical Co.) in tetrahydrofuran (5.3 mL), add 1,1'- (azodicarbonyl)dipiperidine (1.48 g, 5.85 mmol, Aldrich Chemical Co.). After 12 hours at ambient temperature, add diethyl ether (white percipitate forms) and filter, collect liquid and remove solvents under reduced pressure. Purify residue by flash chromatography to obtain the title compound as a white solid (854 mg, 2.35 mmol): MS (m/z): 286 (M- Br+1). The following compound is prepared essentially by the method of Preparation 117. WO 2006/057860 PCT/US2005/041367 119 Example 60 Synthesis of 3-[6-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-pyridin-2-ylsulfanyl]- benzoic acid. To a solution of 3-mercaptobenzoic acid (361 mg, 2.35 mmol) in dimethylfonnamide (15 mL) add sodium hydride (23 mg, 9.38 mmol) at 0 °C, stir 10 min. Add l-[4-(6-bromo-pyridin-2-ylmethoxy)-2-hydroxy-3-propyl-phenyl]-ethanone(854 mg, 2.35 mmol), heat to 100°C for 6 hours. Cool to ambient temperature and add diethyl ether, collect the resulting red precipitate by filtration (290 mg). Purify by the residue by preparative LC (inject 110 mg) to yield the title compound as a white solid (50 mg, 0.12 mmol): JH NMR (DMSO-d6) 8 0.38 (t, 3H), 1.50 (q, 2H), 2.55 (s, 3 H), 2.61 (m, 2H), 5.25 (s, 2H), 6.65 (d, 1H), 6.97 (d, 1H), 7.26 (d, 1H), 7.62 (t, 1H), 7.76 (m, 1H), 7.83 (m, 1H), 8.02 (m, 1H), 8.07 (m, 1H), 12.85 (s, 1H), 13.25 (br s, 1H); MS (m/z): 436 (M-l). The following compound is prepared essentially by the method of Example 60. Preparation 119 Synthesis of 3-(5-hydroxymethyl-pyridin-3-ylsulfanyl)-benzoic acid methyl ester. WO 2006/057860 PCT/US2005/041367 120 Dissolve 3-bromo-5-hydroxymethyl-pyridinium chloride' [Kelly, T. R., Howard, H. R., Koe, K., Sarges, R. J. Med. Chem. 1985, 28, 1368-1371] (1.00 g, 4.45 mmol) in saturated aqueous sodium bicarbonate, extract three times with ethyl acetate, dry combined organic phases over sodium sulfate, condense to afford (5-bromo-pyridin-3-yl)- methanol. Employing the procedure of general method 1 using (5-bromo-pyridin-3-yl)- methanol (832 mg) and 3-mercapto-benzoic acid methyl ester (1.50 g, 8.91 mmol). Purify by SCX column, elute with dichloromethane, then 1:1 dichloromethane/methanol then 1:1 dichloromethane/methanol, 10% ammonia, compound elutes in the ammonia, to yield the title compound as a dark brown oil (380 mg, 1.38 mmol): MS (m/z): 276 (M+l). The following compound is prepared essentially by the method of Preparation 119. Preparation 121 Synthesis of 3-[5-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-pyridin-3-ylsulfanyl]- benzoic acid methyl ester. Using the procedure essentially of Preparation 117 using 3-(5-hydroxymethyl- pyridin-3-ylsulfanyl)-benzoic acid methyl ester (370 mg, 1.34 mmol), l-(2,4-dihydroxy- 3-propyl-phenyl)-ethanone (261 mg, 1.34 mmol) provides the title compound as colorless oil (379 mg, 0.84 mmol): MS (m/z): 452 (M+l). The following compounds are prepared essentnilly by the method of Preparation 121. WO 2006/057860 PCT/US2005/041367 121 Dissolve 3-[5-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-pyridin-3- ylsulfanyl]-benzoic acid methyl ester (379 mg, 0.84 mmol) in metlianol (2 mL) and water (0.5 mL). Add 2N aqueous lithium hydroxide solution (0.42 mL, 0.84 mmol). After 12 hours, concentrate under reduced pressure and dissolve residue in 4N hydrochloric acid in dioxane. Add water until white precipitate forms, and collect by filtration. Triturate in ethyl acetate, then methanol. Collect the title compound by filtration as a white solid (317 mg, 0.73 mmol): !H NMR (DMSO-ds) 5 0.76 (t, 3H), 1.37 (m, 2H), 2.47 (m, 2H), 2.58 (s, 3 H), 5.30 (s, 2H), 6.70 (d, 1H), 7.52 (t, 1H), 7.63 (m, 1H), 7.77 (m, 1H), 7.80 (m, 1H), 7.86 (m, 1H), 7.90 (d, 1H), 8.60 (m, 2H), 12.83 (s, jlH), 13.21 (br s, 1H); MS (m/z): 438 (M+l). The following compound is prepared essentially by the method of Example 62. WO 2006/057860 PCT/US2005/041367 122 Preparation 124 Synthesis of l-[4-(6-chloro-pyridin-3-ylmethoxy)-2-hydroxy-3-propyl-phenyl]-ethanone. Add 5-chloromethyl-2-chloropyridine (4.12 g, 25.4 mmol) to a solution of of 1- (2,4-dihydroxy-3-propyl-phenyl)-ethanone (4.94 g, 25.4 nutnol) in dknethylformamide (40 mL). After 10 minutes add potassium carbonate (5.27 g, 38.1 mmol) and cesium carbonate (8.28 g, 25.4 mmol). Stir at room temperature for one hour, and then heat to 70 °C for 2 hours. Cool, partition between ethyl acetate (300 mL) and water (300 mL). Wash twice with water, brine, dry, and concentrate. Dissolve the crude solid in dichloromethane, and add hexane (70 mL) slowly. Triturate and filter to afford the title compound as an orange powder (2.95 g, 36%): ]H NMR (CDC13) 5 0.94 (t, 3H), 1.55 (sextet, 2H), 2.58 (s, 3H), 2.67 (t, 2H), 5.14 (s, 2H), 6.47 (d, 1H), 7.38 (d, 1H), 7.60 (d, 1H), 7.73 (d, 1H), 8.47 (s, 1H), 12.75 (s, 1H). Example 64 Synthesis of 3-[5-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-pyridin-2-ylsulfanyl]- benzoic acid. WO 2006/057860 PCT/US2005/041367 123 Dissolve 3-mercapto-benzoic acid (482 mg, 3.13 mmol, commercially available) in dimethylforraamide (20 mL) at 0 °C. Add washed sodium hydride (300 mg), and stir the mixture for 10 minutes. Add l-[4-(6-chloro-pyridin-3-ylmethoxy)-2-hydroxy-3- propyl-phenyl]-ethanone (1.00 g, 3.13 mmol). Stir the mixture at room temperature for 2 hours; then stir at 65 °C for 2 hours and finally stir at 120 °C overnight. Dilute in ethyl acetate, and wash with water twice. Extract the organic layer with saturated aqueous sodium bicarbonate. Acidify the aqueous layer with 2N hydrochloric acidhydrochloric acid to pH 3. Extract with ethyl acetate, wash with brine, dry and concentrate to afford 620 mg of a crude red solid. Purify the residue via chromatography, eluting with 1:1 hsxane:ethyl acetate to afford the title compound as a light yellow powder (120 mg): 'H NMR (DMSO-4) S 0.84 (s, 3H), 1.44 (sextet, 2H)j 2.55 (t, 2H), 2.58 (s, 3H), 5.24 (s, 2H), 6.74 (d, 1H), 7.14 (d, 1H), 7.63 (t, 1H), 7.75 (d, 1H), 7.81-7.84 (m, 2H), 8.02 (d, 1H), 8.05 (s, 1H), 8.51 (s, 1H), 12.84 (s, 1H), 13.21 (bs, 1H); MS (APCI-neg mode) mlz (rel intensity) 436 (100). Preparation 125 Synthesis of 1 -[2-hydroxy-4-(3-iutro-benzyloxy)-3-propyl-phenyl]-ethanone. Add 3-bromomethyl nitrobenzene (10.00 g, 46.3 mmol) to a solution of l-(2,4- dihydroxy-3-propyl-phenyl)-ethanone (8.99 g, 46.3 mmol) in dimethylformamide (60 mL). After 10 minutes add potassium carbonate (9;60 g, 69.4 mmol) and cesium carbonate (15.08 g, 46.3 mmol). Stir at room temperature for one hour, then heat to 70°C for 1.5 hours. Cool and add water (250 mL). Triturate for 15 minutes. Filter. Wash the solid with water several times, and then wash with hexanes. Dry to afford the title compound as an off white/light gray powder (12.9 g, 85%): 'H NMR (DMSO-d6) 5 0.91 (t, 3H), 1.52 (m, 2H), 2.58 (s, 3H), 2.63 (m, 2H), 5.42 (s, 2H), 6.72 (d, 1H), 7.73 (t, 1H), 7.83 (d, 1H), 7.90 (d, 1H), 8.21 (d, 1H), 8.34 (s, 1H), 12.88 (bs, 1H). The following compound is prepared essentially by, the method of Preparation 125. WO 2006/057860 PCT/US2005/041367 124 Preparation 127 Synthesis of l-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone. Add zinc (21.6 g, 331 mmol) slowly lo a solution of l-[2-hydroxy-4-(3-nitro- benzyloxy)-3-propyl-phenyl]-ethanone (10.9 g, 6.07 mmol) in glacial acetic acid (120 mL). Stir the mixture for 3 hours. Dilute with dichloromethane (600 rnL). Filter the reaction mixture through celite. Wash the celite pad several times with dichloromethane. Concentrate the combined filtrates. Partition the residue between ethyl acetate and saturated sodium bicarbonate. Wash the organic layer with brine, dry and concentrate to afford the title compound as a yellow solid (9.75 g, 98%): lH NMR (CDC13) 5 0.96 (t, 3H), 1.58 (sextet, 2H), 2.54 (s, 3H), 2.71 (t, 2H), 5.07 (s, 2H), 6.46 (d, 1H), 6.62 (d, 1H), 6.71 (s, 1H), 6.78 (d, 1H), 7.16 (t, 1H), 7.54 (d, 1H), 12.75 (s, 1H). The following compound is prepared essentially by the method of Preparation 127. WO 2006/057860 PCT/US2005/041367 125 Preparation 129 Synthesis of 3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-benzoic acid methyl ester. Combine 1 -[4-(3-ammo-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (500 mg, 1.67 mmol), 3-bromo-benzoic acid methyl ester (326 ing, 1.52 mmol) and cesium carbonate (693 mg, 2.13 mmol) in toluene (25 mL):and stir. Purge reaction vessel with argon. AddBINAP [rac-2,2'-Bis(diphenyl-phosphino)-l,r-binaphthy!] (142 mg, 0.228 mmol), and palladium acetate (34 mg, 0.152 mmol). Purge reaction vessel with argon. Heat to 100 °C. After 18 hours, cool to ambient temperature. Add 10% aqueous citric acid, and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate to dryness. Purify the resulting residue by flash chromatography eluting with ethyl acetate:hexanes to yield the title compound as a white solid (280 mg, 43%): 'H NMR (DMSO-d6) 5 0.81 (t, 3H), 1.46 (sextet, 2H), 2.57 (m, 5H), 3.82 (s, 3H), 5.23 (s, 2H), 6.71 (d, 1H), 6.95 (d, 1H), 7.01 (d, 1H), 7.19 (m, 1H), 7.28-7.41 (m, 411), 7.65 (m, 1H), 7.81 (d, 1H), 8.49 (bs, 1H), 12.84 (s, 1H). Preparation 130 Synthesis of 5-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-nicotinic acid methyl ester. WO 2006/057860 PCT/US2005/041367 126 Combine l-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (500 mg, 1.67 mmol), 5-bromo-nicotinic acid methyl ester (328 mg, 1.52 mmol) and cesium carbonate (693 mg, 2.13 mmol) in toluene (25 mL) and stir. Purge reaction vessel with Argon. Add BINAP [rac-2,2'-Bis(diphenyl-phosphino)-l,l'-binaphthyl] (142 mg, 0.228 mmol), and palladium acetate (34 mg, 0.152 mmol). Purge reaction vessel with argon. Heat to 100 °C. After 18 hours, cool to ambient temperature. Add 10% aqueous citric acid, and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate to yield a residue. