MXPA01010788A - Tri-aryl acid derivatives as ppar receptor ligands - Google Patents

Abstract

This invention is directed to triaryl acid derivatives of formula (I) and their pharmaceutical compositions as PPAR ligand receptor binders. The PPAR ligand receptor binders of this invention are useful as agonists or antagonists of the PPAR receptor. In formula (I), (a), (b), and (c) are independently aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkemyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, or fused heteroarylheterocyclyl;A is -O-, -S-, -SO-, -SO 2-, -NR 13-, -C(O)-, -N(R 14)C(O)-, -C(O)N(R 15)-, -N(R 14)C(O)N(R 15)-, -C(R 14)=N-, (d), (e), (f) a chemical bond, (g) or (h);B is -O-, -S-, -SO-, -SO 2-, -NR 17-, a chemical bond, ethynylene, -C(O)-, -N(R 18)C(O)-, or -C(O)NR 18-;D is -O-, -S-, -NR 19-, a chemical bond, ethynylene, -C(O)-, -N(R 20)C(O)-, or -C(O)N(R 20)-;E is a chemical bond or an ethylene group;Z is R 21O 2C-, R 21OC-, cyclo-imide, -CN, R 21O 2SHNCO-, R 21O 2SHN-, (R 21) 2NCO-, R 21O-2,4-thiazolidinedionyl, or tetrazolyl.

Description

DERIVATIVES OF TRI-ARITHIC ACID AS A LEAGUE OF PPAR RECEPTORS BACKGROUND OF THE INVENTION This invention focuses on the use of triaryl acid derivatives and their pharmaceutical compositions as PPAR ligand receptor binders. The PPAR ligand receptor binders of this invention are useful as PPAR receptor agonists or antagonists. FIELD OF THE INVENTION Peroxisome proliferator activated receptors (PPAR) can be subdivided into three subtypes, namely: PPARa, PPARd, and PPAR ?. They are encoded by different genes (Motojima, Cell Structure and Function, 18: 267-277, 1993). In addition, 2 isoforms of PPAR? there are also, PPAR ?. and PPAR? 2. These 2 proteins differ in terms of the 30 amino acids of the NH2 terminal and are the result of the use of alternative promoter and differential instep of RA (Vidal-Puig, Jiménez, Linan, Lowell, Hamann, Hu, Spiegelman, Flier, Moller , J. Clin. Invest., 97: 2553-2561, 1996). Biological processes modulated by PPAR are the processes modulated by receptors or combinations of receptors that respond to the PPAR receptor ligands described here. These processes include, for example, transport of plasma lipids and fatty acid catabolism, regulation of insulin sensitivity and blood glucose levels that are involved in hypoglycemia / hyperinsulinism (resulting, for example, from abnormal function of pancreatic beta cells, tumors that secrete insulin and / or autoimmune hypoglycemia caused by antibodies against insulin, the insulin receptor, or antibodies that stimulate beta pancreatic cells), differentiation of macrophages that cause the formation of atherosclerotic plaques, inflammatory response , carcinogenesis, hyperplasia or adipocyte differentiation. Obesity is an excessive accumulation of adipose tissue. Recent works in this area indicate that PPAR? plays a central role in the expression and differentiation of adipocyte gene. An excess of adipose tissue is related to the development of severe medical conditions, for example, non-insulin dependent diabetes mellitus (NIDDM), hypertension, coronary artery disease, hyperlipidemia and certain malignancies. The adipocyte can also influence the homeostasis of glucose through the production of tumor necrosis factor (TNFa) and other molecules. Non-insulin dependent diabetes mellitus (NIDDM), or type II diabetes, is the most common form of diabetes, with 90-95% of hyperglycemic patients presenting this form of the disease. In NIDDM there seems to be a reduction in pancreatic β-cell mass, several specific defects in terms of insulin secretion or a decrease in tissue sensitivity to insulin. These symptoms of diabetes include fatigue, frequent urination, thirst, blurred vision, frequent infections and slow healing of wounds, nerve damage and kidney disease. Resistance to the metabolic actions of insulin is one of the essential characteristics of non-insulin-dependent diabetes (NIDDM). Insulin resistance is characterized by impaired absorption and utilization of glucose in white organs sensitive to insulin, for example, adipocytes and skeletal muscle, and by impaired inhibition of hepatic glucose production. Functional insulin deficiency and the inability of insulin to suppress hepatic glucose production results in fasting hyperglycemia. Pancreatic cells compensate for insulin resistance by secreting increased levels of insulin. However, ß cells can not maintain this high insulin production and eventually glucose-induced insulin secretion falls, causing the deterioration of glucose homeostasis and the subsequent development of overt diabetes. Hyperinsulinemia is also related to insulin resistance, hypertriglyceridemia and increased plasma concentration of low density lipoprotein. The association of insulin resistance and hyperinsulinemia with these metabolic disorders is known as "Syndrome X" and has been strongly associated with an increased risk of hypertension and coronary artery disease. The use of metformin in the art for the treatment of diabetes in humans is known (US Pat. No. 3,174,901). Metformin acts primarily to decrease the production of glucose in the liver. It is known that Troglitazone® acts primarily to increase skeletal muscle's ability to respond to insulin and absorb glucose. It is known that a combination therapy comprising metformin and troglitazone can be used in the treatment of abnormalities associated with diabetes (DDT 3: 79-88; 1998). Activators of PPAR ?, particularly Troglitazone® convert cancerous tissue into normal cells in liposarcoma, a fat tumor (PNAS 96: 3951-3956, 1999). In addition, it has been suggested that PPAR activators? they may be useful in the treatment of breast and colon cancer (PNAS: 95: 8806-8811, 1998, Nature Medicine 4: 1046-1052, 1998). In addition, activators of PPAR ?, for example Troglitazone®, have been implicated in the treatment of polycystic ovarian syndrome (PCO). It is a syndrome in women that is characterized by chronic anovulation and hyperandrogenism. Women with this symptom frequently have insulin resistance and also have an increased risk for the development of non-insulin-dependent diabetes mellitus. (Dunaif, Scott, Finegood, Quintana, Whitcomb, J. Clin Endocrinol, Metab., 81: 3299, 1996.). In addition, it has recently been discovered that PPAR activators? they increase the production of progesterone and inhibit steroidogenesis in granulosa cell cultures and therefore may be useful in the treatment of climacteric. (US Patent No. 5,814,647 Urban et al., September 29, 1998; B. Lohrke et al., Journal of Endocrinology, 159, 429-39, 1998). The climacteric is defined as the syndrome of endocrine, somatic and psychological changes that occur at the end of the reproductive period in the female. Peroxisomes are cellular organelles that play a role in the control of the redox potential and oxidative stress of cells by metabolizing various substrates such as hydrogen peroxide. There is a significant number of disorders associated with oxidative stress. For example, the inflammatory response to tissue injury, pathogenesis of emphysema, organ injury associated with ischemia (shock), cardiac injury induced by doxorubicin, drug-induced hepatotoxicity, atherosclerosis as well as pulmonary and peroxic lesions are associated with the production of species of reactive oxygen and a change in the reducing capacity of the cell. Accordingly, it is contemplated that PPARa activators, which, among other things, regulate the redox potential and the oxidant tension in the cells, would be effective for the treatment of these disorders. (Poynter et al, J. Biol. Chem. 273, 3283-41, 1998). It has also been discovered that PPARα agonists inhibit NFKB-mediated transcription thereby modulating various inflammatory responses such as the inducible pathways of the nitric oxide synthase (NOS) and cyclooxygenase-2 (COX-2) enzymes (Pineda-Torra, IT Al, 1999, Curr, Opinion in Lipidology, 10,151-9) and therefore can be used in the therapeutic intervention of a wide range of inflammatory diseases and other pathologies (Colville-Nash, et al., Journal of Immunology, 161, 978 -84, 1988; Staels et al, Nature, 393, 790-3, 1998). Peroxisome proliferators activate PPAR, which in turn acts as a transcription factor and causes differentiation, cell growth and proliferation of peroxisomes. PPAR activators also play a role in hyperplasia and carcinogenesis as well as in altering the enzymatic capacity of animal cells such as rodent cells, but these PPAR activators appear to have minimal negative effects on human cells (Green , Biochem. Pharm. 43 (3): 393, 1992). The activation of PPAR results in the rapid increase of gamma glutamyltranspeptidase and catalase. PPARa is activated by numerous medium and long chain fatty acids and is involved in the stimulation of ß-oxidation of fatty acids in tissues such as liver, heart, skeletal muscle, and brown adipose tissue (Isseman and Green, supra; Beck et al. al., Proc. R. Soc. Lond. 247: 83-87, 1992; Gottlicher et al., Proc. Natl. Acad. Sci. USA 89: 4653-4657, 1992). Activators of pharmacological PPARa, for example, fenofibrate, clofibrate, genfibrozil, and bezafibrate, are also involved in a substantial reduction of plasma triglycerides along with a moderate reduction of LDL cholesterol, and can be used particularly for the treatment of hypertriglyceridemia, hyperlipidemia and obesity. PPARa is also involved in inflammatory disorders (Shoonjans, K., Current Opinion in Lipidology, 8, 159-66, 1997). The human nuclear receptor PPARd has been cloned from a cDNA library of human osteosarcoma cells and is fully described in A. Schmidt et al., Molecular Endocrinology, (Molecular Endocrinology) 6: 1634-1641 (1992) , whose contents are incorporated here by reference. It will be noted that PPARd is also known in the literature as PPARβ and as NUCÍ, and that each of these names refers to the same receptor. For example, in A. Schmidt et al., Molecular Endocrinology, 6: pages 1634-1641, 1992, the receptor is known as NUCÍ. PPARd is observed in both embryonic and adult tissues. This receptor has been reported to be involved in the regulation of the expression of certain fat-specific genes and plays a role in the adipogenic process (Amri, E. Et al., J. Biol. Chem. 270, 2367-71, 1995) . It is known that atherosclerotic disease is caused by numerous factors, for example, hypertension, diabetes, low levels of high density lipoprotein (HDL), and high levels of low density lipoprotein (LDL). In addition to a reduction in risk through effects on plasma lipid concentrations and other risk factors, PPARa agonists exert direct atheroprotective effects (Frick, MH et al., 1997., Circulation 96: 2137-2143, by Farire, et al., 1997, Cardiovasc Drugs Ther, 11 Suppl 1: 257-63: 257-263). It has recently been discovered that PPARd agonists are useful for raising HDL levels and therefore useful for treating atherosclerotic diseases (Leibo itz et al., O / 9728149). Atherosclerotic diseases include vascular disease, coronary heart disease, cerebrovascular disease as well as peripheral vessel disease. Coronary heart disease includes death from CHD, myocardial infarction, and coronary revascularization. Cerebrovascular disease includes ischemic or hemorrhagic attacks as well as transient ischemic attacks. Subtypes of PPAR? they are involved in the activation of adipocyte differentiation, and are not involved in the stimulation of peroxisome proliferation in the liver. The activation of PPAR? is involved in the differentiation of adipocytes through the activation of adipocyte-specific gene expression (Lehmann, Moore, Sith-Oliver, Wilkison, Willson, Kliewer, J. Biol. Chem., 270: 12953-12956, 1995) . The DNA sequences for PPAR? are described in Elbrecht et al., BBRC 224; 431-437 (1996). Although peroxisome proliferators, including fibrates and fatty oxides, activate the transcription activity of PPAR, only prostaglandin J2 derivatives such as the metabolite of arachidonic acid 15-deoxy-delta12, 14-prostaglandin J2 (15d-PGJ2) have been identified as specific natural ligands for the PPAR subtype, which also binds with thiazolidinediones. This prostaglandin activates adipogenesis dependent on PPAR ?, but activates PPARa only in high concentrations (Forman, Tontonoz, Chem. Brun, Spiegelman, Evans, Cell, 83: 803-812, 1995; Kliewer, Lenhard, Wilson, Patel, Morris, Lehman, Cell, 83: 813-819, 1995). It is further evidence that the subtypes of the PPAR family are different among themselves in terms of their pharmacological response to the ligands. It has been suggested that compounds that activate both PPARa and PPAR? must be potent hypotriglyceridemic drugs, which can be used in the treatment of dyslipidemia associated with atherosclerosis, non-insulin dependent diabetes mellitus, Syndrome X, (Staels, B. et al., Curr. Pharm.Des 3 (1), 1 -14 (1997)) as well as familial combined hyperlipidemia (FCH). Syndrome X is the syndrome characterized by a state of initial insulin resistance, generating hyperinsulinemia, dyslipidemia and impaired glucose tolerance, which can progress to non-insulin-dependent diabetes mellitus (type II diabetes), which is characterized by hyperglycemia . FCH is characterized by hypercholesterolemia and hypertriglyceridemia within the same patient and family. The present invention is directed to a series of compounds that are useful for modulating PPAR receptors, as well as numerous other pharmaceutical uses associated therewith. COMPENDIUM OF THE INVENTION This invention offers new aromatic compounds and pharmaceutical compositions prepared therewith which are PPAR ligand receptor binders and which are useful as PPAR receptor agonists or antagonists. The invention also includes the discovery of new uses for previously known compounds.

The compounds for use in accordance with the present invention, including the novel compounds of the present invention, are of the formula I wherein (Ar1, (Ar1) and (Ar1) are, independently, aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, or fused heteroarylheterocyclyl; O-, -S-, -SO-v -S0: -, -NR_3, -C (O) -, -N (R1) C (O) -, -C (0) N (R_5) -, -N (R? 4) C (0) N (Ri5) - .C (R _.) = N-, a chemical bond, B is -O-, -S-, -SO-, -S0_-, -NR_7-, a chemical bond, ethynylene, -C (0) -, -N (R18) C (0) -, or -C (0) NR_8-; D is -0-, -S-, -NR19-, a chemical bond, ethynylene, -C (0) -, - N (R20) C (0) -, or -C (O) N (R20) -; E is a chemical bond or an ethylene group; a is 0-4, b is 0-4, c is 0-4, d is 0-5, e is 0-4, f is 0-6; g is 1-4, h is 1-4, i / 3 / Rdí R7. R9, and Rii are independently hydrogen, halogen, alkyl, carboxyl, alkoxycarbonyl or aralkyl; R 2, R 4, R 6 / R b t Rio / and R 12 are independently - (CH 2) q-X; q is 0-3; X is hydrogen, halogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, aralkoxy, heteroaralkoxy, carboxyl, alkoxycarbonyl, tetrazolyl, acyl, acyl HNS02-, - SR23, and N- O or Y3Y4NCO -; Y1 and Y2 are independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl, one of Y1 and Y2 is hydrogen, or alkyl and the other of Y1 and Y2 is acyl or aroyl; Y3 and Y4 are independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl; Z is R.iO.C-, R2iOC, cycloimide, -CN, R2_0_SHNCO-, R2_02SHN-, (R2?) 2NC0-, R2? 0-, 2,4-thiazolidinedione, or tetrazolyl; Y R19 and R2? are independently hydrogen, alkyl, aryl, cycloalkyl, or aralkyl; Ri3 / Ri7 / R? 9 and R23 are independently R22OC-, R22NHOC-, hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroaralkyl, or aralkyl; Ri4 is / Ri6 i8 and R2o are independently hydrogen, alkyl, aralkyl, carbonyl, or alkoxycarbonyl; or R_4 and R_5 together with the carbon and nitrogen atoms through which they are attached form a 5 or 6 membered azaheterocyclyl group; or when a is 2-4, then R. radicals together with the carbon atoms on which the R. radicals are attached form an ethylene group; or when b is 2-4, then neighboring radicals R3 together with the carbon atoms on which the radicals R_ are attached form an ethylene group; or when c is 2-4, then neighboring radicals R5 together with the carbon atoms on which the radicals R5 are attached form an ethylene group; or when d is 2-5, then radicals and neighbors together with the carbon atoms on which the radicals R7 are attached form an ethylene group; or when e is 2-4, then R. radicals together with the carbon atoms on which the R9 radicals are bonded form an ethylene group; or when f is 2-6, then neighboring radicals R__ together with the carbon atoms on which the radicals R__ are attached form an ethylene group; and R22 is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroaralkyl, or aralkyl; or a pharmaceutically acceptable salt, an N-oxide thereof, a hydrate thereof or a solvate thereof. DETAILED DESCRIPTION OF THE INVENTION As used above, and throughout the description, the following terms, unless otherwise indicated, shall have the following meanings: Definitions In the present specification, the term "compounds for use in accordance with invention "and equivalent expressions encompass compounds of the general formula (I) in accordance with that described above, which expression includes prodrugs, pharmaceutically acceptable salts and solvates, for example hydrates, when the context allows it. Similarly, reference to intermediate products, claimed or not themselves, covers their salts and solvates, when the context permits. For greater clarity, particular cases, when the context permits, are sometimes indicated in the text, but these cases are merely illustrative and do not intend to exclude other cases when the context allows it. The term "prodrug" refers to a compound that can be converted in vivo by metabolic means (by hydrolysis) into a compound of the formula (I), including N-oxides thereof. For example, an ester of a compound of the formula (I) containing a hydroxy group can be converted by hydrolysis in vivo into the parent molecule. Alternatively, an ester of a compound of the formula (I) containing a carboxy group can be converted by hydrolysis in vivo into the parent molecule. "Patient" refers to both humans and other mammals. The expression "chemical bond" means a simple direct bond between atoms. The term "acyl" means a group H-CO or an alkyl-CO- group in which the alkyl group is in accordance with what is described herein. Preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl. The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched chain having from about 2 to about 15 carbon atoms in the chain. Preferred alkyl groups have from 2 to about 12 carbon atoms in the chain and more preferably from about 2 to about 4 carbon atoms in the chain. The term "branched" means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. The term "lower alkenyl" means about 2 to about 4 atoms in the chain, which may be straight or branched. The alkenyl group is optionally substituted by one or more halo groups. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl and decenyl. The term "alkoxy" refers to an alkyl-0- group in which the alkyl group is in accordance with that described above. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy. The term "alkoxycarbonyl" refers to an alkyl-0-CO- group, wherein the alkyl group is as defined herein. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl or t-butyloxycarbonyl. The term "alkyl" refers to an aliphatic hydrocarbon group which may be straight or branched chain having from about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have from 1 to about 13 carbon atoms in the chain. The term "branched" means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. The term "lower alkyl" means that there are about 1 to about 4 carbon atoms in the chain, which may be straight or branched. The alkyl is optionally substituted by one or more "alkyl group substituents" which may be the same or different, and include halo, carboxy, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, alkoxy, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, Y1Y2NC0-, where Y1 and Y2N are independently hydrogen, alkyl, aryl, aralkyl or heterocyclyl, or Y1 and Y2, together with the nitrogen atom on which Y1 and Y2 are attached form heterocyclyl. Exemplary alkyl groups include methyl, trifluoromethyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, and 3-pentyl. Preferably, the substituent alkyl group is selected from acyl, halo, carboxy, carboxymethyl, methoxycarbonylethyl, benzyloxycarbonylmethyl, and pyridylmethyloxycarbonylmethyl and alkoxycarbonyl. The term "alkylsulfinyl" means an alkyl-SO- group in which the alkyl group is in accordance with that defined above. Preferred groups are the groups in which the alkyl group is lower alkyl. The term "alkylsulfonyl" means an alkyl-S02-group in which the alkyl group is in accordance with that defined above. Preferred groups are the groups in which the alkyl group is lower alkyl. The term "alkylthio" means an alkyl-S- group in which the alkyl group is in accordance with that defined above. Exemplary alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio. The term "aralkoxy" means an aralkyl-O- group in which the aralkyl group is in accordance with that defined herein. Exemplary aralkoxy groups include benzyloxy and 1- and 2-naphthalenemethoxy. The term "aralkoxycarbonyl" means an aralkyl-O-CO- group wherein the aralkyl group is as defined herein. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl. The term "aralkyl" means an aryl-alkyl group - wherein the aryl and alkyl groups are as defined herein. Preferred aralkyls contain a lower alkyl portion. Exemplary aralkyl groups include benzyl, 2-phenethyl and naphthalenemethyl. The term "aralkylsulfonyl" means an aralkyl-S02- group in which the aralkyl group is as defined herein. The term "aralkylsulfinyl" means an aralkyl-S0- group in which the aralkyl group is in accordance with that defined herein. The term "aralkylthio" means an aralkyl-S- group in which the aralkyl group is in accordance with that defined herein. An exemplary aralkylthio group is benzylthio. The term "aroyl" means an aryl-CO- group in which the aryl group is in accordance with that defined herein. Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl. The term "aryl" means an aromatic monocyclic or multicyclic ring system of about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl is optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Exemplary aryl groups include phenyl, naphthyl, substituted phenyl and substituted naphthyl. The term "arildiazo" refers to an aryl-diazo group, wherein the aryl and diazo groups are as defined herein. The term "fused arylcycloalkenyl" refers to an aryl and cycloalkenyl fused as defined herein. The preferred fused arylcycloalkenyls are arylcycloalkenyls in which the aryl moiety is phenyl and the cycloalkenyl moiety consists of about 5 to about 6 ring atoms. A fused arylcycloalkenyl group can be attached to the remainder of the compound through any atom of the fused system capable of said linkage. The fused arylcycloalkenyl may be optionally substituted by one or more ring system substituents, wherein the term "ring system substituent" is in accordance with that defined herein. Fused arylcycloalkenyl groups include 1,2-dihydronaphthylenyl; indenyl; 1,4-naphthoquinonyl, and the like. The term "fused arylcycloalkyl" refers to aryl and cycloalkyl fused in accordance with that defined herein. Preferred fused arylcycloalkyls are the arylcycloalkyls wherein the aryl portion thereof is phenyl and the cycloalkyl portion consists of about 5 to about 6 ring atoms. A fused arylcycloalkyl group can be attached to the remainder of the compound through any atom of the fused system capable of said linkage. The fused arylcycloalkyl may be optionally substituted by one or more ring system substituents, wherein the term "ring system substituent" is in accordance with that defined herein. Exemplary fused arylcycloalkyl and substituted fused arylcycloalkyl groups include 1, 2, 3, 4-tetrahydronaphthyl; 1,4-dimethyl-2, 3-dihydronaphthyl; 2, 3-dihydro-l, 4-naphthoquinonyl, atetralonyl, β-tetralonyl and the like. The term "fused arylheterocyclenyl" refers to a fused aryl and heterocyclenyl wherein the aryl portion and the heterocyclenyl portion are as defined herein. Preferred fused arylheterocyclenyl groups are those wherein the aryl portion is phenyl and the heterocyclenyl portion consists of about 5 to about 6 ring atoms. A fused arylheterocyclenyl group can be attached to the remainder of the compound through any atom of the fused system capable of said linkage. The designation of aza, oxa or thia as a prefix before the heterocyclenyl portion of the fused arylheterocyclenyl indicates that a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The fused arylheterocyclenyl may be optionally substituted by one or more ring system substituents, wherein the "ring system substituent" is as defined herein. "The nitrogen atom of a fused arylheterocyclenyl may be a nitrogen atom. The nitrogen or sulfur atom of the heterocyclenyl portion of the fused arylheterocyclenyl is also optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide Fused arylheterocyclenyl and fused substituted arylheterocyclenyl groups include 3H-indolinyl 2- (1H) quinolinonyl, 4-oxo-1,4-dihydroquinolinyl, 2H-1-oxoisoquinolyl, 1/2-dihydroquinolinyl, (2H) quinolinyl-N-oxide, 3,4-dihydroquinolinyl, 1, 2- dihydroisoquinolinyl, 3,4-dihydroisoquinolino, chromonyl, 3,4-dihydroisoquinoxalino, 4- (3H) quinazolinonyl, 4H-chromen-2-yl, and the like, preferably 2 (1H) quinolinonyl, 1,2-dihydroquinolinyl or, N- (2H) quinolinyl oxide, or 4- (3H) quinazolinonyl. The term "fused arylheterocyclyl" refers to a fused aryl and heterocyclyl wherein the aryl and heterocyclyl groups are as defined herein. Preferred fused arylheterocyclyls are those in which the aryl portion thereof is phenyl and the heterocyclyl portion consists of about 5 to about 6 ring atoms. A fused arylheterocyclic can be attached to the rest of the compound through any atom of the fused system capable of said linkage. The designation aza, oxa, or tia as a prefix before the heterocyclyl portion of the fused arylheterocyclyl indicates that a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The fused arylheterocyclyl group may be optionally substituted by one or more ring system substituents, wherein the "ring system substituent" is in accordance with that defined herein. The nitrogen atom of a fused arylheterocyclyl can be a basic nitrogen atom. The nitrogen or sulfur atom of the heterocyclyl portion of the fused arylheterocyclyl is also optionally oxidized on the N-oxide, S-oxide or S, S-dioxide corresponding. Fused arylheterocyclyl and fused substituted arylheterocyclyl groups include indolinyl, o-benzoic sulfimidyl, 4-chromanonyl, oxindole, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 1H-2,3-dihydroisoindole- 2-yl, 2,3-dihydrobenz [f] isoindol-2-yl, 1, 2, 3, 4-tetrahydrobenz [g] isoquinolin-2-yl, chromanyl, isochromanonyl, 2,3-dihydrochromonyl, 1, 4- benzodioxane, 1, 2, 3, 4-tetrahydroquinoxalinyl, and the like. Preferably 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinoxalinyl, and 1, 2, 3, 4-tetrahydroquinolinyl. The term "aryloxy" means an aryl-0- group in which the aryl group is in accordance with that defined herein. Exemplary groups include phenoxy and 2-naphthyloxy. The term "aryloxycarbonyl" refers to an aryl-O-CO- group wherein the aryl group is as defined herein. Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The term "arylsulfonyl" refers to an aryl-S02-group wherein the aryl group is in accordance with that defined herein. The term "aryisulfinyl" refers to an aryl-SO- group in which the aryl group is in accordance with that defined herein. The term "arylthio" refers to an aryl-S- group in which the aryl group is in accordance with that defined herein. Exemplary arylthio groups include phenylthio and naphthylthio. The term "carbamoyl" refers to an NH2-C0 group. The term "carboxy" refers to a group H0 (0) C- (carboxylic acid). The term "compounds of the present invention", and equivalent expressions, encompass compounds of the general formula (I) in accordance with that described above, said expression includes prodrugs, pharmaceutically acceptable salts, and solvates, eg, hydrates. , when the context allows it. Similarly, reference to intermediate products, claimed or not themselves, covers their salts and solvates, when the context permits. For greater clarity, particular cases when the context permits, are sometimes indicated in the text, but these cases are merely illustrative and do not intend to exclude other cases when the context permits. The term "cycloalkoxy" refers to a cycloalkyl-O- group in which the cycloalkyl group is in accordance with that defined herein. Exemplary cycloalkoxy groups include cyclopentyloxy and cyclohexyloxy. The term "cycloalkenyl" refers to a non-aromatic monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms, and containing at least one carbon-double bond. carbon. Preferred ring sizes of the rings of the ring system include from about 5 to about 6 ring atoms. The cycloalkenyl is optionally substituted with one or more "ring system substituent" which may be the same or different, and are as defined herein. Exemplary monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. An exemplary multicyclic cycloalkenyl is norbornylenyl. The term "cycloalkyl" refers to a non-aromatic monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred ring sizes of the rings of the ring system include from about 5 to about 6 ring atoms. The cycloalkyl is optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Exemplary monocyclic cycloalkyls include cyclopentyl, cyclohexyl, cycloheptyl, and the like. Exemplary multicyclic cycloalkyl includes 1-decalin, norbornyl, adamant- (1- or 2) yl, and the like. The term "cycloalkylene" refers to a saturated divalent carbocyclic group having from about 3 to about 6 carbon atoms. Preferred cycloalkylene groups include 1, 1-, 1,2-, 1 / 3-, and 1,4- cis or trans-cyclohexylene; and 1 1- 1 / 2-, and 1 / 3- cyclopentylene. The term "cycloimide" refers to a compound of the formulas The cycloimide portion may be attached to the parent molecule through either a carbon atom or a nitrogen atom of the carbamoyl portion. An exemplary imide group is N-phthalimide. The term "diazo" refers to a divalent -N = N radical.

The term "halo" refers to fluoro, chloro, bromo, or iodo.

Fluoro, chloro and bromo are preferred, fluoro and chloro being more preferred. The term "heteroaralkyl" refers to a heteroaryl-alkyl- group in which the heteroaryl and alkyl groups are in accordance with that defined herein.