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to yield a yellow solid (250 mg, 38%):!H NMR (DMSO-de) 8 0.81 (t, 3H), 1.46 (sextet, 2H), 2.57 (m, 5H), 3.86 (s, 3H), 5.25 (s, 2H), 6.72 (d, 1H), 7.03 (d, 1H), 7.08 (d, 1H), 7.24 (bs, 1H), 7.35 (t, 1H), 8.54 (dd, 1H), 8.69 (bs, Hi), 12.84 (s, 1H). Example 65 Synthesis of 3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-benzoic acid. Add 1M aqueous lithium hydroxide (3.23 mL, 3.23 mmol) to a solution of 3-[3- (4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-benzoic acid methyl ester (280 mg, 0.646 mmol) in isopropanol (25 mL) and stir. Heat to 80 °C. After 1 hour, pour reaction into IN aqueous hydrochloric acid (50 mL) and extract with ethyl acetate. Combine organic layers, dry with sodium sulfate, filter and concentrate to dryness. Purify the resulting residue by trituration (ether:hexanes) to yield the title compound as a yellow solid (200 mg, 74%): JH NMR (DMSO-d6) 5 0 81 (t, 3H), 1.46 (sextuplet, 2H), 2.58 (m, 5H), 5.23 (s, 2H), 6.71 (d, 1H), 6.94 (d, IK), 7.02 (d, 1H), 7.19 (s, 1H), 7.29 (m, 3H), 7.40 (d, 1H), 7.65 (s, 1H), 7.81 (d, 1H), 8.44 (s, 1H), 12.73-12.92 (bs, 1H), 12.84 (s, 1H); MS (esi negative) m/z (rel intensity) 418 (100). WO 2006/057860 PCT/US2005/041367 127 Example 66 Synthesis of sodium 5-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]- nicotinate. Add 1M aqueous lithium hydroxide (2.88 mL, 2.88 mmol) to a solution of 5-[3- (4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-nicotinic acid methyl ester (250 mg, 0.575 mmol) in isopropanol (10 mL):tetrahydrofuran (5 mL) and stir. Heat to 80 °C. After 1 hour, pour reaction into water (50 mL) and wash with methyl /er/-butyl ether. Acidify with 2N aqueous hydrochloric acid, and extract with ethyl acetate. Combine organic layers, dry with sodium sulfate, filter and concentrate to dryness. Dissolve the resulting residue in ethyl acetate (10 mL), and add a solution of sodium ethyl hexanoate (83 mg, 0.499 mmol) in ethyl acetate (5 mL). After 30 minutes, filter tbe resulting precipitate to yield the title product as a white solid (77 mg, 30%): 1H NMR (Methanol) 8 0.88 (t, 3H), 1.54 (sextuplet, 2H), 2.56 (s, 3H), 2.67 (t, 2H), 3.64 (s, 1H), 5.19 (s, 2H), 6.66 (d, 1H), 7.02 (d, 1H), 7.11 (dd, 1H), 7.25"(s, 1H), 7.31 (t, 1H), 7.74 (d, 1H), 8.05 (m, 1H), 8.28 (d, 1H), 8.52 (d, 1H); MS (esi negative) mlz (rel intensity) 419 (100). Example 67 Synthesis of 2-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-nicotinic acid. Heat a mixture of 2-chloro-nicotinic acid (132 mg, 0.835 mmol) and l-[4-(3- amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (250 mg, 0.835 mmol) to 130 °C. After 18 hours, cool to ambient temperature and purify via flash chromatography (ethyl acetate:hexanes) to give a residue which was further purified by reverse phase WO 2006/057860 PCT/US2005/041367 128 chromatography (methanol:acetic acid:water) to yield the title product as a yellow solid (32 mg, 9%): 1H NMR (DMSO-d6) 5 0.88 (t, 3H), 1.51 (sextet, 2H), 2.57 (s, 3H), 2.63 (t, 2H), 5.27 (s,.2H), 6.73 (d, 1H), 6.87 (dd, 1H), 7.06 (d, IE), 7.34 (t, 1H), 7.67 (d, 1H), 7.81 (d, 1H), 7.88 (s, IE), 8.26 (dd, IE), 8.36 (dd, 1H), 10.66 (bs, 1H), 12.85 (s, 1H), 13.63 (bs, 1H); MS (esi negative) m/z (rel intensity) 419 (100). Preparation 131 Synthesis of 2- [3 -(4-acetyl-3 -hydroxy 2-propyl-phenoxymethyl)-phenylamino] - isonicotinic acid methyl ester. Combine 1 -[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (500 mg, 1.67 mmol), 2-chloro-isonicotinic acid methyl ester (287 mg, 1.67 tnmol) and cesium carbonate (762 mg, 2.34 mmol) in toluene (25 mL) and stir. Purge reaction vessel with argon. Add 2-(bicyclohexylphosphino)biphenyl (234 mg, 0.668 mmol), and tris(dibenzylideneacetone)dipalladium (153 mg, 0.167 mmol). Purge reaction vessel with argon. Heat to 110 °C. After 18 hours, cool to ambient temperature. Add diethyl ether (25 mL) and filter. Concentrate filtrate under reduced pressure to dryness. Purify the resulting residue by flash chromatography eluting with ethyl acetate:hexanes to yield the title compound as a yellow solid (282 mg, 39%): 'H NMR (DMSO-d6) 5 0.86 (t, 3H), 1.52 (sextet, 2H), 2.57 (s, 3H), 2.63 (t, 2H), 3.88 (s, 3H), 5.25 (bs, 2H), 6.72 (d, IE), 6.99 (d, 1H), 7.14 (d, 1H), 7.31 (t, 1H), 7.39 (s, 1H), 7.58 (d, IE), 7.80 (d, 1H), 7.91 (s, IE), 8.29 (d, 1H), 9.43 (s, 1H), 12.85 (s, IE). Example 68 Synthesis of 2-[3-(4-aceryl-3-hydroxy-2-propyl--phenoxymethyl)-phenylamino]- isonicotinic acid. Add 1M aqueous lithium hydroxide (2.14 mL, 2.14 mmol) to a solution of 2-[3- (4-acetyl-3-hydroxy-2-propyl-phenoxyniethyl)-phenylamino]-isonicotinic acid methyl ester (282 mg, 0.649 mmol) in tetrahydrofuran (20 mL):water (20 mL) and stir. Heat to 80 °C. After 1 hour, pour reaction into IN aqueous hydrochloric acid (50 niL) and filter WO 2006/057860 PCT/US2005/041367 129 the resulting precipitate to yield the title compound as a yellow solid (59 mg, 22%): 1H NMR (DMSO-d6) 6 0.86 (t, 3H), 1.52 (sextet, 2H),j2.57 (s, 3H), 2.63 (t, 2H), 5.25 (s, 2H), 6.72 (d, 1H), 6.99 (d, 1H), 7.13 (d, 1H), 7.30 (t, 1H), 7.37 (s, 1H), 7.56 (d, 1H), 7.80 (d, 1H), 7.91 (s, 1H), 8.28 (d, 1H), 9 37 (s, 1H), 12.85 (s, 1H), 13.44 (bs, 1H); MS (esi negative) m/z (rel intensity) 419 (100). Example 69 Synthesis of 2-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-nicotinic acid. Heat a mixture of 6-chloro-pyridine-2-carboxylic acid (263 mg, 1.67 mmol) and l-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (500 mg, 1.67 mmol) to 130 °C. After 18 hours, cool to ambient temperature. Purify the resulting residue by reverse phase chromatography (methanohacetic acid:water) to yield the title product as a yellow solid (75 mg, 11%): 1H NMR (DMSO-d6) 5 0.84 (t, 3H), 1.48 (sextet, 2H), 2.57 (s, 3H), 2.60 (t, 2H), 5.22 (s, 2H), 6.73 (d, 1H), 6.99 (d, 1H), 7.03 (d, 1H), 7.31 (t, 1H), 7.43 (d, 1H), 7.70 (t, 1H), 7.77 (s, 1H), 7.79 (d, 1H), 7.89 (d, 1H), 9.34 (s, Hi), 12.84 (s, 1H), 12.89 (bs, 1H); MS (esi negative) m/z (rel intensity) 419 (100). Preparation 132 Synthesis of 3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]- benzonitrile. Combine l-[4-(3-arnino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (1.65g, 5.51 mmol), 3-bromo-benzonitrile (912 mg, 5.01 mmol), cesium carbonate (2.29 g, 7.01 mmol), and 18-crown-6 (132 mg, 0.501 mmol) in toluene (25 mL) and stir. Purge reaction vessel with argon. Add BINAP [rac-2,2'-bis(diphenyl-phosphino)-l,l '- binaphthyl] (468 mg, 0.752 mmol), and palladium acetate (112 mg, 0.501 mmol). Purge reaction vessel with argon. Heat to 100 °C for 18 hours and cool to ambient temperature. Add 10% aqueous citric acid, and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate to dryness. Purify the resulting residue by flash chromatography eluting with 30% ethyl acetate:hexanes to yield a yellow oil (1.36g, WO 2006/057860 PCT/US2005/041367 130 68%): 'H NMR (CDCI3) 5 0.92 (t, 3H), 1.56 (sextet, 2H), 2.56 (s, 3H), 2.69 (t, 2H), 5.15 (s, 2H), 5.86 (bs, 1H), 6.49 (d, 1H), 7.06 (m, 2H), 7.15-7.21 (m, 3H), 7.27-7.37 (m, 3H), 7.59 (d, 1H), 12.75 (s, 1H). Preparation 133 Synthesis of 4-[3-(4-acetyl-3-hydrox7-2-propyl-phenoxymewyl)-phenylanTino]- benzonitiile. Combine l-[4-(3'3mino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (l.OOg, 3.34 mmol), 4-bromo-benzonitrile (553 mg, 3.03 mmol), cesium carbonate (1.39 g, 4.25 mmol), and 18-crown-6 (80 mg, 0.304 mmol) in toluene (25 mL) and stir. Purge reaction vessel with argon. Add BINAP [rac-2,2'-bis(diphenyl-phospMno)-l,r-binaphthyl] (284 mg, 0.456 mmol), and palladium acetate (68 mg, 0.304 mmol). Purge reaction vessel with argon. Heat to 100 °C. After 18 hours, cool to ambient temperature. Add 10% aqueous citric acid, and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate to dryness. Purify the resulting residue by flash chromatography eluting with 30% ethyl acetate:hexanes to yield the title compound as a yellow solid (760 mg, 63%):'H NMR (CDC13) 6 0.92 (t, 3H), 1.58 (sextet, 2H), 2.56 (s, 3H), 2.69 (t, 2H), 5.15 (s, 2H), 6.07 (bs, 1H), 6.47 (d, 1H), 6.98 (d, 2H), 7.13 (t, 2H), 7.23 (m, 1H), 7.38 (t, 1H), 7.49 (d, 2H), 7.58 (d, 1H), 12.75 (s, 1H). Example 69 Synthesis of l-(2-hydroxy-3-propyl-4-{3-[3-(2H-tetrazol-5-yl)-phenylarnino]- benayloxy} -phenyl)-ethanone. Using the general procedure for formation of tetrazole (Et3NHCl method) of Example 1 using 3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]- benzonitrile (1.36 g, 3.39 mmol), sodium azide (662 mg, 10.2 mmol), and triethylamine hydrochloride (1.40 g, 10.2 mmol) to yield the title product as a yellow solid (313 mg, 21%): 1H