Preferred heteroalkyl contain a lower alkyl portion. Exemplary heteroaralkyl groups include thienylmethyl, pyridylmethyl, imidazolylmethyl and pyrazinylmethyl. The term "heteroaralkylthio" refers to a heteroaralkyl-S- group in which the heteroaralkyl group is in accordance with that defined herein. An exemplary heteroaralkylthio is 3-pyridinepropantiol. The term "heteroalkoxy" refers to a heteroaralkyl-O- group wherein the heteroaralkyl group is in accordance with that defined herein. An exemplary heteroaralkoxy group is 4-pyridylmethyloxy. The term "heteroaroyl" refers to a heteroaryl-CO- group wherein the heteroaryl group is in accordance with that defined herein. Exemplary heteroaryl groups include thiophenenyl, nicotinoyl, pyrrol-2-ylcarbonyl and 1- and 2-naphthoyl and pyridinoyl. The term "heteroaryldiazo" refers to a heteroaryl-diazo group wherein the heteroaryl and diazo groups are as defined herein. The term "heteroaryl" refers to an aromatic monocyclic or multicyclic ring system of about 5 to about 14 carbon atoms, preferably about 5 to about 10 carbon atoms, wherein at least one of the carbon atoms in the ring system is replaced by a heteroatom, that is, other than carbon, for example nitrogen, oxygen, or sulfur. Preferred ring sizes of the rings of the ring system include from about 5 to about 6 ring atoms. The heteroaryl ring is optionally substituted by one or more "ring system substituents" which may be the same or different and are as defined herein. The designation of aza, oxa or thia as a prefix before heteroaryl means that a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. A nitrogen atom of a heteroaryl can be a basic nitrogen atom and can also be optionally oxidized to corresponding N-oxide. Exemplary substituted heteroaryl and heteroaryl groups include pyrazyl, thienyl, isothiazolyl, oxazolyl, pyrazolyl, cinolinyl, pteridinyl, benzofuryl, furazanyl, pyrrolyl, 1,2,4-oxadiazolyl, benzoxazole, 1,2,4-thiadiazolyl, pyridazinyl, indazolyl, quinoxalinyl , phthalazinyl, imidazo [2, lb] thiazolyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, naphthyridinyl, benzoazaindole, 1, 2,4-triazinyl, benzothiazolyl, furyl, imidazolyl, indolyl, isoindolyl, indolizinyl , isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl. Preferred substituted heteroaryl and heteroaryl groups include quinolinyl, indazolyl, indolyl, quinazolinyl, pyridyl, pyrimidinyl, furyl, benzothiazolyl, benzoxazole, benzofuryl, quinoxalinyl, benzimidazolyl, 1,2,4-oxadiazolyl, benzothienyl, and isoquinolinyl. The term "fused heteroarylcycloalkenyl" refers to a fused heteroaryl and cycloalkenyl wherein the heteroaryl and cycloalkenyl groups are as defined herein. Preferred fused heteroarylcycloalkenyls are the heteroarylcycloalkenyls wherein the heteroaryl portion is phenyl and the cycloalkenyl portion consists of about 5 to about 6 ring atoms. A fused heteroarylcycloalkenyl may be attached to the reder of the compound through any atom of the fused system capable of said linkage. The aza designation, oxa or thia as a prefix before the heteroaryl portion of the fused heteroarylcycloalkenyl means that a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The fused heteroarylcycloalkenyl may be optionally substituted by one or more ring system substituents wherein the "ring system substituent" is in accordance with that defined herein. The nitrogen atom of a fused heteroarylcycloalkenyl can be a basic nitrogen atom. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkenyl may also be optionally oxidized to the corresponding N-oxide. Exemplary fused heteroarylcycloalkenyl groups include 5,6-dihydroquinolyl; 5,6-dihydroisoquinolyl; 5,6-dihydroquinoxalinyl; 5,6-dihydroquinazolinyl; 4, 5-dihydro-lH-benzimidazolyl; 4,5-dihydrobenzoxazolyl; 1,4-naphthoquinolyl and the like. The term "fused heteroarylcycloalkyl" refers to a fused heteroaryl and cycloalkyl wherein the heteroaryl and cycloalkyl groups are as defined herein. Preferred fused heteroarylcycloalkyls are those wherein the heteroaryl consists of about 5 to about 6 ring atoms and the cycloalkyl consists of about 5 to about 6 ring atoms. A fused heteroarylcycloalkyl can be attached to the remainder of the compound through any atom of the fused system capable of said linkage. The designation aza, oxa or thia as a prefix before the heteroaryl portion of the fused heteroarylcycloalkyl refers to the presence respectively of a nitrogen, oxygen or sulfur atom as a ring atom. The fused heteroarylcycloalkyl may be optionally substituted by one or more ring system substituents wherein the term "ring system substituent" is as defined herein. The nitrogen atom of a fused heteroarylcycloalkyl can be a basic nitrogen atom. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkyl may be optionally oxidized to the corresponding N-oxide. Exemplary fused heteroarylcycloalkyls include 5, 6, 7, 8-tetrahydroquinolinyl; 5, 6, 7, 8-tetrahydroisoquinolyl; 5, 6, 7, 8-tetrahydroquinoxalinyl; 5, 6, 7, 8-tetrahydroquinazolyl; 4,5,6,7-tetrahydro-lH-benzimidazolyl, 4,5,6,7-tetrahydrobenzoxazolyl; lH-4-oxa-1, 5-diazanphthalen-2-onyl; 1,3-dihydroimidizole- [4, 5] -pyridin-2-onyl; 2, 3-dihydro-1,4-dinaphthoquinonyl and the like, preferably 5, 6, 8-tetrahydroquinolinyl or 5,6,7,8-tetrahydroisoquinolyl. The term "fused heteroaryl heterocyclenyl" refers to a fused heteroaryl and heterocyclenyl wherein the heteroaryl and heterocyclenyl groups are in accordance with that defined herein. Preferred fused heteroarylcyclenyls are those wherein the heteroaryl portion thereof consists of about 5 to about 6 ring atoms and the heterocyclenyl portion consists of about 5 to about 6 ring atoms. A fused heteroarylheterocyclenyl can be attached to the remainder of the compound through any atom of the fused system capable of said linkage. The designation aza, oxa or thia as a prefix before the heteroaryl or heterocyclenyl portion of the fused heteroarylheterocyclenyl indicates that a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The fused heteroarylheterocyclenyl may be optionally substituted by one or more ring system substituents wherein the "ring system substituent" is as defined herein. The nitrogen atom of a fused heteroarylazaheterocyclenyl may be a basic nitrogen atom. The nitrogen or sulfur atom of the heteroaryl or heterocyclenyl portion of the fused heteroarylheterocyclenyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Exemplary fused heteroarylheterocyclenyl groups include 7,8-dihydro [1,] naphthyridinyl; 1/2-dihydro [2,] naphthyridinyl; 6,7-dihydro-3H-imidazo [4,5-c] pyridyl; 1,2-dihydro-l, 5-naphthyridinyl; 1,2-dihydro-l, 6-naphthyridinyl; 1,2-dihydro-l, 7, naphthyridinyl; 1,2-dihydro-1,8-naphthyridinyl; 1,2-dihydro-2,6-naphthyridinyl, and the like. The term "fused heteroarylheterocyclyl" refers to a fused heteroaryl and heterocyclyl wherein the heteroaryl and heterocyclyl groups are as defined herein. Preferred fused heteroaryl heterocyclyls are those wherein the heteroaryl portion consists of about 5 to about 6 ring atoms and the heterocyclyl portion consists of about 5 to about 6 ring atoms. A fused heteroarylheterocyclyl can be attached to the rest of the compound through any atom of the fused system capable of said linkage. The aza designation, oxa or a thia as a prefix before the heteroaryl or heterocyclyl portion of the fused heteroarylheterocyclyl means that a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The fused heteroarylheterocyclyl may be optionally substituted by one or more ring system substituents wherein the "ring system substituent" is in accordance with that defined herein. The nitrogen atom of a fused heteroarylheterocyclyl can be a basic nitrogen atom. The nitrogen or sulfur atom of the heteroaryl or heterocyclyl portion of the fused heteroarylheterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Fused heteroarylheterocyclic groups include 2,3-dihydro-1H-pyrrole [3,4-b] quinolin-2-yl; 1,2,3,4-tetrahydrobenz [b] [1,] naphthyridin-2-yl; 1,2,3,4-tetrahydrobenz [b] [1,6] naphthyridin-2-yl; 1, 2, 3, 4-tetrahydro-9H-pyrido [3,4-b] indol-2-yl; 1, 2, 3, 4-tetrahydro-9H-pyrido [4, 3-b] indol-2-yl, 2,3-dihydro-lH-pyrrolo [3,4-b] indol-2-yl; 1H-2, 3, 4, 5-tetrahydroazepino [4, 5-b] indol-2-yl, 5, 6, 7, 8-tetrahydro [1,7] naphthyridinyl; 1,2,3, 4-terthidro [2,7] naphthyridyl; 2, 3-dihydro [1,4] dioxino [2, 3-b] pyridyl; 2, 3-dihydro [1,4] dioxino [2, 3-b] pyridyl; 3,4-dihydro-2H-l-oxa [4, 6] diazanaphthalenyl; 4,5,6,7-tetrahydro-3H-imidazo [4, 5-c] pyridyl; 6,7-cyhydro [5,8] diazanaphthalenyl; 1,2,3,4-tetrahydro [1,5] naphthyridinyl; 1,2,3,4-tetrahydro [1,6] naphthyridinyl; 1,2,3,4-tetrahydro [l,] naphthyridinyl; 1,2,3,4-tetrahydro [1,8] naphthyridinyl; 1,2,3,4-tetrahydro [2,6] naphthyridinyl, and the like. The term "heteroarylsulfonyl" refers to a heteroaryl-S02- group wherein the heteroaryl group is in accordance with that defined herein. An exemplary heteroarylsulfonyl group is 3-pyridinepropanesulfonyl. The term "heteroarylsulfinyl" refers to a heteroaryl-SO- group in which the heteroaryl group is in accordance with that defined herein.

The term "heteroarylthio" refers to a heteroaryl-S- group in which the heteroaryl group is in accordance with that defined herein. Exemplary heteroaryl groups include pyridylthio and quinolinylthio. The term "heterocyclenyl" refers to a non-aromatic monocyclic or multicyclic hydrocarbon ring system of about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms, wherein at least one or more of the carbon atoms in the ring system is replaced by a heteroatom, for example a nitrogen, oxygen or sulfur atom, and containing at least one carbon-carbon double bond or one. carbon-nitrogen double bond. Preferred ring sizes of the rings of the ring system include from about 5 to about 6 ring atoms. The designation aza, oxa or thia as a prefix before the heterocyclenyl means that a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The heterocyclenyl may be optionally substituted by one or more ring system substituents wherein the "ring system substituent" is in accordance with that defined herein. The nitrogen atom of a heterocyclenyl can be a basic nitrogen atom. The nitrogen or sulfur atom of the heterocyclenyl is also optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Exemplary monocyclic substituted monocyclic azaheterocyclenyl groups and azaheterocyclenyl include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 4 (3H) pyrimidone, 1,4 , 5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Exemplary oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuryl, and fluorodihydrofuryl. An exemplary multicyclic oxaheterocyclenyl group is 7-oxabicyclo [2.2. l] heptenyl. Exemplary monocyclic thiaheterocyclenyl rings include dihydrothiophenyl and dihydrothiopyranyl. The term "heterocyclyl" refers to a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms, wherein at least one of the carbon atoms is Carbon in the ring system is replaced by a heteroatom, for example, nitrogen, oxygen or sulfur. Preferred ring sizes of the rings of the ring system include from about 5 to about 6 ring atoms. The designation aza, oxa or thia as a prefix before heterocyclyl means that a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The heterocyclyl may be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen atom of a heterocyclyl can be a basic nitrogen atom. The nitrogen or sulfur atom of the heterocyclyl is also optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Exemplary monocyclic heterocyclic rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorphonyl, thiazolidinyl, 1,3-dioxolanyl, 1, -dioxanyl, tetrahydrofuryl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. Exemplary multicyclic heterocyclic rings include 1,4-diazabicyclo [2, 2, 2] octane and 1/2-cyclohexanedicarboxylic acid anhydride. The "ring system substituent" includes hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl , alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, aryisulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, fused cycloalkyl, fused cycloalkenyl, fused heterocyclyl, fused heterocyclenyl, arylazo, heteroarylazo, R ^^ -, RcRdNCO-, Rc02CN-, and RcRdNS02- wherein Ra and Rb are independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl, or one of Ra and Rb is hydrogen or alkyl and the other of Ra and Rb is aroyl or heteroaroyl. Rc and Rd are independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkyl or heteroaralkyl. When the ring is cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl, the ring system substituent may also include methylene (H2C =., Oxy (0 =), thioxo (S =), at carbon atom (s) thereof. Preferably, the ring substituents are selected from oxo (0 =), (lower) alkyl, aryl, alkoxy, aralkoxy, halo, trifluoromethyl, carboxy, alkoxycarbonyl, optionally substituted phenyl, optionally substituted benzyloxy, optionally substituted cyclohexyl, optionally substituted cyclobutyl, optionally substituted heteroaryl, and Re02CN-, wherein R is cycloalkyl The term "tetrazolyl" refers to a group of the formula wherein the hydrogen atom thereof is optionally replaced by alkyl, carboxyalkyl or alkoxycarbonylalkyl. The term "PPAR ligand receptor binder" refers to a ligand that binds to the PPAR receptor. PPAR ligand receptor binders of this invention are useful as PPAR-a, PPAR-β or PPAR-? Receptor agonists or antagonists. The term "pharmaceutically acceptable salt" refers to a relatively non-toxic organic or inorganic acid addition salt of a compound of the present invention. A salt may be prepared in situ during isolation and final purification of a compound or by separate reaction of the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt formed in this manner. Representative salts include the salts of hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, lauryl sulphonate, and the like. (See, for example, S.M. Berge, and colleagues, "Pharmaceutical Salts," J. Pharm. Sci., 66: 1-19, 1977, the contents of which are incorporated herein by reference.). The term "treatment" refers to the release or partial or complete prevention of one or more physiological or biochemical parameters associated with PPAR activity. The term "modulates" refers to the ability of a compound to induce either directly (by binding to the receptor as a ligand) or indirectly (as a precursor to a ligand or an inducer that promotes the production of a ligand from a precursor ) the expression of gene (s) under hormonal control, or to suppress the expression of gene (s) maintained under said control. The term "obesity" generally refers to individuals who are at least about 20-30% above the average weight for the person's age, sex and height. Technically, in the case of men, the term "obese" refers to individuals whose body mass index is greater than 27.3 kg / m2. Those skilled in the art will readily recognize that the method of the present invention is not limited to persons who fall within the criteria set forth above. In fact, the method of the present invention can be applied beneficially to individuals who are outside of these traditional criteria, for example, in the case of individuals who have a tendency to obesity. The term "effective amount to lower blood glucose levels" refers to levels of a compound that are sufficient to provide circulating concentrations high enough to achieve the desired effect. Said concentration is typically within a range of about 10 μM to 2 μM, with concentrations in the range of about 100 nM to about 500 nM being preferred. The term "effective amount to lower triglyceride levels" refers to levels of a compound sufficient to provide circulating concentrations high enough to achieve the desired effect. Said concentration is typically within the range of about lOnM to 2 μM, with concentrations being preferred within a range of about 100 nM to about 500 nM. PREFERRED MODALITIES Preferred embodiments in accordance with the present invention include the use of compounds of the formula I (and their pharmaceutical compositions) as binders for PPAR receptors. More particularly, the use of compounds of the formula I that bind to the PPAR-a receptor, compounds of the formula I that bind to the PPAR-d receptor, compounds of the formula I that bind to the PPAR-a and PPAR receptors - ?, Compounds of formula I that bind PPAR- receptors? and PPAR-d, compounds of formula I which act as PPAR receptor agonists, compounds of formula I which act as PPAR-a receptor agonists, compounds of formula I which act as PPAR-d receptor agonists, compounds of formula I which they act as PPAR- receptor agonists, compounds of formula I that act as agonists of both PPAR-a receptor and PPAR- receptor, compounds of formula I that act as agonists of both PPAR-a and PPAR receptor. -d, compounds of the formula I that act as agonists of both PPAR- receptor? as PPAR-d receptor, compounds of formula I that act as both PPAR-receptor antagonists to receptor as agonists PPAR- ?, compounds of formula I that act as both PPAR-receptor antagonists to as PPAR receptor agonists -d, compounds of formula I that act as PPAR- receptor antagonists? as PPAR-d receptor agonists, compounds of formula I which act both as PPAR-a receptor agonists and PPAR-? receptor antagonists, compounds of formula I which act as both PPAR-a receptor agonists and receptor antagonists PPAR-d, compounds of formula I that act as both PPAR-? Receptor agonists as PPAR-d receptor antagonists, compounds of formula I which act as PPAR receptor antagonists, compounds of formula I which act as PPAR-a receptor antagonists, compounds of formula I which act as PPAR-d receptor antagonists , compounds of the formula I which act as PPAR- receptor antagonists, compounds of the formula I which act as antagonists of both PPAR-d receptor, compounds of the formula I which act as PPAP receptor antagonists. the formula I acting as antagonists of both the PPAR-a receptor and the PPAR-? receptor, compounds of the formula I which act both as PPAR-a receptor antagonists and PPAR-d receptor antagonists, and compounds of the formula I which they act as antagonists of both PPAR-? receptor as PPAR-d receptor. An embodiment according to the present invention is focused towards the treatment of a patient suffering from a physiological disorder capable of being modulated by a compound of the formula I having a ligand binding activity.

PPAR, which comprises administering to the patient a pharmaceutically effective amount of the compound, or a pharmaceutically acceptable salt thereof. Physiological disorders that can be modulated include, for example, cell differentiation to produce lipid accumulation cells, regulation of insulin sensitivity and blood glucose levels involved in hypoglycemia / hyperinsulinism (resulting, for example, from a function of pancreatic β cells, abnormal, tumors that secrete insulin and / or autoimmune hypoglycemia caused by autoantibodies to insulin, autoantibodies to the insulin receptor, or autoantibodies that stimulate pancreatic β cells), differentiation of macrophages that causes the formation of atherosclerotic plaques , inflammatory response, carcinogenesis, hyperplasia, adipocyte gene expression, adipocyte differentiation, pancreatic ß cell mass reduction, insulin secretion, tissue sensitivity to insulin, liposarcoma cell growth, chronic anovulation, hyperandrogenism, production of progeste rona, steroidogenesis, oxidative stress and redox potential in cells, production of nitric oxide synthase (NOS), increased levels of gamma glutamyltranspeptidase, catalase, plasma triglycerides, HDL and LDL cholesterol and the like. Another embodiment in accordance with the present invention is directed to a method for the treatment of a disease in a patient with a pharmaceutically effective amount of a compound of the formula I or a pharmaceutically acceptable salt thereof, wherein the disease is associated with a physiologically damaging blood level of insulin, glucose, free fatty acids (FFA), or triglycerides. An embodiment according to the present invention is focused on the treatment of a patient suffering from a physiological disorder associated with physiologically harmful levels of triglycerides in the blood, by administering to the patient a pharmaceutically effective amount of the compound, or of a salt pharmaceutically acceptable thereof. One embodiment in accordance with the present invention is the use of compounds of the formula I and their pharmaceutical compositions as antidiabetic, antilipidemic, antihypertensive or antiarteriosclerotic agents in the treatment of obesity. Another embodiment in accordance with the present invention is directed to a method for the treatment of hyperglycemia in a patient, by administering to the patient a pharmaceutically effective amount to decrease the blood glucose levels of a compound of the formula I or or a pharmaceutically acceptable salt thereof. Preferably, the hyperglycemia form treated in accordance with this invention is type II diabetes.

Another embodiment in accordance with the present invention focuses on a method for reducing triglyceride levels in a patient, comprising administering to the patient a therapeutically effective amount (to lower triglyceride levels) of a compound of formula I , or a pharmaceutically acceptable salt thereof. Another embodiment according to the present invention focuses on a method for the treatment of hyperinsulinism in a patient, comprising administering to a patient a therapeutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof. . Another embodiment in accordance with the present invention is directed to a method for the treatment of insulin resistance in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the formula I, or a pharmaceutically salt acceptable of it. Another embodiment in accordance with the present invention is directed to a method for the treatment of a cardiovascular disease, for example atherosclerosis in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the formula I, or pharmaceutically acceptable salt thereof.

Another embodiment according to the present invention focuses on the treatment of hyperlipidemia in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof. Another embodiment in accordance with the present invention is directed to the treatment of hypertension in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof. Another embodiment in accordance with the present invention is directed to the treatment of eating disorders in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof. The treatment of eating disorders includes the regulation of appetite and / or food intake in patients suffering from undernourishment disorders such as anorexia nervosa as well as overeating disorders such as obesity and bulimia anorexia. Another embodiment in accordance with the present invention is directed toward the treatment of a disease state associated with low levels of HDL, which comprises administering to the patient a therapeutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof. same. Diseases associated with low HDL levels include atherosclerotic diseases. Another embodiment in accordance with the present invention focuses on the treatment of polycystic ovarian syndrome, which comprises administering to the patient a therapeutically effective amount of a compound of the formula I, or of a pharmaceutically acceptable salt thereof. Another embodiment according to the present invention is focused on the treatment of the climacteric, which comprises the administration to the patient of a therapeutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof. Another embodiment according to the present invention focuses on the treatment of inflammatory diseases such as rheumatoid arthritis, chronic obstructive pulmonary disease (emphysema or chronic bronchitis), or asthma, which comprises administering to the patient a therapeutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof. Another aspect of the invention is to provide a novel composition that is effective, in itself, for use in a beneficial combination therapy since it includes several active ingredients that can be used in accordance with the invention. In another aspect, the present invention provides a method for treating a disease in a patient, said disease being related to a physiologically damaging level of insulin, glucose, free fatty acids (FFA), or triglycerides in the blood, comprising administration to the of a therapeutically effective amount of a compound of the formula I, and also the administration of a therapeutically effective amount of an additional hypoglycemic agent. In another aspect, the present invention provides a method for treating a disease in a patient, wherein the disease is related to a physiologically damaging level of insulin, glucose, free fatty acids (FFA), or triglycerides, in the blood, comprising administering to the patient a therapeutically effective amount of a compound of the formula I, and also administering a therapeutically effective amount of a biguanidine compound. In another aspect, the present invention provides a method for the treatment of a disease in a patient, wherein the disease is associated with a physiologically damaging level of insulin, glucose, free fatty acids (FFA), or triglycerides, in the blood, comprising administering to the patient a therapeutically effective amount of a compound of the formula I, and also administering a therapeutically effective amount of metformin. The invention also offers sets of individual items or packages that combine two or more active ingredients useful for the treatment of the disease. A set of elements can provide (alone or in combination with a pharmaceutically acceptable diluent or carrier), a compound of the formula I and an additional hypoglycemic agent (alone or in combination with diluent or carrier). There are numerous hypoglycemic agents known in the art, for example insulin, biguanidines such as metformin and buformin; sulfonylureas such as acetohexamide, chloropropamide, tolazamide, tolbutamide, glyburide, glipizide, and gliclazide; thiazolidinediones, such as troglitazone; a-glycosidase inhibitors such as acarbose and miglatol; and adrenoreceptor agonists B_ such as CL-316,243. Since it is known that sulfonylureas can stimulate insulin release, but can not act on insulin resistance, and since it is known that compounds of formula I can act on insulin resistance, a combination is contemplated These drugs could be used as a remedy for conditions associated with both insulin secretion deficiency and insulin resistance. Accordingly, the invention also provides a method for the treatment of type II diabetes mellitus in a patient, comprising the administration of a compound of formula I and one or more additional hypoglycemic agents selected from the group consisting of sulfonylureas, biguanidines, thiazolidinediones, B3 adrenoreceptor agonists, a-glycosidase inhibitors and insulin. The invention also provides a method for the treatment of type II diabetes mellitus in a patient, comprising the administration of a compound of formula I, and a sulfonylurea selected from the group consisting of acetohexamide, chlorpropamide, tolazamide, tolbutamide, glyburide, glipizide and gliclazide. The invention also provides a method for the treatment of type II diabetes mellitus in a patient, comprising the administration of a compound of the formula I and a biguanidine selected from the group consisting of metformin and buformin. The invention also provides a method for the treatment of type II diabetes mellitus in a patient, comprising the administration of a compound of the formula I and a selected a-glycosidase inhibitor within the group consisting of acarbose and miglatol. The invention also provides a method for the treatment of type II diabetes mellitus in a patient, which comprises the administration of a compound of the formula I and a thiazolidinedione, for example troglitazone. In accordance with the above, a compound of the formula I can be administered alone or in combination with one or more additional hypoglycemic agents. A combination therapy includes the administration of a single pharmaceutical dosage formulation containing a compound of the formula I and one or more additional hypoglycemic agents, as well as the administration of the compound of the formula I and each additional hypoglycemic agent in its own formulation of separate pharmaceutical dosage. For example, a compound of the formula I and a hypoglycemic agent can be administered to the patient together with a single oral dosage composition such as for example in the form of a tablet or capsule, or each agent can be administered in separate oral dosage formulations. . When separate dosage formulations are employed, the compound of the formula I and one or more hypoglycemic agents can be administered essentially at the same time, i.e. concurrently, or at separate staggered moments, i.e., sequentially. For example, the compound of formula I can be administered in combination with one or more of the following additional hypoglycemic agents: insulin; biguanidines such as metformin or buformin; sulfonylureas such as acetohexamide, chloropropamide. tolazamide, tolbutamide, glyburide, glipizide or gliclazide; thiazolidinediones such as troglitazone; a-glycosidase inhibitors such as acarbose or miglatol; or B3 adrenoreceptor agonists such as CL-316,243. The compound of the formula I is preferably administered with a biguanidine, particularly metformin. The compounds of formula I contain at least three aromatic or heteroaromatic rings, which may be designated according to that shown in formula II below, and for which their substitution patterns along the chain relative to each other are It also shows below. ring I linker I ring II linker II ring III linker III (II) A preferred aspect of the compounds of formula II is a compound in which Arl) is selected from quinolinyl, benzothiophenyl, benzoimidazolyl, quinazolinyl, benzothiazolyl, quinoxalinyl, naphthyl, pyridyl, 1H-indazolyl, 1, 2, 3, 4-tetrahydroquinolinyl, benzofuranyl, thienyl, or indolyl, and one end of the linker, linker I, are clamped on! Arl) preferably in the 2-position of the ring portion. Another aspect of the compounds of the formula II is a 6-membered aryl or heteroaryl group and the linker I and linker II are linked at the 1,2-, 1,3- or 1,4-positions to each other. aspect of the compounds of the formula II is a compound wherein (Arll) is a naphthyl group, the linker I and the linker II are attached to (Arlli in positions 1,4-, or 2,4- among them in the Naphthyl portion Another aspect of the compounds of formula II is a compound wherein Arylene is 6-membered aryl or heteroaryl, and has a preferred position of binding of linker II and linker III in ring III at positions 1,2 between them. Another aspect of the compounds of formula II, is a compound wherein (ArlII) is a 6-membered aryl or heteroaryl and has a preferred position of binding of linker II and linker III on ring III at positions 1,2- , 1,3-, among them Another aspect of the compounds of the formula II, is a compound wherein ArlIlJ is a 6-membered aryl or heteroaryl, and has a preferred position of binding of linker II and linker III in the ring III in positions 1,4- among them. A further preferred aspect of the compound of formula II is described by formula V below: where Ri, R2, c, d, e, f, F, E and Z are in accordance with what is defined above, c + d = 1-3, and R 'and R "are substituents of a ring system. aspect of this invention is a compound of the invention wherein optionally substituted aryl, optionally substituted aryheteroaryl, or optionally substituted fused arylheterocyclenyl, aryl is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted fused arylheterocyclenyl, and (rlll) is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted fused arylheterocycloalkyl, or optionally substituted fused arylheterocyclenyl Another aspect of this invention is a compound of the invention wherein a = 1 or 2; Ri and R2 is hydrogen; A is a bond; chemical, and b = o Another aspect of this invention is a compound of the invention wherein a = 0; A is ; Ri5 and R_6 are hydrogen; g is 1, 2, or 3; and b = 0.

Another aspect of this invention is a compound of the invention wherein a = 0; A is NR? 3-, b = 1, R3 and R4 are hydrogen. Another aspect of this invention is a compound of the invention wherein a = 2; Ri radicals together with the carbon atoms with which the Ri radicals are bonded form an ethylene group; R2 is hydrogen; A is a chemical bond; and b = 0. Another aspect of the invention is a compound of the invention wherein a = 1.2 or 3; Ri and R2 are hydrogen; A is -0-; and b = 0. Another aspect of this invention is a compound of the invention wherein a = 1; R_, R2 R3 and R4 are hydrogen; A is - 0-; and b = 1. Another aspect of this invention is a compound of the invention wherein c = 1 or 2; Rs and are hydrogen or alkyl; B is a chemical bond; and d = 0. Another aspect of this invention is a compound of the invention wherein c = 2; neighboring radicals R5 together with the carbon atoms with which the radicals Rs are attached form an ethylene group; R6 is hydrogen; B is a chemical bond; and d = 0. Another aspect of this invention is a compound of the invention wherein c = 0 or 1; R_ and R_ are hydrogen; B is -0-; and d = 0 or 1. Another aspect of this invention is a compound of the invention wherein c = 0; B is -C (O) - or -S (0) 2; d = 1 and -i and R8 are independently hydrogen or alkyl. Another aspect of this invention is a compound of the invention wherein e = 0; f = 0; D and E are a chemical bond; Z is R__02SHNCO-, and R2? It is phenyl. Another aspect of this invention is a compound of the invention wherein e = 0; f = 0 or 1; D and E are a chemical bond; Z is tetrazolyl, NH.CO- or -C0_R_; and R2_ is hydrogen or lower alkyl. Another aspect of this invention is a compound of the invention wherein e = 0; f = 0 or 1; D is -O- or a chemical bond; E is a chemical bond; and Z is tetrazolyl, NB7CO- or -C02R2_; and R__ is hydrogen or lower alkyl.