NMR (DMSO-d6) 8 0.791 (t, 3H), 1.43 (sextuplet, 2H), 2.57 (m, 5H), 5.24 (s, 2H), 6.72 (d, 1H), 6.98 (d, 1H), 7.08 (d, 1H), 7.24 (m, 2H), 7.32 (t, 1H), 7.44 (m, 2H), 7.79 (m, 2H), 8.55 (s, 1H), 12.84 (s, 1H); MS (esi negative) m/z (rel intensity) 442 (100). WO 2006/057860 PCT/US2005/041367 131 Example 70 Synthesis of l-(2-hydroxy-3-propyl-4-{3-[4-(2H-tetrazol-5-yl)-phenylamino]- benzyloxy} -phenyl) -ethanone. Using the general procedure for formation of tetrazole (Et3NHCl method) of Example 1 using 4-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]- benzonitrile (380 mg, 0.949 mmol), sodium azide (308 mg, 4.74 mmol), and triethylamine hydrochloride (653 mg, 4.74 mmol) to yield the title product as a white solid (120 mg, 29%): 'H NMR (DMSO-d6) 5 0.785 (t, 3H), 1.44 (sextuplet, 2H), 2.52 (s, 3H), 2.55 (t, 2H), 5.20 (s, 2H), 6.68 (d, 1H), 6.97 (d, 1H), 7.04 (d, 1H), 7.15 (d, 2H), 7.24 (s, 1H), 7.29 (t, 1H), 7.76 (d, 1H), 7.82 (d, 2H), 8.69 (s, 1H), 12.80 (s, 1H); MS (esi negative) m/z (rel intensity) 442 (100). Preparation 134 Synthesis of 1 -[4-(4-bromomethyl-benzyloxy)-3-chloro-2-hydroxy-phenyl]-ethanone Combine 1 -(3-chloro-2,4-dihydroxy-phenyl)-3thanone (6.00 g, 32.2 mmol) and 1,4-bis-bromomethyl-benzene (8.48 g, 31.2 mmol) and potassium carbonate (4.44 g, 32.2 mmol) in acetone (400 ml) and heat to reflux. After 1 h, cool to room temperature and add 10% hydrochloric acid (300 mL). Filter to collect and triturate resultant solid in 1:1 ether/hexanes. Purify by column chrornatography, eluting with 40% tetrahydrofuran/hexanes to obtain l-[4-(4-bromomethyl-benzyloxy)-3-chloro-2-hydroxy- phenyl]-ethanone (3.00 g, 8.12 mmol) as a white solid. MS (m/z): 368.9 (M-l). Preparation 135 Synthesis of l-(3-bromo-phenyl)-3-dimethylamino-propenone. Combine l-(3-bromo-phenyl)-ethanone (10 g, 50.2 mmol) and dimethylformamide dimethylacetal (60 g, 502 mmol) in a sealed tube, heat to 150 °C for 12 hours. Cool the solution and evaporate the excess dimethylformamide dimethylacetal. Purify residue by column chromatography to obtain the title compound (3.05 g, 12.0 mmol) as a white solid. MS (m/z): 254.1 (M). WO 2006/057860 PCT/US2005/041367 132 Preparation 136 Synthesis of 4-(3-bromo-phenyl)-pyrimidin-2-ol. Combine l-(3-bromo-phenyl)-3-dimethylamino-propenone (3.00 g, 11.8 mmol), urea (544 mg, 11.8 mmol), sodium ethoxide (4.00 g, 21% wt in ethanol) and ethanol (24 mL) and heat to 150 °C in sealed tube overnight. Cool to room temperature and pour into 1% hydrochloric acid (50 mL). Collect white solid by filtration to obtain 4-(3-bromo- phenyl)-pyrimidiri-2-ol (2.60 g, 10.4 mmol). MS (m/z): 251.2 (M+l). Preparation 137 Synthesis of 4-[3-(5,5-dimethyl-[l,3,2]dioxaborinan-2-yl)-phenyl]-pyrimidin-2-ol. Combine 4-(3-bromo-phenyl)-pyrimidin-2-ol (1.50 g, 5.97 mrnol), bis(neopentyl glycolato)diboron (1.62 g, 7.17 mmol), Pd(dppf)Cl2 (505 mg, 0.597 mmol) and potasium acetate (1.76 g, 17.9 mmol) hi a purged (N2) flask, add dry DMSO (50 mL) and plunge into a 80 °C bath. Heat overnight, then pour into 1 % hydrochloric acid (100 mL). Neutralize with sodium bicarbonate, and extract with ethyl acetate, dry, filter and condense to afford 4-[3-(5,5-dibmethyl-[l,3,2]dioxaborinan-2-yl)-phenyl]-pyrirnidin-2-ol (300 mg) as a brown solid. MS (m/z): 173.1 (M-C5H10BO2+l). Preparation 138 Synthesis of 4-(3-bromo-phenyl)-pyrimidin-2-ylarnine. Combine l-(3-bromo-phenyl)-3-dimethylamino-propenone (3.00 g, 11.8 mmol) and guanidinium chloride (1.12 g, 11.8 mmol), sodium ethoxide (5 mL, 21% wt solution in ethanol), absolute EtOH (24 mL) and heat to reflux overnight. Cool to room temperature and pour into 1% hydrochloric acid (200 mL). Extract with ethyl acetate, dry over sodium sulfate and condense to afford 4-(3-bromo-phenyl)-pyrimidin-2-ylamine (930 mg, 3.72 mmol) as a white solid. MS (m/z): 250.2 (M). Preparation 139 Synthesis of 4-[3-(5,5-dunemyI-[l,3,2]dioxaborinan-2-yl)-phenyl]-pyrmiidin-2-ylamine. The title compound is prepared essentially as described for Preparation 137 using 4-(3-bromo-phenyl)-pyrimidin-2-ylamine (2.00 g, 8.00 mrnol). The title compound is isolated (1.71 g, 6.04 mmol) as a brown solid. MS (m/z): 216.2 (M-C5H8+1). WO 2006/057860 PCT/US2005/041367 133 Preparation 140 Synthesis of 3-(tetrahydro-pyran-2-yloxymethyl)-benzonitrile. Add p-toluene sulphonic acid (2.11 g, 12.2 mmol) to a solution of 3- hydroxymethyl-benzonitrile(16.30 g, 122.4 mmol) and 3,4-dihydro-2//-pyran (51.5 g, 612 mmol) in dichloromethane (500 ml) and stir. After'90 minutes, pour reaction into saturated sodium bicarbonate, remove organics, dry with sodium sulfate, filter and concentrate to give a dark brown oil. Purify the residue by flash chromatography eluting with a gradient of 10-15% ethyl acetate:hexanes to yield the title product as a clear oil (16.20 g, 61%): 'H NMR (CDC13) 8 1.53-1.91 (m, 6H), 3.56 (m, 1H), 3.88 (m, 1H), 4.53 (d, 1H), 4.72 (t, 1H), 4.81 (d, 1H), 7.45 (t, 1H), 7.58 (m, 2H), 7.69 (s, 1H) Preparation 141 Synthesis of 3-[3-(tetrahydro-pyran-2-yloxyniethyl)-phenyl]-4//-[l,2,4]oxadiazol-5-one. Add 50% aqueous hydroxylamine(9.73 g, 147 mmol) dropwise to a refluxing solution of 3-(tetrahydro-pyran-2-yloxymethyl)-benzonitrile(8.00 g, 36.8 mmol) in isopropanol (0.1M). After 2 hours, cool to room temperature and concentrate under reduced pressure to give a residue. Dissolve the residue in dioxane (0.1M). Add carbonyldiimidazole (7.16 g, 44.2 mmol) and heat to 110 °C. After 30 minutes, cool to room temperature and pour into water. Extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to yield the title product as a white solid (9.10g, 89%): 'H NMR (CDCI3) 8 1.53-1.95 (m, 6H), 3.59 (m, 1H), 3.93 (m, 1H), 4.58 (d, 1H), 4.77 (t, 1H), 4,88 (d, 1H), 7.52 (t, 1H), 7.57 (d, 1H), 7.71 (d, 1H), 7.82 (s, 1H), 11.16 (bs, 1H) Preparation 142 Synthesis of 3-(3-hydroxymethyl-phenyl)-4H-[l,2,4]oxadiazol-5-one. Add 10% hydrochloric acid (100 ml) to a solution of 3-[3-(tetrahydro-pyran-2- yloxymethyl)-phenyl]-4#-[l52,4]oxadiazol-5-one(4.50 g, 16.3 mmol) in tetrahydrofuran (0.1M) and stir. After 18 hours, pour reaction into brine and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to yield the title product as a white solid (3.10 g, 99%): 1H NMR (DMSO-d6) 8 4.57 (s, 2H), 7.55 (m, 2H), 7.67 (dt, 1H), 7.81 (m, 1H), 12.95 (bs, 1H). WO 2006/057860 PCT/US2005/041367 134 Preparation 143 Synthesis of 3-(5-oxo-4,5-dihydro-[l,2,4]oxadiazol-3-yl)-benzaldehyde. Add pyrdinium chloro chromate (5.22 g, 24.2 mmol) to a solution of 3-(3-hydroxymethyl-phenyl)-4i7-[l,2,4]oxadiazol-5-one(3.10 g, 16.1 mmol) in tetrahydrofuranrdichloromethane (125 mL:125mL) and stir. After 4 hours concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes:acetic acid (50%:50%:0.1%) to yield the title product as a white solid (2.20 g, 72%): !H NMR (DMSO-d6) 5 7.83 (t, 1H), 8.10-8.17 (m, 2H), 8.35 (m, 1H), 10.09 (s, 1H), 13.15 (bs, 1H). Preparation 144 Synthesis of 1 -[2-hydroxy-4-(4-iodo-benzyloxy)-3-propyl-phenyl]-ethanone. Add l-bromomethyl-4-iodo-benzene (10.00 g, 33.7 mmol) to a solution of l-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (6.54 g, 33.7 mmol) and cesium carbonate (13.2 g, 40.4 mmol) in acetone (500 mL) and stir. After 48 hours, pour the reaction into water and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with a gradient of ethyl acetate:hexanes to yield the title product as a yellow solid (7.20 g, 52%): 'H NMR (CDC13) S 0.95 (t, 3H), 1.56 (sextet, 2H), 2.56 (s, 3H), 2.69 (t, 2H), 5.09 (s, 2H), 6.43 (d, 1H), 7.15 (d, 2H), 7.57 (d, 1H), 7.73 (d, 2H), 12.74 (s, 1H). Preparation 145 Synthesis of l-(4-iodo-benzyloxy)-2-propyl-3-trimethylsilanyloxy-4-(l- trimethylsilanyloxy-vinyl)-benzene. Add lithium hexamethyJdisilazide (1M solution in tetrahydrofuran, 5.36 ml, 5.36 mmol) to a solution of l-[2-hydroxy-4-(4-iodo-benzyloxy)-3-propyl-phenyl]- ethanone(l .00 g, 2.44 mmol) in tetrahydrofuran (25 mL) cooled to -78 °C. After 1 hour, add trimethylsilyl chloride (794 rng, 7.31 mmol). After 1 hour, warm reaction to room temperature and stir overnight. Pour the reaction into saturated sodium bicarbonate and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter, and concentrate. Dry on high-vac overnight to yield the title product as a dark yellow oil (1.35 g, 99%): 'H NMR (CDC13) 5 0.16 (s, 9H), 0.23 (s, 9H), 0.94 (t, 3H), 1.52 (sextet, WO 2006/057860 PCT/US2005/041367 135 2H), 2.60 (t, 2H), 4.49 (s, 1H), 4.53 (s, 1H), 4.99 (s, 2H), 6.49 (d, 1H), 7.10 (d, 1H), 7.17 (d,2H),7.71(d,2H). Preparation 146 Synthesis of l-[3-chloro-2-hydroxy-4-(4-iodo-benzyloxy)-phenyl]-ethanone. Add l-bromomethyl-4-iodo-benzene (10.00 g, 33.7 mmol) to a solution of l-(3-chloro-2,4-dihydroxy-phenyl)-ethauone (7.92 'g, 42.4 mmol) and cesium carbonate (16.6 g, 50.9 mmol) in dimethylfonuamide (250 mL) and stir. After 18 hours, pour reaction into water and extract with ethyl acetate. Combine organic layers and wash with 2N NaOH. Dry with sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with a gradient of ethyl acetate.-hexanes to yield the title product as a tan solid(4.00 g, 23%): !H NMR (DMSO-d6) 5 2.62 (s, 3H), 5.33 (s, 2H), 6.87 (d, 1H), 7.27 (d, 2H), 7.78 (d, 2H), 7.94 (d, 1H), 13.13 (s,lH). Preparation 147 Synthesis of 2-chloro-l-(4-iodo-benzyloxy)-3-trimethylsilanyloxy-4-(l-trimethy]- silanyloxy-vinyl)-benzene. Add sodium hexamethyldisilazide (1M solution in tetrahydrofuran, 21.9 mL, 21.9 mmol) to a solution of l-[3-chloro-2-hydroxy-4-(4-iodo-benzyloxy)-phenyl]-ethanone (4.00 g, 9.94 mmol) in tetrahydrofuran(100 ml.) chilled to -78 °C. After 1 hour, add trimethylsilyl chloride (3.24 g, 29.8 mmol). After 1 hour, warm reaction to room temperature and stir overnight. Pour reaction into saturated sodium bicarbonate and extract with ethyl acetate. Combine organic layers,'dry with sodium sulfate, filter, and concentrate. Dry in vacuo overnight to yield the title product as a dark yellow oil (5.30 g, 98%): 'H NMR (CDC13) 5 0.21 (s, 9H), 0.28 (s, 9H), 4.55 (s, 1H), 4.79 (s, 1H), 5.08 (s, 2H), 6.56 (d, 1H), 7.22 (m, 3H), 7.71 (d, 2H) Preparation 148 Synthesis of 3-(tert-butyl-dimethyl-silanyloxymethyl)-benzonitrile. Add tert-butyl-chloro-dimcthyl-silane (11.9 g, 78.9 mmol) to a solution of 3-hydroxymethyl-benzonitrile (10.00 g, 75.10 mmol) and imidazole (6.14 g, 90.1 mmol) in dichloromethane (1 L) and stir. After 18 hours, pour reaction into 1% hydrochloric acid. Remove organic layer, dry with sodium sulfate, filter, and concentrate under WO 2006/057860 PCT/US2005/041367 136 reduced pressure to yield the title product as a clear yellow oil (18.5 g, 99%): *H NMR (CDC13) 5 0.12 (s, 6H), 0.95 (s, 9H), 4.75 (s, 2H), 7.43 (t, 1H), 7.53 (d, 2H), 7.63 (s, III). Preparation 149 Synthesis of [3-(2-oxo-2,3-dihydro-2λ4-[1,2,3,5Joxathiadiazol-4-yl)-phenyl]-methanol. Add hydroxylamine (50% aqueous solution, 5.34 g, 80.8 mmol) dropwise to a refluxing solution of 3-(tert-butyl-dimethyl-silanyloxymethyl)-benzonitrile(5.00 g, 20.2 mmol) in isopropanol (0.1 M). After 2 hours, concentrate the reaction under reduced pressure and azeotrope with toluene. Add dichloromethane (0.1 M) and pyridine (1.92 g, 24.3 mmol) and cool reaction to -78 °C. Add thionyl chloride (2.64 g, 22.2 mmol) via syringe. After 4 hours, warm the reaction to room temperature. Concentrate the reaction under reduced pressure. Add tetrahydrofuran (0.1M) and 10% hydrochloric acid (0.1M) and stir. After 18 hours, add brine and extract with 25% isopropyl alcohol:75% dichloromethane. Combine organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to yield the title product as a yellow solid (3.90 g, 91%): *H NMR (DMSO-d6) 8 4.63 (s, 2H), 5.42 (bs, 1H), 7.59 (m, 2H), 7.75 (dt, 1H), 7.88 (s, 1H), 12.23 (bs, 1H). Preparation 150 Synthesis is of l-[3-chloro-2-hydroxy-4-(3-iodo-benzyloxy)-phenyl]-ethanone. Add triphenylphosphine (13.6 g, 51.7 mmol) and DIAD (10.5 g, 51.7 mmol) to a solution of (3-iodo-phenyl)-rnethanol (11.0 g, 47.0 mmol) and l-(3-Chloro-2,4-di- hydroxyphenyl)-ethanone (8.77 g, 47.0 mmol) in dichloromethane:tetrahydrofuran (250 ml:250 ml) and stir. After 18 hours, concentrate the reaction, and load directly onto silica. Purify the residue by flash chromatography eluting with acetone:hexanes to yield the title product as a white solid (12.2 g, 64%): 'H NMR (DMSO-d6) 6 2.62 (s, 3H), 5.34 (s, 2H), 6.88 (d, 1H), 7.23 (t, 1H), 7.48 (d, 1H), 7.72 (d, 1H), 7.87 (s, 1H), 7.96 (d, 1H), 13.14 (s,lH) Preparation 151 Synthesis of 2-chloro-l-(3-iodo-benzyIoxy)-3-trimethylsilanyloxy-4-(l-trimethyl- silanyloxy-vinyl)-benzene. Add sodium hexamethyldisilazide (1 M solution in tetrahydrofuran, 20.2 ml, 20.2 mmol) to a solution of l-[3-chloro-2-hydroxy-4-(4-iodo-benzyloxy)-phenyl]-ethanone (3.70 g, 9.19 mmol) in tetrahydrofuran (100 mL) chilled to -78 °C. After 1 hour, add WO 2006/057860 PCT/US2005/041367 137 trimethylsilyl chloride (3.00 g, 27.6 mmol). After i hour, warm reaction to room temperature and stir overnight. Pour reaction into saturated sodium bicarbonate and extract with ethyl acetate. Combine organic layers, dry with sodium sulfate, filter, and concentrate. Dry on high-vac overnight to yield the title product as a dark yellow oil (5.0 g, 99%): 1H NMR (CDC13) 6 0.21 (s, 9K), 0.28 (s, 9H), 4.55 (d, 1H), 4.79 (d, 1H), 5.08 (s, 2H), 6.56 (d, 1H), 7.12 (t, 1H), 7.24 (d, 1H), 7.42 (d, 1H), 7.65 (d, 1H), 7.82 (s, 1H) Preparation 152 Synthesis of 2-hydroxymethyl-isonicotinonitrile. Add ammonium persultate (70.1 g, 307 mmol) to a solution of isonicotinonitrile (16.00 g, 154 mmol) in methanol:water:sulfuric acid (275 mL:135 mL:l 1 mL). Heat solution to reflux. After 24 hours, pour reaction onto ice and neutralize with ammonium hydroxide (70 ml). Extract solution with chloroform (3x600 ml). Combine the organic layers, dry with sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with acetone:dichloromethane (1:6) to yield the title compound as a white solid (5.86 g, 28%): 'H NMR (CDCI3) 5 3.17 (t, 1H), 4.84 (d, 1H), 7.45 (m, 1H), 7.58 (s, 1H), 8.74 (d, 1H) Preparation 153 Synthesis of 5-(3-(hydroxymetl)yl)phenylthio)nicotinonitrile. Add K2CO3 (6.91 g, 50.0 mmol) to a solution of (3-mercaptophenyl)methanol (2.94 g, 21.0 mmol) and 5-bromonicotinonitrile (3.66 g, 20.0 mmol) in DMA (100 mL). Heat the mixture at 110 °C for 2 h. Cool to room temperature. Dilute with EtOAc. Filter. Wash the residue with EtOAc. Concentrate. Dissolve the residue in EtOAc and filter. Concentrate to afford the title compound (4.80 g, quant.): [H NMR (CDC13) 5 2.20 (t, J- 5.5 Hz, 1 H), 4.74 (d, J= 5.5 Hz, 2 H), 7.38-7.44 (m, 3 H), 7.52-7.53 (m, 1 H), 7.62 (dd, J™ 2.0, 2.3 Hz, 1 H), 8.62 (dd, J= 2.0,2.3 Hz, 2 H). Preparation 154 Synthesis of 5-(4-(hydroxymethyl)phenylthio)nicotinonitrile. Using the method of Preparation 153 using (4-mercaptophenyl)methanol (4.42 g, 31.5 mmol) and 5-bromonicotinonitrile (5.49 g, 30.0 mmol) affords the title compound (3.60 g, 50%): :H NMR (CDC13) 5 1.92 (t, J= 5.9 Hz, 1 H), 4.77 (d, J= 5.9 Hz, 2 H), 7.48 (q, J= 8.2 Hz, 4 H), 7.58 (t, J= 2.0 Hz, 1 H), 8.61 (dd, J= 2.0, 3.1 Hz, 2 H). WO 2006/057860 PCT/US2005/041367 138 Preparation 155 Synthesis of 5-(3-(Hydroxymethyl)phenylthio)picolinonitrile. Add NaHCO3 (12.0 g, 143 mmol) to a solution of (3-mercaptophenyl)methanol (10.0 g, 71.3 mmol) and 5-bromopicolinonitrile (13.0 g, 71.3 mmol) in DMF. Heat the mixture overnight. Dilute with ethyl acetate. Wash the mixture with water. Dry, filter and concentrate to afford the title compound (10.1 g, 59%) (Solidifies after standing). MS (APCI-pos) m/z (rel intensity): 243 (M+H, 100%). Preparation 156 Synthesis of 5-(4-(hydroxymethyl)phenylthio)picolinonitrile. Using the method of Preparation 155 using (4-mercaptophenyl)methanol (10.0 g, 71.3 mmol) and 5-bromopicolinonitrile (13.0 g, 71.3 mmol) affords the title compound (4.90 g, 28%).): 243 (M+H, 100%). Preparation 157 Synthesis of 6-(3-(hydroxymethyl)phenylthio)nicotinonitrile. Using the method of Preparation 155 using (3-mercaptophenyl)methanol (10.0 g, 71.3 mmol) and 6-chloronicotinonitrile (19.8 g, 142.7 mmol) affords the title compound (13.1 g, 76%): 243 (M+H, 100%). Preparation 158 Synthesis of 2-(3-(hydroxymethyl)phenylthio)isonicotinonitrile. Using the method of Preparation 155 using (3-mercaptophenyl)methanol (6.00 g, 42.8 mmol) and 2-chloroisonicotinonitrile (5.65 g, 40.8 mmol) affords the title compound (6.22 g, 63%): 243 (M+H, 100%). Preparation 159 Synthesis of 6-(4-(hydroxymethyl)phenyIthio)isonicotinonitrile. Using the method of Preparation 155 using (4-mercaptophenyl)methanol (6.00 g, 42.8 mmol) and 6-chloronicotinonitrile (5.65 g, 40.8 mmol) affords the title compound (7.24 g, 73%): 243 (M+H, 100%). Preparation 160 Synthesis of 5-(3-((4-acetyl-3-hydroxy-2-methylphenoxy)methyl)phenylthio)- nicotinonitrile. WO 2006/057860 PCT/US2005/041367 139 Add triphenylphosphine (5.24 g, 20.0 mmol) and diisopropylazodicarboxylate (4.04 g, 20.0 mmol) to a solution of 5-(3-(hydroxymethyl)phenylthio)nicotinonitrile (4.84 g, 20.0 mmol) and l-(2,4-dihydroxy-3-methylphenyl)ethanone (3.32 g, 20.0 mmol) in THF(l00mL). Stir the reaction for 24 h. Quench the reaction with water and extract with EtOAc. Dry, filter and concentrate. Purify the residue by flash chromatography on silica gel eluting with a mixture of EtOAc and hexanes (15:85 to 20:80) to give an off- white solid. Recrystallize the solid from a mixture of EtOAc and hexanes to afford the title compound (3.94 g, 50%): lH NMR (CDC13) 5 2.14 (s, 3 H), 2.57 (s, 3 H), 5.18 (s, 2 H), 6.44 (d, J= 9.0 Hz, 1 H), 7.46-7.49 (m, 3 H), 7.52 (s, 1 H), 7.59 (d, J= 9.0 Hz, 1 H), 7.62-7.63 (m, 1 H), 8.63-8.64 (m, 2 H), 12.78 (s, 1 H). Preparation 161 Synthesis of 5-(3-((4-acetyl-3-hydroxy-2-propylphenoxy)methyl)phenylthio)- nicotinonitrile. Using the method of Preparation 160 using 5-(3-(hydroxymethyl)phenylthio) nicotinonitrile (3.90 g, 16.1 mmol) and l-(2,4-dihydroxy-3-propylphenyl)ethanone (3.13 g, 16.1 mmol) affords the title compound (4.80 g, 71%): ]H NMR (CDC13) 5 0.92 (t, J= 7.2 Hz, 3 H), 1.50-1.59 (m, 2 H), 2.57 (s, 3 H), 2.68 (t, J= 7.6 Hz, 2 H), 5.18 (s, 2 H), 6.43 (d, J = 9.0 Hz, 1 H), 7.44-7.49 (m, 3 H), 7.53 (s, 1 H), 7.59 (d, J= 9.0 Hz, 1 H), 7.62 (dd, 7= 1.6, 2.3 Hz, 1 H), 8.63 (dd, J= 1.6,2.3 Hz, 2 H), 12.75 (s, 1 H). Preparation 162 Synthesis of 5-(3-((4-acetyl-2-ethyl-3-hydroxyphenoxy)methyl)phenylthio)- nicotinonitrile. Using the method of Preparation 160 using 5-(3-(hydroxymethyl)phenylthio) nicotinonitrile (3.90 g, 16.1 mmol) and l-(3-ethyl-2,4-dihydroxyphenyl)ethanone (2.90 g, 16.1 mmol) affords the title compound (2.20 g, 34%): 1HNMR (CDC13) 5 1.10 (t, J- 7.4 Hz, 3 H), 2.57 (s, 3 H), 2.71 (q, J= 7.4 Hz, 2 H), 5.18 (s, 2 H), 6.43 (d, J= 9.0 Hz, 1 H), 7.44.7.49 (m, 3 H), 7.51 (s, 1 H), 7.59 (d, J= 9.0 Hz, 1 H), 7.63 (dd, J= 2.0,2.3 Hz, 1 H), 8.64 (t, J = 2.0 Hz, 2 H), 12.75 (s, 1 H). WO 2006/057860 PCT/US2005/041367 140 Preparation 163 Synthesis of 5-(4-((4-acetyl-3-hydroxy-2-memylphenoxy)methyl)phenylthio)- nicotinonitrile. Using the method of Preparation 160 using 5-(4-(hydroxymethyl)phenylthio) nicotinonitrile (1.20 g, 4.95 mmol) and l-(2,4-dihydroxy-3-raethylphenyl)ethanone (0.86 g, 5.20 mmol) affords the title compound (787 mg, 41%): 1H NMR (d6-DMSO) 5 2.06 (s, 3 H), 2.58 (s, 3 H), 5.30 (s, 2 H), 6.72 (d, J= 9.0 Hz, 1 H), 7.51-7.55 (m, 4 H), 7.81 (d, J = 9.0 Hz, 1 H), 8.23 (t, J= 2.0 Hz, 1 H), 8.72 (d, J = 2.0 Hz, 2 H), 8.91 (d, J = 2.0 Hz, 1 H), 12.85 (s, 1 H). Preparation 164 Synthesis of 5-(4-((4-acetyl-3-hydroxy-2-propylphenoxy)methyl)phenylthio)- nicotinonitrile. Using the method of Preparation 160 using 5-(4-(hydroxymethyl)phenylthio) nicotinonitrile (1.20 g, 4.95 mmol) and l-(2,4-dihydroxy-3-propylphenyl)ethanone (1.01 g, 5.20 mmol) affords the title compound. MS (APCI-neg) m/z (rel intensity): 417 (M-H, 100%). Preparation 165 Synthesis of 5-(4-((4-acetyl-2-ethyl-3-hydroxyphenoxy)methyl)phenylthio)- nicotinonitrile. Using the method of Preparation 160 using 5-(4-(hydroxymethyl)phenylthio) nicotinonitrile (1.20 g, 4.95 mmol) and l-(3-ethyl-2,4-dihydroxyphenyl)ethanone (937 mg, 5.20 mmol) affords the title compound (750 mg, 37%): 'H NMR (CDC13) S 1.15 (t, J = 7.64 Hz, 3 II), 2.57 (s, 3 H), 2.76 (q, J= 7.6 Hz, 2 H), 5.22 (s, 2 H), 6A1 (d, J= 9.0 Hz, 1 H), 7.49 (d, J = 8.2 Hz, 2 H),), 7.52 (d, J= 8.2 Hz, 2 H), 7.60 (d, J- 9.0 Hz, 1 H), 7.63 (dd, ./= 2.0, 2.3 Hz, 1 H), 8.64 (t, J= 2.0 Hz, 2 H), 12.75 (s, 1 H). Preparation 166 Synthesis of 5-(3-((4-acetyl-3-hydroxy-2-methylphenoxy)methyl)phenylthio) picolinonitrile. WO 2006/057860 PCT/US2005/041367 141 Add triphenylphosphine (1.84 g, 7.02 mmol) and diisopropylazodicarboxylate (1.42 g, 7.02 mmol) to a solution of 5-(3-(hydroxymemyl)phenylthio)picolinonitrile (1.70 g, 7.02 mmol) and l-(2,4-dihydroxy-3-methylphenyl)ethanone (1.17 g, 7.02 mmol) in THF (35.1 mL). Stir overnight. Dilute with ethyl acetate. Wash the mixture with water and brine. Dry, iilter and concentrate to afford the'title compound (2.00 g, 73%). Use as is. MS (APCI-neg) m/z (rel intensity): 390 (M+H, 100%). Preparation 167 Synthesis of 5-(3-((4-acetyl-2-ethyl-3-hydroxypherioxy)methyl)phenylthio) picolinonitrile. Using the method of Preparation 166 using 5-(3-(hydroxymethyl)phenylthio) picolinonitrile (1.70 g, 7.02 mmol) and l-(3-ethyl-2,4-dihydroxyphenyl)ethanone (1.26 g, 7.02 mmol) affords the title compound (2.20 g, 78%). MS (APCI-neg) m/z (rel intensity): 403 (M-H, 100%). Preparation 168 Synthesis of 5-(3-((4-acetyl-3-hydroxy-2-propylphenoxy)methyl)phenylthio) picolinonitrile. Using the method of Preparation 166 using 5-(3-(hydroxymethyl)phenylthio) picolinonitrile (1.70 g, 7.02 mmol) and l-(2,4-dihydroxy-3-propyIphenyl)ethanone (1.36 g, 7.02 mmol) affords the title compound (1.25 g, 43%). MS (APCI-neg) m/z (rel intensity): 417 (M-H, 100%). Preparation 169 Synthesis of 5-(4-((4-Acetyl-3-hydroxy-2-methylphenoxy)methyI)phenylthio) picolinonitrile. Using the method of Preparation 166 using 5-(4-(hydroxymethyl)phenylthio) picolinonitrile (1.90 g, 7.84 mmol) and l-(2,4-dihydroxy-3-methylphenyl)ethanone (1.30 g, 7.84 mmol) affords the title compound (1.98 g, 65%). MS (APCI-neg) m/z (rel intensity): 389 (M-H, 100%). Preparation 170 Synthesis of 6-(3-((4-aceryl-3-hydroxy-2-propylphenoxy)methyl)phenylthio) nicotinonitrile. WO 2006/057860 PCT/US2005/041367 142 Using the method of Preparation 166 using 6-(3-(hydroxymethyl)phenylthio) nicotinonitrile (1.25 g, 5.15 mmol) and l-(2,4-dihydroxy-3-propylphenyl)ethanone (1.00 g, 5.15 mmol) affords the title compound (3.00 g). MS (APCI-neg) m/z (rel intensity): 417(M-H, 100%). Preparation 171 Synthesis of 6-(3-((4-acetyl-3-hydroxy-2-methylphenoxy)methyl)phenylthio) nicotinonitrile. Using the method of Preparation 166 using 6-(3-(hydroxymethyl)phenylthio) nicotinonitrile (1.46 g, 6.02 mmol) and l-(2,4-dihydroxy-3-methylphenyl)ethanone (1.00 g, 6.02 mmol) affords the title compound (3.00 g). MS (APCI-neg) m/z (rel intensity): 389 (M-H, 100%). Preparation 172 Synthesis of 2-(3-((4-acetyl-3-hydroxy-2-methylphenoxy)methyl)phenylthio) isonicotinonitrile. Using the method of Preparation 166 using 2-(3-(hydroxymethyl)phenylthio) isonicotinonitrile (1.46 g, 6.02 mmol) and l-(2,4-dihydroxy-3-methylphenyl)ethanone (1.00 g, 6.02 mmol) affords the title compound (1.22 g, 52%). MS (APCI-neg) m/z (rel intensity): 389 (M-H, 100%). Preparation 173 Synthesis of 2-(3-((4-acetyl-3-hydroxy-2-propylphenoxy)methyl)phenylthio) isonicotinonitrile. Using the method of Preparation 166 using 2-(3-(hydroxymethyl)phenylthio) isonicotinonitrile (1.25 g, 5.15 mmol) and l-(2,4-dihydroxy-3-propylphenyl)ethanone (1.00 g, 5.15 mmol) affords the title compound (1.75 g, 81%). MS (APCI-neg) m/z (rel intensity): 417 (M-H, 100%). Preparation 174 Synthesis of 6-(3-((4-acetyl-2-ethyl-3-hydroxyphenoxy)methyl)phenylthio) isonicotinonitrile. Using the method of Preparation 166 using 6-(3-(hydroxymethyl)phenylthio) isonicotinonitrile (1.35 g, 5.56 rnmol) and l-(3-ethyl-2,4-dihydroxyphenyl)ethanone (1.00 g, 5.56 mmol) affords the title compound (1.80 g, 80%). MS (APCI-neg) m/z (rel intensity): 403 (M-H, 100%). WO 2006/057860 PCT/US2005/041367 Preparation 175 Synthesis of 6-(4-((4-acetyl-3-hydroxy-2-raethylphenoxy)methyl)phenylthio) isonicotinonitrile. Using the method of Preparation 166 using 6-(4-(hydroxymethyl)phenyltliio) isonicotinonitrile (1.10 g, 4.54 mmol) and l-(2,4-dihydroxy~3-methylphenyl)ethanone (754 rag, 4.54 mmol) affords the title compound (1.23 g, 69%). MS (APCI-neg) m/z (rel intensity): 389 (M-H, 100%). Preparation 176 Synthesis of 6-(4-((4-acetyl-2-ethyl-3 -hydroxyphenoxy)methyl)phenylthio) isonicotinonitrile. Using the method of Preparation 166 using 6-(4-(hydroxymethyl)phenylthio) isonicotinonitrile (1.10 g, 4.54 mmol) and l-(3-ethyl-2,4-dihydroxyphenyl)ethanone (818 mg, 4.54 mmol) affords the title compound (1.84 g, quant.). MS (APCI-neg) m/z (rel intensity): 403 (M-H, 100%). Preparation 177 Synthesis of 6-(4-((4-acetyl-3-hydroxy-2-propylphenoxy)methyl)phenylthio) isonicotinonitrile. Using the method of Preparation 166 using 6-(4-(hydroxymethyl)phenylthio) isonicotinonitrile (1.00 g, 4.13 mmol) and l-(3-ethyl-2,4-dihydroxyphenyl)ethanone (802 mg, 4.13 mmol) affords the title compound (1.50 g,, 87%). MS (APCI-neg) m/z (rel intensity): 417 (M-H, 100%). Example 71 Synthesis of 5-(3-((4-acetyl-3-hydroxy-2-methylphenoxy)methyl)phenylthio)nicotinic acid. Add LiOH monohydrate (1.29 g, 30.7 mmol) to a solution of 5-(3-((4-acetyl-3- hydroxy-2-methylphenoxy)methyl)phenylthio)nicotinonitrile (1.20 g, 3.07 mmol) in a mixture of dioxane (30 mL) and water (15 mL). Heat the mixture at reflux for 2.5 h. Cool to room temperature. Add 17 mL of 2.0 M HC1 aq. solution (pH 2-3). Extract with WO 2006/057860 PCT/US2005/041367 144 EtOAc. Dry, filter and concentrate. Add EtOAc (30 mL) and CH2C12 (15 mL) to the white solid. Sonicate for 2 min. Filter to afford the title compound (1.25 g, 99%): 'H NMR (de-DMSO) 5 1.96 (s, 3 H), 2.58 (s, 3 H), 5.26 (s, 2 H), 6.68 (d, J= 9.0 Hz, 1 H), 7.42-7.50 (m, 4 H), 7.78 (d, J= 9.0 Hz, 1 H), 8.06 (t, /= 2.0 Hz, 1 H), 8.74 (d, J= 2.3 Hz, 1 H), 8.95 (d, 7= 1.6 Hz, 1 H), 12.83 (s, 1 H), 13.62 (s, 1 H); MS (APCI-neg mode) m/z (rel intensity): 408 (M-H, 100%). Example 72 Synthesis of 5-(3-((4-acetyl-3-b.ydroxy-2-propylphenoxy)methyl)phenylthio)m'cotinic acid. Using the method of Example 71 using 5-(3--((4-acetyl-3-hydroxy-2- propylphenoxy) methyl)phenylthio)nicotinonitrile (1.29 g, 3.08 mmol) affords the title compound (1.35 g, quant.): 1H NMR (CDC13) 8 0.91 (t, J= 7.4 Hz, 3 H), 1.48-1.58 (m, 2 H), 2.55 (s, 3 H), 2.65 (t, /= 7.6 Hz, 2 H), 5.15 (s, 2 H), 6.42 (d, J= 9.0 Hz, 1 H), 7.39- 7.42 (m, 3 H), 7.46 (s, 1 H), 7.56 (d, 7= 9.0 Hz, 1 H), 8.22 (dd, J= 2.0, 2.3 Hz, 1 H), 8.71 (d, J= 2.3 Hz, 1 H), 9.10 (d, J= 2.0 Hz, 1 H), 12.73 (s, 1 H); MS (APCI-neg mode) m/z (rel intensity): 436 (M-H, 100%). Example 73 Synthesis of 5-(3-((4-acetyl-2-ethyl-3-hydroxyphenoxy)methyl)phenylthio)nicotinic acid. Using the method of Example 71 using 5-(3-((4-acetyl-2-ethyl-3- hydroxyphenoxy) methyl)phenylthio)nicotinonitrile (1.02 g, 2.52 mmol) affords the title compound (1.04 g, 97%): [H NMR (CDCI3) 5 1.08 (t, /= 7.4 Hz, 3 H), 2.56 (s, 3 H), 2.69 (q. J= 7.4 Hz, 2 H), 5.15 (s, 2 H), 6.42 (d, J= 9.0 Hz, 1 H), 7.39-7.42 (m, 3 H), 7.44 (s, 1 H), 7.56 (d, J= 9.0 Hz, 1 H), 8.21 (dd, J = 2.0,2.3 Hz, 1 H), 8.71 (d, J= 2.3 Hz, 1 H), WO 2006/057860 PCT/US2005/041367 145 9.09 (d, J = 2.0 Hz, 1 H), 12.73 (s, 1 H); MS (APCI-neg mode) m/z (rel intensity): 422 (M-H, 100%). Example 74 Synthesis of 5-(4-((4-acetyl-3-hydroxy-2-methylphenoxy)methyl)phenylthio)nicotinic acid. Using the method of Example 71 using 5-(4-((4-acetyl-3-hydroxy-2- methylphenoxy) methyl)phenylthio)nicotinonitrile (787 mg, 2.02 