Another aspect of this invention is a compound of the invention wherein e = 0; f = 1; D is -0- or a chemical bond; E is a chemical bond; Ru and R 2 are hydrogen or alkyl; and Z is tetrazolyl, NH2C0- or -C02R_ ?; and R2? it is hydrogen or lower alkyl. Another aspect of this invention is a compound of the invention wherein e = 2, then R. radicals together with the carbon atoms with which the R9 radicals are bonded form an ethylene group; f = 0; D and E are a chemical bond; and Z is -C02R_ ?; and R ?, is hydrogen. Another aspect of this invention is a compound of the invention wherein e = 0; f = 3; D is -0-; E is a chemical bond; R__ and R__ are hydrogen or alkyl, or at least one of Rn is carboxyl or alkoxycarbonyl; Z is tetrazolyl, or -C02R2 ?; and R2? it is hydrogen or lower alkyl. Another aspect of this invention is a compound of the invention wherein e = 0; f = 1,2 or 3; D is -C (O) -; E is a chemical bond, R__ and R_ are hydrogen or alkyl; Z is tetrazolyl or -CO.R.i; and R ?? it is hydrogen or lower alkyl. A preferred aspect of this invention is a compound of the present invention wherein (Arlj is a quinolinyl, quinoxalinyl, quinazolinyl, isoquinolinyl, N-alkyl-quinolin-4-onyl, quinazolin-4-onyl, benzoxazolyl, benzimidazolyl, benzothiazolyl group benzofuranyl, benzothiophenyl, indolinyl, oxazolyl, thiazolyl, oxadiazolyl isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, triazolyl, pyridylpyrimidinyl, pyrazinyl, pyridazinyl, phenyl, or optionally substituted naphthalenyl, wherein the substituent is a ring system substituent in accordance with as defined herein, more preferably a substituent selected from the group consisting of phenyl, substituted phenyl, thienyl, substituted thienyl, cycloalkyl, lower alkyl, branched alkyl, fluoro, chloro, alkoxy, aralkyloxy, trifluoromethyl, and trifluoromethyloxy. of this invention is a compound of the invention wherein (Arl) is quinolin-2-yl unsubstituted, q uinolin-2-yl substituted in position 3, quinolin-2-yl substituted in position 4, quipolin-2-yl substituted in position 6 or quinolin-2-yl substituted in position 7; an unsubstituted quinozalin-2-yl, substituted cholothalin-2-yl in position 3, quinozalin-2-yl substituted in position 6 or quinozalin-2-yl disubstituted in positions 3,6; unsubstituted quinazolin-2-yl, quinazolin-2-yl substituted in position 4 or quinazolin-2-yl substituted in position 6; unsubstituted isoquinolin-3-yl, isoquinolin-3-yl substituted in position 6 or isoquinolin-3-yl substituted in position 7; quinazolin-4-on-2-yl substituted in position 3; N-substituted quinolin-4-on-2-yl; oxazol-4-yl substituted in position 2 or oxazol-4-yl disubstituted in positions 2,5; oxazol-2-yl substituted in position 4 or oxazol-2-yl disubstituted in positions 4,5; thiazol-4-yl substituted in position 2 or thiazol-4-yl disubstituted in positions 2,5; thiazol-2-yl substituted in position 4 or thiazol-2-yl disubstituted in positions 4,5; [1, 2, 4] oxadiazol-3-yl substituted in position 5; [1, 2, 4] oxadiazol-5-yl substituted in position 3, imidazol-2-yl substituted in position 5 or imidazol-2-yl disubstituted in positions 3,5; imidazol-5-yl substituted in position 2 or imidazol-5-yl disubstituted in positions 2,3; isoxazol-5-yl substituted in position 3; isoxazol-3-yl substituted in position 5; [1, 2, 4] thiadiazol-3-yl substituted in position 5; [1, 2, 4] -thiadiazol-5-yl substituted in position 3; [1, 3, 4] -thiadiazol-5-yl substituted in position 2; [1, 3, 4] -oxadiazol-5-yl substituted in position 2; pyrazol-3-yl substituted in position 1; pyrazol-5-yl substituted in position 3; [1, 2, 4] -triazol-5-yl substituted in position 3; [1, 2, 4] -triazol-5-yl substituted in position 1; pyridin-2-yl substituted in position 3; pyridin-2-yl substituted in position 5; pyridin-2-yl substituted in position 6 or pyridin-2-yl disubstituted in positions 3,5; pyrazin-2-yl substituted in position 3, pyrazyl-2-yl substituted in position 5, pyrazin-2-yl substituted in position 6 or pyrazin-2-yl disubstituted in positions 3,5; substituted pyrimidin-2-yl in position 5 or pyrimidin-2-yl substituted in position 6; pyridazin-3-yl substituted in position 6 or pyridazin-3-yl disubstituted in positions 4,6; unsubstituted naphthalene-2-yl, naphthalene-2-yl substituted in position 3, naphthalene-2-yl substituted in position 4, naphthalene-2-yl substituted in position 6 or naphthalen-2-yl substituted in position 7; phenyl substituted in position 2, phenyl substituted in position 4, phenyl disubstituted in positions 2,4; unsubstituted benzothiazol-2-yl or benzothiazol-2-yl substituted in position 5; unsubstituted benzoxazol-2-yl or benzoxazol-2-yl substituted in position 5; unsubstituted benzimidazol-2-yl or benzimidazol-2-yl substituted in the 5-position; unsubstituted thiophen-2-yl, thiophen-2-yl substituted in position 3, thiophen-2-yl substituted in position 6 or thiophen-2-yl disubstituted in positions 3,6; unsubstituted benzofuran-2-yl, benzofuran-2-yl substituted in position 3, benzofuran-2-yl substituted in position 6 or benzofuran-2-yl disubstituted in positions 3, 6; 3-substituted benzofuran-6-yl or 3-disubstituted benzofuran-6-yl at positions 3,7, wherein the substituent is a ring system substituent as defined herein, more preferably a substituent selected from the group which consists of phenyl, substituted phenyl, thienyl, substituted thienyl, cycloalkyl, lower alkyl, branched alkyl, fluoro, chloro, alkoxy, aralkyloxy, trifluoromethyl and trifluoromethyloxy. Another more preferred aspect of this invention is a compound of the invention wherein R_ and R2 are both H, a = 1, A is -0- and b = 0. Another most preferred aspect of this invention is a compound of the invention wherein Ri and R2 are both H, a = 2, A is -0- and b = 0. Another more preferred aspect of this invention is a compound of the invention wherein a = 0, A is -0- or -NR13-; R_ is hydrogen or alkyl; R3 and R4 are both, independently, hydrogen; and b = 1. Another more preferred aspect of this invention is a compound of the invention wherein a = 0, A = -O- or -NR13-; R13 is hydrogen or alkyl; R3 and R4 are both independently hydrogen; b = 1; and Arl is quinolin-2-yl substituted in position 3, quinolin-2-yl substituted in position 4, quinolin-2-yl substituted in position 6, quinolin-2-yl substituted in position 7, quinoxalin-2-yl unsubstituted, quinoxalin-2-yl substituted in position 3, quinoxalin-2-yl substituted in position 6, quinoxalin-2-yl disubstituted in positions 3,6, quinazolin-2-yl unsubstituted, quinazolin-2-yl substituted in position 4, quinazolin -2-yl substituted in position 6, unsubstituted isoquinolin-3-yl, isoquinolin-3-yl substituted in position 6, isoquinolin-3-yl substituted in position 7, oxazol-2-yl substituted in position 4, oxazol-2 ilo disubstituted in positions 4,5, thiazol-2-yl substituted in position 4, thiazol-2-yl disubstituted in positions 4,5, imidazol-2-yl substituted in position 5, imidazol-2-yl disubstituted in positions 3, 5, pyrazole-3-yl substituted in position 1, pyrazol-5-yl substituted in position 3, pyridin-2-yl substituted in position 3, pyridin-2-yl substituted in posi 5, pyridin-2-yl substituted in position 6 or pyridin-2-yl disubstituted in positions 3,5, pyrazin-2-yl substituted in position 3, pyrazin-2-yl substituted in position 5, pyrazin-2 ilo substituted in position 6, disubstituted pyrazin-2-yl in positions 3,5, pyrimidin-2-yl substituted in position 5, pyrimidin-2-yl substituted in position 6, pyridazin-3-yl substituted in position 6, pyridazin- 3-disubstituted ilo in positions 4,6, unsubstituted benzothiazol-2-yl, benzothiazol-2-yl substituted in position 5, unsubstituted benzoxazol-2-yl, benzoxazol-2-yl substituted in position 5, unsubstituted benzimidazol-2-yl , benzimidazol-2-yl substituted in position 5, benzofuran-6-yl substituted in position 3 or benzofuran-6-yl disubstituted in positions 3,7. Another aspect of the present invention is a compound of the formula I in accordance with that described by the formula (la) wherein I rjjy (Arll) are independently fused aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl or fused heteroarylheterocyclyl; c + d = 1 or 2; B is -O-; Rs, R6 R-7 / Re are independently hydrogen e = 0; f = 0; D and E are a chemical bond; Z is R.iO.C-, R2? OC-, cycloimide, -CN, R..O.SHNCO-, R2? 02SHN-, (R2i) _NC0-, R.?O-2, 4-thiazolidinedione or tetrazolyl; R 'and R "are ring system substituents as defined herein, more preferably R' is lower alkyl, halo, alkoxy, aryloxy or aralkyl, and R" is lower alkyl or halo. Another aspect of this invention is a compound of formula I in accordance with that described by formula (la) below: fused enyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl or fused heteroarylheterocyclyl; c + d = 1 or 2; B is -O-; Rs # Re, R7, Re are independently hydrogen; e = 0; f * 0; Dy E are a chemical bond; Z is -C02H; R 'and R "are ring system substituents as defined herein, more preferably R' is lower alkyl, halo, alkoxy, aryloxy or aralkyl, and R" is lower alkyl or halo. Another aspect of this invention is a compound of formula I in accordance with that described by formula (la) below: where: a = 0-2; b = 0-1; A is -O- or -NR_3-; c + d = 1 or 2; B is -O-; Ri, R2, R3, R4, Re, Re / Ri, and R? they are independently hydrogen; R_3 is hydrogen, R22OC-, or alkyl; e = 0; f = 0; D and E are a chemical bond; Z is -C02H; R 'and R "are ring system substituents as defined herein, more preferably R' is lower alkyl, halo, alkoxy, aryloxy or aralkyl; and R" is lower alkyl or halo. A more preferred aspect of this invention is a compound of formula I in accordance with that described by the formula (la) where: a = 1 or 2; A is -O-; b = 0; Ri, R2, R7 and Re are independently hydrogen; (Arll J is optionally substituted phenyl; c = 0; B is -O-; d = 1; e = 0; f = 0; D and E are a chemical bond; R 'is hydrogen, halo or benzyloxy; R "is lower alkyl, preferably methyl, Z is -C02H A more preferred aspect of this invention is a compound of formula I according to that described in formula (la) wherein: a = 1 or 2; A is -O-, b = 0, Ri, R_, R5 and R6 are independently hydrogen, (Arll) is optionally substituted phenyl, c = 1, B is -0-, d = 0, e = 0, f = 0; D and E is a chemical bond: R 'is hydrogen, halo or benzyloxy; R "is lower alkyl, preferably methyl; Z is -C02H. A more preferred aspect of this invention is a compound of formula I in accordance with that described in formula (la) wherein: a = 1 or 2; A is -0-; b - 0 Ri, R 2, R 7, R 8, Ru and R 2 are independently hydrogen; (Arll) is optionally substituted phenyl; c = 0 B is -0-; d = 1, e = 0, f = 1. D and E are a chemical bond; R 'is halo; R "is lower alkyl, preferably methyl, Z is -C02H A more preferred aspect of this invention is a compound of formula I in accordance with that described by the formula (la) where: a = 1; A is -O-; b is 0; c = 0-1; B is -O-; d is 0 or 1; where c + d = 1 or 2; e = 0; f = 0; D and E are a chemical bond; R 'is hydrogen, aralkoxy, or halo; R "is lower alkyl, preferably methyl, Z is -C02H A more preferred aspect of this invention is a compound of formula I in accordance with that described by the formula (la) where: a = 1; A is -O-; b = 0; c = 0; B is -O-; d = 1; e = 0; f = 0; D and E are a chemical bond; R 'is hydrogen; R "is lower alkyl, Z is -C02H A more preferred aspect of this invention is a compound of formula I in accordance with that described by the formula (la) wherein: (Arl) and (Arll) are aryl or heteroaryl; a = 1; A is -O-; b = 0; c = 0; B is -O-; d = 1; e = 0; f = 0; D and E are a chemical bond; R 'is hydrogen; R "is lower alkyl, Z is -C02H A more preferred aspect of this invention is a compound of formula I in accordance with that described by the formula (la) wherein: Arl) is optionally substituted azaheteroaryl; fArll) is optionally substituted phenyl; a = 1; A is -O-; b = 0; c = 0; B is -O-; d = 1, e = 0; f = 0, D and E are a chemical bond; R 'is hydrogen; R "is lower alkyl, Z is C02H A more preferred aspect of this invention is a compound of formula I in accordance with that described by the formula (la) wherein: (optionally substituted quinolinyl aryl, or a 5-membered heteroaryl group wherein the heteroaryl group is substituted by optionally substituted phenyl or optionally substituted cyclohexyl; ArlIJ is optionally substituted phenyl; a = 1; A is - O-; b = 0, c = 0, B is -0-, d = 1, e = 0, f = 0, D and E are a chemical bond, R 'is hydrogen, R "is lower alkyl, Z is C02H Compounds according to the present invention are selected from the group consisting of: C? O ^ S: ( twenty A preferred compound according to the present invention is selected from the group consisting of: A more preferred compound according to the present invention is selected from the group consisting of a preferred compound according to the invention having PPARa and PPAR? is in accordance with the following formula: A preferred compound according to the present invention which is selective for PPARa is selected within the group consisting of: XXXXTS and A preferred compound according to the invention that is selective for PPARd is of the formula: A preferred compound according to the invention that is selective for PPARd and PPAR? is selected within the group which consists of: and A preferred compound according to the present invention that is selective for PPARa and PPARd is selected within the group consisting of: and More preferred compounds of the present invention having a PPAR activity? They have the formula: This invention also encompasses all combinations of preferred aspects of the invention mentioned herein. Useful compounds according to the invention can be prepared in segments as is common for a long chain molecule. Therefore, it is convenient to synthesize these molecules by using condensation reactions at sites A, B and D of the molecule. Compounds of the formula I can be prepared by the application or adaptation of known methods, said methods being the methods used to date or described in the literature. Compounds of the formula I can be prepared by recognized processes from known compounds or easily preparable intermediates. Thus, for the purpose of preparing a compound of the formula below, wherein Z is generally CN or C02R (I) The following reactions or combinations of reactions can be used: Scheme 1 Scheme 2 Scheme 3 In the above schemes (1-3) a displacement reaction can be employed where A, B and D are O, S or NR, and L is a leaving group such as halo, tosylate or mesylate. A base such as for example sodium hydride, sodium hydroxide, potassium carbonate or triethylamine can be used when A, B or D is 0 or S. An alternative coupling reaction is the Mitsunobu reaction (diethylazodicarboxylate / triphenylphosphine see synthesis, 1981, 1) . This chemistry can be used to condense fragments when the functionality lends itself to this reaction. An example of this would be the coupling of compounds of scheme 1 where formula VI (L = OH, a >; 0) and formula VII (A = 0, b = 0). The reaction temperatures are within a range of about -78 ° C to 80 ° C and the reaction times vary from about 1 hour to 48 hours. The reactions are usually carried out in an inert solvent that dissolves the reagents. Solvents include, but are not limited to, N, N-dimethylformamide, acetone, acetonitrile, tetrahydrofuran. Alternatively, the reactions shown in schemes 1-3 can be achieved by employing a fragment of the formula described. For example, as shown in scheme 4, a compound of formula VI (scheme 1) can be combined with a compound of formula VII, wherein formula VII optionally contains Ar III and Z. This notation used for the Formula VII in scheme 4 is used throughout this document and is used to generalize the reaction described.

Accordingly, all reactions of schemes 1-3 can be achieved as shown or by using a fragment of the formula described. In some cases, the use of a protecting group may be required when a fragment of the formula is used Scheme 4 A method for the preparation of compounds wherein Z = tetrazole is the reaction of an intermediate product wherein Z = CN with sodium azide and ammonium chloride at an elevated temperature. A method for the preparation of compounds wherein Z = C02H, is the hydrolysis of an intermediate product in which Z is CN or C02R. This can be achieved under acidic or basic conditions, the preferred method is generally sodium or potassium hydroxide in a protic solvent such as for example aqueous ethanol at a temperature of about 20 ° C to 100 ° C. An alternative method for the conversion of a nitrile in a carboxylic acid is to reduce the nitrile in the corresponding aldehyde using a reducing agent such as for example diisobutylaluminum hydride, followed by oxidation of the aldehyde in the carboxylic acid using a reagent such as sodium chlorite, sodium dihydrogen phosphate, isobutene (cf. , JACS 1980, 45, 1176) or other standard conditions. Another alternative method for the preparation of compounds wherein Z = C02H is the oxidation of a primary alcohol using an appropriate oxidant such as PDC in DMF, RuCl3 / NalO. in 3: 2: 2 water acetonitrile: CC14 or the S erm system (to produce the intermediate aldehyde and then oxidation of this functionality in the carboxylic acid according to what is described above). Some other methods for the preparation of compounds where Z = C0? H appear in scheme 5. A carboxylic acid (2) can be generated directly by halogen-metal exchange of the corresponding aromatic halide (1) with an alkyllithium reagent such as n-butyllithium, followed by quenching of the resulting anion with carbon dioxide. Alternatively, an alkoxycarbonylation of an aromatic bromide, iodide or triflate in an atmosphere of carbon monoxide in the presence of a suitable alcohol (usually methanol) can be achieved using a catalyst such as Pd (PPh3) 2Cl / Et2NH, Pd (Ph_P ( CH2) 3PPh _) _ / Et3N or alternatively cobalt, ie Co (OAc) 2, plus a base (NaH or K.CO.). The resulting benzoate (3) is then converted to% acid benzoic acid by hydrolysis according to what is described above.

Scheme 5 The preparation of phenylacetic acid derivatives can be achieved from an appropriate aryl halide or triflate as shown in scheme 6. A Stille coupling of this type of compound with a vinyl stannane using a palladium catalyst or for example Pd (OAc) _, P (o-tolyl)., provides an olefin (5). Hydroboration of this vinylbenzene derivative, followed by oxidation of the primary highlighting alcohol with an oxidant, such as for example Jones reagent, provides the phenylacetic acid (6).

X = Br. 1. OTf Scheme 6 In one embodiment of the present invention, Arl can be a five-membered ring heterocycle thereby generating structures of the general formula shown in Figure 1.

W »CR ,. N: X • CR ,. N; AND CR,. t * 2 »S. O. NR, Figure 1 In particular, the heterocycle can be thiazole, oxazole, oxadiazole, imidazole, isoxazole, pyrazole, thiadiazole or substituted triazole. These systems can be prepared using methods known in the chemical literature (for reviews, see Katritzky, AR, Rees, CW Eds. Comprehensive Heterocyclic Chemistry, Vol. 5, Pergarr.on Press (1984), Katritzky, AR, Rees, CW, Scriven , EFV Eds. Comprehensive Heterocyclic Chemistry II, Vols. 3 and 4, Pergamon Press (1996)). More specifically, oxazoles, imidazoles and thiazoles can be prepared by melting an amide, amidine or thioamide, respectively, with an a-halo-ketone at temperatures within a range of about 40 ° C to 150 ° C (scheme 7) .

Scheme 7 These reactions can be carried out clearly or in a solvent such as toluene, dichlorobenzene, or ethanol. Substituted oxazoles can also be prepared from a diazoketone and a nitrile using BF3 etherate (Scheme 8), Ibata, T; Isogami; Y. Bull. Chem. Soc. Jpn. 1989, 62, 618).

Scheme 8 1, 2, 4-Oxad? Azoles can be prepared by reaction of a nitrile with hydroxylamine followed by condensation of the resulting hydroxyamidine with an acid chloride in the presence of a base and heating the adduct in a solvent such as toluene or dichlorobenzene to effect ring closure. (Scheme 9, Banavara, L.M., Beyer, T.A., Scott, P.J., Aldmger, CE, Dee, M.F., Siegel, T.W .; Ze browsky, W.J.J. Med. Chem., 1992, 35, 457).

R-C-ßN NH2 ° H Scheme 9 1, 3, 4-Oxadiazoles (scheme 10) are prepared by the condensation of an acyl hydrazide with a synthon acid (such as, for example, ester, acyl azide, acid chloride), then by cyclization of the resulting diacyl hydrazide by heating in a solvent such as for example benzene or ethanol with or without an acid catalyst such as for example sulfuric acid (for examples, see Weidinger, H., Kranz, J. Chem. Ver., 1963, 96, 1049 and Vakula, TR; Srinivarsan , VR Indian J. Chem. 1973, 11, 732).

Scheme 10 Substituted 1, 2, 4-thio azoles can be prepared by condensation of a thioamide with dimethylacetal derivative of N, N-dimethylamide in a solvent such as benzene (scheme 11, MacLeod, A., Baker, R., Freedman, SF, Patel, S., Merchant, KJ, Roe, M. Saunders, JJ Med. Chem. , 1990, 33, 2052, also Patzel, M. Liebscher, J., Siegfried, A. Schmitz, E. Synthesis, 1990, 1071) followed by reaction with an electrophilic amination agent such as, for example, mesitylsulfonyloxyamine in methanol or dialkyloxaziridine in a solvent such as toluene.

Scheme 11 In another embodiment of this invention, Arl can be a 1,3,4-thiadiazole. This system is assembled by condensation of a dithioester with an ester salt of imidate in a solvent such as ethanol at a temperature between room temperature and reflux (scheme 12. Stillings, MR, Welbourn, AP, Walter, DSJ Med. ., 1986, 29, 2280). The dithioester precursor is obtained from a corresponding Grignard reagent and carbon disulfide / Mel. The imidate ester is prepared from the corresponding nitrile by reaction with HCl gas in the presence of an appropriate alcohol.

R 'Br or BuLi / THF / MgBr2 -78 ° C - room temperature NH_ H_; ethanol after H CN In scheme 12, pyrazoles can be prepared by condensation of 1, 3-icetone (scheme 13) or a synthetic envalent with substituted hydrazine (eg, a β-aminoenone, Alberola, A., Calvo, L., Ortega, AG, Sadaba. , HL; Sañudo, MC; Granda, SG; Rodríguez, EG "..," eterocycies, 1999, 51, 2615).

In a similar manner, isoxazoles can be prepared by reaction of a 1,3-dicarbonyl compound with a hydroxylamine (scheme 14. Pei, Y .; Wickham, BOS; Tetrahedron Letts, 1993, 34, 7509) in a solvent such as for example ethanol at a temperature between 20 ° C and reflux temperature.

Scheme 14 Alternatively, isoxazoles can be prepared by the condensation of a hydroxamyl chloride with an alkyne (scheme 15, Kano, H., Adachi, I., Kido, R., Hirose, K, J.

Med. Chem. 1967, 10, 411) in the presence of a base such as for example triethylamine. The hydroxamyl chloride unit can, in turn, be prepared from the corresponding oxime by oxidation with chlorine gas at low temperature (such as -60 ° C) in a solvent such as ether (Casanti, G. Rica, A., Tetrahedron Let t., 1967, 4, 327).

Scheme 15 Triazoles are prepared by the Einhorn-Brunner reaction or a variant thereof (scheme 16) In addition, 1, 2, 4-triazoles substituted by 5-hydroxy ethyl can be prepared by condensation of an imidate ester with a 2-hydroxy-acetohydrazide unit (scheme 17, Browne, EJ; Jun, EE; Polya, JBJ Chem. Soc, C 1970, 1515).

Scheme 17 Five-member heterocycles formed in this manner may, in some cases, be directly coupled to a fragment containing Arll using a standard methodology presented in detail elsewhere in the description of this invention (schemes 1-4). These methods include the alkylation of a metal alkoxide containing Arll with a heterocycle substituted by chloromethyl, or conversely, the alkylation of a heterocycle having a hydroxyl (in the presence of a base) with a reactive Chloromethyl containing Arll. In another approach to fragment condensation, substituents on the preformed heterocycle are first modified to incorporate a suitable reactive functionality and then this system is coupled to a fragment containing Arll. For example (scheme 18), the treatment of a 1,4-disubstituted imidazole with a base such as for example n-butyllithium at a temperature of about -78 ° C followed by alkylation of the resulting anion with an electrophilic such as, for example, ethylene provides the imidazole substituted by hydroxyethyl (other useful electrophiles are DMF or formaldehyde For examples, see Manoharan, TS; Brown, RSJ Org Chem. 1989, 54, 1439). This intermediate product can then be coupled to a fragment of Arll which contains an aromatic alcohol through a Mitsunobu reaction.

Scheme 18 Another example of this general approach appears in scheme 19. A ring substituent such as for example an ester can be reduced in the corresponding alcohol using a reagent such as for example lithium aluminum hydride or lithium borohydride in a solvent, such as for example, THF or ether. This is followed by halogenation of the resulting alcohol with a reagent system such as NCS / Ph3P, Ph.P / Br2 or PBr3 (Pei, Y .; Wickham, B.O.S; Tetrahedron Lett., 1993, 34, 7509). The alkyl halide produced in this way can be coupled with a nucleophilic substituent attached to Arll, using a base, such as K2C0. in the case of an aromatic alcohol, (thiol) or NaH in the case of an alcohol at Scheme 19 In a third general approach towards fragment condensation, Arll can be incorporated into a precursor of the five-membered heterocycle. For example (scheme 20) the amination of the 3-aryl-propionate and the resulting thionation of the amide offer a functionalized system suitable for the synthesis of thiazole ring. Similarly, the formation of thio-urea from the aryl eti lamina (via B) offers a suitable precursor for the fusion with a? -halo ketone leading to the obtaining of a thiazole substituted by 2-amino (Collins, J.L .; Blapchard, S.G .; Boswell, G.E .; Charifson, .; Cobb, J.E .; Henke, B.R .; Hull-Ryde, E.A .; Kazmierski, W.M .; Lake, D.H .; Leesnitzer, L.M .; Lehmann, J .; Lenhard, J.M .; Orband-Miller L.A .; Gray-Nunez, Y .; Parks, D.J .; Plunkett, K. D .; Tong, Wei-Qin. J. Med. Chem. 1998, 41, 5037). 2. Lawesson's reagent Scheme 20 In another embodiment of this invention, Arl is a five-membered heterocycle of the general formula shown in Figure 2.

W = CRi; N; X = CR :, N; Y = CRi, N; Z = CR; N Provided that when A = 0, N or S then "a" is > 1. Figure 2 In particular, this heterocycle can be a pyrazole, an imidazole or a triazole. These systems can be prepared by alkylation of an N-unsubstituted heterocycle using a base such as for example sodium hydride, in a solvent such as DMF, THF, DMPU or a combination of these solvents, at a temperature of 0 ° C or about 0 °. C and an electrophilic such as, for example, alkyl halide, cyclic carbonate or epoxide (scheme 21).

W = CR. N. X = CR. N. Y = CR, N. Z = CR N Scheme 21 These electrophiles can incorporate Arll or the alkylation products can be additionally modified and coupled to a fragment containing Arll in a subsequent step in accordance with what is described above. For example (scheme 22), 3,5-disubstituted pyrazole is prepared by the reaction of an aldehyde with a β-tosylhydrazinophosphonate, using the literature procedure (Admiral, N.; Benicchio, A .; Cerri, A .; Fedrizzi, G .; Marazzi, G .; Santagostino, M. Synlet t 1999, 299). This intermediate product can be rented cor. sodium hydride / ethylene carbonate in DMF (for a specific example, see Collins, JL; Blanchard, SG; Boswell, GE; Charifson, PS; Cobb, JE; Henke, BR; Hull-Ryde, EA; Kazmierski, WM; Lake, DH; Leesnitzer, LM; Lehmann, J .; Lenhard, JM; Orband-Miller LA; Gray-Nunez, Y .; Parks, DJ; Plunkett, KD; Tong, Wei-Qin., Med. Chem. 1998 , 41, 5037). This intermediate product can be coupled in turn with a fragment containing Arll through a Mitsunobu reaction in accordance with that described above. 2 equivalent of NaH RCHO after reflow 1. NaH / ethylene carbonate Scheme 22 In another embodiment of this invention, Arl is benzene, pyridine, pyrimidine, pyrazine or substituted pyridazine (figure 3). These systems can be prepared by applying several of the general synthetic methods presented in detail elsewhere in the description of this invention.

W = CR ,. N. X - CR ,. N; Y = CR ,. N; Z = CR, N Figure 3 More specifically (scheme 23), the treatment of the known 5-bromo-2-methy1pyridine (Graf, J. Prakt, Chem., 1932, 133, 19) with LDA and then formaldehyde in THF at low temperature (typically approximately -78 ° C) followed by Mitsunobu coupling of the resulting alcohol with an aromatic alcohol containing Arll provides the bromo-pyridine derivative which can be further modified to provide various pyridines substituted by alkyl and aryl by cross coupling with alkyl or aryl organometallic appropriate with palladium or nickel catalysis (for general reviews, see Knight, DW and Billington, DC in Comprehensive Organic Synthesis) Vol. 3, page 413 and 481, Trost, BM and Fleming, I; Eds. Pergamon Press 1993).

Scheme 23 Similar procedures employing the appropriate 5-bromo-2-methyl-pyridymine (Kosolapoff, GM, Roy, CHJ Org. Chem. 1961, 26, 1895), 2-iodo-5-methyl-pyrazine (Hirshberg, A. Spoerr, PE; J. Org. Chem., 1961, 26, 1907) and 3-bromo-6-methyl-pyridazine (Countereot-Potman, A., van der Pias, HC; J. Heterocyclic Chem., 1983, 20, 1259) offer access to the corresponding pyrimidines, pyrazines and pyridazines, respectively. In another variant of this general class, Arl is a pyridazine substituted by 3-heteroatom. For example (scheme 24), the treatment of the known -3,6-dibromo-pyridazine with a metal alkoxide (containing Arll and corresponding alcohol derivative and sodium hydride) in a solvent such as DMSO offers the bromo- pyridazine substituted by alkoxy. The bromide can be converted into a range of substituents in accordance with that described above for the pyridines. In particular, the coupling of Suzuki with a boronic acid in the presence of a base and a palladium catalyst provides the corresponding aryl-substituted pyridazines.

Scheme 24 In another embodiment of this invention, Arl can be a substituted quinoxaline (Figure 4). These systems are assembled by condensation of a 1,2-dicarbonyl compound with 1,2-diaminobenzene (for review see Katritzky, AR, Rees, CW, Scriven, EFV Eds. Comprehensi ve Heterocyclic Chemi s try II, vol 6 Pergamon Press (1996).