mmol) affords the title compound (790 mg, 96%): JH NMR (d6-DMSO) 8 2.05 (s, 3 H), 2.58 (s, 3 H), 5.30 (s, 2 H), 6.72 (d, J= 9.0 Hz, 1 H), 7.50-7.55 (m, 4 H), 7:81 (d, /= 9.0 Hz, 1 H), 8.02 (dd, J= 2.0,2.3 Hz, 1 H), 8.73 (d, J= 2.3 Hz, 1 H), 8.93 (d,7= 2.0 Hz, 1 H), 12.85 (s, 1 H), 13.61 (s, 1 H); MS (APCI-neg mode) m/z (rel intensity): 408 (M-H, 100%). Example 75 Synthesis of 5-(4-((4-acetyl-3-hydroxy-2-propylphenoxy)methyl)phenylthio)nicotinic acid. Using the method of Example 71 using 5-(4-((4-acetyl-3-hydroxy-2- propylphenoxy) methyl)phenylthio)nicotinonitrile (2.0 g) affords the title compound (134 mg, 6% (over 2 steps)): 'H NMR (CDC13) 8 0.95 (t, ./= 7.2 Hz, 3 H), 1.53-1.63 (m, 2 H), 2.56 (s, 3 H), 2.70 (t, /= 7.6 Hz, 2 H), 5.17 (s, 2 H),| 6.46 (d, J= 9.0 Hz, 1 H), 7.45 (q, J = 8.6 Hz, 4 H), 7.58 (d, /= 9.0 Hz, 1 H), 8.22 (dd, J= 2.0, 2.3 Hz, 1 H), 8.70 (d, J= 2.3 Hz, 1 H), 9.10 (d, 7= 2.0 Hz;, 1 H), 12.75 (s, 1 H); MS (APCI-neg mode) m/z (rel intensity): 436 (M-H, 100%). Example 76 Synthesis of 5-(4-((4-acetyl-2-ethyl-3-hydroxyphenoxy)methyl)phenylthio)nicotinic acid. WO 2006/057860 PCT/US2005/041367 146 Using the method of Example 71 using 5-(4-((4-acetyl-2-ethyl-3- hydroxyphenoxy) methyl)phenylthio)nicotinonitrile (750 mg, 1.85 mmol) affords the title compound (350 mg, 45%): 1H NMR (d6-DMSO) S 1.04 (t, J= 7.4 Hz, 3 H), 2.58 (s, 3 H), 2.62 (q, J= 7.4 Hz, 2 H), 5.30 (s, 2 H), 6.72 (d, J = 9.0 Hz, 1 H), 7.52 (s, 4 H), 7.81 (d,./--- 9.0 Hz, 1 H), 8.03 (dd, J= 2.0, 2.3 Hz, 1 H), 8.73 (d, J= 2.3 Hz, 1 H), 8.93 (d, J = 2.0 Hz, 1 H), 12.84 (s, 1 H); MS (A?CI-neg mode) m/z (rel intensity): 422 (M-H, 100%). Example 77 Synthesis of 5-(3-((4-acetyl-3-hydroxy-2-methylphenoxy)methyl)phenylthio)picolinic acid. Using the method of Example 71 using 5-(3-((4-acetyl-3-hydroxy-2- methylphenoxy)methyl)phenylthio)picolinonitrile (2.70 g, 6.92 mmol) affords the title compound (mg, %): !H NMR (dg-DMSO) 5 1.98 (s, 3H), 2.58 (s, 3H), 5.27 (s, 2H), 6.69 (d, J= 9.0 Hz, 1H), 7.41 (m, 1H), 7.48 (m, 3H), 7.73 (m, 1H), 7.80 (d, J= 9.0 Hz, 1H), 7.94 (d, J= 8.2 Hz, 1H), 8.48 (s, 1H), 12.85 (s, 1H); MS (APCI-neg mode) m/z (rel intensity): 408 (M-H, 100%). Example 78 Synthesis of 5-(3-((4-acetyl-2- ethyl-3-hydroxyphenoxy)methyl)phenylthio)picolinic acid. Using the method of Example 71 using 5-(3-((4-acstyl-2-ethyl-3-hydroxy- phenoxy)methyl)phenylthio)picolinonitrile (2.8 g, 6.9 mmol) affords the title compound (2.11 g, 72 %): 'H NMR (ds-DMSO) 8 0.96 (t, J= 7.2 Hz, 3H), 2.54 (q, J= 7.4 Hz, 2H), 2.57 (s, 3H), 5.29 (s, 2H), 6.68 (d, /= 9.0 Hz, 1H), 7.50-7.53 (m, 4H), 7.72 (m, 1H), 7.80 WO 2006/057860 PCT/US2005/041367 147 (d, J= 9.0 Hz, 1H), 7.95 (d, 7= 8.2 Hz, 1H), 8.55 (d, J= 2.3 Hz, 1H), 12.83 (s, 1H); MS (APCI-neg mode) m/z (rel intensity): 422 (M-H, 100%). Example 79 Synthesis of 5-(3-((4-acetyl-3-hydroxy-2-propylphenoxy)methyl)phenyltliio)picolinic acid, Using the method of Example 71 using 5-(3-((4-acetyl-3-hydroxy-2- propylphenoxy)methyl)phenylthio)picolinonitrile (2.90 g, 6.93 mmol) affords the title compound (1.97 g, 65%): 'H NMR (d6-DMSO) 5 0.80 (t, J= 7.2 Hz, 3H), 1.46-1.37 (m, 2H), 2.53-2.55 (m, 2H) 2.58 (s, 3H), 5.28 (s, 2H), 6.69 (d, ./= 9.0 Hz, 1H), 7.44-7.56 (m, 4H), 7.71 (m, 1H), 7.80 (d, J= 9.0 Hz, 1H), 7.93 (d, J= 8.6 Hz, 1H), 8.53 (s, 1H), 12.84 (s, 1H); MS (APCI-neg mode) m/z (rel intensity): 436 (M-H, 100%). Example 80 Synthesis of 5 -(4-((4-acetyl-3 -hydroxy-2-methylphenoxy)methyl)phenylthio)picolinic acid. Using the method of Example 71 using 5-(4-((4-acetyl-3-hydroxy-2- methylphenoxy)-methyl)phenylthio)picolinonitrile (3.0 g, 7.7 mmol) affords the title compound (2.25 g, 72%): 'H NMR (dfi-DMSO) S 2;06 (s, 3H), 2.59 (s, 3H), 5.32 (s, 2H), 6.74 (d, J= 9.0 Hz, 1H), 7.56 (s, 4H), 7.70 (m, 1H), 7.82 (d, J= 9.0 Hz, 1H), 7.97 (d, J= 8.2 Hz, 1H), 8.52 (m 1H), 12.85 (s, 1H); MS (APCI-neg mode) m/z (rel intensity): 408 (M-H, 100%). Example 81 Synthesis of 6-(3 -((4-acety 1-3 -hydroxy-2-propylphenoxy)methyl)phenylthio)nicotinic acid. WO 2006/057860 PCT/US2005/041367 148 Using the method of Example 71 using 6-(3-((4-acetyl-3-hydroxy-2- propylphenoxy)methyl)phenylthio)nicotinonitiile (2.16 g, 5.15 mmol) affords the title compound (700 mg, 31%): lH NMR (d6-DMSO) 5 0.83 (t, J = 7.4 Hz, 3H), 1.46 (q, J = 9.9 Hz, 2H), 2.52 (s, 3H), 2.62 (t, J= 7.4 Hz, 2H), 5.30 (s, 2H), 6.68 (d, J= 9.0 Hz, 1H), 6.91 (d, J= 8.6 Hz, 1H), 7.57 (s, 3H), 7.61 (m, 1H), 7.68 (s, 1H), 7.99 (q, y = 6.9 Hz, 1H), 8.82 (s, 1H), 13.8 (s, 1H). Example 82 Synthesis of 2-(3 -((4-acety 1-3 -hydroxy-2 -methylphenoxy)methyl)phenylthio)iiicotinic acid. Using the method of Example 71 using 2-(3-((4-acetyl-3-hydroxy-2- methylphenoxy) methyl)phenylthio)nicotinonitrile (2.35 g, 6.02 mmol) affords the title compound (80 mg, 3%): 1H NMR (d6-DMSO) 5 2.08 (s, 3H), 2.52 (s, 3H), 5.33 (s, 2H), 6.68 (d, J = 9.0 Hz, 1H), 6.85 (d, J= 8.2 Hz, 1H), 7.58-7.60 (m, 5H), 7.95 (q, /= 7.2 Hz, 1H), 8.79 (d, J= 2.0 Hz, 1H), 12.84 (s, 1H), 13.82 (s, 1H); MS (APCI-neg mode) m/z (rel intensity): 408 (M-H, 100%). Example 83 Synthesis of 6-(3-((4-acetyl-3-hydroxy-2-methylphenoxy)methyl)phenylthio)isonicotinic acid. Using the method of Example 71 using 6-(3-((4-acetyl-3-hydroxy-2- methylphenoxy)methyl)phenylthio)isonicotinonitrile (250 mg, 0.640 mmol) affords the WO 2006/057860 PCT/US2005/041367 149 title compound (60.5 mg, 23%): 'H NMR (d6-DMSO) 8 2.13 (s, 3H), 2.56 (s, 3H), 5.18 (s, 2H), 6.47 (d, J = 9.0 Hz, 1HJ, 7.49 (s, 2H), 7.55 (d, 7= 5.9 Hz, 2H), 7.58 (s, 2H), 7.65 (s, 1H), 8.59 (d, J= 5.1 Hz, 1H), 12.76 (s, 1H); MS (APCI-neg mode) m/z (rel intensity): 408 (M-H, 100%). Example 84 Synthesis of 6-(3-((4-acetyl-3-hydroxy-2-propylphenoxy)methyI)phenyIthio)isonicotinic acid. Using the method of Example 71 using 6-(3-((4-acetyl-3-hydroxy-2- propylphenoxy)methyl)phenylthio)isonicotlnonitrile (2.16 g, 5.15 mmol) affords the title compound (700 mg, 31%): 'H NMR (d6-DMSO) 5 0.78 (t, J= 7.4 Hz, 3H), 1.43 (m, 2H), 2.51 (s, 3H), 2.56 (t, 7= 8.4 Hz, 2H), 5.32 (s, 2H), 6.72 (d, J= 9.0 Hz, 1H), 7.35 (s, 1H), 7.57 (m, 4H), 7.70 (s, 1H), 7.81 (d, /= 9.0 Hz, 1H),8.59 (d, J= 5.1 Hz, 1H), 12.84 (s, 1H); MS (APCI-neg mode) m/z (rel intensity): 436 (M-H, 100%). Example 85 Synthesis of 6-(3 -((4-acetyl-2-ethyl-3 -hydroxyphenoxy)methyl)phenylthio)isonicotinic acid. Using the method of Example 71 using 6-(3-((4-acetyl-2-ethyl-3- hydroxyphenoxy)methyl)phenylthic)isonicotinonitrile (2.25 g, 5.55 mmol) affords the title compound (750 mg, 32%): lH NMR (d6-DMSO) 8 0.98 (t, J= 7.4 Hz, 3H), 2.50 (s, 3H), 2.57 (m, 2H), 5.32 (s, 2H), 6.71 (d, J= 9.0 Hz; 1H), 7.36 (s, 1H), 7.56 (m, 4H), 7.69 (s, 1H), 7.80 (d, J= 9.0 Hz, 1H), 8.59 (d, /= 5.1 Hz, 1H), 12.83 (s, 1H); MS (APCI-neg mode) m/z (rel intensity): 422 (M-H, 100%). WO 2006/057860 PCT/US2005/041367 150 Example 86 Synthesis of 6-(4-((4-acetyl-3-hydroxy-2-methylphenoxy)methyl)phenylthio)isonicotinic acid. Using the method of Example 71 using 6-(4-((4-acetyl-3-hydroxy-2- methylphenoxy) methyl)phenylthio)isonicotinonitrile (1.77 g, 4.54 mmol) affords the title compound (750 mg,-40%): !H NMR (d6-DMSO) 5 2.08 (s, 3H), 2.59 (s, 3H), 5.36 (s, 2H), 6.75 (d, J= 9.0 Hz, 1H), 7.35 (s, IK), 7.54 (m, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 7.83 (d, J= 9.0 Hz, 1H), 8.59 (d, J= 5.1 Hz, 1H), 12.86 (s, 1H); MS (APCI-neg mode) m/z (rel intensity): 408 (M-H, 100%). Example 87 Synthesis of 6-(4-((4-acetyl-2-ethyI-3-hydroxyphenoxy)methyl)phenylthio)isonicotinic acid. Using the method of Example 71 using 6-(4-((4-acetyl-2-ethyl-3- hydroxyphenoxy) methyl)pheuylthio)isonicotinonitrile (1.84 g, 4.54 mmol) affords the title compound (300 mg, 16%): 1H NMR (dg-DMSO) 5 1.07 (t, J= 7.4 Hz, 3H), 2.50 (s, 3H), 2.65 (q, J= 9.9 Hz, 2H), 5.36 (s, 2H), 6.74 (d, 7= 9.0 Hz, 1H), 7.35 (s, 1H), 7.55 (d, 7= 5.1 Hz, 1H), 7.59 (d, /= 8.2 Hz, 2H), 7.67 (d, J= 8.2 Hz, 2H), 7.82 (d, J= 9.0 Hz, 1H), 8.59 (d, J" = 5.1 Hz, 1H), 12.85 (s, 1H); MS (APCI-neg mode) m/z (rel intensity): 422 (M-H, 100%). Example 88 Synthesis of 6-(4-((4-acetyl-3-hydroxy-2-propylphenoxy)methyl)phenylthio)isonicotinic acid. WO 2006/057860 PCT/US2005/041367 151 Using the method of Example 71 using 6-(4-((4-acetyl-3-hydroxy-2-propyl- phenoxy) methyl)phenylthio)isonicotinonitrile (1.73 g, 4.13 mmol) affords the title compound (350 mg, 19%): 'H NMR (d6-DMSO) o 0.89 (t, J= 7.4 Hz, 3H), 1.51 (q, J= 9.9 Hz, 2H), 2.59 (s, 3H), 2.62 (t, J= 7.4 Hz, 2H), 5.35 (s, 2H), 6.74 (d, ./= 9.4 Hz, 1H), 7.35 (m, 2H), 7.58 (d,7= 8.2 Hz, 2H), 7.67 (d, J= 8.2 Hz, 2H), 7.83 (d, J= 9.0 Hz, III), 8.59 (d, J = 5.1 Hz, 1H), 12.86 (s, 1H); MS (APCI-neg mode) m/z (rel intensity): 436 (M- H, 100%). Example 89 Synthesis of 5-(3-((4-acetyl-3-hydroxy-2-methylpheuoxy)methyl)phenylsulfmyl)nicotinic acid. Add a 0.5 M solution of potassium peroxymonosulfate (0.61 g, 1.00 mmol) in water (2.0 mL) to a solution of 5-(3-((4-acetyl-3-hydroxy-2-methylphenoxy)methyl)- phenylthio)nicotinic acid (205 mg, 0.50 mmol) in methanol (7.5 mL) at 0 °C. Allow the solution to warm to room temperature and stir for 1.5 d. Add water and 2.2 mL of 2.0 M HC1 to the mixture. Extract the mixture with EtOAc. Dry, filter and concentrate. Recrystallize the residue from a mixture of CH2CI2 and hexanes to give a light yellow solid. Purify