Figure 4 The functionalization of these systems and the coupling with Arll can be carried out using procedures described for the related pyrazines. For example (scheme 25), the condensation of 1,2-diamino-benzene with 2,3-butadione gives the 2,3-dimethylquinoxaline. N-oxidation of this intermediate product with a peroxycarboxylic acid and treatment of the product with acetyl chloride provides 2-chloromethyl-3-methyl-quinoxaline (Ahmed, Y .; Aviv, MS; Bakhtiari, B. Bakhtiaria, ZJ Org Chem., 1996, 31, 2613). This intermediate product is then coupled with a fragment containing Arll under standard conditions. 1 . butan-2, 3-dione a Scheme 25 In another embodiment of the present invention Arl can be a quinazoline (scheme 26). Such systems are commonly prepared by condensation of an o-amino-benzaldehyde or o-amino-aryl-ketone derivative with an acid chloride followed by heating with ammonia. For example, the condensation of o-amino-benzaldehyde with acetyl chloride in the presence of pyridine followed by reaction of the product with ammonia. ethanolic at room temperature (Armarego, W.L.F .; Smith, J.I.C. J. Chem. Soc., C, 1966, 234) provides a quinazoline substituted by 2-chloromethyl which can be coupled with a fragment containing Arll in accordance with that described above. x = 0, NR, S Scheme 26 The related quinazolin-4-one ring system (scheme 27) can be prepared by condensation of an o-amino-benzonitrile or an acid chloride followed by ring closure using a reagent such as, for example, urea hydrogen peroxide in the presence of a base such as potassium carbonate (Bavetsias, V. Synth, Commun, 1998, 28, 4547). In another variant of the quinazoline system, quinazolines substituted by 4-heteroatom can be prepared by condensation of an amino-benzonitrile with chlorocetonitrile in the presence of an acid such as for example HCl or HBr (Chhabria, MT; Shishoo, CJ Heterocycles 1999, 51 , 2723). The resulting system can be coupled with Arll in accordance with what is described above. The 4-halo substituent can then be modified by nucleophilic displacement by a metal alkoxide in a solvent such as DMSO. . urea hydrogeperoxide / K2C03 Scheme 27 A general reaction for the preparation of reagents for compounds of formulas VI, IX, X, XIII and XIV (schemes 1-3) is shown in scheme 28. The halogenation of aromatic substituted by methyl with a reagent as for example N -bromosuccinimide under free radical conditions offers the aromatic reagents substituted by halomethyl.

Ar Ar V-CHj pero or AlBN Scheme 28 An alternative preparation of certain alkylation reagents is shown in Scheme 29. For example, substituted 2-chloromethylquinoline derivatives can be prepared using a two-step procedure (see J. Med. Chem. 1991, 34, 3224). Oxidation of the nitrogen to form the N-oxide can be achieved with an oxidant such as m-chloroperbenzoic acid or hydrogen peroxide. Reaction of the N-oxide with a reagent "such as toluene sulfonylchloride at elevated temperatures can produce the white chloromethyl derivative.This chemistry can also be extended to 2-picoline derivatives where the 6-position is not hydrogen.

Also Scheme 29 The preparation of reagents that can be employed as alkylating agents of formula VI (scheme 1) is shown in scheme 30. With the quinoxaline ring system, the use of trichloroisocyanuric acid (TCC) can produce the analog of corresponding chloromethyl (see, Chem. Ver. 1987, 120, 649).

In a particular embodiment of this invention, B of formula I can be an amide linker of any of the general forms shown in Figure 5. Compounds of this formula can be prepared from a carboxylic acid fragment and an amine fragment using standard peptide coupling reagents. They can also be prepared by reaction with an activated carboxylic acid derivative such as, for example, without limitation, acid chloride or acid anhydride in combination with an amine fragment in the presence of a suitable base such as for example triethylamine. It should be clear that essentially the same procedures can be employed in the case in which the group A of the formula I is an amide, using the appropriate carboxylic acid and amine fragments.

More specifically, the benzoic acid system substituted in the 6-position by 2-aminomethyl (7) can be prepared using the chemistry shown in scheme 31. A selective reduction of the substituted phthalic anhydride (9) with a sterically hindered lithium trialkylhydride, such as for example L-selectride, provides lactone (10) in a regioselective manner (see Krishnamurthy, Heterocycles, 1982, 18, 4525). Reaction of this lactone with potassium phthalamide provides the protected amine according to the procedure of Bornstein, Org. Syn. Collective Vol IV, 1963, 810. Removal of the phthalimide protecting group using standard deprotection conditions with hydrazine can provide the amino acid (7).

Scheme 31 Half-esters of 1,2-carboxylic acid such as 12 (scheme 32) are precursors of structures linked to amides (Figure 5) wherein the fragment containing ArlII is the acyl donor. These systems can be prepared in various ways: alcoholysis of phthalic anhydride (9) can provide an isomer selectively (11) smaller amounts of isomer (12). Esterification to provide the diester (13) can be achieved using various conditions, as for example Fisher esterification. Hydrolysis of the diester can provide the regioisomer (12) as the main isomer in addition to the isomer (11).

Scheme 32 Phthalic anhydride derivatives such as (9) can, in turn, be prepared from the corresponding diacid (14) as shown in scheme 33 using, but not limited to, dehydration conditions such as hot acetic anhydride.

Scheme 33 In one embodiment of this invention, ArlII- (CR9R? O) e-D- (CRnRi.) F-E-Z together constitutes a substituted benzoic acid. A useful sequence of reactions for constructing this type of system is shown in scheme 34. A lactone (obtained according to that described in scheme 31) can be heated with hydrobromic acid to provide the bro or ethylcarboxylic acid. The carboxylate can be esterified by the preparation of the acid chloride, followed by reaction with an alcohol to provide an intermediate bromide which can be used as presented in scheme 2, formula XIII.

Scheme 34 A substitution pattern of alternative benzoate can be accessed using the Alder-Rickert reaction as shown in Scheme 35 (see J. Org Chem. 1995, 60, 560). A 2-silyloxydiene can be formed from an enone using a strong base such as for example LDA and trapping the enolate with a silylating reagent. The heating of this diene with an acetylene dicarboxylate at elevated temperatures can then provide the Alder-Rickert product. The alkylation of the phenolic hydroxyl under standard conditions (using the alkylation reagent R'-L, wherein L is a leaving group) followed by saponification of the diester can provide a diacid intermediate which can be handled in accordance with the chemistry described in Figures 31-34 to provide intermediates useful for the preparation of compounds of formula I.

X = halide, o-alkyl, alkyl Scheme 35 Another particular embodiment of this invention is a mode in which the substituted benzoic acid moiety described above has a substituent pattern of 6-alkyl-2-alkoxy. The preparation of this type of system is illustrated using the 6-methyl derivative shown in scheme 36 (see Hamada, Tetrahedron, 1991, 47, 8635). Ethyl acetoacetate and crotonaldehyde can be condensed to form the cyclic β-ketoester. The subsequent aromatization mediated by lithium chloride / dichloride of this intermediate product can be achieved at elevated temperatures to provide the white salicylate ester. The phenolic hydroxyl of this system can be further derivatized by alkylation in accordance with what is presented elsewhere in the description of this invention.

Esquena 36 Additionally, 6-alkyl-2-alkoxy benzoate systems can be prepared by nucleophilic aromatic substitution of a 2-fluorobenzaldehyde, at elevated temperatures, with an alkoxide (scheme 37) to produce a 2-alkoxy-benzaldehyde. Oxidation of the aldehyde in the acid can be achieved using conditions such as sodium chlorite, sodium dihydrogen phosphate, isobutene (see, JACS 1980, 45, 1176).

In another embodiment of this invention, B of formula I can be a sulfur atom that forms a thioester bond (scheme 2, formulas XI and XII). This type of system can be prepared by standard alkylation of thiols using a suitable base (such as for example sodium or potassium carbonate, hydroxide, hydride or an amine such as triethylamine) to form a thionyl anion and then by the reaction of this species with an appropriate electrofile such as for example alkyl halide or sulfonate ester. Similarly, groups A and D of formula I can also be, independently, a sulfur atom. It should be clear that the same transformations described in the following schemes can be applied to the compounds of the formulas (VII, VIII, XI, XII and XVI, schemes 1-3). Aromatic thiols can be prepared from the corresponding phenols. For example, the preparation of a 2-thio-benzoate (10) from the salicylate (7) can be carried out in accordance with that shown in scheme 38.

(See, Guise J. Chem Soc., Perkin Trans. 1, 1982, 8, 1637). The thionocarbamate (8) can be obtained from the corresponding phenol (7) using a thiocarbamoyl chloride. The pyrolysis of (8) (temperature greater than 300 ° C) can provide the rearrangement product (9), which, through hydrolysis, can provide the thiol (10).

Scheme 38 Another transformation of useful ring substituent is the conversion of an aniline to an aromatic thiol. As shown in Scheme 39, the diazotization of an aniline such as (11") is followed by the conversion of the diazonium salt (12) into a disulfide (13) using sodium sulfide. / acetic acid can provide thiol (14) (see Guise, J. Chem. Soc., Perkin Trans. 1, 1982, 8, 1637).

Scheme 39 In a particular embodiment of the invention, Ar 11 can be an aromatic substituted by halo. The synthesis of a particularly relevant system is shown in scheme 40. A regioselective halogenation of a disubstituted phenol at positions 2,6 to provide a 4-halophenol system can be achieved with a halogenation reagent such as sulfuryl chloride (see J). Het Chem. 1989, 26, 1547). The phenolic hydroxyl group can be further derivatized according to what is presented elsewhere in the description of this invention. halogenation Scheme 40 An alternative method for preparing. of a benzoate substituted by halo (or alkoxy) is shown in scheme 41. An aniline is converted, first, into its diazonium salt using nitrous acid, followed by transformation into the corresponding nitrile using a reactant such as cuprous cyanide ( see Chem. Ver. 1983, 116, 1183). The cyano group is then hydrolysed in the acid (see, Fuson, JACS 1941, 63, 1679). The acid can then be protected as an ester to allow additional derivation of the system in accordance with what is presented elsewhere in the description of this invention. X = halogen or alkoxy Scheme 41 An ortho-halobenzoate can be prepared in a similar manner, by diazotization of an o-carboxyaniline, followed by reaction with a copper halide (scheme 42).

Scheme 42 In another embodiment of this invention, ArlII is a benzofuranyl or dihydrobenzofurar.ilcarboxylic acid in accordance with that illustrated in Figure 6.

Figure 6 Benzofuran-2-carboxylate derivatives can be prepared as shown in Scheme 43 by cyclization of the 2-carbonyl-phenoxyacetate appropriately substituted under basic conditions. The reduction of the resulting benzofuran in the corresponding 2, 3-dihydro-benzofuran can be achieved by using a mercury sodium amalgam under basic conditions. (See J. Med. Chem. 1984, 27, 570).

Scheme 43 An alternative synthesis of the 2,3-dihydrobenzofuran-2-carboxylate ring system is shown in scheme 44 (see J. Med. Chem. 1981, 865). A Ciaisen rearrangement of a substituted allyl phenyl ether at elevated temperature such as 250 ° C, either alone or in a solvent such as dimethylaniline, can provide the o-allyl-phenol. A peracid oxidation of this intermediate product offers 2-hydroxymethyl-2,3-dihydrobenzofuran which can be further oxidized to the carboxylic acid using various oxidizing agents such as Jones reagent.

Scheme 44 In another embodiment of this invention, "A" may be an imidazolidin-2-one, tetrahydropyrimidin-2-one, imidazolin 2,4-dione, or tetrahydropyrimidin-2,4-dione (Figure 7).

X. Y »(CR, R.) N. C »0 n * 1.2 Figure 7 These systems are prepared from an amine containing Arl by acylation, aminolysis, ring closure and reduction, in sequences, according to what is illustrated in scheme 45 (for examples see Kitazaki, T Asaka, A., Tamura, N, Matsushita, Y .; Ozone, H., Hayashi, R., Okonogi, K .; Itoh, K. Chem. Pharm. Bull., 1999, 47, 351 and Basha. , A., Tetrahedron Lett., 1988, 20, 2525). Coupling with Arll can be effected by derivatization of the cyclic N urea by treatment with a base such as for example NaH in THF at a temperature of about 0 ° C, and then alkylation of the resulting anion with an electrophilic such as for example alkyl bromide / triflate containing Arll).

X «Br. I OH Y -O. CH, «• 1.2 Scheme 45 In another embodiment of this invention, Arll is a six-membered ring aromatic of the general substituted form shown in Figure 8. In particular, Arll is benzene, pyridine, pyrimidine, pyridazine or substituted pyrazine.

U »CR ,. N. C-: W = CR ,. N. C-. X * CR ,. N. C-. AND CR,. N. C-: 2 * CR ,. N. C- FIG. 8 In principle, appropriately functionalized ring systems of this type can be prepared by the functionalization of specific precursors followed by ring synthesis or by derivation of a previously formed ring system. There are numerous approaches to the synthesis and functionalization of the cyclic structures mentioned above in the chemical literature (for examples, see (a) Katritzky, A.R .; Rees, C.W .; Scriven, E.F.V. Eds.

Comprehensi sees Heteracyclic Chemistry II, Vol. 5 and vol. 6 Elsevier Science 1996 and references there). For example, (scheme 46) the alkylation of methyl glycolate with ur. Alkyl halide containing Arl utilizes a base such as for example sodium hydride in a solvent such as THF or DMSO provides the ester. Claisen condensation of this ester with t-butyl acetate at low temperature (typically below -15 ° C) using a base such as, for example, LDA in THF provides the intermediate product of ketone ester. This reacts with formamidine acetate in the presence of a base such as, for example, sodium methoxide in methanol to provide the pyrimidinone (Butters, M.J. Heterocyclic Chem., 1992, 29, 1369). This type of substituted aromatic system can be further functionalized to incorporate Arl according to what is described elsewhere in the description of this invention.

Scheme 46 In certain cases, Arll (in Figure 8) can be assembled by ring transformation of another heterocycle, for example, treatment of the known 4-bromo-2-methoxy-furan (scheme 47, Marini-Bettolo, R., Flecker, R., Tsai, T.Y.R .; Wiesner, K. Can. J. Chem. 1981, 59, 1403) with an alkyllithic at low temperature and the reaction of this anion with ur. electrophile containing ArlII (such as for example bromide, aldehyde, epoxide) provides the substituted furan in position 4. Oxidative dissociation of this intermediate with dioxirane followed by treatment with hydrazine provides the pyridazinone which can be further modified to incorporate Arl in accordance with what is illustrated elsewhere in the description of this invention. 3 . NH2NH:. HC1 Scheme 47 A particularly useful protocol in relation to the functionalization of "heterocycles" includes the etherification of Mitsunobu of heterocycles substituted by hydroxyl (or keto-tautose) in accordance with that presented in scheme 48. The treatment of known bromo-pyridin-2-one (Wobaut, JP; Waayman, PW; Vandijk, J. Rec., Trav. Chim. Pays-Bas, 1940, 59, 202) with an alcohol containing an Arl (or ArlII) in Mitsunobu conditions provide the pyridyl ether substituted with corresponding bromine (for typical procedures (see Mitsunobu, O. Synthesis, 1981, 1).

Scheme 48 The heterocyclic bromide formed in this way can be further functionalized in numerous ways. For example, coupling with a vinyl stannane can be carried out under palladium (o) catalysis in order to provide systems with alkenyl linkers (scheme 49).

Scheme 49 The choice of catalyst and reaction temperature for this transformation depends on the substrate used but, in general, is tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium chloride, 1,1'-bis (diphenylphosphino) ferrocene / bis-dibenzylidenacetonpalladium or 1,2-bis- (diphenylphosphino) ethane / bis (acetonitrile) dichloropalladium at a temperature between 50 ° C and 150 ° C. Suitable solvents include DMF, DMPU, HMPA, DMSO, toluene, and DME (for examples, see, Fariña, V. Krishnamurthy, V .; Scott, W.J. Organic Reactions, 1997, 50, 1). The reduction of the olefin using, for example, a Wiikinson catalyst in a solvent such as toluene, THF or an alcohol at a temperature between about 20 and 80 ° C offers the corresponding alkane-linked system. In certain heterocyclic systems in which a bromide or chloride is in the ortho or para position relative to a ring nitrogen, the halogen can be easily displaced by an alcohol (in the presence of a base such as, for example, sodium hydride in a solvent as for example toluene, DMSO, THF, DMPU or HMPA) at room temperature or above room temperature (for examples, see Kelly, TR et al., J. Amer. Chem. Soc, 1994, 116, 3657 and Newcome , GR et al., J. Org. Chem. 1977, 42, 1500). For example, alcoholysis of a 2,4-dichloro-pyrimidine (scheme 50) using a controlled stoichiometric amount of an alcohol reagent containing Arl (or ArlII) provides the alkoxy-substituted bromopyridine. Subsequent reaction of this product (generally above ambient temperature) with an additional equivalent of another alcohol containing ArlII (or Arl) provides the dialkoxy-substituted heterocycle in a non-symmetric manner. Since position 4 of the dichloro-pyrimidine is generally displaced first, the order in which the alkoxy substituents are introduced will determine its orientation in the product. 2. NaH / rílH-cj-rj-OH "Scheme 50 Similar procedures using 2,6-dibromo-pyridipa or 2,6-dibromo-pyridazine provide the corresponding dialkoxy-substituted pyridines and pyridazines A simple alkoxy group placed in the ortho position relative to a nitrogen in these heterocyclic systems can to be hydrolyzed in the corresponding hydroxy substituent using aqueous hydrochloric acid at a temperature normally between room temperature and reflux (Scheme 51).

A methyl, methyl or methine group placed in ortho position relative to a ring nitrogen in these heterocyclic systems can be deprotonated with a base such as for example alkyl lithium or LDA in a solvent such as THF, ether or HMPA, generally at low temperature (below 0 ° C) and the resulting anion can react with electrophiles such as aldehydes, epoxides, alkyl halides or α, β-unsaturated carbonyl compounds in order to provide various functionalized heterocycles.

Martin 3. H _ / (Ph3P); RhCl Scheme 52 For example (scheme 52) the 2-alkoxy-4-methyl-pyrimidine is treated, sequentially, with LDA and an aldehyde at a temperature of -78 ° C to provide the adduct substituted or hydroxy. A subsequent dehydration of this product to N-phenyl Scheme 51 For example (scheme 51), the treatment of the pyridine derivative substituted with 2-methoxy-6-alkyl with hydrochloric acid provides the pyridin-2-one substituted with 6-alkyl. This intermediate product, in turn, can be further derivatized in the systems substituted by corresponding 2-alkoxy or 2-alkenyl according to what is presented in details elsewhere in the description of this invention.

Intermediate with martin sulphuran in a solvent such as, for example, dichloromethane at room temperature followed by dehydrogenation of the resulting olefin yields the alkyl-2-alkoxy-pyrimidine containing 4-ArI. Similar procedures applied to 2-chloro-6-methyl-pyrazine (Karmas, G., Spoerri, P.E., J. Amer. Chem. Soc, 1952, 74, 1580) to the corresponding pyrazine. In another embodiment of this invention, A can be an amide thereby generating compounds of the formulas shown in Figure 9 Figure 9 The preparation of an illustrative example within this series is shown in Scheme 53. A hydroxyaldehyde may react with a bromoalkyl ester to provide an intermediate product of the aldehyde ester. Reductive amination of the aldehyde followed by acylation may provide the amide.

Ph (Ch2) 3NH :, Scheme 53 In addition, compounds of this invention can be easily synthesized by solid phase methods, as shown in schemes 54 and 55, using entries (XII) - (XVII) listed in table I Scheme 55 Table 1 (Continued) A further exemplification of the amide linker is shown in Scheme 56. The reaction of an activated carboxylic acid derivative such as, for example, without limitation, acid chloride or anhydride with an amine of the general formula (15) and a base suitable as for example triethylamine provides the amide (16). A more explicit exemplification is shown in scheme 57. Carboxylic acid (17) is activated with oxalyl chloride to provide the acid chloride and then 2-amino-6-methylbenzoic acid (18) is added to provide the amide (19) . Alternatively, 2-aminomethyl-6-methylbenzoic acid (20) can be used to provide the amide ( twenty-one ) .

Scheme 56 1) oxalyl chloride (20) Scheme 57 The preparation of 2-aminomethyl-6-methylbenzoic acid (20), can be achieved using the chemistry shown in scheme 31 (X = Me, R '= H) .7 Useful compounds according to the present invention they can also be prepared by applying or adapting known methods, these methods include the methods used to date or described in the literature, for example, the methods described by RC Larock in Comprehensive Organic Transformations, VCH publishers, 1989. In the reactions described above, it may be necessary to protect reactive functional groups such as, for example, hydroxy, amino, iminium, thio or carboxy groups, when these groups are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protection groups can be used in accordance with standard practice, for examples, see T.W. Green and P.G.M. Wuts in "Protective Group in Organic Chemistry" (protective groups in organic chemistry), John Wiley and Sons, 1991; JFW McOmie in "Protective Groups in Organic Chemistry" Plenum Press, 1973. In accordance with a further feature of the present invention, compounds useful in accordance with the invention can be prepared by the interconversion of other compounds of the invention. A compound of the invention that includes a group containing one or more nitrogen ring atoms, preferably imine (= N-), can be converted into the corresponding compound wherein one or more ring nitrogen atoms of the group are oxidized in an N-oxide, preferably by reaction with a peracid, for example, peracetic acid in acetic acid or m-chloroperoxybenzoic acid in an inert solvent such as for example dichloromethane, at a temperature from about room temperature to reflux, preferably at High temperature.

The products of this invention can be obtained as racemic mixtures in their dextro and levorotatory isomers since at least one asymmetric carbon atom can be present. When two asymmetric carbon atoms are present, the product can exist as mixtures of diastereomers based on both syn and anti configurations. These diastereomers can be separated by fractional crystallization. Each diastereomer can then be resolved into dextro and levorotatory optical isomers by conventional methods. It will also be apparent to the person skilled in the art that certain compounds of the formula I may exhibit geometric isomerism. Geometric isomers include the cis and trans forms of compounds of the invention having an alkenyl moiety. The present invention comprises the individual geometric isomers and stereoisomers and mixtures thereof. Such isomers - can be separated from their mixtures, by the application or adaptation of known methods, for example, chromatographic techniques and recrystallization techniques, or they can be prepared separately from the appropriate isomers of their intermediates, for example, by applying or adapting the methods described herein. The resolution can be best effected in the intermediate stage where it is convenient to combine the racemic compound with an optically active compound by salt formation, ester formation or amide formation to form two diastereomeric products. If an acid is added to an optically active base, then two diastereomeric salts are produced which have different properties and different solubilities and can be separated by fractional crystallization. When the salts have been completely separated by repeated crystallization, the base is dissociated by hydrolysis of acid and enantiomerically purified acids are obtained. Useful compounds according to the present invention are useful in the form of the free base or free acid or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the present invention. When a compound useful in accordance with the present invention is replaced by a basic portion, acid addition salts are formed and are simply a more convenient form of use; in practice, the use of the salt form inherently means the use of the free base form. The acids which can be used to prepare the acid addition salts preferably include the acids which, when combined with the free base, produce pharmaceutically acceptable salts, that is, salts whose anions are not toxic to the patient in pharmaceutical doses of the salts, in such a way that the beneficial pharmaceutical effects of these compounds in the free base are not vitiated by collateral effects attributable to the anions. Even when pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product, such as, for example, , when the salt is formed only for purposes of purification and identification, or when it is used as an intermediate product for the preparation of a pharmaceutically acceptable salt by ion exchange processes. Useful pharmaceutically acceptable salts within the scope of the present invention are salts derived from the following acids: mineral acids such as hydrochloric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like. The corresponding acid addition salts comprise the following: hydrohalides, for example, hydrochloride and hydrobromide, trifluoroacetate, sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartarate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-β-hydroxynaphthoates, gentisatos, mesylates, isothionates, di-p-toluyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulfamates and quinate, respectively. The acid addition salts of the compounds useful in accordance with the present invention are prepared by reaction of the free base with an appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous solution or aqueous-alcohol solution or other suitable solvent containing the appropriate acid and isolating the salt by evaporation of the solution, or by reacting the free base and the acid in an organic solvent, in which case the salt is separated directly or can be obtained by concentrating the solution. The compounds useful in accordance with the present invention can be regenerated from the acid addition salts by the application or adaptation of known methods. For example, useful starting compounds according to the present invention can be regenerated from their acid addition salts by treatment with an alkaline substance, for example, aqueous solution of sodium bicarbonate or aqueous solution of ammonia. When the compound useful according to the present invention is substituted with an acidic portion, base addition salts can be formed and are simply a more convenient way of use; in practice, the use of the salt form inherently means the use of the free acid form. The bases which can be used to prepare the base addition salts preferably include the bases which, when combined with the free acid, produce pharmaceutically acceptable salts, that is, salts whose cations are not toxic to the animal organism in pharmaceutical doses. of the salts, in such a way that the beneficial pharmaceutical effects on the activity of the compounds of the present invention in the free acid are not vitiated by collateral effects attributable to the cations. Pharmaceutically acceptable salts useful in accordance with the present invention include, for example, alkali metal salts and ferrous alkali metal salts, including the salts derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl- glucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, diethylamine, N-benzylphenethylamine, piperazine, tris (hydroxymethyl) aminomethane, tetramethylammonium hydroxide, and the like. Metal salts of compounds useful in accordance with the present invention can be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the selected metal in an aqueous or organic solvent with the free acid form of the compound. The aqueous solvent used can be water or it can be a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester as for example ethyl acetate. Such reactions are usually carried out at room temperature but can be carried out, if desired, with heating. Amine salts of compounds useful in accordance with the present invention can be obtained by contacting an amine in an aqueous or organic solvent with the free acid form of the compound. Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitriles such as acetonitrile, or ketones such as acetone. Amino acid salts can be prepared in a similar manner. The base addition salts of the compounds useful in accordance with the present invention can be generated from the salts by the application or adaptation of known methods. For example, useful source compounds according to the present invention can be regenerated from their base addition salts by treatment with an acid, for example, hydrochloric acid. Forms of salts useful in accordance with the present invention also include compounds having a quaternized nitrogen. The quaternized salts are formed by methods such as by alkylation of nitrogen hybridized with sp3 or sp2 in the compounds. As will be apparent to those skilled in the art, some of the useful compounds according to the present invention do not form stable salts. However, acid addition salts are more likely to be formed through compounds useful in accordance with the invention having nitrogen-containing heteroaryl group and / or wherein the compounds contain an amino group as a substituent. Preferably, acid addition salts of the compounds useful in accordance with the present invention are the salts wherein there is no labile group of acid. If they are useful as active compounds themselves, the salts of the compounds useful in accordance with the present invention are useful for the purification purposes of the compounds, for example, by exploiting the differences in solubility between the salts and the compounds of origin. , collateral products and / or initial materials by techniques well known to those skilled in the art. Various substituents in the compounds useful according to the invention, for example, in accordance with that defined in R, Ri and R2 can be present in the initial compounds, added to any of the intermediates or added after the formation of the end products by known methods of substitution or conversion reactions. If the substituents themselves are reactive, then the substituents may be deprotected in accordance with known techniques. Various protection groups known in the art may be employed. Examples of many of these possible groups can be found in "Protective Groups in Organic Synthesis" (Protection Groups in Organic Synthesis) by T.W.