the yellow solid by flash chromatograhpy on silica gel eluting with a mixture of acetone, hexanes, and acetic acid (50:50:1 to 90:10) to afford the title compound (31 mg, 15%): lH NMR (ds-DMSO) 8 2.01 (s, 3 H), 2.58 (s, 3 H), 5.33 (s, 2 H), 6.67 (d, J= 9.0 Hz, 1 H), 7.61-7.63 (m, 2 H), 7.77 (d, 7= 9.0 Hz, 1 H), 7.81-7.83 (m, 1 H), 7.88 (s, 1 H), 8.49 (t, J= 2.0 Hz, 1 H), 9.08 (d, J= 2.0 Hz, 1 H), 9.12 (d, J= 2.0 Hz, 1 H), 12.84 (s, 1 H); MS (APCI-neg mode) m/z (rel intensity): 424 (M-H, 100%). WO 2006/057860 PCT/US2005/041367 152 Example 90 Synthesis of 5-(3-((4-acetyl-3-hydroxy-2-propylphenoxy)methyl)phenylsulfinyl)nicotinic acid. Using the method of Example 89 using 5-(3-((4-acetyl-3-hydroxy-2- propyl- phenoxy) methyl)phenylthio)nicotiiiic acid (219 mg, 0.50 mmol) affords the title compound (90 mg, 40%): *H NMR (CDC13) 5 0.93 (t,J= 7.2 Hz, 3 H), 1.50-1.60 (m, 2 H), 2.56 (s, 3 H), 2.67 (t, J= 7.6 Hz, 2 H), 5.20 (s, 2 H), 6.39 (d, J = 9.0 Hz, 1 H), 7.55 (d,y = 9.0 Hz, 1 H), 7.57-7.58 (m, 2 H), 7.69 (dt, .7= 1.6,4.3 Hz, 1 H), 7.76 (s, 1 H), 8.64 (t, J=2.0 Hz, 1 H), 8.99 (d, .7 = 2.0 Hz, 1 H), 9.32 (d, J- 2.0 Hz, 1 H), 12.73 (s, 1 H); MS (APCI-neg mode) m/z (rel intensity): 452 (M-H, 100%). Example 91 Synthesis of 5-(3-((4-acetyl-2-ethyl-3-hydroxyphenoxy)methyl)phenylsulfinyl)nicotinic acid. Using the method of Example 89 using 5-(3-((4-acetyl-2-ethyl-3-hydroxy- phenoxy) methyl)phenylthio)nicotinic acid (212 mg, 0.50 mmol) affords the title compound (50 mg, 23%): 1H NMR (ds-DMSO) 8 1.00 (t, J= 7.4 Hz, 3 H), 2.57 (s, 3 H), 2.57 (q, J= 7.4 Hz, 2 H), 5.33 (s, 2. H), 6.67 (d, J= 9.0 Hz, 1 H), 7.61-7.63 (m, 2 H), 7.76 (d, J= 9.4 Hz, 1 H), 7.82-7.85 (m, 1 H), 7.87 (s, 1 H), 8.48 (dd,7=2.0,2.3 Hz, 1 H),9.08 (d, J=2.3 Hz, 1 H), 9.11 (d,.7=2.0 Hz, 1 H), 12.83 (s, 1 H), 13.83 (s, 1 H);MS (APCI-neg mode) m/z (rel intensity): 438 (M-H, 100%). Example 92 Synthesis of 5-(4-((4-acetyl-3 -hydroxy-2-methylphenoxy)methyl)phenylsulfinyl)nicotinic acid. WO 2006/057860 PCT/US2005/041367 153 Using the method of Example 89 using 5-(4-((4-acetyl-3-hydroxy-2-methyl- phenoxy) methyl)phenylthio)nicotinic acid (205 mg, 0.50 mmol) affords the title compound (100 mg, 47%): 'H NMR (d6-DMSO) 5 2.04 (s, 3 H), 2.57 (s, 3 H), 5.32 (s, 2 H), 6.69 (d, J = 9.0 Hz, 1 H), 7.65 (d, J= 8.2 Hz, 2 H), 7.79 (d, J- 9.4 Hz, 1 H), 7.87 (d, J= 8.2 Hz, 2 H), 8.50 (dd, J= 2.0,2.3 Hz, 1 H), 9.12 (d, J= 2.3 Hz, 1 H), 9.13 (d, J= 2.0 Hz, 1 H), 12.84 (s. 1 ED; MS (APCI-neg mode) m/z (rel intensity): 424 (M-H, 100%). Example 93 Synthesis of 5-(4-((4-acetyl-2-ethyl-3 -hydroxyphenoxy)methyl)phenylsulfinyl)nicotinic acid. Using the method of Example 89 using 5-(4-((4-acetyl-2-ethyl-3- hydroxyphenoxy) methyl)phenylthio)nicotinic acid (126 mg, 0.30 mmol) affords the title compound (20 mg, 15%): lH NMR (d6-DMSO) 5 1.03 (t, J= 7.4 Hz, 3 H), 2.56 (s, 3 H), 2.62 (q, J= 7.4 Hz, 2 H), 5.32 (s, 2 H), 6.69 (d, J= 9.0 Hz, 1 H), 7.64 (d, J= 8.6 Hz, 2 H), 7.79 (d, J= 9.0 Hz, 1 H), 7.88 (d, J= 8.6 Hz, 2 H), 8.50 (dd, J= 2.0, 2.3 Hz, 1 H), 9.12 (d, 7= 2.3 Hz, 1 H), 9.13 (d, J= 2.0 Hz, 1 H), 12.83 (s, 1 H), 13.82 (s, 1 H); MS (APCI-neg mode) m/z (rel intensity): 438 (M-H, 100%). Example 94 Synthesis of 6-(3-((4-acetyl-3-hydroxy-2-methylphenoxy)methyl)phenylsulfinyl) isonicotinic acid. WO 2006/057860 PCT/US2005/041367 154 Using the method of Example 89 using 6-(3-((4-acetyl-3-hydroxy-2-methy- lphenoxy)methyl)phenylthio)isonicotinic acid (130 mg, 0.317 mmol) affords the title compound(40.2 mg, 30%): 1H NMR(d6-acetone) 52.10 (s, 311), 2.58 (s, 3H), 5.34 (s, 2H), 6.66 (d, J= 9.0 Hz, 1H), 7.59-7.64 (m, 2H), 7.75 (d, J= 9.4 Hz, 1H), 7.81 (d, J= 7.4 Hz, 1H), 7.94 (s, 2H), 8.51 (s, 1H), 8-78 (d, J= 5.1 Hz, 1H), 12.89 (s, 1H); MS (APCI- neg mode) m/z (rel intensity): 424 (M-H, 100%). Example 95 Synthesis of 6-(3-((4-acetyl-2-ethyl-3-hydroxyphenoxy)methyl)phenylsiUfinyl) isonicotinic acid. Using the method of Example 89 using 6-(3-((4-acetyl-2-ethyl-3-hydroxy- phenoxy)methyl)phenylthio)isonicotinic acid (200 mg, 0.472 mmol) affords the title compound (18 mg, 9%): 'H NMR (dfi-DMSO) 5 1.02 (t, J= 7.4 Hz, 3H), 2.57 (m, 2H), 2.57 (s, 3H), 5.32 (s, 2H), 6.66 (d, J= 9.0 Hz, 1H), 7.59 (d, J = 5.1 Hz, 2H), 7.74 (m, 3H), 7.84 (d, J= 5.1 Hz, 1H), 8.31 (s, 1H), 8.71 (d, J=4.7 Hz, 1H), 12.83 (s, 1H); MS (APCI- negmode) m/z (rel intensity): 438 (M-H, 100%). Example 96 Synthesis of 5-(3-((4-acetyl-3-hydroxy-2-methylphenoxy)methyl)phenylsulfonyl1- nicotinic acid. Add a 0.5 M solution of potassium peroxymonosulfate (1.54 g, 2.50 mmol) in water (5.0 mL) to a solution of 5-(3-((4-acct}'l-3-hydroxy-2-methylphenoxy)methyl)- phenylthio)nicotinic acid (205 mg, 0.50 mmol) in methanol (7.5 mL) at room temperature. Heat the reaction mixture at 40 °C for 3 d. Add a 0.5 M solution of potassium peroxymonosulfate (1.54 g, 2.50 mmol) in water (5.0 mL) and DMF (10 mL) to the mixture. Heat the mixture at 80 °C for 19 h. Cool to room temp. Add water and WO 2006/057860 PCT/US2005/041367 155 0.50 mL of 2.0 M HC1 to the mixture. Extract the mixture with EtOAc. Dry, filter and concentrate. Purify the residue by flash chromatograhpy on silica gel eluting with a mixture of acetone, CH2CI2, and acetic acid (20:80:1) to afford the title compound (74 mg, 34%): !H NMR (dg-DMSO) 5 2.03 (s, 3 H), 2.58 (s, 3 H), 5.37 (s, 2 H), 6.70 (d, J= 9A Hz, 1 H), 7.71 (t, J= 7.8 Hz, 1 H), 7.79 (d, J= 9.0 Hz, 1 H), 7.82 (d, J= 7.8 Hz, 1 H), 8.07 (d, J= 7.8 Hz, 1 H), 8.16 (s, 1 H), 8.63 (dd, y = 2.0, 2.3 Hz, 1 H), 9.28 (d, J= 2.0 Hz, 1 H), 9.35 (d, /= 2.3 Hz, 1 H), 12.84 (s, 1 H); MS (APCI-neg mode) m/z (rel intensity): 440 (M-H, 100%). Example 97 Synthesis of 5-(3-((4-acetyl-3-hydroxy-2-propylphenoxy)methyl)phenyIsuIfonyl) nicotinic acid. Using the method of Example 96 using 5-(3-((4-acetyl-3-hydroxy-2- propyl- phenoxy) methyl)phenylthio)nicotinic acid (219 mg; 0.50 mmol) affords the title compound (135 mg, 58%): 'H NMR (CDCI3) 8 0.95 (t, J = 7.2 Hz, 3 H), 1.52-1.62 (m, 2 H), 2.57 (s, 3 H), 2.69 (t, J= 7.6 Hz, 2 H), 5.22 (s, 2 H), 6.41 (d, /- 9.0 Hz, 1 H), 7.57 (d, 7= 8.6 Hz, 1 H), 7.63 (t, J= 7.8 Hz, 1 H), 7.70 (d, J= 7.4 Hz, 1 H), 7.99 (d, J= 8.2 Hz, 1 H), 8.05 (s, 1 H), 8.83 (dd, J= 2.0,2.3 Hz, 1 H), 9.32 (d, J= 2.0 Hz, 1 H), 9.42 (d, J = 2.0 Hz, 1 H), 12.74 (s, 1 H); MS (APCI-neg mode) m/z (rel intensity): 468 (M-H, 100%). Example 98 Synthesis of 5-(3-((4-acetyl-2-ethyl-3-hydroxyphenoxy)methyl)phenylsulfonyl)nicotinic acid. Using the method of Example 96 using 5-(3-((4-acetyl-2-ethyl-3-hydroxy- phenoxy)methyl)phenylthio)nicotinic acid (212 mg,'0.50 mmol) affords the title compound (130 mg, 57%): JH NMR (d6-DMSO) 5 1.03 (t, J= 7.4 Hz, 3 H), 2.57 (s, 3 H), WO 2006/057860 PCT/US2005/041367 156 2.60 (q, J= 1A Hz, 2 H), 5.38 (s, 2 H), 6.69 (d, J= 9.4 Hz, 1 H), 7.72 (t, J= 7.8 Hz, 1 H),7.79(d,J=9.0Hz,lH),7.81(d,J=7.SHz,lH), 8.08 (d, J=7.8 Hz, 1 H), 8.15(S, 1 H), 8.62 (dd, J= 2.0, 2.3 Hz, 1 H), 9.28 (d, 7= 2.0 Hz, 1 H), 9.33 (d, J= 2.3 Hz, 1 H), 12.84 (s, 1 H); MS (APCI-neg mode) m/z (rel intensity): 454 (M-H, 100%). Example 99 Synthesis of 5-(4-((4-acetyl-3-hydroxy-2-methylphenoxy)methyl)phenylsulfonyl) nicotinic acid. Using the method of Example 96 using 5-(4-((4-acetyl-3-hydroxy- 2-methyl- phenoxy) methyl)phenyithio)nicotinic acid (205 mg, 0.50 mmol) affords the title compound (145 mg, 66%): 'H NMR (d6-DMSO) 5 2.06 (s, 3 H), 2.57 (s, 3 H), 5.38 (s, 2 H), 6.68 (d, J= 9.0 Hz, 1 H), 7.72 (d, /= 8.2 Hz, 2 H), 7.79 (d, J= 9.0 Hz, 1 H), 8.14 (d, J= 8.2 Hz, 2 H), 8.63 (t, J= 2.0 Hz, 1 H), 9.28 (d, ./ = 2.0 Hz, 1 H), 9.38 (d, J= 2.3 Hz, 1 H), 12.84 (s, 1 H), 14.01 (s, 1 H); MS (APCI-neg mode) m/z (rel intensity): 440 (M-H, 100%). Example 100 Synthesis of 5-(4-((4-acetyl-3 -hydroxy-2-propylphenoxy)methyl)phenylsulfonyl) nicotinic acid. Using the method of Example 96 using 5-(4-((4-acetyl-3-hydroxy-2-propyl- phenoxy)methyl)phenylthio)nicotinic acid (75 mg, 0.17 mmol) affords the title compound (46 mg, 57%): 'H NMR (d6-DMSO) 5 0.88 (t, J= 7.4 Hz, 3 H), 1.44-1.54 (m, 2 H), 2.56 (s, 3 H), 2.61 (t, J = 7.6 Hz, 2 H), 5.38 (s, 2 H), 6.67 (d, J = 9.0 Hz, 1 H), 7.70 (d, J - 8.2 Hz, 2 H), 7.79 (d, J= 9.0 Hz, 1 H), 8.16 (d, J= 8.6 Hz, 2 H), 8.64 (t, 7= 2.0 Hz, 1 H), 9.28 (d, J= 1.7 Hz, 1 H), 9.38 (d, J= 2.3 Hz, 1 H), 12.84 (s, 1 H), 14.02 (s, 1 H); MS (APCI-neg mode) m/z (rel intensity): 468 (M-H, 100%). WO 2006/057860 PCT/US2005/041367 157 Example 101 Synthesis of 5-(4-((4-acetyl-2-ethyl-3-hydroxyphenoxy)methyl)phenylsulfonyl)nicotinic acid. Using the method of Example 96 using 5-(4-((4-acetyl-2-ethyl-3-hydroxy- phenoxy) methyl)phenylthio)nicotinic acid (140 mg, 0.33 mmol) affords the title compound (72 mg, 48%): 'H NMR (d6-DMSO) 6 1.05 (t, J= 7.4 Hz, 3 H), 2.56 (s, 3 H), 2.63 (q, J= 7.4 Hz, 2 H), 5.39 (s, 2 H), 6.67 (d, J= 9.4 Hz, 1 H), 7.71 (d, J= 8.2 Hz, 2 H), 7.79 (d, J= 9.0 Hz, 1 H), 8.15 (d, J= 8.2 Hz, 2 H), 8.64 (dd, J= 2.0, 2.3 Hz, 1 H), 9.28 (d, J= 2.0 Hz, 1 H), 9.38 (d, J= 2.3 Hz, 1 H), 12.84 (s, 1 H), 14.01 (s, 1 H); MS (APCI-neg mode) m/z (rel intensity): 454 (M-H, 100%). Example 102 Synthesis of 5-(3-((4-acetyl-3-hydroxy-2-methylphenoxy)methyl)phenylsulfonyl) picolinic acid. Using the method of Example 96 using 5-(3j((4-acetyl-3-hydroxy-2-methyl- phenoxy)methyl)phenyltluo)picolinic acid (250 