Green, John Wiley and Sons, 1981. For example, nitro groups can be added to the aromatic ring by nitration, and the nitro group can be converted into other groups, such as, for example, amino, by reduction, and halo by diazotization of the amino group and diazo group replacement. Acyl groups may be substituted on the aryl groups by Friedel-Crafts acylation. The acyl groups can then be transformed into the corresponding alkyl groups by various methods, including the Wolf-Kishner reduction and the Clemmenson reduction. Amino groups can be alkylated to form monoalkylamino and dialkylamino groups; and mercapto and hydroxy groups can be alkylated to form corresponding ethers. Primary alcohols can be oxidized by oxidation of agents known in the art to form carboxylic acids or aldehydes, and secondary alcohols can be oxidized to form ketones. In this way substitution or alteration reactions can be employed to provide various substituents in the starting material molecule, intermediates or final product. The starting materials, intermediates, and certain compounds of the invention are prepared through the application or adaptation of known methods such as, for example, the methods described in U.S. Patent Nos. 4,920,132; 4,920,131; and 5,059,610; publications Huang, Fu Chih et al, J. Med. Chem. (1991), 34 (5), 1704-7; and Huang Fu Chih et al, J. Med (1990), 33 (4), 1194-200; and the Reference Examples or their apparent chemical equivalents. The present invention is further exemplified but not limited by the following examples which illustrate the preparation of the compounds according to the invention. EXAMPLE 1 Methyl 6,2-dimethylbenzoate To a cooled solution (0 ° C) of 2,6-dimethylbenzoic acid 820.2 g, 134 mmol) in dichloromethane (200 mL) was added DMF (1 mL) followed by sodium chloride. oxalyl (14 mL, 162 mmol). At the end of the addition, the cold bath is stirred and stirred continuously for 3 hours. The resulting solution is concentrated in vacuo and the residue is added slowly to a cooled solution (0 ° C) comprising methanol (200 ml) and triethylamine (40 ml). At the end of the addition, the reaction mixture is stirred for 30 minutes and then poured into a hydrochloric acid solution (400 mL, 2N), which is then extracted with ether. The ether extract is washed with a solution of hydrochloric acid (IN), a solution of sodium bicarbonate and brine and then dried in MgSO and concentrated to provide the title compound which is used without further purification. MS (El) 164 (M) * EXAMPLE 2 Methyl 2-bromomethyl-6-methyl-benzoate To a solution of 2,6-dimethyl-benzoate methyl (22.0 g, 134 mmol, ~ example 1) in CC1. (250 mL) is added N-bromosuccinimide (19 g, 107 mmol) followed by benzoyl peroxide (1.0 g, 4.0 mmol). The resulting solution is heated to reflux and stirred at this temperature for 20 minutes. The reaction mixture is then allowed to cool before being diluted with ether (200 mL), filtered and concentrated. The residue is purified by flash chromatography (silica, 4% acetone in hexanes) to give the title compound. This product (approximately 85% pure, the rest is 2,6-dimethylbenzoate methyl) is used without further purification. MS (El) 242.244 (M +, Br standard). Example 3 3- (quinolin-2-ylmethoxy) -phenol 2-Chloromethylquinoline hydrochloride (25.0 g, 117 mmol) and resorcinol monobenzoate (37.5 g, 175 mmol) are suspended in dimethyl sulfoxide (180 mL) and mixed with the aid of an upper agitator. The mixture is cooled to a temperature of 15 ° C and a 50% solution of sodium hydroxide (25 L) is slowly added over a period of 10 minutes with light exotherm. The reaction is allowed to come to room temperature and stirring is allowed overnight. The reaction is then heated to a temperature of 95 ° C and a 50% solution of sodium hydroxide is added (25 mL). After 20 minutes, warm water (300 mL) is added to the reaction and stirred for 15 minutes. The reaction is filtered hot and the filtrate is cooled to give a red-colored solid which is vacuum-dried to provide sodium salt pentahydrate. A portion of the salt (15.6 g, 43.0 ml) is neutralized by heating in water (30 mL) with IN HCl (43 mL) followed by cooling to give a brown solid. The solid is dissolved in dichloromethane (550 mL) and methanol (14 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a tan solid. A portion is recrystallized from ethyl acetate to provide an analytically pure sample; melting point 152-153 ° C, MS (ESI) 252 (M + H) Example 4 methyl 2-methyl-6- [3- (guinolin-2-ylmethoxy-phenoxymethyl-benzoate 3- (quinolin-2-ylmethoxy) ) -phenol (5.2 g, 21 mmol, example 3), methyl 2-bromomethyl-6-methyl-benzoate (example 2) (5.0 g, 21 mmol) and potassium carbonate (4.4 g, 32 mmol) are combined in DMF (50 ml) and heated at a temperature of 85 ° C for 3 hours.The reaction is poured into ethyl acetate (500 ml) and washed with water (4 x 120 ml) and brine (100 ml). it is dried over magnesium sulfate, filtered and concentrated in vacuo to provide a residue which is purified by column chromatography (silica, 10 to 20% ethyl acetate in hexane) to give the title compound MS (ESI) 414 ( M + H) The following compounds are prepared using essentially the same procedure as the procedure used in Example 4, except that the above-mentioned phenol is used in place of 3- (quinolin-2-ylmethoxy) -phenol with methyl benzoate or isobutyl benzoate (example 2). Example 4a. { 2-methyl-6- [3- (2-quinolin-2-yl-vinyl) -phenoxymethyl} Methylbenzoate MS (ESI) 410 (M + H) Prepared from 3- (2-quinolin-2-yl-vinyl) -phenol (example 15). Example 4b (Methyl 2-methyl-6-. {3 - [2- (pyridin-2-yloxy) -ethoxy] -phenoxymethyl] -benzoate XH NMR (300 MHz, CDC13) d 8.15 (m, 1H ), 7.60 (t, 1H), 7.1-7.3 (m, 4H), 6.89 (dd, 1H), 6.81 (d, 1H), 6.56 (m, 3H), 5.08 (s, 2H), 4.70 (t, 2H), 4.32 (t, 2H), 3.85 (s, 3H) 2.36 (s, 3H). Prepared from 3- [2- (pyridin-2-yloxy) -ethoxy] -phenol (example 15a). Example 4c 2-. { 3- [(benzoxazol-2-yl-methyl-amino) -methyl] -phenoxymethyl} Methyl-6-methyl-benzoate MS (ESI) 417 (M + H) Prepared from 3- [(N-benzoxazol-2-yl-N-methyl-amino) -methyl] -phenol (example 10a). Example 4d 2-methyl-6-. { 3- [(Methyl-quinolin-2-ylamino) -methyl] -phenoxymethyl} methyl-methylbenzoate MS (ESI) 427 (M + H) Prepared from 3- [(N-methyl-N-quinolin-2-ylamino) -methyl] -phenol (example 10b). Example 4e 2-Methyl-6- [3- (quinolin-2-yloxymethyl) -phenoxymethyl] -isobutylbenzoate MS (ESI) 456 (M + H) Prepared from 3- (quinolin-2-yloxymethyl) -phenol (example 15b). Example 4f 2-. { 3- [2- (5-ethyl-pyridin-2-yl) -ethoxy] -phenoxymethyl} Methyl-6-methyl-benzoate XH NMR (300 MHZ, CDCl 3) d 8.39 (bs, 1H). 7.46. { d, 1H), 7.28 (m, 2H), 7.16 (m, 3H), 6.52 (m 3H), 5.06 (s, 2H), 4.31 (t 2H), 3.82 (s, 3H), 3.22 (t, 2H), 2.63 (q, 2H), 2.38 (s, 3H), 1.24 (t, 3H). MS (ESI) 406 (M + H) Y Prepared from 3- [2- (5-ethyl-pyridin-2-yl) -ethoxy] -phenol (example 71). Example 4g Methyl 2-methyl-6- [3- (2-pyridin-2-yl-ethoxy) -phenoxymethyl] -benzoate XH NMR (300 MHZ CDCl3) d 8.56 (d, 1H), 7.62 (m, 2H) , 7.28 (m, 2H), 7.16 (m, 3H), 6.52 (m 4H), 5.06 (5, 2H), 4.34 (t, 2H), 3. 82 (s, 3H), 3.25 (t, 2H), 2.38 (s, 3H). MS (ESI) 378 (M + H) Prepared from 3- (2-pyridin-2-yl-ethoxy) -phenol (example 71a). Example 4h 2- [3- (Benzooxazol-2-ylaminomethyl) -phenoxymethyl] methyl 6-benzoate XH NMR (300 MHz, CDC13) d 7.54 (m, 1H), 7.38 (d, 1H), 7.26 (m, 3H ), 7.18 (m, 2H), 7.05 (m, 1H), 6.98 (m, 2H), 6.88 (dd, 1H), 5.10 (s, 2H), 4.64 (bs, 2H), 3.80 (s, 3H), 2.37 (s, 3H). MS (ESI) 403 (M + H) Prepared from 3- (benzooxazol-2-ylaminomethyl) -phenol (Example 10c). Example 4i methyl 2-methyl-6- [3- (pyridin-2-ylmethoxymethyl) -phenoxymethyl] -benzoate XH NMR (300 MHz, CDC13) d 8.56 (d, 1H), 7.71 (m, 1H), 7.48 ( d, 1H), 7.25 (m, 5H), 6.99 (m, 2H), 6.87 (dd, 1H), 5.1 (s, 2H), 4.69 (s, 2H), 4.63 (s, 2H), 3.82 (s) , 3H), 2.38 (s, 3H). MS (ESI) 378 (M + H) Prepared from 3- (pyridin-2-ylmethoxymethyl) -phenol (Example 74). Example 4j methyl 2-methyl-1-6 [3- (quinolin-2-ylmethoxymethyl) -phenyl-methyl-3-benzoate H NMR (300 MHz, CDC13) d 8.19 (d, IH), 8.06 (d, 1H), 7.82 (d , 1H), 7.69 (m, 2H), 7.53 (m, 1H), 7.24 (m, 4H), 7.01 (m, 2H), 6. 88 (dd, 1H), 5.12 (s, 2H), 4.86 (s, 2H), 4.66 (s, 2H), 3.82 (s, 3H), 2.38 (s, 3H). MS (ESI) 428 (M + H) Y Prepared from 3- (quinolin-2-ylmethoxymethyl) -phenol (Example 74a). Example 5 Methyl 2-methyl-6- [(3-hydroxy-phenoxy) -methyl] -benzoate To a solution of 3-hydroxy-phenol (1.5 g, 13.6 mmol) in acetonitrile (50 ml) is added 2- ( bromomethyl) -6-methyl-benzoate (0.82 g, 3.4 mmol, Example 2) followed by K2C03 (3.76 g, 27.2 mmol). The resulting mixture is heated to a temperature of 50 ° C and stirred at that temperature for more than 90 minutes, then the mixture is cooled, filtered and the filtrate is concentrated under vacuum. The residue is purified by flash chromatography (silica, 5% ethyl acetate in dichloromethane) to give the title compound as a white solid.

MS (El) 272 (M +). Example 6 Methyl 2-methyl-6- [3- (2-phenyl-oxazol-4-ylmethoxy) -phenoxymethyl-benzoate To a solution of 4-chloromethyl-2-phenyl-oxazole (100 mg, 0.5 mmol, Example 19 ) in DMF (2 mL) is added methyl 2-methyl-6- [(3-hydroxy-phenoxy) -ethyl-benzoate (136 mg, 0.5 mmol, Example 5) followed by K2CO3 (75 mg, 0.54 mmol). The resulting mixture is heated to a temperature of 60 ° C and stirred at this temperature for 8 hours. This mixture is then cooled to room temperature, diluted with ether washed with water and brine, dried in MgSO and concentrated. The residue is purified by flash chromatography (silica, 20% ethyl acetate in hexanes) to give the title compound. MS (ESI) 429 (M + H) Y The following compounds are prepared using essentially the same procedure used in Example 6, except that the aforementioned alkyl halide was used in place of 4-chloromethyl-2-phenyl-oxazole with 2. methyl-6- [(3-hydroxy-phenoxy) -methyl] -benzoic acid (ethyl or isobutyl) (Example 5). Example 6a Methyl 2-methyl-6- [3- (2-phenyl-thiazol-4-ylmethoxy) -phenoxymethylbenzoate MS (ESI) 446 (M + H) Prepared from 4-chloromethyl-2-phenyl- thiazole (Example 20). Example 6b 2- [3- (3, 5-dimethyl-isoxazol-4-ylmethoxy) -phenoxymethyl] -6-methyl-methyl-benzoate MS (ESI) 382 (M + H) Prepared from 3: 5 chloride -dimethyl-isoxazol-4-ylmethyl. Example 6c Methyl 2-methyl-6- [3- (5-phenyl- [1,2,4] cxadiazol-3-ylme oxy] -phenoxymethyl] -benzoate MS (ESI) 431 (M + H) Y Prepared to from 5-phenyl- [1,2,4] oxadiazol-3-ylmethyl chloride Example 6d 2- [3-2,5-dimethyl-benzyloxy) -phenoxymethyl] -6-methyl-methyl-benzoate MS (ESI) ) 391 (M + H) Y Prepared from 2,5-dimethyl-benzyl chloride. Example 6e 2- [3- (2,4-Dichloro-benzyloxy) -phenoxymethyl] -6-methyl-benzoate methyl. S (ESI) 431 (M + H, standard of C1_) Y Prepared from 2,4-dichloro-benzyl chloride. Example 6f 2- [3- (5- tert -Butyl- [1,2,4] oxadiazol-3-ylmethoxy) -phenoxymethyl] -6-methyl-benzoate methyl. MS (ESI) 411 (M + H) Y Prepared from 5-tert-butyl- [1,2,4] oxadiazol-3-ylmethyl chloride. Example 6g 2- [3 [3- (2,6-dichloro-phenyl) -5-methyl-isoxazol-4-ylmethoxy] -phenoxymethyl] -6-methyl-methyl-benzoate MS (ESI) 512 (M + H) Y Prepared from (3- (2,6-dichloro-phenyl) -5-methyl-isoxazol-4-yl) -methyl chloride. Example 6h methyl 2-methyl-6- [3- (2, 4, 5-trimethyl-benzyloxy) -phenoxymethyl] -benzoate. MS (ESI) 405 (M + H) Prepared from 2,4,5-trimethyl-benzyl chloride. Example 6i Methyl 2-methyl-6- [3- (3-methyl-naphthalen-2-ylmethoxy) -phenoxymethyl] -benzoate MS (ESI) 427 (M + H) Y Prepared from (3-methyl) bromide -naphthalen-2-yl) -methyl. Example 6j 2- [3- (5-Acetyl-2-methoxy-benzyloxy) -phenoxymethyl] -6-methyl-methyl-benzoate S (ESI) 435 (M + H) +. Prepared from 5-acetyl-2-methoxy-benzyl chloride. Example 6k 2- [3- (6-fluoroquinolin-2-ylmethoxy) phenoxymethyl] -6-methylbenzoate methyl. MS (ESI) 432 (M + H) Y Prepared from 6- fluoroquinolin-2-ylmethyl bromide (Example 27b). Example 61 Methyl 2- [3- (4-tert-butylbenzyloxy) phenoxymethyl] -6-methylbenzoate MS (ESI) 419 (M + H) "Prepared from 4- (erc-butyl) benzyl bromide Example 6m 2- [3- (4-isopropylbenzyloxy) phenoxymethyl) methyl-6-methylbenzoate MS (ESI) 405 (M + H) Y Prepared from 4-isopropylbenzyl chloride Example 6n 2-methyl-6- [ Methyl 3- (3-phenoxybenzyloxy) phenoxymethyl] benzoate MS (ESI) 455 (M + H) Y Prepared from 3-phenoxybenzyl chloride Example 6 or 2- [3- (4-tert-butylcyclohexylmethoxy) phenoxymethyl] - Methyl 6-methylbenzoate MS 425 (M + H) Y Prepared from 4-tert-butylcyclohexylmethyl bromide (Example 29a) Example 6p 2-methyl-1-6- [3- (guinoxal in-2-ylmethoxy) phenoxymethyl ] methyl benzoate MS 415 (M + H) Prepared from quinoxalin-2-ylmethyl chloride (see Chem., 120, 649-651). Example 6 Methyl 2-methyl-6- [3- (2-methylbenzyloxy) phenoxymethyl] benzoate MS 377 (M + H) Y Prepared from a-bromo-o-xylene. Example 6r 2-methy1-6- [3- [2-5-methylthiophen-2-yl] -oxazol-4-ylmethoxyphenoxymethyl} methyl benzoate MS (ESI) 450 (M + H) Y Prepared from 2- (5-methylthiophen-2-yl) oxazol-4-ylmethyl chloride (Example 19a). Example 6s 2- [3- (2-cyclohexyloxazol-4-ylmethyl] -6-methylbenzoate methyl MS (ESI) 436 (M + H) Y Prepared from 2-dicyclohexyloxazol-4-ylmethyl chloride (Example 19b). Example 6t Methyl 2- [3- [2- (3-fluorophenyl) oxazol-4-ylmethoxy] phenoxymethyl] -6-methylbenzoate MS (ESI) 448 (M + H) Y Prepared from 2- (3-chloride fluoro-phenyl) oxazol-ylmethyl (Example 19c). Example 6u 2-. { 3- [2- (4-fluorophenyl) oxazol-4-ylmethoxy] phenoxymethyl] -6-methyl-methylbenzoate MS (ESI) 448 (M + H) Y Prepared from 2- (4-fluorophenyl) oxazole-4-chloride ilmethyl (Example 19d) Example 6v 2- [3- (6-chloropyridin-2-ylmethoxy) phenoxymethyl] -6-methylbenzoate ethyl MS (ESI) 412, 414 (M + H) +, Cl standard. Prepared from from 2-chloro-methy1-6-chloropyridine (Example 27c). Example 6w Ethyl 2-methyl-6- [3- (5-methyl-2-phenyloxazol-4-ylmethoxy) phenoxymethylbenzoate MS (ESI) 458 (M + H) Y Prepared from 4-chloromethyl-5-methyl- 2-phenyloxazole. Example 6x Methyl 2- (3-benzyloxy-phenoxymethyl) -6-methyl-benzoate MS (El) 362 (M) Y Prepared from benzyl bromide.

Example 6 and methyl 2-raethyl-6- [3- (pyridin-2-ylmethoxy) -phenoxymethyl] benzoate Prepared from 2-chloromethyl-pyridine. Example 6z Methyl 2- [3- (7-chloroquinolin-2-ylmethoxy) phenoxymethyl] -6-methylbenzoate MS (ESI) 447 (M + H) +, Cl standard. Prepared from 7-chloroquinolin-2-ylmethyl bromide (Example 46a). Example 6aa Methyl 2- [3- (6-methoxyquinolin-2-ylmethoxy) phenoxymethyl] -6-methylbenzoate MS (ESI) 443 (M + H) Y Prepared from 6-methoxyquinolin-2-ylmethyl bromide (Example 46b) ). Example 6ab 2- [3- (2,4-Diisopropyl-5-methyl-benzyloxy) -phenoxymethyl] -6-methyl-benzoic acid ethyl ester XH NMR (300 MHz, CDC13) d 7.14 (m, 6H), 6.62 (m , 3H), 5.10 (s, 2H), 5.00 (s, 2H), 4.32 (m, 2H), 3.20 (m, 1H), 2.86 (m, 1H), 2. 40 (bs, 6H), 1.28 (m, 15H). MS (El) 484 (M) +. Prepared from l-chloromethyl-2,4-diisopropyl-5-methyl-benzene. Example 6ac 2- [3- (2, 4-bis-trifluoromethyl-benzyloxy) -phenoxymethyl] -6-methyl-benzoic acid ethyl ester X H NMR (300 MHz, CDCl 3) d 7.92 (m, 2 H), 7.82 (m, 1 H ), 7.30 (m, 2H), 7.18 (m, 2H), 6.57 (m, 3H), 5.29 (s, 2H), 5.10 (s, 2H), 4.31 (q, 2H), 2.39 (s, 3H), 1.29 (t, 3H) ). MS (El) 512 (M) +.

Prepared from 2, 4-bis bromide (trifluoromethyl) benzyl. Example 6ad 2- [3- (Bipheni-4-ylmethoxy) -phenoxymethyl] -6-methyl-benzoic acid ethyl ester X H NMR (300 MHz, CDCl 3) d 7.60 (m, 4 H), 7.40 (m, 7 H), 7.18 ( m, 2H), 6.58 (m, 3H), 5.09 (s, 2H), 5.07 (s, 2H), 4.30 (q, 2H), 2. 39 (s, 3H), 1.28 (t, 3H). MS (El) 452 (M) +. Prepared from 4-phenylbenzyl chloride. Example 6ae Ethyl 2-methyl-6- [3- (naphthalen-1-ylmethoxy) -phenoxymethyl] -benzoate XH NMR (300 MHz, CDCl 3) d 8.04 (m, 1H), 7.38 (, 2H), 7.52 (m, " 4H), 7.24 (m, 4H), 6.67 (m, 2H), 6.59 (m, IH), 5.46 (s, 2H), 5.10 (s, 2H), 4.30 (q, 2H), 2.39 (s, 3H) ), 1.28 (t, 3H). MS) 426 (M) +. Prepared from 1-chloromethyl-naphthalene. Example 6af Methyl 2- [3- (5-ethyl-pyridin-2-ylmethoxy) -phenoxymethyl] -6-methyl-benzoate XH NMR (300 MHz, CDC13) d 8.44 (bs, 1H), 7.54 (dd, 1H ), 7.42 (d, IH), 7.32 (m, 2H), 7.17 (m, 2H), 6.58 (m, 2H), 5.15 (s, 2H), 5.08 (s, 2H), 3.82 (s, 3H), 2.67 (?, 2H), 2.38 (s, 3H), 1. 26 (t, 3H). MS (ESI) 392 (M + H) *. Prepared from 5-ethyl-2-chloromethyl pyridine (Example 68). Example 6ag 2- [3- (4-ethyl-benzyloxy) -phenoxymethyl] -6-methyl-benzoic acid methyl ester XH NMR (300 MHz, CDCl 3) d 7.28 (m, 8H), 6.58 (m, 3H), 5.08 ( d, 2H), 5.00 (d, 2H), 3.81 (d, 3H), 2.68 (ir., 2H), 2.38 (s, 3H), 1.24 (m, 3H). MS (El) 390 (M) Y Prepared from 1- chloromethyl-4-ethyl-benzene. Example 6ah 2- [3- (3-bromo-benzyloxy) -phenoxymethyl] -6-methyl-methyl-benzoate! H NMR (300 MHz, CDC13) d 7.58 (s, 1H), 7.44 (d, 1H), 7.25 (m, 6H), 6.57 (m, 3H), 5.08 (s, 2H), 5.00 (s, 2H), 3.81 (s, 3H), 2. 38 (s, 3H). MS (El) 440 (M) Y Prepared from 3-bromobenzyl bromide Example 6ai Ethyl 2-methyl-6- [3- (quinolin-2-ylmethoxy) -phenylethynyl] -benzoate The title compound is prepared using essentially the same procedure as that employed in example 6, except that ethyl 2- (3-hydroxy-phenylethynyl) -6-methyl-benzoate (Example 15 c) is used instead of 2-methyl-6- [( Methyl 3-hydroxy-phenoxy) -methyl] -benzoate and 2-chloromethylquinoline in place of 4-chloromethyl-2-phenyl-oxazole.

MS (ESI) 422 (M + H) Example 6aj Methyl 2-methyl-6- [3- (5-phenylpyridin-2-ylmethoxy) phenoxymethyl] benzoate MS (ESI) 440 (M + H) Prepared from chloride of 5-phenylpyridin-2-ylmethyl (Example 27 g). Example 6ak methyl 2- [3- (2-chloro-benzyloxy) -phenoxymethyl-6-methyl-benzoate XH NMR (300 MHz, CDC13) d 7.55 (m, 1H), 7.40 (m, 1H), 7.30 (m , 4H), 7.20 (m, 2H), 6.60 (m, 3H), 5.14 (s, 2H), 5.09 (s, 2H), 3.82 (s, 3H), 2.38 (s, 3H). MS (El) 396 (M] Y), Cl pattern.

Prepared from 2-chlorobenzyl chloride. Example 6: methyl 2- [3- (4-chloro-benzyloxy) -phenoxymethyl) -6-methyl-benzoate XH NMR (300 MHz, CDC13) d 7.32 (m, 6H), 7.18 (m, 2H), 6.56 (m, 3H), 5.08 (s, 2H), 5.00 (s, 2H), 3.81 (s, 3H), 2.38 (s, 3H).

MS (El) 396 (M +.), Cl pattern. Prepared from 4-chlorobenzyl chloride. Example 6am 2-Methyl-6- [3-3 (-methyl-quinoxaline-2-ylmethoxy) -phenoxymethyl] -benzoic acid methyl ester (ESI) 429 (M + H) Y Prepared from 2-methyl- 3-chloromethylquinoxaline (see Chem. Ber, 1987, 120, 649). Example 6: 2-Methyl-6- [3- (naphthalen-2-ylmethoxy) -phenoxymethyl] -benzoic acid methyl ester (EI) 412 (M +). Example 7 2-Methyl-6- [3- (quinolin-2-ylmethoxy) -phenoxymethyl] -benzoic acid A solution of 2-methyl-6- [3- (quinolin-2-ylmethoxy) -phenoxymethyl) -benzoate (1.6 g, 3.8 mmol, Example 4) in ethanol (25 mL) is heated with a solution of ION sodium hydroxide (4.0 mL, 40 mmol) at a temperature of 70 ° C for 14 hours. The reaction is cooled, neutralized with a 2N HCl solution (20 mL) and concentrated to remove the ethanol. Ethyl acetate is added and washed with water. The aqueous layer is saturated with sodium chloride and extracted again with ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and concentrated to give a crude solid. The solid is purified by column chromatography (silica, 5 to 10% methanol in dichloromethane to give the title compound.) An analytically pure sample is prepared by recrystallization from methanol: melting point 167-168 ° C XH NMR ( 300 MHz, CDC13) d.15 (d, 2H), 7.80 (d, 1H), 7.71 (t, 1H), 7.61-7.51 (m, 2H), 7.26-7.10 (m, 3H), 7.90 (t, 1H), 6.66 (s, IH), 6.52 (d, 1H), 6.46 (d, 1H), 5.26 (s, 2H), 5.15 (s, 2H), 2.44 (s, 3H), MS (ESI) 400 (M + H) Y An alternate set of conditions that can be used for the hydrolysis of a benzoate ester is to heat a 0.1 M solution of the ester in THF / methanol (1: 1) with 10 equivalents of a sodium hydroxide solution ( 10 N) at a temperature of 60 ° C for 3 hours or until the disappearance of the initial material as monitored by TLC analysis The following compounds are prepared using essentially the same procedure as the procedure used in the test. 7 except that the mentioned ester is used in place of methyl 2-methyl-6- [3- (quinolin-2-ylmethoxy) -phenoxymethyl] -benzoate. Example 7a 2-Methyl-6- [3- (2-quinolin-2-yl-vinyl) -phenoxymethyl] -benzoic acid XH NMR (300 MHz, DMSO) d 8.87 (bd, 1H), 8.14-8.36 (m, 4H), 8. 00 (t, 1H), 7.81 (d, 1H), 7.71 (m, 1H), 7.34-7.48 (m, 5H), 7. 29 (bd, 1H), 7.08 (m, 1H), 5.22 (s, 2H), 2.35 (s, 3H). MS - (ESI) 396 (M + H) Y Prepared from methyl [2-methyl-6- [3- (2-quinolin-2-yl-vinyl) -phenoxymethyl] benzoate (Example 4a). Example 7b 2-Meth1-6- acid. { 3- [2- (pyridin-2-yloxy) -ethoxy] -phenoxymethyl} benzoic XH NMR (300 MHz, DMSO) d 8.17 (d, 1H), 7.71 (m, 1H), 7.22 (d, IH), 7.04-7.19 (m, 3H), 6.99 (dd, 1H), 6.86 (d , IH), 6.55 (m, 3H), 5.13 (s, 2H), 4.53 (bs, 2H), 4.28 (bs, 2H), 2.25 (bs, 3H). MS (ESI) 380 (M + H) Prepared from (2-methyl-6- { 3- [2-pyridin-2-yloxy) -ethoxy] -phenoxymethyl} ) methylbenzoate (Example 4b). Example 7c 2- (3- [Benzoxazol-2-yl-methyl-amino) -methyl] -phenoxymethyl acid} -6-me-benzoic acid EI NMR (300 MHz, CDCl.) D 7. 27 (bd, 1H), 7. 07-7. 3 (m, 5H), 7. 03 (t, 1H), 6.80 (m, 3H), 5.10 (bs, 2H), 4.6 (bs, 2H), 3.03 (s, 3H), 2.38 (bs, 3H). MS (ESI) 403 (M + H) Y Prepared from 2-. { 3- [(benzoxazol-2-yl-methyl-amino) -methyl] -phenoxymethyl} Methyl-6-methylbenzoate (Example 4c). Example 7d 2-Methyl-6-acid. { 3- [(Methyl-quinolin-2-ylamino) -methyl] phenoxymethyl} benzoic H NMR (300 MHz, CDC13) d 8.09 (d, 1H), 7.74 (d, 1H), 7.50 (m, 3LI), 7.20 (m, 4H), 6.85 (m, 3H), 6.65 (d, 1H), 5.20 (s, 2H), 4. 75 (s, 2H), 3.29 (s, 3H), 2.05 (s, 3H). MS (ESI) 413 (M + H) Y Prepared from 2-methyl-6-. { 3- [(Methyl-quinolin-2-ylamino) -methyl] -phenoxymethyl} methyl-benzoate (Example 4d).

Example 7e 2-Methyl-6- [3- (2-phenyl-oxazol-4-ylmethoxy) -phenoxy-butyl] -benzoic acid ^ NMR acid (300 MHz, DMSO) d 8.30 (s, 1H), 8.00 (m, 2H) , 7.55 (m, 3H), 7.30 (m, 2H), 7.22 (m, 2H), 6.66 (d, 1H), 5.10 (s, 2H), 5.06 (s, 2H), 2.34 (s, 3H). MS (ESI) 416 (M + H) "Prepared from methyl 2-methyl-6- [3- (2-phenyl-oxazol-4-ylmethoxy) -phenoxymethyl] -benzoate (Example 6).

Example 7f 2-Methyl-6- [3- (2-phenyl-thiazol-4-ylmethoxy) -phenoxymethyl] -benzoic acid XH NMR (300 MHz, CDC13) d 7.95 (m, 2H), 7.43 (m, 3H) , 7.32 (m, 2H), 7.24 (d, 1H), 7.20 (m, 1H), 7.14 (t, 1H), 6.66 (m, 1H), 6. 56 (m, 1H), 5.20 (s, 2H), 5.15 (s, 2H), 2.41 (s, 3H). MS (ESI) 432 (M + H) Prepared from methyl 2-methyl-6- [3- (2-phenyl-thiazol-4-ylmethoxy) phenoxymethyl] -benzoate (Example 6a). Example 7g 2- [3- (3, 5-Dimethyl-isoxazol-4-ylmethoxy) -phenoxymethyl) -6-ethyl-benzoic acid: H NMR (300 MHz, CDCl 3) d 7.34 (m, 2H), 7.20 (m , 1H), 7.15 (t, 1H), 6.56 (m, 3H), 5.19 (s, 2H), 4.71 (s, 2H), 2.43 (s, 3H), 2.34 (s, 3H), 2.22 (s, 3H). MS (ESI) 368 (M + H) +. Prepared from 2- [3- (3, 5-dimethyl-isoxazol-4-ylmethoxy) -phenoxymethyl] -6-methyl-benzoic acid (Example 6b). Example 7h Acid 2-methyl-1-6- [3- (5-phenyl- [1,2,4] oxadiazol-3-ymethyl) -phenoxymethyl) -benzoic acid XH NMR (300 MHz, CDC13) d 8.15 ( m, 2H), 7.59 (m, 1H), 7.50 (m, 2H), 7.33 (m, 2H), 7.20 (m, 1H), 7.14 (t, 1H), 6.70 (m, 1H), 6. 61 (m, 2H), 5.19 (s, 2H), 2.44 (s, 3H). MS (ESI) 417 (M + H) Y Prepared from methyl 2-methyl-6- [3- (5-phenyl- [1, 2, 4] oxadiazol-3-ylmethoxy) -phenoxymethyl] benzoate (Example 6c). Example 7i 2- [3- (2, 5-Dimethyl-benzyloxy) -phenoxymethyl) -6-methyl-benzoic acid XH NMR (300 MHz, CDD3) d 7.35 (m, 2H), 7.13-7.24 (m, 3H) , 7.09 (d, 1H), 7.04 (d, 1H), 6.60 (m, 3H), 5.17 (s, 2H), 4.90 (s, 2H), 2.44 (s, 3H), 2.30 (s, 3H), 2.26 (s, 3H). MS (ESI) 375 (M + H) Prepared from methyl 2- [3- (2, 5-dimethyl-benzyloxy) -phenoxymethyl] -6-methyl-benzoate (Example 6d). Example 7j 2- [3- (2,4-Dichloro-benzyloxy) -phenoxymethyl) -6-methyl-benzoic acid XH NMR (300 MHz, CDC13) d 7.40 (m, 2H), 7.34 (, 2H), 7.24 ( m, 2H), 7.17 (t, 14), 6.59 (m, 3H), 5.19 (s, 2H), 5.03 (s, 2H), 2. 45 (s, 3H). MS (ESI) 415 (M-H, Cl 2 standard). Prepared from methyl 2- [3- (2, 4-dichloro-benzyloxy) -phenoxymethyl] -6-methyl-benzoate (Example 6e). Example 7k 2- [3- (5-tert-Butyl- [1, 2, 4] oxadiazol-3-ylmethoxy) -phenoxymethyl) -6-methyl-benzoic acid XH NMR (300 MHz, CDCl 3) d 7.32 (m, 2H), 7.19 (m, 1H), 7.15 (t, 1H), 6.66 (d, 1H), 6.60 (d, 1H), 6.59 (d, 1H), 5.17 (s, 2H), . 10 (s, 2H), 1.45 (s, 9H). MS (ESI) 395 (M-H). Prepared from methyl 2- [3- (5-tert-butyl- [1, 2, 4] oxadiazol-3-ylmethoxy) -phenoxymethyl] -6-methyl-benzoate (Example 6f). Example 71 2- (3- [3- (2,6-Dichloro-phenyl) -5-methyl-isoxazol-4-ylmethoxy] -phenoxymethyl] -6-methyl-benzoic acid XH NMR (300 MHz, CDD3) d 7.24-7.41 (m, 5H), 7.21 (m, 1H), 7.08 (t, 1H), 6.53 (m, 1H), 6.40 (m, 2H), 5.1 (s, 2H), 4.65 (s, 2H), 2.48 (s, 3H), 2.41 (s, 3H). MS (ÉSI) 496 (M-H) Y Prepared from 2-. { 3 [methyl 3- (2,6-dichloro-phenyl) -5-methyl-isoxazol-4-ylmethoxy] -phenoxymethyl) -6-methyl-benzoate (Example 6g). Example 7m 2-Methyl-6- (3- (2,, 5-trimethyl-benzyloxy) -phenoxymethyl) -benzoic acid XH NMR (300 MHz, CDCY) d 7.35 (m, 2H), 7.20 (m, 1H), 7.15 (t, 1H), 7.10 (s, 1H), 6.97 (s, 1H), 6.60 (m, 3H), 5.16 (s, 2H), 4. 87 (s, 2H), 2.42 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H). MS (ESI) 389 (M-H) Y Prepared from methyl 2-methyl-6- [3- (2,4,5-trimethyl-benzyloxy) -phenoxymethyl] -benzoate (Example 6h). Example 7n 2-Methyl-6- [3- (3-methyl-naphthalen-2-ylmethoxy) -phenoxymethyl] -benzoic acid X H NMR (300 MHz, CDCl 3) d 7.77 (m, 3 H), 7.64 (s, 1 H ), 7.41 (m, 2H), 7.33 (m, 2H), 7.19 (m, 2H), 6.61 (m, 3H), 5.17 (s, 2H), 5.09 (s, 2H), 2.47 (s, 3H) 2.43 (s, 3H). MS (ESI) 41) (M-H) Y Prepared from methyl 2-methyl-6- [3- (3-methyl-naphthalen-2-ylmethoxy) -phenoxymethyl] -benzoate (Example 6i). Example 7o 2- [3- (5-Acetyl-2-methoxy-benzyloxy) - phenoxymethyl-6-methyl-benzoic acid XH NMR (300 MHz, CDC13) d 8.05 '(bs, 1H), 7.93 (bd) , 1H), 7.33 (m, 2H), 7.20 (m, 1H), 7.13 (t, 1H), 6.91 (d, 1H), 6.60 (m, 3H), 5.16 (s, 2H), 5.03 (s, 2H), 3.89 ( s, 3H), 2.53 (s, 3H), 2. 43 (s, 3H). MS SI) 419 (M-H). Prepared from methyl 2- [3- (5-acetyl-2-methoxy-benzyloxy) -phenoxymethyl] -6-methyl-benzoate (Example 6j). Example 7p 2- [3-6-Fluoroquinolin-2-ylmethoxy) phenoxymethyl] -6-methylbenzoic acid Melting point 153-154 ° C. : H NMR (300 MHz, CDCl.): D 8.12 (m, 2H), 7.61 (d, 1H), 7.43. (m, 2H), 7.28 (m, 2H), 7.17 (m, 1H), 7. 05 (m, 1H), 6.66 (s, 1H), 6.51 (m, 2H), 5.26 (s, 2H), 5.14 (s, 2H), 2.45 (s, 3H). MS (ESI) 418 (M + H) Y Prepared from methyl 2- [3- (6-fluoroquinolin-2-ylmethoxy) phenoxymethyl) -6-methylbenzoate (Example 6k). Example 7q 2- [3- (4- tert -Butylbenzyloxy) phenoxymethyl) -6-methylbenzoic acid Melting point. 122-123 ° C: H NMR (300 MHz, CDC13); d 7.41-7.28 (m, 5H), 7.23-7.12 (m, 3H), 6.61-6.55 (m, 3H), 5.16 (s, 2H), 4.95 (s, 2H), 2.45 (s, 3H), 1.32 (s, 9H). MS (ESI) 405 (M + H) Y Prepared from methyl 2- [3- (4-tert-butylbenzyloxy) phenoxymethyl) -6-methylbenzoate (Example 61). Example 7r 2- [3- (4-Isopropylbenzyloxy) phenoxymethyl-6-methylbenzoic acid mp 132-133 ° C. lH NMR (300 MHz, CDC13): d 7.35 (m, 5H), 7.22 (m, 2H) , 7.17 (m, 1H), 6.58 (m, 3H), 5.15 (s, 2H), 4.97 (s, 2H), 2.92 (m, 1H), 2.46 (s, 3H), 1.25 (d, 6H). MS (ESI) 391 (M + H) Y Prepared from methyl 2- [3- (4-isopropylbenzyloxy) phenoxymethyl] -6-methylbenzoate (Example 6m). Example s 2-Methyl-6- [3- (3-phenoxybenzyloxy) f-enoxymethyl] benzoic acid XH NMR (300 MHz, CDC13): d 7.31 (m, 5H), 7.15 (m, 1H), 7.12-6.98 (m , 6H), 6.93 (m, 1H), 6.54 (m, 3H), 5.13 (s, 2H), 4.94 (s, 2H), 2.43 (s, 3H). MS (ESI) 441 (M + H) Y Prepared from methyl 2-methyl-6- [3- (3-phenoxybenzezyloxy) phenoxymethyl] benzoate (Example 6n). Example 7t 2- [3- (4-tert-Butylcyclohexylmethoxy) phenoxymethyl) -6-methylbenzoic acid H NMR (300 MHz, CDC1): d 7.34 (m, 2H), 7.21 (m, 1H), 7.12 (m, 1H), 6.50 (m, 3H), 5.16 (s, 2H), 3.67 (d, 2H), 2.45 (s, 3H), 1.92 - 1.75 (m, 4H), 1.64 (m, 2H), 0.98 (m , 4H), 0.84 (s, 9H). MS 411 (M + H) Y Prepared from methyl 2- [3- (4-tert-butylcyclohexylmethoxy) phenoxymethyl] -6-methylbenzoate (Example 60). Example 7u 2-Methyl-6- [3- (quinoxalin-2-ylmethoxy) phenoxymethyl) benzoic acid Mp 57-60 ° C H NMR (300 MHz, CDC13): d 8.96 (s, 1H), 8.08 (m , 2H), 7.74 (m, 2H), 7.24 (m, 2H), 7.12 (m, 1H), 7.00 (m, 1H), 6.64 (s, 1H), 6.49 (m, 2H), 5.24 (s, 2H), 5.14 (s, 2H), 2.39 (s, 3H). MS 401 (M + H) Y Prepared from methyl 2-methyl-6- [3- (quinoxalin-2-ylmethoxy) phenoxymethyl] benzoate (Example 6p). Example 7v 2-Methyl-6- [3- (2-methylbenzyloxy) phenoxymethyl) benzoic acid XH NMR (300 MHz, CDC13): d 7.35 (m, 3H), 7.20 (m, 5H), 6.59 (m, 3H), 5.17 (s, 2H), 4.95 (s, 2H), 2.44 (s, 3H), 2.32 (s, 3H). MS (APd) 385 (M + H + Na) Y Prepared from methyl 2-methyl-6- [3,2-methylbenzyloxy) -phenoxymethyl] benzoate (Example 6q). Example 7w 2-methyl-6-acid. { 3- [2- (5-methylthiophen-2-yl) -oxazol-4-ylmethoxy] phenoxymethyl} Benzoic Melting point 129-130 ° C: H NMR (300 MHz, CDC13): d 7.54 (s, 1H), 7.48 (d, 1H), 7.27 (m, 2H), 7.1 (, 2H), 6.74 (m, 1H), 6. 66 (s, 1H), 6.53 (m, 2H), 5.12 (s, 2H), 4.95 (s, 2H), 2.51 (s, 3H), 2.39 (s, 3H). MS (ESI) 436 (M + H) +. Prepared from 2-methyl-6-. { 3- [2- (5-methylthiophen-2-yl) -oxazol-4-ylmethoxy] phenoxymethyl} methyl benzoate (Example 6H). Example 7x 2- [3, 2-Cyclohexyloxazol-4-ylmethoxy) phenoxymethyl) -6-methylbenzoic acid Melting point 158-159 ° C. XH NMR (300 MHz, CDC13): d 7.57 (s, 1H), 7.30 (m, 2H), 7.20 (m, 1H), 7.12 (m, 1H), 6.72 (m, IH), 6. 53 (m, 2H), 5.13 (s, 2H), 4.95 (s, 2H), 2.84 (m, 1H), 2.45 (s, 3H), 2.06 (, 2H), 1.81 (m, 2H), 1.73- 1.20 (m, 61).

Prepared from methyl 2- [3- (2-cyclohexyloxazol-4-ylmethoxy) -phenoxymethyl] -6-methylbenzoate (example 6s). Example 7 and Acid 2-. { 3- [2- (3-fluorophenyl) oxazol-4-ylmethoxy] phenoxymethyl} - 6-methylbenzoic Melting point 152-154 ° C. H NMR (300 MHz, 5: 1 CDC13: CD3OD): d 7.84 (d, 1H), 7.80 (s, IH), 7.74 (d, 1H), 7.46 (m, 1H), 7.31 (m, 2H), 7.19 (m, 3H), 6.64 (m, 3H), 5.17 (s, 2H),. . 04 (s, 2H), 2.4 (s, 3H). MS (ESI) 434 (M + H) Y Prepared from methyl 2- (3- [2- (3-fluorophenyl) oxazol-4-ylmethoxy] phenoxymethyl] -6-methylbenzoate (Example 6t).

Example 7z 2- [3-2- (4-fluorophenyl) oxazol-4-ylmethoxy] phenoxymethyl acid} -6-methylbenzoic Melting point 159-160 ° C. XH NMR (300 MHz, CDC13): d 8.03 (m, 2H), 7.70 (s, 1H), 7.32 (d, 2H), 7.16 (m, 3H), 6.93 (m, 1H), 6. 69 (m, 1H), 6.55 (m, 2H), 5.16 (s, 2H), 5.03 (s, 2H), 2.44 (S, 3H). MS (ESI) 434 (M + H) Prepared from 2-. { 3- [2- (4-fluorophenyl) oxazol-4-ylmethoxy] phenoxymethyl} Methyl-6-methylbenzoate (Example 6u). Example 7aa 2- [3-6-Chloropyridin-2-ylmethoxy) phenoxymethyl] -6-methylbenzoic acid Melting point 97-98 ° C: H NMR (300 MHz, 5: 1 CDC12: CD; OD): d 7.73 (m, 1H), 7.47 (m, 1H), 7.28 (m, 3H), 7.16 (m, 2H), 6.60 (m, 3H), 5.16 (s, 2H), 5.12 (s, 2H), 2.42 ( s, 3H). MS (ESI) 384, 386 (M + H) +, Cl standard. Prepared from ethyl 2- [3- (6-chloropyridin-2-ylmethoxy) phenoxymethyl] -methylbenzoate (Example 6v). Example 7ab 2-Methyl-6- [3- (5-r.ethyl-2-phenyloxazol-4-ylmethoxy) phenoxymethyl] benzoic acid mp 144-145 ° C * H NMR (300 MHz, 3: 1 CDC13 : CD30D): d 7.99 (m, 2H), 7.42 (m, 3H), 7.30 (, 2H), 7.19 (m, 2H), 6.63 (m, 3H), 5.17 (s, 2H), 4.95 (s, 2H), 2.45 (s, 3H), 2.43 (s, 3H). MS (ESI) 430 (M + H) Y Prepared from ethyl 2-methyl-6- [3- (5-niethyl-2-phenyloxazol-4-ylmethoxy) -phenoxymethyl] benzoate (Example 6w). Example 7ac 2- (3-Benzyloxy-phenoxymethyl) -6-methyl-benzoic acid XH NMR (300 MHz, CD3OD) d 7.40-7.19 (m, 8H), 7.14 (t, 1H), 6.61-6.51 (m, 3H ), 5.07 (s, 2H), 5.03 (s, 2H), 2.40 (s, 3H); MS (El) 348 (M) Y Prepared from methyl 2- (3-benzyloxy-phenoxymethyl) -6-methyl-benzoate (Example 6x). Example 7ad 2-Methyl-6- [3- (pyridin-2-ylmethoxy) -phenoxymethyl) -benzoic acid E NMR (300 MHz, CD;, OD) d 8.53 (d, 1H), .8 ^ (t, 1HY 7.60 (d, 1H), 7.37-7.13 (m, 5H), 6.64-6.59 (, 3H), 5.15 (d, 4H), 2.40 (s, 3H), MS (ESI) 350 (M + H) +. Prepared from methyl 2-methyl-6- [3- (pyridin-2-ylmethoxy) -phenoxymethyl] -benzoate (Example 6y) Example 7ae 2-3- (7-Chloroquinolin-2-ylmethoxy) phenoxymethyl acid) -6-methyl-benzoic melting point 188-193 ° C; XH NMR (300 MHz, DMSO-d6) d 8.47 (d, 1H), 8.09 (s, 1H), 8.08 (d, 1H), 7.69 (dd, 2H), 7.29-7.14 (m, 4H), 6.68- 6.56 (m, 3H), 5.34 (s, 2H), 5.10 (s, 2H), 2.31 (s, 3H); MS (ESI) 434.436 (M + H; C1) Y Prepared from methyl 2- [3- (7-chloroquinolin-2-ylmethoxy) phenoxymethyl) -6-methylbenzoate (Example 4bc). Example 7a f 2- [3- (6-Methoxyquinolin-2-ylmethoxy) phenoxymethyl] -6-methylbenzoic acid Melting point 176-179 ° C; XH NMR (300 MHz, DMSO-d6) d 8.29 (d, 1H), 7.91 (d, 1H), 7.60 (d, 1H), 25 7.42-7.39 (m, 2H), 7. 28-7.14 (m, 4H), 6.67-6.55 (m, 3H), 5.27 (s, 2H), 5.09 (s, 2H), 3.90 (s, 3H), 2.31 (s, 3H); MS (ESI) 430 (M + H) Y Prepared from methyl 2- [3- (6-methoxyquinolin-2-ylmethoxy) phenoxymethyl] -6-methylbenzoate (Example 6aa). Example 7ag 2-Methyl-6- [3- (quinolin-2-yloxymethyl) -phenoxymethyl) -benzoic acid mp 68-72 ° C; XH NMR (300 MHz, DMSO-d6) d 8.25 (d, 1H), 7.88 (d, 1H), 7.78 (d, 1H), 7.67 (dd.1H), 7.43 '(dd, 1H), 7.30-7.05 (m, 7H), 6.89 (d, 1H), 5.45 (s, 2H), 5.1) (s, 2H), 2.30 (s, 3H) MS (ESI) 400 (M + H) Prepared from 2-methyl-6- [3- (quinolin-2-yloxymethyl) phenoxymethyl] -isobutylbenzoate (Example 4e). Example 7ah 2-Methyl-3- (quinolin-2-ylmethoxy) -benzyloxymethyl-benzoic acid Mp 39-65 ° C; XH NMR (300 MHz, CDC13) d 8.44 (d, 1H), 8.26 (d, 1H), 7.85-7.75 (m, 3H), 7.59 (dd, IH), 7.38 (s, 1H), 7.23 (obs, 2H), 7.15-7.10 (m, 2H), 6.88 (dd, 1H), 6.71 (d, 1H), 5.59 (s, 2H), 4.67 (s, 2H), 4.44 (s, 2H), 2.64 (s) , 3H); MS (ESI) 414 (M + H) Y Prepared from methyl 2-methyl-6- [3- (quinolin-2-ylmethoxy) -benzyloxymethyl] -benzoate (Example 53). Example 7ai 2- [3- (Quinolin-2-ylmethoxy) -benzyloxy] -benzoic acid Melting point. 149-154 ° C; XH NMR (300 MHz, CDC13) d 8.19 (d, 1H), 8.15 (dd, 1H), 8.11 (d, 1H), 7.83 (dd, 1H), 7.77-7.71 (m, 1H), 7.66 (d, 1H), 7.58-7.53 (m, 1H), 7.52-7-46 (m, 1H), 7.33 (t, 1H), 7.18-7.17 (m, 1H), 7.1 (t, 1H), 7.07-7.00 ( m, 3H), 5.41 (s, 2H), 5.24 (s, 2H); MS (ESI) 386 (M + H) Y Prepared from methyl 2- [3- (quinolin-2-ylmetox?) -benzyloxy] -benzoate (Example 60). Example 7aj 3-Methoxy-2- [3- (quinolin-2-ylmethoxy) -benzyloxy-benzoic acid XH NMR (300MHz, CDC13) d 8.20 (d, 1H), 8.10 (d, 1H), 7.84 (d, 1H ), 7.74 (t, 1H), 7.69-7.65 (m, 2H), 7.56 (t, 1H), 7.30 (t, 1H), 7.20-7.12 (m, 3H), 7.02 (d, 1H), 5.41 ( s, 2H), 5.22 (s, 2H), 3.93 (s, 3H); MS (ESI) 416 (M + H) +. Prepared from methyl 3-methoxy-2- [3- (quinolin-2-ylmethoxy) -benzyloxy] -benzoate (Example 60a). Example 7ak 4-Methoxy-2 [3- (quinolin-2-ylmethoxy) -benzyloxy] -benzoic acid mp 117-118 ° C; l NMR (300 MHz, CDCl 3) d 8.20 (d, 1H), 8.14 (d, 1H), 8.09 (d, 1H), 7.83 (d, 1H), 7.74 (ddd, 1H), 7.65 (d, 1H) , 7.56 (ddd, 1H), 7.34 (t, 1H), 7.14-7.13 (m, 1H), 7.06-7.01 (m, 2H), 6.64 (dd, 1H), 6.56 (d, 1H), 5.41 (s) , 2H), 5.21 (s, 2H), 3.84 (s, 3H); MS (ESI) 416 (M + H) Y Prepared from methyl 4-methoxy-2- [3- (quinolin-2-ylmethoxy) -benzyloxy] -benzoate (Example 60b). Example 7a 5-Methoxy-2- (3- (quinolin-2-ylmethoxy) -benzyloxy-benzoic acid Melting point 248-249 ° C; XH NMR (300 MHz, DMSO-d.) D 8.40 (d, 1H) , 8.01 (t, 2H), 7.78 (t, 1H), 7.68 (d, 1H), 7.61 (t, 1H), 7.28-7.21 (m, 2H), 7.04 (d, 1H), 6.94 (dd) , 1H), 6.78-6.71 (m, 2H), 6.56 (dd, 1H), 5.36 (s, 2H), 4.98 (s, 2H), 3.64 (s, 3H), MS (ESI) 416 (M + H ) Y Prepared from methyl 5-methoxy-2- [3- (quinolin-2-ylmethoxy) -benzyloxy) -benzoate (Example 60c). Example a 2-Methoxy-6- [3- (quinolin-2-ylmethoxy) -benzyloxy] -benzoic acid mp 149-152 C; XH NMR (300 MHz, CDD3) d 8.34 (d, 1H), 8.16 (d, 1H), 7.80 (d, 1H), 7.75 (ddd, 1H), 7.69 (d, 1H), 7.55 (t, 1H), 7.40 (s, 1H), 7.27 (t, 1H), 7.18 (t, 1H), 6.91-87 (m, 2H), 6.60 (d, 2H), 5.45 (s, 2H), 5.08 (s, 2H), 3.89 (s, 3H), MS (ESI) 416 (M + H) Y Prepared from methyl 2-methoxy-6- [3- (quinolin-2-ylmethoxy) -benzyloxy] -benzoate (Example 60d).

Example 7an 2-Methyl-6-13- (quinolin-2-ylmethoxy) -benzyloxy) -benzoic acid Melting point 154-156 ° C, XH NMR (300 MHz, CD3OD) d 8.37 (d, 1H), 8.05 ( d, 1H), 7.95- (d, 1H), 7.81-7.71 (m, 2H), 7.63-7.59 (t, 1H), 7.31-7.15 (m, 3H), 7.06-6.97 (m, 2H), 6.87. (d, 1H), 6.82 (d, 1H), 5.35 (s, 2H), 5.12 (s, 2H), 2.31 (s, 3H); MS (ESI) 400 (M + H) +. Prepared from ethyl 2-methyl-6- [3- (quinolin-2-ylmethoxy) -benzyloxy) -benzoate (Example 60e). Example 7ao 5- [3- (Quinolin-2-ylmethoxy) -benzyloxy] -nicotinic acid XH NMR (300 MHz, CDC13) d 8.90 (s, 1H), 8.52 (s, 1H), 8.19 (d, 1H), 8.12 (d, 1H), 7.87-7.70 (m, 4H), 7.55 (t, 1H), 7.30 (t, IH), 7.13 (s, 1H), 7.01 (t, 2H), 5.44 (s, 2H) 5.10 (s, 2H); MS (ESI) (M + H) Y Prepared from methyl 5- [3- (quinolin-2-ylmethoxy) -benzyloxy] -nicniconate (Example 62). Example 7ap 2- [3- (2,4-Diisopropyl-5-methyl-benzyloxy) phenoxymethyl] -6-methyl-benzoic acid: H NMR (300 MHz, CDCl.) D 7.35 (m, 2H); 7.08 (m, 4H); 6.60 (m, 3H); 5.18 (s, 2H); 4.98 (s, 2H); 3.19 (m, 1H); 2.86 (m, 1H); 2.44 (s, 3H); 2.35 (s, 3H); 1.22 (m, 12H). MS (El) 484 (M) +. Prepared from methyl 2- [3- (2, 4-diisopropyl-5-methyl-benzyloxy) -phenoxymethyl] -6-methyl-benzoate (Example 6ab). Example 7aq 2- [3- (2,4-Bis-trifluoromethyl-benzyloxy) -phenoxymethyl] -6-methyl-benzoic acid XH NMR (300 MHz, CDC13) d 7.91 (s, 1H), 7.80 (m, 2H) , 7.33 (d, 2H), 7.18 (m, 2H), 6.60 (m, 2H), 6.52 (dd, 1H), 5.24 (s, 2H), 5.17 (s, 2H), 2.45 (s, 3H). MS (El) 484 (M) +. Prepared from ethyl 2- [3- (2, 4-bis-trifluoromethyl-benzyloxy) -phenoxymethyl] -6-methyl-benzoate (Example 6ac). Example 7ar 2- [3- (Biphenyl-4-ylmethoxy) -phenoxymethyl) -6-methyl-benzoic acid XH NMR (300MHz, CDCl 3) d 7.58 (m, 4H), 7.44 (m, 4H), 7.35 (m, 3H), 7.18 (, 2H), 6.60 (m, 3H), 5.17 (s, 2H), 5.02 (s, 2H), 2.44 (s, 3H). MS (El) 424 (M) +. Prepared from ethyl 2- [3- (biphenyl-4-ylmethoxy) -phenoxymethyl] -6-methyl-benzoate (Example 6ad). Example 7as 2-Methyl-6- [3-naphthalen-1-ylmethoxy) -phenoxymethyl] benzoic acid XH NMR (300 MHz, CDCl 3) d 8.00 (m, 1H), 7.85 (m, 2H), 7.47 (m, 4H ), 7.34 (m, 2H), 7.17 (m, 2H), 6.62 (m, 3H), 5.40 (s, 2H), 5.16 (s, 2H), 2.43 (s, 3H). MS (El) 398 (M) Y Prepared from ethyl 2-methyl-6- [3- (naphthalen-1-ylmethoxy) -phenoxymethyl] -benzoate (Example 6ae). Example 7at 2- [3- (5-Ethyl-pyridin-2-ylmethoxy) -phenoxymethyl] -6-methyl-benzoic acid XH NMR (300 MHz, DMSO) d 8.42 (bs, 1H), 7.65 (d, 1H) 7.39 (d, 1H), 6.63 (bs, 1H), 6.56 (m, 2H), 2.60 (q, 2H), 2.29 (s, 3H), 1.21 (t, 3H). MS (ESI) 378 (M + H) Y Prepared from methyl 2- [3- (5-ethyl-pyridin-2-ylmethoxy) -phenoxymethyl] -6-methyl-benzoate (Example 6af). Example 7au 2- [3- (4-Ethyl-benzyloxy) -phenoxymethyl) -6-methyl-benzoic acid XH NMR (300 MHz, DMSO) d 7.2 (m, 8H), 6.6 (m, 3H), 5.13 (s, 2H), 5.05 (d, 2H), 2.64 (m, 2H), 2.28 (s, 3H) , 1.17 (t, 3H).

MS (ESI) 375 (M-H) Y Prepared from methyl 2- [3- (4-ethyl-benzyloxy) -phenoxymethyl) -6-methyl-benzoate (Example 6ag). Example 7av 2- [3- (3-Bromo-benzyloxy) -phenoxymethyl) -6-methyl-benzoic acid XH NMR (300 MHz, DMSO) d 7.62 (s, 1H), 7.50 (d, 1H), 7.42 (d, 1H), 7.33 (d, 1H), 7.08 (m, 4H), 6.67 (s, 1H), 6.54 (, 2H), . 13 (s, 2H), 5.08 (s, 2H), 2.28 (s, 3H). MS (ESI) 425 (M-H).