mg,' 0.61 mmol) affords the title compound (57 mg, 21%): lE NMR (dfl-DMSO) 5 2.04 (s, 3H), 2.58 (s, 3H), 5.38 (s, 2H), 6.70 (d, J- 9.0 Hz, 1H), 7.72 (t, J= 7.8 Hz, 1H), 7.82 (q, J= 13.5 Hz, 2H), 8.04 (d, J= 8.2 Hz, 1H), 8.15 (s, 1H), 8.21 (d, /= 8.2 Hz, 1H), 8.51 (m, 1H), 9.24 (s, 1H), 12.85 (s, 1H); MS (APCI-neg mode) m/z (rel intensity): 440 (M-H, 100%). Example 103 Synthesis of 5-(3-((4-acetyl-2-ethyl-3-hydroxyphenoxy)methyl)pheaylsulfonyl)picolinic acid. WO 2006/057860 PCT/US2005/041367 158 Using the method of Example 96 using 5-(3-((4-acetyl-2-ethyl-3-hydroxy- phenoxy)methyl)phenylthio)picolinie acid (250 rag, 0.59 mmol) affords the title compound (160 mg, 59%): lE NMR (d6-DMSO) S 1.03 (t, /= 7.4 Hz, 3H), 2.57 (s, 3H), 2.60 (q, «/= 10.2 Hz, 2H), 5.38 (s, 2H), 6.69 (d, J= 9.0 Hz, 1H), 7.83-7.70 (m, 3H), 8.04 (d, J= 7.8 Hz, 1H), 8.13 (s, 1H), 8.20 (d, J= 8.2 Hz, 1H), 8.50 (m, 1H), 9.21 (d, J= 2.3 Hz, 1H), 12.84 (s, 1H); MS (APCI-neg mode) m/z (rel intensity): 454 (M-H, 100%). Example 104 Synthesis of 5-(3 -((4-acetyl-3-hydroxy-2-p.ropylphenoxy)methyl)phenylsulfonyl) picolinic acid. Using the method of Example 96 using 5-(3-((4-acetyl-3-hydroxy-2-propyl- phenoxy)methyl)phenylthio)picolinic acid (250 mg, 0.57 mmol) affords the title compound (170 mg, 63%): 1H NMR (d6-DMSO) 8 0.86 (t, J= 7.2 Hz, 3H), 1.47 (m, 2H), 2.58 (s, 3H), 2.58 (t, J= 11.9 Hz, 2H), 5.37 (s, 2H), 6.70 (d, J = 9.0 Hz, 1H), 7.72 (t, J= 7.8 Hz, 1H), 7.80 (d, J= 9.0 Hz, 2H), 8.04 (d, J= 7.8 Hz, 1H), 8.13 (s, 1H), 8.20 (m, 1H), 8.50 (q, /= 7.0 Hz, 1H), 9.21 (m, 1H), 12.85 (s, 2H); MS (APCI-neg mode) m/z (rel intensity): 468 (M-H, 100%). Example 105 Synthesis of 6-(3 -((4-acetyl-3 -hydroxy-2-methylphenoxy)methyI)phenylsulfonyl) isonicotinic acid. WO 2006/057860 PCT/US2005/041367 159 Using the method of Example 96 using 6-(3-((4-acetyl-3-hydroxy-2-methyl- phenoxy) methyl)phenylthio)isonicotinic acid (100 mg, 0.244 mmol) affords the title compound (23.0 mg, 24%): JH NMR. (d6-DMSO) 6 2.03 (s, 3H), 2.58 (s, 3H), 5.38 (s, 2H), 6.69 (d, 7= 9.0 Hz, 1H), 7.70 (c, J= 7.6 Hz, 1H), 7.80 (d, J= 9.0 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.98 (d, J= 7.8 Hz, 1H), 8.07 (s, 1H), 8.08 (s, 1H), 8.49 (s, 1H), 8.89 (d, J = 4.7 Hz, 1H), 12.85 (s, 1H); MS (APCI-neg mode) m/z (rel intensity): 440 (M-H, 100%). Example 106 Synthesis of 6-(3-((4-acetyl-3-hydroxy-2-propylphenoxy)methyl)phenylsulfonyl) isonicotinic acid. Using the method of Example 96 using 6-(3-((4-acetyl-3-hydroxy-2- propylphenoxy) methyl)phenylthio)isonicotinic acid (200 mg, 0.457 mmol) affords the title compound (87 mg, 41%): !H NMR (d6-DMSO) 5 0.86 (t, J= 7.4 Hz, 3H), 1.51-1.42 (2, 1H), 2.58 (m, 2H), 2.58 (s, 3H), 5.37 (s, 1H), 6.69 (d, J= 9.0 Hz, 1H), 7.71 (t, J= 7.6 Hz, 1H), 7.80 (d, y= 9.0 Hz, 2H), 7.99 (d, J= 7.8 Hz, 1H), 8.07 (s, 1H), 8.08 (s, 1H), 8.49 (s, 1H), 8.88 (d, J= 4.7 Hz, 1H), 12.84 (s, 1H);.MS (APCI-neg mode) m/z (rel intensity): 469 ?? (M-H, 100%). Example 107 Synthesis of 6-(3-((4-acetyl-2-ethyl-3-hydroxyphenoxy)methyl)phenylsulfonyl) isonicotinic acid. Using the method of Example 96 using 6-(3-((4-acetyl-2-ethyl-3-hydroxy- phenoxy) methyl)phenylthio)isonicotinic acid (200 mg, 0.472 mmol) affords the title compound (125 mg, 58%): 'H NMR (d5-DMSO) 5 1.02 (t, J= 7.4 Hz, 3H), 2.57 (s, 3H), 2.60 (q, J= 7.4 Hz, 2H), 5.38 (s, 2H), 6.68 (d, /= 9.0 Hz, 1H), 7.71 (t, J= 7.6 Hz, 1H), 160 We claim: 1. A compound of formula I wherein R1 is selected from the group consisting of C1-C5 alkyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, phenyl and substituted phenyl; R2 is selected from the group consisting of hydrogen, C1-C5 alkyl, substituted C1-C5 alkyl, halo, phenyl, substituted phenyl, C1-C3 fluoroalkyl, CN, CO2R3, thiophenyl, substituted thiophenyl, thiazolyl, substituted thiazoyl, furanyl, substituted furanyl, pyridinyl, substituted pyridinyl, oxazolyl, substituted oxazloyl, isothiazolyl, substituted isothiazoyl, isoxazolyl, substituted isoxazolyl, 1,2,4-oxadiazolyl, substituted 1,2.4-oxadiazolyl, pyrimidinyl, substituted pyrimidinyl, pyridazinyl, and substituted pyridazinyl; X is selected from the group consisting of O, S(O)m, and NR3; Y is selected from the group consisting of C1-C3 alkanediyl and substituted Cl-C3alkanediyl; Ar1 and Ar2 are independently selected from the group consisting of phenylene, substituted phenylene, thiophenediyl, substituted thiophenediyl, thiazolediyl, substituted thiazolediyl, furanediyl, substituted furanediyl, pyridinediyl, substituted pyridinediyl, oxazolediyl, substituted oxazolcdiyl, isothiazolediyl, substituted isothiazolediyl, isoxazolediyl, substituted isoxazolediyl, pyrimidinediyl, substituted pyrimidinediyl, pyridazinediyl, substituted pyridazinediyl and l,2,4-oxadiazole-3,5-diyl; L is selected from the group consisting of-G-O-J-, -G-S(O)p-J-, and -G-N(R4)-J-; G is a bond; J is independently selected from the group consisting of a bond and C1-C3 alkanediyl; 161 R1 is independently hydrogen or C1-C5 alkyl; R4 is independently selected from the group consisting of hydrogen, C1-C5 alkyl, C(=O)R\ C(=O)NR3R3and SO2R3; Z is selected from the group consisting of (CH2)nC00H, m and p are independently 0, 1, or 2; n and q are independently 0, 1, 2 or 3; and pharmaceutically acceptable salts thereof. 2. A compound according to Claim 1 wherein X is O. 3. A compound according to Claim 1 or 2 wherein Y is C1-C3 alkanediyl. 4. A compound according to Claim 1, 2 or 3 wherein Ar1 and Ar2 are independently phenylene or pyridinediyl. 5. A compound according to Claim 1, 2, 3 or 4 wherein R is selected from the group consisting of C1-C5 alky 1, halo and C1-C3 fluoroalky 1. 6. A compound according to Claim 1, 2, 3. 4 or 5 wherein L is O. 7. A compound according to Claim 1, 2, 3, 4 or 5 wherein L is S. 8. A compound according to Claim 1, 2, 3, 4, 5, 6, or 7 wherein Z is selected from the group consisting of (CH2)nCOOH and and n and q are 0. 9. A compound according to Claim 1, 2, 3, 4, 5, 6. 7, or 8 wherein Ar1 is phenylene. 10. A compound according to Claim 1, 2, 3, 4, 5, 6, 7, 8, or 9 wherein Ar2 is pyridinediyl. 162 II. A compound according to Claim 1, 2, 3, 4, 5, 6. 7, 8, 9, or 10 wherein Ar2 is attached at the 1-4 position. 12 A compound according to Claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 wherein Ar2 is attached at the 1-3 position. 13. A compound according to Claim 11 or Claim 12 wherein An is attached at the 1-3 position or 1-4 position. 14. A compound according to any one of Claims 1-13 wherein R1 is methyl. 15. A compound according to any one of Claims 1,6,7 and 9-14 wherein R1 is methyl or ethyl; R2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, fluoro, chloro, trifluoromethyl, and COOH, X is O; Y is methylene; Ar1 is phenylene or pyridinediyl; Ar2 is selected from the group consisting of phenylene, trifluoromethylphenylene, and pyridinediyl; L is selected from the group consisting of O, S, SO, SO2 and NH; and Z is COOH or 16. A compound according to Claim 1 selected from the group consisting of l-(2-hydroxy-3-methyl-4-{4-[4-(lH-tetrazol-5-yl)-pyridin-2-yloxy]-benzy!oxy}-phenyl)- ethanone, l-(2-hydroxy-3-methyl-4-{4-[3-(lH-tetrazol-5-yl)-phenoxy]-benzyloxy}- phcnyl)-ethanone and l-(2-hydroxy-4-{3-[4-(2H-tetrazol-5-yl)-pyridin-2-yloxy]- benzyloxy}-3-trifluoromethyI-phenyl)-ethanone. 17. A compound according to Claim 1 which is 6-(3-((4-acetyl-3-hydroxy-2-propyl- phenoxy)inethyl)phenylthio)isonicotinic acid. 18. A pharmaceutical composition comprising a compound of any one of Claims 1-17 and a pharmaceutically acceptable carrier, diluent or excipicnt. 19. A compound according to any one of Claims 1-17 for use as a medicament. 20. The use of a compound of any one of Claims 1-17 for the manufacture of a medicament for treating migraine. 163 21. A process for preparing the compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R , R , X, Y, Ar1, L and Ar2 are defined as in Claim I comprising the step selected from (A) for a compound of formula I where Z is tetrazolyl, hydrolysis of a compound of formula II wherein R10 is COOR14 and R14 is selected fron the group consisting of C1-C5 alkyl, phenyl and benzyl; 164 whereafter, when a pharmaceutically acceptable salt of the compound of formula is required, it is obtained by reacting the acid of formula 1 with a physiologically acceptable base or by reacting a basic compound of formula 1 with a physiologically acceptable acid or by any other conventional procedure. 22. A compound of formula II 165 wherein R1, R2, X, Y, Arj, Ar2 and L are defined as in Claim 1; and Rl0 is CN or COOR14 in which R14 is selected from the group consisting of C1-C5 alky 1, phenyl and benzyl; other than 5-[[6-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-2-pyridinyl]- methoxy]-2-butoxybenzoic acid ethyl ester. 23. A compound according to Claim 22 wherein Ru is methyl. 24. A compound and/or a pharmaceutical composition and/or the use of a compound and/or a process for preparing substantially as herein described with reference to the given examples. 166 The present invention provides compounds of formula I: pharmaceutical compositions thereof, and methods of using the same, processes or preparing the same, and intermediates thereof.