Prepared from methyl 2- [3- (3-bromo-benzyloxy) -phenoxymethyl] -6-methyl-benzoate (Example 6ah). Example 7aw 2- (3- [2- (5-Ethyl-pyridin-2-yl) -ethoxy-phenoxymethyl] -6-methyl-benzoic acid XH NMR (300 MHZ, DMSO) d 8 .36 (bs) , 1H), 7. 56 (d, 1H), 7.14 (m, 5H), 6. 49 (m, 3H), 5. H, 2H), 4. 27 (t, 2H), 3. 09 (t, 2H), 2.56 (q, 2H), 2.29 (s, 3H), 1.17 (t, 3H). MS (ESI) 392 (M + H) +. Prepared from methyl 2-. { 3- [2- (5-ethyl-pyridin-2-yl) -ethoxy] -phenoxymethyl} Methyl-6-methylbenzoate (Example 4f). Example 7ax 2-Methyl-6- [3- (2-quinolin-2-yl-ethoxy) -phenoxymethyl] -benzoic acid H NMR (300 MHz, CD3OD) d 8.28 (d, 1H), 7.97 (d, 1H) 7.88 (d, 1H), 7.74 (t, 1H), 7.51 (m, 1H), 7.26 (d, 2H), 7.16 (m, 2H), 7.02 (m, 1H), 6.38 (m, 3H), 5.10 (s, 2H) ), 3.83 (t, 2H), 3.22 (t, 2H), 2.39 (s, 3H). Prepared from methyl 2-methyl-6- [3- (2-quinolin-2-yl-ethoxy) -phenoxymethyl] -benzoate (Example 21 b). Example 7a 2-Methyl-6- [3- (2-pyridin-2-yl-ethoxy) -phenoxymethyl] -benzoic acid: H NMR (300 MHz, DMSO) d 8.49 (d, 1H), 7.69 (m, 1H ), 7.26 (m, 3H), 7.04 (m, 2H), 6.38 (m, 4H), 5.03 (s, 2H), 3.67 (t, 2H), 2. 94 (t, 2H), 2.31 (s, 3H). MS (ESI) 364 (M + H) Y Prepared from methyl 2-methyl-6- [3- (2-pyridin-2-yl-ethoxy) -phenoxymethyl] -benzoate (Example 4g). Example 7az 2-3- (Benzooxazol-2-ylaminomethyl) -phenoxymethyl-6-methyl-benzoic acid: H NMR (300 MHz, DMSO) d 8.61 (bt, 1H), 7.34 (d, 1H), 7.04 (m, 10H), 5.12 (s, 2H), 4.47 (bd, 2H), 2.29 (3H). MS (ESI) 389 (M + H) Y Prepared from methyl 2- [3- (benzooxazol-2-ylaminomethyl) -phenoxymethyl] -6-methyl-benzoate (Example 4h). Example 7ba 2-Methyl-6-13- (pyridin-2-ylmethoxymethyl) -phenoxymethyl) -benzoic acid H NMR (300 MHz, DMSO) d 8.52 (bd, 1H), 7.81 (m, 1H), 7.47 (d, 1H), 7.20 (m, 5H), 6.94 (m, 3H), 5.12 (s, 2H), 4.59 (s, 2H), 4.56 (s, 2H), 2.30 (s, 3H). MS (ESI) 364 (M + 1) Y Prepared from methyl 2-methyl-6- [3- (pyridin-2-ylmethoxymethyl) -phenoxymethyl] -benzoate (Example 4i). Example 7bb 2-Methyl-6- [3-quinolin-2-ylmethoxymethyl) -phenoxymethyl] -benzoic acid XH NMR (300 MHz, DMSO) d 8.40 (d, 1H), 7.98 (d, 2H), 7.76 (m, 1H), 7.64 (m, 1H), 7.31 (m, 5H), 7.00 (m, 2H), 6.92 (dd, 1H), . 12 (s, 2H), 4.79 (s, 2H), 4.62 (s, 2H), 2.32 (s, 3H). MS (ESI) 414 (M + H) Y Prepared from methyl 2-methyl-6- [3- (quinolin-2-ylmethoxymethyl) -phenoxymethyl] -benzoate phenoxymethyl) -benzoate (Example 4j). Example 7bc 2-Methyl-6-acid. { 3- [2- (5-Methyl-2-phenyloxazol-4-yl) ethoxy] phenoxymethyl] benzoic XH NMR (300 MHz, CD30D) d 8.28 (d, 1H), 7.97 (d, 1H), 7.88 (d, 1H), 7.74 (t, 1H), 7.51 (m, 1H), 7.26 (d, 2H), 7.16 (m, 2H), 7.02 (m, 1H), 6.38 (m, 3H), 5.10 (s, 2H), 3.83 (t, 2H), 3. 22 (t, 2H), 2.39 (s, 3H). Prepared from methyl 2-methyl-6- [3- (2-quinolin-2-yl-ethoxy) -phenoxymethyl] -benzoate (Example 21a). Example 7bd 2-Methyl-6- [3- (6-phenylpyridin-2-yl-methoxy) phenoxymethyl] benzoic acid XH NMR (300 MHz, DMSO) d 8.49 (d, 1H), 7.69 (m, 1H), 7.26 (m, 3H), 7.04 (m, 2H), 6.38 (m, 10 4H), 5.03 (s, 2H), 3.67 (t, 2H), 2.94 (t, 2H), 2.31 (s, 3H). MS (ESI) 364 (M + H) Y Prepared from ethyl 2-methyl-6- [3- (2-pyridin-2-yl-ethoxy) -phenoxymethyl) -benzoate (Example 33). Example 7be 2-Methyl-6- (3- (quinolin-2-ylmethoxy) -phenylsulfanylmethyl) -benzoic acid XH NMR (300 MHz, DMSO) d 8.40 (d, 1H), 7.99 (t, 2H), 7.78 (t , 1H), 7.65-7.57 (m, 2H), 7.20-7.01 (m, 6H), 6.85 (t, 1H), 5.33 (s, 2H), 4.25 (s, 2H), 2.26 (s, 3H); MS (ESI) 415 (M + H) +. Prepared from 2-methyl-6- [3- (quinolin-2-ylmethoxy) -phenylsulfanylmethyl-isobutyl benzoate (Example 84). Example 7bf 2-Methyl-6- [3- (quinolin-2-ylmethoxy) -phenylsulfinylmethyl] -benzoic acid XH NMR (300 MHz, DMSO-d6) d 8.43 (d, 1H), 8.01 (t, 2H), 7.78 (t, 1H), 7.68 (d, 1H), 7.62 (t, 1H), 7.48 (t, 1H), 7.25-7.22 (m, 4H), 7.10 (d, 1H), 6.94 (t, 1H), 5.41 (s, 2H), 4.22 (d, IH), 4.1 (d, 1H), 2.33 (s, 3H); MS (ESI) 432 (M + H) Y Prepared from 2-methyl-6- [3- (quinolin-2-ylmethoxy) -phenylsulfinylmethyl] -isobutylbenzoate (Example 85). Example 7bg 2-Methyl-6- [3- (quinolin-2-ylmethoxy). Phenylsulfonyl ethyl] -benzoic acid XH NMR (300 MHz, DMSO-d6) d 8.43 (d, 1H), 8.05-7.98 (m , 2H), 7.77 (t, 1H), 7.67 (d, IH), 7.60 (t, 1H), 7.51 (t, IH), 7.43-7.35 (m, 2H), 7.26-7.20 (m, 3H), 6.95-6.92 (m, 1H), 5.42 (s, 2H), 4.81 (s, 2H), 2.32 (s, 3H), MS (ESI) 448 (M + H) Y Prepared from 2-methyl-6 - [3- (quinolin-2-ylmethoxy) -phenylsulfonylmethyl] -isobutylbenzoate (Example 86) Example 7bh 2-Methyl-6- [3- (quinolin-2-ylmethoxy) -phenylethynyl) -benzoic acid XH NMR ( 300 MHZ, CDC13) d 8.19 (d, 1H), 8.04 (d, 1H), 7.89 (d, 1H), 7.82 (d, 1H), 7.73 (dt, 2H), 7.64 (t, 2H), 7.54 (t, 1H), 7.26 (t, 1H), 6.94 (dd, 1H), 6.81-6.85 (m, 2H), 5.34 (s, 2H), 2.76 (s, 3H); MS (ESI) 394 (M + H) Y Prepared from ethyl 2-methyl-6- [3- (quinolin-2-ylmethoxy) -phenylethynyl] -benzoate (Example 6ai). Example 7bi 2-Methyl-6- [3- (5-phenylpyridin-2-ylmethoxy) -phenoxymethyl] benzoic acid. Melting point 80-83 ° C. XHMR (300 MHZ, 5: 1 CDCl .: CD3OD): d 8. 76 (s, 1H), 7.97 (d, 1H), 7.62 (m, 3H), 7.48 (m, 3H), 7.30 (m, 2H), 7.19 (m, 2H), 6.68 (s, 1H), 6.62 (d, 2H), 5.21 (s, 2H), 5.17 (s, 2H), 2.44 (s, 3H). MS (ESI) 426 (M + H) Prepared from methyl 2-methyl-6- [3- (5-phenylpyridin-2-ylmethoxy) phenoxymethyl] benzoate (Example 6a j). Example 7bj 2- [3- (2-Chloro-benzyloxy) -phenoxymethyl) -6-methyl-benzoic acid. X H NMR (300 MHz, DMSO) d 7.56 (m, 1 H), 7.50 (m, 1 H), 7.38 (m, 2H), 7.14 (m, 2H), 7.06 (m, 2H), 6.67 (s, 1H), 6.58 (m, 2H), . 13 (bd, 4H), 2.28 (s, 3H). MS (El) 382 (M ~), Cl pattern.

Prepared from 2 (Example 6ak). Example 7bk 2- [3- (4-Chloro-benzyloxy) -phenoxymethyl) -6-methyl-benzoic acid XH NMR (300 MHz, DMSO) d 7.42 (m, 3H), 7.08 (m, 5H), 6.66 ís, 1H), 6.54 (m, 2H), 5.13 (s, 2H), 5.07 (s, 2H), 2.28 (s, 3H).

MS (El) 382 (M +), Cl pattern. Prepared from 2- [3- (chloro-benzyloxy) -phenoxymethyl) -6-methyl-benzoate (Example 6al). Example 7bl 2-Methyl-6- [3-methyl-quinoxalin-2-ylmethoxy) -phenoxymethyl] benzoic acid XH NMR (300 MHz, DMSO) 5 8.05 (m, 2H), 7.82 (m, 2H), 7.14 (m , 4H), 6.75 (s, 1H), 6.61 (m, 2H), 5.41 (s, 2H), 5.11 (s, 2H), 2.76 (s, 3H), 2.27 (s, 3H). MS (ESI) 415 (M + H) +. Prepared from 2-methyl-6- [3- (3-methyl-quinoxalin-2-ylmethoxy) -phenoxymethyl) -benzoic acid methyl ester (Example 6am). Example 7bm 2-Methyl-6- [3- (naphthalen-2-ylmethoxy) -phenoxymethyl] -benzoic acid XH NMR (300 MHz, DMSO) d 7.94 (m, 4H), 7.54 (m, 3H), 7.16 (m , 4H), 6.69 (s, 1H), 6.58 (m, 2H), 5.24 (s, 2H), 5.11 (s, 2H), 2.29 (s, 3H). Prepared from 2-methyl-6- [3- (naphthalen-2-ylmethoxy) -phenoxymethyl] -benzoic acid methyl ester (Example 6an). EXAMPLE 8 3- [(2-Methoxyethoxy]) -methoxy] -benzonitrile To a cooled (0 ° C) suspension of sodium hydride (840 mg, 60% dispersion to 605 in mineral oil, 21 mmol in THF (20 mL) was add a solution comprising benzonitrile (2.4 g, 20 mmol), MEM chloride (2.25 mL, 20 mmol) and DMPU (2 mL) in THF (20 mL)., the cold bath is removed and stirred continuously for 3 hours. The reaction mixture is then diluted with ether, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 30% ethyl acetate, 10% dichloromethane in hexane) to give the title compound as an oil. MS (ESI) 207 (M + H) + EXAMPLE 8a 3- [(2-Methoxyethoxy) -methoxy] -benzaldehyde The title compound is prepared using essentially the same procedure as the procedure used in Example 8, except that it is used 3-hydroxy-benzaldehyde in place of 3-hydroxy-benzonitrile. MS (E) 210 (M) Y Example 9 3- 2- methoxy-ethoxy-methoxy-benzylamine To a cooled solution (0 ° C) of 3- [(2-methoxyethoxy) -methoxy] -benzonitrile (3.9g, 18.8 mmoles, Example 8) in THF (40 mL) is added LAH (40 mL, 1 M in THF). The resulting solution is stirred for 10 minutes. Then the cold bath is removed and stirred continuously for two hours. The resulting mixture is cooled to a temperature of 0 ° C and then water (1.5 mL) is added dropwise followed by a solution of NaOH (1.5 mL, 5M) and water (1.5 mL). The resulting suspension is diluted with ether and then filtered through Celite. The filtrate is concentrated to provide the title compound that is employed without further purification. MS (ESI) 21) (M + H) +. Example 10 3- (Quinolin-2-ylaminomethyl) -phenol To a solution of 3- [(2-methoxyethoxy) -methoxy] -benzylamine (422 mg, 2 mmol, Example 9) in DMSO (4 mL) is added 2- chloroquinoline (328 mg, 2 mmol). The resulting solution is heated to a temperature of 140 ° C and stirred at this temperature for 3 hours. The resulting mixture is cooled, diluted with water, and then extracted with ethyl acetate. The organic extract is washed with brine, dried in MgSO and concentrated. The residue is taken up in methanol (10 mL) and then P-toluenesulfonic acid monohydrate (190 mg, 1 mmol) is added. This mixture is heated to a temperature of 60 ° C and stirred at this temperature for 2 hours. The reaction mixture is then cooled, concentrated under reduced pressure and the residue is purified by flash chromatography (silica, 30% ethyl acetate in dichloromethane) to give the title compound. MS (ES) 251 (M + H) *. The following compounds are prepared using essentially the same procedure as the procedure used in Example 10, except that the above-mentioned chloride and amine are used instead of 2-chloro-quinoline and 3 - [(2-methoxyethoxy) -methoxy] benzylamine . Example 10a 3- [N-Benzoxazol-2-yl-N-methyl-amino) -methyl] phenol MS (ESI) 255 (M + H) + prepared from 3- [(methylamine) -methyl] - (2 -methoxyethoxy-methoxy) -benzene (example 28) and 2-chloro-benzoxazole. Also, omitting heating at 140 ° C. Reaction stirred at room temperature Example 10b 3- [(N-methyl-N-quinolin-2-yl-amine) -methyl] -phenol MS (ESI) 265 (M + H) Y Prepared from 3- [(methylamine ] -methyl] - (2-methoxyethoxy-methoxy) -benzene (example 28) and 2 chloro-quinoline Example 10c 3- (Benzooxazol-2-ylaminomethyl) -phenol The title compound is prepared using essentially the same procedure as the title compound. procedure used in Example 10 except that 2-chloro-benzoxazole is used in place of 2-chloro-quinoline, also omitting heating at 140 ° C. Reaction stirred at room temperature MS (ESI) 241 (M + H) Y Example 11 2- (3- ([2-methoxyethoxy] -methoxy) -phenoxy]) ethanol To a cooled (0 ° C) solution of (3- ([2-methoxyethoxy] -methoxy) -phenoxy]) acetate -butyl (1.2 g, 3.8 mmol, example 12) in THF (10 mL) is added a solution of lithium aluminum hydride (5 mL, 1 M in THF) The resulting solution is stirred for 10 minutes, and then water drop is added dropwise (0.2 mL). or a solution of NaOH (0.2mL, 5M) and water (0.2 mL). The resulting mixture is diluted with ether, filtered on Celite, and the filtrate is concentrated to give the title compound as an oil which is used without further purification. MS (El) 242 (M) Y- Example lia 2- (5-methyl-2-phenyloxazol-4-yl) ethanol The title compound is prepared using essentially the same procedure as the procedure used in Example 11, except that methyl 2- (5-methyl-2-phenyloxazol-4-yl) acetate (Example 32) is used instead of (3 - ([2-methoxyethoxy] -methoxy) -phenoxy]) -acetate. -butyl MS (ESI) 204 (M + H) + Example 12 (3- ([2-methoxyethoxy] -methoxy) -phenoxy] -t-butyl acetate The title compound is prepared using essentially the same procedure as the process used in Example 4, except that 3- ([2-methoxyethoxy] -methoxy) -phenol (Example 13) is used in place of 3- (quinolin-2-yl-tetoxy) -phenol and t-butyl bromoacetate in place of methyl 2-bromomethyl-6-methyl-benzoate MS (El) 312 (M) Y Example 13 3- (2-methoxyethoxy) -methoxyl-phenol To a cooled (0 ° C) suspension of NaH (440 mg , 60% dispersion in oil, 11 mmol) in THF (10 mL) is slowly added a solution comprising 3-benzoyl-phenol (2.14 g, 10 mmol), MEM chloride (1.28 mL, 10.5 mmol) and DMPU ( 3 mL in THF (20 mL) To the addition terminal in a cold bath is removed and stirring continues for 2.5 hours. a saturated solution of NH 4 Cl is added and the mixture is diluted with ether, washed with water and brine, dried over MgSO 4 and concentrated. The residue is taken up in methanol (ML) and THF (10 mL) and then a solution of sodium hydroxide (10 mL, 2N) is added. This mixture is stirred for 20 minutes and then hydrochloric acid (10 mL, 2N) is added. The mixture is then diluted with ether, washed with a saturated solution of NaHCO 3 and brine dried in MgSO. and concentrated. The residue is purified by flash chromatography (silica, 30% ethyl acetate in hexanes) to give the title compound as an oil. XH NMR (300 MHz, CDC13) 8 7.00 (t, xH), 6.52 (bd, 1H), 6.48 (bs, 1H), 6.38 (bd, 1H), 5.14 (s 2H), 3.71 (, 2H), 3.47 (m, 2H), 3.30 (s, 3H). Example 14 [(2-Methoxyethoxy) -methoxy-3- [2- (pyridin-2-yloxy) -ethoxy] -benzene To a solution of 2- (3- ([2-methoxyethoxy] -methoxy) -phenoxy]) Ethanol (242 mg, 1 mmol, Example 11) in DMSO (1.5 mL) is added sodium hydride (44 mg, 60% dispersion in mineral oil, 1.1 mmol) followed by 2-fluoro-pyridine (176 mL, 2 mmol). ). The resulting solution is heated to a temperature of 60 CU and stirred at that temperature for 3 hours cooled, diluted with ether, washed with water and brine, dried in MgSO and concentrated. The residue is purified by flash chromatography (silica, 30% ethyl acetate in hexanes) to give the title compound. MS (ESI) 320 (M + H) Y Example 15 3- (2-Quinolin-2-yl-vinyl) -phenol To a solution of 1- (2-methoxyethoxy) -methoxy-3- (2-quinoline-2) -yl-vinyl) -benzene (120 mg, 0.35 mmol, Example 16) p-Toluenesulfonic acid monohydrate is added. (74 mg, 0.39 mmol). The resulting solution is heated to a temperature of 60 ° C and stirred at this temperature for 4 hours. The reaction mixture is then cooled, concentrated and the residue taken up in dichloromethane. This solution is washed with a saturated solution of NaHCO3, dried over MgSOj. and then concentrated to provide the title compound as a solid. MS (ESI) 248 (M + H) Y The following compounds were prepared using essentially the same procedure as the procedure used in Example 15 except that the aforementioned MEM ether was used in place of 1- (2-methoxyethoxy) -methoxy -3- (2-quinolin-2-yl-vinyl) -benzene. Example 15a 3- [2- (pyridin-2-yloxy) -ethoxy-phenol MS (ESI) 232 (M + H) Y Prepared from [2-methoxyethoxy) -methoxy] -3- [2-pyridine-2 -yloxy) -ethoxy] -benzene (Example 14). Example 15b 3- (Quinolin-2-yloxymethyl) -phenol MS (ESI) 252 (M + H) Prepared from 2- [3- (2-methoxy-ethoxymethoxy) -benzyloxy] -quinoline (example 81). Example 15C Ethyl 2- (3-hydroxy-phenylethynyl) -6-methyl-benzoate MS (El) 280 (M) Y Prepared from 2- [3- (2-methoxy-ethoxymethoxy) -phenylethynyl] -6- ethyl methylbenzoate (Example 98). Example 16 1- (2-methoxyethoxy) -methoxy-3- (2-quinolin-2-yl-vinyl) -benzene To a cooled suspension (-78 ° C) of triphenyl- (quinolin-2-yl-methyl) -phosphonium chloride (1.76 g, 4 mmol, Example 17) in THF (24 mL) is added, drop by drop, a solution of n-butyllithium (1.7 mL, 2.5 M in hexanes). The resulting mixture is stirred for 30 minutes. And then a solution of 3- [(2-methoxyethoxy) -methoxy] -benzaldehyde (756 mg, 3.6 mmol, Example 8a) in THF (3 mL) is added. This is stirred for 30 minutes and then the cold bath is removed and stirring continues for 2 hours. The reaction mixture is then diluted with ethyl acetate, washed with a saturated solution of ammonium acetate and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 40% ethyl acetate in hexanes) to give the title compound as an oil.

(ESI) 336 (M + H) Example 17 Trifenyl- (quinolin-2-yl-methyl) -phosphonium chloride To a solution of 2-chloromethyl-quinoline (2.9 g, 20 mmol) in acetonitrile (32 mL) is added triphenylphosphine (4.49 g, 17 mmol). The mixture is heated to a temperature of 60 ° C and stirred at that temperature for 15 hours. This mixture is cooled, diluted with ether, and then filtered. The solid is washed with ether and then dried under high vacuum to provide the title compound as a solid.

XH NMR (300 MHz, CDC13) d 8.20 (d, 1H), 8.06 (d, 1H), 7.95 (m, 6H), 7.42-7.8 (m, 13H), 6.10 (d, 2H). Example 18 Acid (2-methyl-6-3- (2-quinolin-2-yl-ethyl) -phenoxymethyl) -phenoxy} -acetic To an acid solution. { 2-methyl-6- [3- (2-quinolin-2-yl-vinyl) -phenoxymethyl] -phenoxy} -acetic acid (94 mg, 0.23 mmol, Example 41a) in DMF (1.5 mL) is added tristriphenylphosphine rhodium chloride (25 mg, 0.027 mmol). The resulting solution is placed in a hydrogen atmosphere, heated to a temperature of 60 ° C and stirred at this temperature for 5 hours. The reaction mixture is cooled to room temperature and the system is then rinsed with nitrogen and concentrated under a ford. The residue is purified by reverse phase HPLC to provide the title compound in the form of a trifluoroacetate salt. XH NMR (300 MHz, CDC13) d 8.57 (d, 1H), 8.40 (d, IH), 8.0 (m, 2H), 7.80 (t, 1H), 7.52 (d, 1H), 7.24 (bd, 1H), 7.14 (m, 2H), 7.04 (t, 1H), 6.93 (bs, 1H), 6.83 (d, 1H) ), 6.74 (d, 1H), 5.1) (s, 2H), 4.50 (s, 2H), 3.68 (t, 2H), 3.20 (t, 2H), 2.28 (s, 3H). MS (ESI) 428 (M + H) Y The following compound is prepared using essentially the same procedure as the procedure employed in Example 18 except that the aforementioned acid is used instead of Acid. { 2-methyl-6- [3- (2-quinolin-2-yl-vinyl) -phenoxymethyl] phenoxy} -acetic. Example 18a 2-Meth1-6- [3- (2-quinolin-2-yl-ethyl) -phenoxymethyl] -benzoic acid XH NMR (300 MHz, CDCl 3) d 8.62 (d, 1H), 8.44 (d, 1H) , 8.0 (m, 2H), 7.80 (t, 1H), 7.61 (d, 1H), 7.21 (d, 1H), 7.11 (d, 1K), 7. 07 (t, 1H), 6.94 (bs, 1H), 6.76 (bd, H), 6.68 (d, 1H), 5.09 (s, 2H), 3.70 (t, 2H), 3.18 (t, 2H), 2.40 (s, 3H). MS (ESI) 398 (M + H) Prepared from Acid. { 2-methyl- [3- (2-quinolin-2-yl-vinyl) -phenoxymethyl] -benzoic acid (Example 4a). Example 19 4-chloro-methy1-2-pheny1-oxazole Benzamide (1.21 g, 10 mmol) is mixed with 1,3-dichloroacetone (1.26 g, 10 mmol) and the mixture is heated to a temperature of 130 ° C and stirred thereto. temperature for 1 hour. The resulting mixture is then cooled, diluted with ethyl acetate, washed with a K2CO3 solution (saturated), then brine, dried over MgSO4 and concentrated to give the title compound as a solid which is used without further purification. MS (ESI) 194 (M + H, Cl standard) Y The following compounds are prepared using essentially the same procedure as the procedure used in Example 19 except that the aforementioned amide is used in place of benzamide. Example 19a Chloride of 2- (S-methylthiophen-2-yl) oxazole-4-ylmethyl MS (ESI) 214, 216 (M + H) +, Cl. Prepared from 5-methylthiophen-2-carboxamide. Example 19b 2-Dichlohexyloxazol-4-ylmethyl chloride MS (ESI) 200, 202 (M + H) +, Cl. Prepared from cyclohexanecarboxamide. Example 19c 2- (3-Fluorophenyl) oxazol-4-ylmethyl MS (ESI) 212,214 (M + H) + Chloride, Cl. Pat. Prepared from 3-fluorobenzamide. Example 19d 2-Fluorohenloxazol-4-ylmethyl chloride.

MS (ESI) 212.214 (M + H) \ Cl pattern. Prepared from 4-fluorobenzamide Example 20 4-Chloro-methyl-2-phenyl-thiazole A solution of thiobenzamide (1.37 g, 10 mmol) and 1,3-dichloro-acetone (1.27 g, 10 mmol) in ethanol (25 mL) it is heated to a temperature of 75 ° C and stirred at this temperature for 1 hour. The resulting solution is cooled, poured on ice and then brought to pH 8 with a K2C03 (saturated) solution. This mixture is extracted with ethyl acetate, dried over MgSO4 and concentrated to give the title compound. This product is used without further purification. MS (ESI) 210 (M + H) Example 21. { 2-methyl-6- [3- (2-pyridin-2-yl-ethoxy) -phenoxymethyl] -phenoxy} acetonitrile To a solution of [2-methyl-6- (3-hydroxy-phenoxymethyl) -phenoxy] -acetonitrile (135 mg, 0.5 30 mmol, Example 25) and 2- (pyridin-2-yl) -ethanol (126 mL, 0.94 mmol) in TRF (2 mL) was added triphenylphosphine (262 mg, 1 mmol) followed by DEAD (1) 8 mL, 0.75 mmol). The resulting solution is stirred for 2 hours, and then concentrated and the residue is purified by flash chromatography (silica, 50% ethyl acetate in hexanes) to give the title compound as an oil. MS (ESI) 375 (M + H) +. The following compound is prepared using essentially the same procedure used in Example 21 except that the aforementioned alcohol and the mentioned phenol are used in place of 2- (pyridin-2-yl) -ethanol and [2-methyl-6- (3 -hydroxy-phenoxymethyl) -phenoxy] -acetonitrile respectively. Example 21a 2-methyl-6-. { 3- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] -phenoxymethyl} methyl methylbenzoate MS (ESI) 458 (M + H) +. Prepared from 2- (5-methyl-2-phenyloxazol-4-yl) ethanol (Example lia) and methyl 2- (3-hydroxyphenoxymethyl) -6-benzoate (Example 5). Example 21b 2-methyl-6- [3. { - (2-quinolin-2-yl-ethoxy) phenoxymethyl] -benzoic acid methyl ester XH NMR (300 MHz, CDC13) d 8.08 (m, 2H), 7.80 (d, 1H), 7.70 (t, 1H), 7.51 (t, 1H), 7.42 (d, 1H), 7.29 (, 2H), 7.16 (m, 2H), 6. 53 (m, 3H), 5.06 (s, 2H), 4.46 (t, 2H), 3.81 (s, 3H), 3.45 (t, 2H), 2. 37 (s, 3H). MS (ESI) 428 (M + H) Y Prepared from 2-quinolin-2-yl-ethanol (Example 69a) and 2- (3-hydroxy-phenoxymethyl) -6-methyl-benzoate (eg 5) . Example 22 2-cyanomethoxy-3-methylbenzaldehyde A mixture of 2-hydroxy-3-methylbenzaldehyde (10.2 g, 75. 0 mmol, Aldrich), bromoacetonitrile (5.70 mL, 82.5 mmol), and potassium carbonate ( 11.4 g, 82.5 mmol) in DMF (150 mL) is heated at a temperature of 55 ° C for 3 hours, cooled, and then diluted with ether. The mixture is washed with distilled water, saturated NaCl solution, and then the organic layer is dried over MgSO. and concentrated to provide the title compound as a yellow solid. X H NMR (300 MHz, CDCl 3): d 10.20 (s, 1 H), 7.70 (d, 1 H), 7.53 (d, 1 H), 7.29 (m, 1 H), 4.81 (5, 2 H), 2.42 (s, 3 H) ). The following compounds are prepared using essentially the same procedure as the procedure used in Example 22 except that the aforementioned phenol was used in place of 2-hydroxy-3-methylbenzaldehyde. Example 22a 2-cyanomethoxy-3,5-dichlorobenzaldehyde MS (El) 229, 231 (M) Y Prepared from 3,5-dichlorosalicylaldehyde. Example 22b 2-Cyanome toxy-5-chloro-3-me toxy-benzaldehyde MS (El) 225 (M) +. Prepared from 5-chloro-2-hydroxy-3-methoxy-benzaldehyde (Example 44). Example 22c Methyl 2- (2-formyl-6-methyl-phenoxy) -propionate The title compound is prepared using essentially the same procedure as the procedure used in example 22 except that methyl 2-bromopropionate is used instead of bromoacetonitrile. Example 23 (2-hydroxymethyl-6-methyl-phenoxy) -acetonitrile The 2M triglyme solution of sodium borohydride (16.0 ml, 32. 1 mmol) is added slowly to a cooled solution (-78 ° C) of 2-cyanomethoxy-3-methylbenzaldehyde (11.25g), 64.2 mmole, Example 22) in THF (180 mL). After stirring for 1 hour, the reaction is heated at 0 ° C for two hours, and then quenched with 2N HCL (16.8 mL) and diluted with ether. The organic layer is isolated and washed twice with distilled water and brine and then dried in MgSO .. The organic solution is concentrated to give the title compound as a yellow oil. The following compounds are prepared using essentially the same procedure as the procedure used in Example 23 except that the above-mentioned aldehyde was used in place of 2-cyanomethoxy-3-methylbenzaldehyde. Example 23a (2-4-Dichloro-6-hydroxymethyl-phenoxy) -acetonitrile Prepared using 2-cyanomethoxy-3,5-dichloro-benzaldehyde (Example 22a) Example 23b (4-Chloro-2-hydroxymethyl-6-methoxy-phenoxy) ) -acetonitrile S (El) 227 (M) Y Prepared using 2-cyanomethoxy-5-chloro-3-methoxy-benzaldehyde (Example 22b) Example 23c 2- (2-Hydroxymethyl-6-methyl-) methyl ester phenoxy.) -propionic MS (El) 194 (M) + .Prepared using methyl 2- (2-formyl-6-methyl-phenoxy) -propionate (Example 10 22c) .Example 24 2-bromomethyl-6 -methyl-phenoxy) -acetonitrile Thifenylphosphine (15.2g, 57.8 mmol) is added to 2-cyanomethoxy-3-methylbenzyl alcohol (9.3g, 52.5 mmol, Example 23) in THF (175 mL). The mixture is stirred until it is homogeneous and cooled to a temperature of 0 ° C, followed by the addition, in three portions, of N-bromosuccinimide (10.3 g, 57.8 mmol). After 90 minutes, the reaction is concentrated and the residue is purified by column chromatography (silica, 5: 1 hex: EtOAc) to give the title compound as a pale yellow crystalline solid. MS (El) 239.241 (M) Y Br standard. The following compounds are prepared using essentially the same procedure as the procedure used in Example 24 except that the mentioned alcohol was used in place of 2-cyanomethoxy-3-methylbenzyl alcohol. Example 24a (2-bromomethyl4,6-dichloro-phenoxy) -acetonitrile MS (El) 277 (M-16) Y Prepared from (2,4-dichloro-6-hydroxymethyl-phenoxy) -acetonitrile (Example 23a). Example 24b (2-bromomethyl-4-chloro-6-methoxy-phenoxy) -acetonitrile MS (El) 289 (M) Y Prepared from (4-chloro-2-hydroxymethyl-6-methoxy-phenoxy) -acetonitrile ( Example 23b). Example 24: Methyl 2- (2-bromomethyl-6-methyl-phenoxy) -propionate MS (El) 286 (M) +, bromine standard. Prepared from methyl 2- (2-hydroxymethyl-6-methyl phenoxy) -propionate (Example 23c). Example 25 (2- [3-Hydroxy-henoxymethyl-6-methylphenoxy) acetonitrile A mixture of 2-cyanomethoxy-3-methylbenzyl bromide (10.2 g, 42.7 mmol, Example 24) is heated at a temperature of (60 ° C) , resorcinol (18.8g, 171mmol), and potassium carbonate (47.2 g, 342 mmol) in acetonitrile (140 mL) for two hours. The reaction is diluted with ether and washed three times with distilled water, once with brine and dried over MgSO .. The organic layer is isolated and concentrated, and the resulting residue is purified by column chromatography (silica, 5% EtOAc / CH2D2 ) to provide the title compound in the form of a white crystalline solid.

MS (EI) 269 (M) Y The following compounds are prepared using essentially the same procedure as the procedure used in example 25 except that the aforementioned bromide was used in place of 2-cyanomethoxy-3-methylbenzyl bromide. Example 25a [4-Chloro-2- (3-hydroxy-phenoxymethyl) -6-methyl-phenoxy-acetonitrile Prepared from (2-bromomethyl-4-chloro-6-methyl-phenoxy) -acetonitrile (Example 43). Example 25b [4,6-Dichloro-2- (3-hydroxy-phenoxymethyl) -phenoxy] -acetonitrile Prepared from (2-bromomethyl-4,6-dichloro-phenoxy) -acetonitrile (Example 24a). Example 26 2-methyl-6,7-difluoroquinoline To a refluxing solution of 3,4-difluoroaniline (2.30 ml, 23.2 mmol), tetrachloro-1,4-benzoquinone (5.70 g, 23.2 mmol), and concentrated hydrochloric acid ( 6 ml) in 2-butanol (40 ml) is added crotonaldehyde (1.92 ml, 23.2 mmol). After 2.5 hours the reaction mixture is concentrated and the resulting residue is stirred in hot THF (50 ° C) (15 ml). This mixture is cooled (0 ° C) and the solid collected by filtration and washing with cold THF. The solid is stirred in distilled water (200 ml), and the resulting solution is basified with K2C03 and extracted with EtOAc (3 x 100 ml). The organic extracts are combined and dried in sodium sulfate and then concentrated to provide the title compound. MS (ESI) 180 (M + H) Y The following compounds are prepared using essentially the same procedure as the procedure used in Example 26 except that the above-mentioned aniline is used in place of 3,4-difluoroaniline. Example 26a 2-methyl-6,8-difluoroquinoline MS (ESI) 180 (M + H) + prepared using 2,4-difluoroaniline.

Example 27 6-8-Difluoroquinolin-2-ylmethyl bromide A solution of 2-methyl-6,8-difluoroquinoline (0.147 g, 0.820 mmol, Example 26a), benzoyl peroxide (9.93 mg, 0.0410 mmol), and N- Bromosuccinimide (0.168 g, 0.943 mmol) in carbon tetrachloride (20 mL) is heated at reflux for 18 hours. The reaction is concentrated and the resulting residue is purified by column chromatography (silica, 3: 1 CH2C12 to give the title compound as a white solid MS (ESI) 258.260 (M + H) +, Br standard. The following compounds are prepared using essentially the same procedure as the procedure used in example 27 except that the aforementioned methyl compound is used in place of 6,8-difluoro-2-methylquinoline Example 27a 6,7-difluoroquinolinium chloride 2-ylmethyl MS (ES 1) 214, 216 (M + H) \ Cl-pattern. Prepared from 6,7-difluoroquinoline (Example 26) and NCS in place of NBS.

Example 27b 6-Fluoroquinolin-2-ylmethyl bromide MS (ESI) 240, 242 (M + H) +, Br standard. Prepared from 6-fluoro-2-methylquinoline. Example 27c 2-chloromethyl-6-chloropyridine MS (ESI) 162, 164, 166 (M + H) +, Cl 2 standard. Prepared from 6-chloro-2-picoline and NCS instead of NBS. Example 27d 2-Bromomethyl-benzonitrile MS (El) 195 (M) +, Br. Prepared from o-tolunitrile. Example 27e Methyl 3-bromomethyl-thiophene-2-carboxylate MS (El) 234 (M) +, Br standard. Prepared from methyl 3-methyl-thiophene-2-carboxylate. Example 27f 6-7-dichloro-2-chloromethyl-quinoline (ESI) 246 (M + H) Y Prepared from 6,7-dichloroquinaldine and NCS in place of NBS. Example 27g 5-Phenylpyridin-2-ylmethyl Chloride MS (ESI) 204, 206 (M + H) Y Cl. Standard. Prepared from 5-phenyl-2-methylpyridine (Example 104) and NCS in place of NBS. Example 28 3- (Methylamino-) methyl] - (2-methoxyethoxy-methoxy-benzene To a solution of 3- (2-methoxyethoxy-methoxy) -benzaldehyde (2.10 g), 10 mmol, Example 8a) in THF (60 mL) is added methylamine (20 mL, 2M in THF) followed by palladium on carbon (210 mg, 10% Pd). The resulting mixture is stirred for 24 hours in an sphere of hydrogen gas, then purged with nitrogen, filtered through Celite and the filtrate is concentrated. The residue is purified by flash chromatography (silica, 10% methanol in dichloromethane) to give the title compound as an oil. EXAMPLE 29 L-Methyl-4-oxo-l, 4-dihydroquinol-n-2-ylmethyl bromide A solution of 1-methyl 4-oxo-l, 4-dihydroquinolin-2-ylmethanol (112 mg, 0.592 mmol, Coppola , GMJ Heterocyclic Chem., 1986, 23, 1717) and phosphorous tribromide (56.2 uL, 0.592 mmol) in 3: 1 CH2C12: DMF (20 mL) is stirred for 18 hours and another portion (20 uL) of phosphorous tribromide is added . After 24 hours, add distilled water (10 mL) and extract with EtOAc. The organic layer is concentrated and the resulting residue is purified by column chromatography (silica, 20: 1 CR2D2: MeOH) to give the title compound as a white solid. MS (ESI) 252, 254 (M + H) \ Br standard. The following compound is prepared using essentially the same procedure as the procedure used in Example 29 except that the mentioned alcohol was used in place of l-methyl-4 -oxo-l, 4-dihydroquinolin-2-ylmethanol. Example 29a Bromide of 4-tert-butylcyclohexylmethyl XH NMR (300 MHZ, CDCl 3): d 3.27 (d, 2H), 1.93 (m, 2H), 1.81 (m, 2H), 1.54 (m, 2H), 0.98 (m , 4H), 0.84 (s, 9H). Prepared from 4-tert-butylcyclohexylmethanol (Example 30). EXAMPLE 30 4-tert-Butylcyclohexylmethanol To a cooled (0 ° C) solution of 4-tert-butylcyclohexanecarboxylic acid (3.00g, 16.3 mmol) in THF (30 mL) is added slowly a THF solution of borane THF complex ( lOM, 21.2 mL, 21.2 mmol). The solution is stirred at room temperature for 18 hours, and then cooled with a solution of 2N HCL (30 mL), and extracted with EtOAc. The organic layer is isolated, washed with NaOH, IN, dried over sodium sulfate, and concentrated to give the title compound as a clear oil. XHMR (300 MHz, CDC13): d 2.06 (d, 2H), 1.82 (m, 4H), 1.52 (, 2H), 0.88 (m, 4H), 0.83 (s, 9H). EXAMPLE 31 Methyl 4-bromo-3-oxopentanoate To a cooled (0 ° C) solution of methyl 3-oxopentanoate (9.62 mL, 76.8 mmol, Acros) in carbon tetrachloride (60 L) is added dropwise over a 45 minutes a solution of bromine (3.96 mL, 76.8 mmol) in carbon tetrachloride (10 mL). After 30 minutes, stir at a low temperature for one hour. N2 is bubbled again from the reaction mixture during minutes. Concentrate to provide the title compound as a brown oil. MS (El) 208.210 (M) +, Br standard. Example 32 Methyl 2- (5-methyl-2-phenyloxazol-4-yl) acetate A solution of benzamide (0.606g, 5.00 mmol) and 4-bromo- Methyl 3-oxopentanoate (1.05 g, 5.00 mmol, Example 31) is heated in toluene (6 ml) at a temperature of 120 ° C for 18 hours. The reaction is then purified by column chromatography (silica, 4: 1 hex: EtOAc) to give the title compound as a clear oil. MS (APd) 232 (M + H) Y Example 33 Ethyl 2-methyl-6- [3- (6-phenylpyridin-2-ylmethoxy) phenoxymethyl] benzoate. A solution of phenylboronic acid (74.0 mg, 0.607 mmol), ethyl 2- [3- (6-chloropyridin-2-ylmethoxy) -phenoxymethyl] -6-methylbenzoate (250 mg, 0.607 mmol, Example 6i), and sodium carbonate (77.8mg, 1.21 mmoles) in 1: 1 H20: AcCN (8 mL) is stirred in ford for five minutes. The reaction is placed under a hydrogen atmosphere, and tetrakis (triphenylphosphine) -palladium (0) (60.7mg) is added followed by heating to 90 ° C. After two hours, another portion (15mg) of phenylboronic acid is added. . After another hour the heating is suspended. Distilled water (10 mL) is added followed by extraction with methyl chloride twice with 20 mL. The organic extracts are combined and concentrated and the resulting residue is purified by column chromatography (silica, 6: 1 hex: EtOAc) to give the title compound. MS (ESI) 454 (M + H) Y Example 34 L-Oxyquinolin-2-ylmethyl Chloride 2- (Chloromethyl) quinoline hydrochloride (1.00 g, 4.67 mmol) between methylene chloride (15 mL) and a solution of Sodium hydroxide (1 M, 15 mL) to form the free base. The organic layer is isolated and cooled (0 ° C), followed by the addition of 3-chloroperbenzoic acid (57-86%, 1.13 g, -4.67 mmol). After stirring at room temperature for 18 hours the reaction mixture is washed with dilute sodium hydroxide. The organic layer is isolated and concentrated. The resulting residue is purified by column chromatography (silica, 1: 1 hex: EtOAc) to provide the title compound as a white solid. MS (ESI) 194, 196 (M + H) +, Cl pattern. Example 35 { 2- [3- (quinolin-2-ylmethoxy) phenoxymethyl] -6-methylphenoxy} acetonitrile 3- (quinolin-2-ylmethoxy) -phenol (1.3g, 5.4 mmol, Example 3), (2-bromomethyl-6-methyl-phenoxy) -acetonitrile (1.56 g, 6.5 mmol, Example 24), tetrabutylammonium iodide (99 mg, 0.27 mmol) and potassium carbonate (0.45 g, 3.3 mmol) are subjected to reflux in acetone (20 mL) for 16 hours. The reaction is filtered, washed with concentrated dichloromethane and purified by column chromatography (silica, 1% ether in dichloromethane) to give the title compound. MS (ESI) 44 (M + H) Y The following compounds are prepared using essentially the same procedure used in Example 35, except that the aforementioned phenol was used in place of 3- (quinolin-2-ylmethoxy) -phenol. Example 35a MS (ESI) 409 (M + H) Prepared from 3 - (quinolin-2-ylaminomethyl) -phenol (Example 10).

Example 35b. { 2-Methyl-6-13- (2-quinolin-2-yl-vinyl) -phenoxymethyl) -phenoxy} -acetonitrile. MS (ESI) 407 (M + H) Y Prepared from 3- (2-quinolin-2-yl-vinyl) -phenol (Example 15). Example 35c (2-Methyl-6-. {3- [2- (pyridin-2-yloxy) -ethoxy] -phenoxymethyl] -phenoxy) -acetonitrile MS (ESI) 391 (M + H) Y Prepared to from 3- [2-pyridin-2-yloxy) -ethoxy] -phenol Example 15a). Example 35d. { 2- [3- (Benzooxazol-2-ylaminomethyl). Phenoxymethyl) -6-methyl-phenoxy} -acetonitrile XH NMR (300 MHz, CDC13) d 7.15 (m, 11H), 5.36 (bs, 1H), 5.08 (s, 2H), 4.67 (s, 4H), 2.37 (s, 3H). MS (ESI) 400 (M + H) Y Prepared from 3-benzooxazol-2-ylaminomethyl) -phenol (Example 10c). Example 35e { 2- [3- (4-Chloro-quinolin-2-ylmethoxymethyl) -phenoxymethyl] -6-methy1-phenoxy} -acetonitrile XH NMR (300 MHz, CDC13) d 8.22 (d, 1H), 8.06 (d, 1H), 7.76 (m, 2H), 7.63 (m, 1H), 7.32 (m, 2H), 7.23 (m, 1H), 7.13 (m, 1H), 7. 04 (m, 2H), 6.94 (m, 1H), 5.09 (s, 2H), 4.83 (s, 2H), 4.72 (s, 2H), 4.68 (s, 2H), 2.39 (s, 3H). MS (ESI) 459 (M + H) Y Prepared from 3- (4-chloro-quinolin-2-ylmethoxymethyl) -phenol (Example 74b). Example 35f (2- [3- (6-methoxy-quinolin-2-ylmethoxymethyl) -phenoxymethyl] -6-methyl-f-enoxy] -acetonitrile XH NMR (300 MHz, CDC13) d 8.08 (d, 1H), 7.96 (d, 1H), 7.60 (d, 1H), 7.19 (m, 8H), 6.92 (dd, 1H), 5.07 (s, 2H), 4.84 (s, 2H), 4.71 (s, 2H), 4.66 (s, 2H), 3.93 (s, 3H) ), 2.39 (s, 3H). MS (ESI) (M + H) Y Prepared from 3- (6-methoxy-quinolin-2-ylmethoxymethyl) -phenol (Example 74c). Example 35g. { 2-Methyl-6- [3- (quinolin-2-ylmethoxymethyl) -phenoxymethyl] -phenoxy} -acetonitrile Prepared from 3- (quinolin-2-ylmethoxymethyl) -phenol (Example 74a). The following compounds are prepared using essentially the same procedure used in Example 35 except using the aforementioned bromide in place of 2-bromomethyl-6-methyl-f-enoxy-acetonitrile. Example 36a Methyl ester of 2- acid. { 2-methyl-6- [3-quinolin-2-ylmethoxy) phenoxymethyl] -phenoxy] -propionic acid MS (ESI) 457 (M + H) +. Prepared using methyl 2- (2-bromomethyl-6-methyl-phenoxy) -propionate (example 24c). Example 36b [2,4-Dichloro-6- [3- (quinolin-2-ylmethoxy) -phenoxymethyl] -phenoxy] acetonitrile MS (ESI) 465 (M + H) Y Cl2 standard. Prepared from (2-bromomethyl-4,6-dichloro-phenoxy) -acetonitrile (Example 24a) Example 36c MS (ESI) 445 (M + H) Y Prepared from (2-bromomethyl-4-chloro-6-methyl-phenoxy) -acetonitrile (Example 43). Example 36d. { 2-tert-Butyl-6- [3- (quinolin-2-ylmethoxy) -phenoxymethyl] -phenoxy} - acetonitrile MS (ESI) 453 (M + H) Y Prepared from (2-bromomethyl-6-tert-butyl-phenoxy) -acetonitrile (Example 43a). Example 36e MS (ESI) 461 (M + H) and Cl standard. Prepared from (2- "gold ome thi 1 -chloro-6-me toxi- er.ox i) -ace or.itrile (Example 24b). Example 36f 2- [3- (quinolin-2-ylmethoxy) -phenoxymethyl] -benzonitrile MS (ESI) 386 (M + H) Y Prepared from 2-bromomethyl-benzonitrile (Example 27d). Example 36g Methyl 2- [3-quinolin-2-ylmethoxy-) phenoxymethyl] -thiophene-2-carboxylate MS (ESI) 406 (M + H) Y Prepared from methyl 3-bromomethyl-thiophene-2-carboxylate (Example 27e). Example 36h. { 2-me ti 1-6- [3- (quinol in-2- lme toxy) -phenoxymethyl] -phenoxy} ethyl acetate MS (ESI) 457 (M + H) +. Prepared from ethyl (2-bromomethyl-6-methyl-phenoxy) -acetate (Example 43b). Example 36i 7- [3- (quinolin-2-ylmethoxy) -phenoxymethyl) -benzofuran-2-carboxylic acid ethyl ester (ESI) 354 (M + H) +. Prepared from ethyl 7-bromomethyl-benzofuran-2-carboxylate (Example 94). Example 36j The title compound is prepared using essentially the same procedure as the procedure used in Example 35 except that 3-methyl-5- (quinolin-2-yl ethoxy) -phenol (Example 53) is used instead of 3- (quinol m-2-ylmethoxy) -phenol (2-bromomethyl-6-methyl-phenoxy) -acetic acid (Example 43b) in place of (2-bromomethyl-6-methyl-phenoxy) -acetonitrile. The following compounds are prepared using essentially the same procedure used in Example 35 except that the above phenol is used in place of 3- (quinolin-2-ylmethoxy) -phenol and (2-bromomethyl-4-chloro-6-methyl-phenoxy) -acetonitrile (Example 43) in place of (2-bromomethyl-6-methyl-phenoxy) -acetonitrile. Example 36k: H NMR (300MHZ, CDC13) d 8.56 (d, 1H), 7.62 (m, 1H), 7.30 (m, 1H), 7.18 (m, 3H), 6.57 (m, 4H), 4.99 (s, 2H), 4.67 (s, 2H), 4.36 (t, 2H), 3.27 (t, 2H), 2.36 (s, 3H). MS (ESI) 409 (M + H) Y Prepared from 3- (2-pyridin-2-yl-ethoxy) -phenol (Example 71a). Example 361 XH NMR (300 MHz, CDCl.) D 7.14 (m, 10H), 5.35 (bs, 1H), 5.04 (s, 2H), 4.67 (d, 2H), 4.63 (s, 2H), 2.34 (s, 3H). MS (ESI) 434 (M + H) Y Prepared from 3- (benzooxazol-2-ylaminomethyl) -phenol (Example 10c). EXAMPLE 37 2- [3- [2-Chloromethyl-benzyloxy) -phenoxymethyl-quinoline The title compound is prepared using essentially the same procedure as the procedure used in Example 35 except that an excess of 1 is used., 2-bis-chloromethyl-benzene in place of (2-bromomethyl-6-methyl-phenoxy) -acetonitrile and without using tetrabutylammonium iodide. (ESI) 390 (M + H) Cl pattern. Example 38. { 2- [3- (Quinolin-2-ylmethoxy). Phenoxymethyl-1-phenyl] -acetonitrile Sodium cyanide (14 mg, 0.28 mmol) is added to a solution of 2- [3- (2-chloromethyl-benzyloxy) - phenoxymethyl] -quinoline (1) 0 mg, 0.28 mmol, Example 37) in DMSO (5 mL) and the reaction is stirred 5 hours. The reaction is partitioned between water and ethyl acetate, the organic phase is washed with water, dried and concentrated to provide the title compound which is used without further purification. MS (ESI) 381 (M + H) Y. { 2- [3-quinoxalin-2-ylmethoxy) phenoxymethyl] -6-methylphenoxy} acetonitrile To a solution of (2- [3-hydroxyphenoxymethyl] -6-methylphenoxy) acetonitrile (100mg, 0.37 mmol, Example 25), quinoxalin-2-ylmethyl chloride [72 mg, 0.40 mmol (see Chem. Ber. 1987, 120, 649-651)] in DMF (1 mL) is heated with potassium carbonate (105 mg, 0.75 mmol) at a temperature of 60 ° C for 16 hours. The reaction is filtered and partitioned between ethyl acetate and water. The organic phase is washed with water, dried in magnesium sulfate, concentrated and purified by column chromatography. (silica, 30% ethyl acetate in hexanes) to provide the title compound. MS (ESI) 412- (M + H) Y The following compounds are prepared using essentially the same procedure using Example 39 except that the quoted halide is used in place of quinoxalin-2-ylmethyl chloride. Example 39a. { 2- [3- (7-Chloro-isoquinolin-3-ylmethoxy) -phenoxymethyl] -6-methyl-phenoxy} acetonitrile MS (ESI) 445 (M + H, C1 Standard) Y Prepared from. { 2-methyl-6- [(3-hydroxy-phenoxy) -methyl] -phenoxy} acetonitrile (Example 25) and (7-chloro-isoquinolin-3-yl) methyl bromide (see Ewing, William R., Becker, Michael R., Choi-Sledeski, Yong Mi, Pauls, Heinz W .; Wei; Condom, Stephen M., Davis, Roderick S .; Hanney, Barbara A .; Spada, Alfred P .; Burns, Christopher J .; Jiang, John Z .; Li, Aiwen; Myers, Michael R .; Lau, Wan F .; Poli, Gregory B; Substi tuted piperazinone derivatives and other oxoazaheterocyclyl compounds useful as factor Xa inhibitors. PCT Int. Appl., (1999), WO 9937304. Example 39b [2-methyl-1-6- [3- (naphthalen-2-ylmethoxy) -phenoxymethyl) -phenoxy} acetonitrile MS (ESI) 410 (M + H) Y Prepared from naphthalen-2-ylmethyl chloride. Example 39c. { 2- [3- (4- tert -3-butyl-benzy! Oxy) -phenoxymethyl] -6-mecyl-phenoxy} -acetonitrile MS (ESI) 416 (M + H) Y Prepared from 4-tert-butylbenzyl chloride. Example 39d. { 2-Methyl-6- (3- (2-phenoxy-ethoxy) -phenoxymethyl] -phenoxy} -acetonitrile MS (ESI) 390 (M + H) Y Prepared from 2-phenoxy-ethyl bromide. 39e {2-methyl-6- [3- (3-phenyl-propoxy) -phenoxymethyl) -phenoxy} -acetonitrile MS (ESI) 388 (M + H) +. Prepared from 3-phenyl-propyl bromide. Example 39f. { 2-methy1-6- [3- (3-phenoxy-benzyloxy) -phenoxymethyl] -phenoxy} -acetonitrile MS (ESI) 452 (M + H) *. Prepared from 3-phenoxy-benzyl chloride. Example 39g. { 2- [3- (3-Methoxy-benzyloxy) -phenoxymethyl] -6-methyl-phenoxy} acetonitrile MS (ESI) 390 (M + H) Y Prepared from 3-methoxy-benzyl chloride. Example 39h. { 2- [3- (3,4-dichloro-benzyloxy) -phenoxymethyl] -6-methyl-phenoxy} -acetonitrile MS (ESI) 428 (M + H) *. Prepared from 3,4-dichloro-benzyl chloride. Example 39i [2- [3- (6,7-difluoroquinoline-2-yl) r.eto i) phenyl-ethyl] -6-me ti 1-f-enoxy} acetonitrile MS (ESI) 446 (M + H) Y Prepared from 6,7-difluoroquinolin-2-ylmethyl chloride (Example 27).

Example 39 { 2- [3- (6,8-difluoroquinolin-2-ylmethoxy) phenoxymethyl] -6-methyl phenoxy} acetonitrile MS (ESI) 446 (M + H) +. Prepared from 6,8-difluoroquinolin-2-ylmethyl bromide (example 27a). Example 39k. { 2-methyl-6- [3- (l-oxyquinolin-2-ylmethoxy) phenoxymethyl] -phenoxy} acetonitrile MS (ESI) 427 (M + H) *. Prepared from l-oxyquinolin-2-ylmethyl chloride (example 34). Example 391. { 2- [3- (6-fluoroquinolin-2-ylmethoxy) phenoxymethyl] -6-methylphenoxy} phenoxymethyl) acetonitrile MS (ESI) 429 (M + H) Y Prepared from 6-fluoroquinolin-2-ylmethyl bromide (example 27b). Example39m. { 2-methyl-6- [3- (l-methyl-4-oxo-l, 4-dihydroquinolin-2-ylmethoxy) phenoxymethyl] -phenoxy} acetonitrile MS (ESI) 441 (M + H) Y Prepared from 1-methyl-4-oxo-l, 4-dihydroquinoin-2-ylmethyl bromide (example 29). Example 39n. { 2- [3- (4-chloroquinolin-2-ylmethoxy) phenoxymethyl] -6-methylphenoxy} acetonitrile MS (ESI) 445 (M + H) Y Prepared from 4-cioroquir.cim-2-ylmethyl chloride (example 46). Example 39o. { 2- [3- (7-Chloroquinolin-2-ylmethoxy) phenoxymethyl] -6-methylphenoxy} acetonitrile MS (ESI) 445 (M + H) Y Prepared from 1-chloroquinolin-2-ylmethyl chloride (example 46a) Example 39p. { 2- [3- (6-methoxyquinolin-2-ylmethoxy) phenoxymethyl] -6-ethylphenoxy} acetonitrile MS (ESI) 441 (M + H) Y Prepared from 6-methoxyquinolin-2-ylmethyl chloride (example 46b) Example 39q. { 2-methyl-6- [3- (pyridin-4-ylmethoxy) -phenoxymethyl] -phenoxy} -acetonitrile XH NMR (300 MHz, CDC13) d 8.62 (bd, 2H), 7.24 (m, 6H), 6.62 (m, 3H), 5.08 (s, 2H), 5.06 (s, 2H), 4.70 (s, 2H), 2.39 (s, 3H). MS (ESI) 361 (M + H) Y Prepared from 4-chloromethyl-pyridine hydrochloride. Example 39r. { 2-methy1-6- [3- (pyridin-2-ylmethoxy) -phenoxymethyl-1-phenoxy} -acetonitrile XH NMR (300 MHz, CDC13) d 8.60 (d, 1H), 7.72 (m, 1H), 7.52 (d, 1H), 7.21 (m, 5H), 6.63 (m, 3H), 5.20 (s, 2H), 5.04 (s, 2H), 4.69 (s, 2H), 2.39 (s, 3H). MS (ESI) 361 (M + H) Y Prepared from 2-chloromethyl-pyridine hydrochloride. Example 39s. { 2-methy1-6- [3- (pyridin-3-ylmethoxy).) Phenoxymethyl] phenoxy} -acetonitrile XH NMR (300.MHz, CDCl 3) d 8.68 (bs, 1H), 8.59 (bd, 1H), 7.78 (m, 1H), 7.24 (m, 5H), 6.63 (m, 3H), 5.07 (s) , 2H), 5.06 (s, 2H), 4.70 (s, 2H), 2.39 (s, 3H). MS (ESI) 361 (M + H) Y Prepared from 3-chloromethyl-pyridine hydrochloride. Example 39t. { 2- [3- (6,7-dichloro-quinolin-2-ylmethoxy) phenoxymethyl] -6-methy1-phenoxy} -acetonitrile XH NMR (300 MHz, CDC13) d 8.20 (s, 1H), 8.10 (d, 1H), 7.94 (s, 1H), 7.70 (d, 1H), 7.20 (m, 4H), 6.65 (m, 3H), 5.34 (s, 2H), 5.05 (s, 2H), 4.69 (s, 2H), 2.38 (s, 3H). MS (ESI; 479 (M + H) Y Prepared from 6,7-dichloro-2-chloromethyl-quinoline (eg, 27 f). Example 39u. { 2-methy1-6- [3- (2-phenyl-thiazol-4-ylmethoxy) -phenoxymethyl] -phenoxy} -acetonitrile MS (ESI) 443 (M + H) Y Prepared from 4-chloromethyl-2-phenyl-thiazole (example 20). The following compounds are prepared using essentially the same procedure as the procedure used in Example 39 except that the above-mentioned phenol is used in place of (2- [3-hydroxyphenoxymethyl) -6-methylphenoxy) acetonitrile and 6-fluoroquinoline-2 bromide. -ylmethylc (example 27b) in place of quinoxalin-2-ylmethyl chloride. Example 40a. { 4-chloro-2- [3- (6-fluoroquinolin-2-ylmethoxy) phenoxymethyl] -6-methylphenoxy} acetonitrile MS (ESI) 463, 465 (M + H) +, Cl standard. Prepared from (2- [3-hydroxyphenoxymethyl] -4-chloro-6-methylphenoxy) acetonitrile (Example 25a). Example 40b. { 2,4-dichloro-6- [3- (6-fluoroquinolin-2-ylmethoxy) phenoxymethyl] phenoxy} acetonitrile MS (ESI) 483, 485, 487 (M + H) +, Cl 2 standard. Prepared from [4,6-dichloro-2- (3-hydroxy-phenoxymethyl) -phenoxy] -acetonitrile (example 25b) Example 41 acid. { 2-methy1-6- [3- (quinolin-2-ylaminomethyl) -phenoxymethyl] -phenoxy} -acetic To a solution of. { 2-methyl-6- [3- (quinolin-2-ylaminomethyl) -phenoxymethyl) -phenoxy} acetonitrile (134 mg, 0.31 mmol, example 35a) in methanol (1 mL) is added THF (1 mL) followed by a solution of sodium hydroxide (0.2 mL, 10 N-). The resulting mixture is heated to a temperature of 60 ° C and stirred at this temperature for 3 hours. The reaction mixture is then cooled to room temperature and acidified to a pH of about 5 with hydrochloric acid (1 mL, 2N), then said mixture is extracted with ethyl acetate, washed with brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 10% 10% methanol in dichloromethane) to provide the title compound. XH NMR (300 MHz, CDC13) d 8.10 (d, 1H), 7.80 (d, 1H); 7.66 (t 2H), 7.40 (t, 1H), 7.25 (m, 2H), 7.04 (m, 3H), 6.90 (m, 3H), 6.6 (bs, 1H), 5.15 (s, 2H), 4.60 ( d, 2H), 4.50 (s, 2H), 2.27 (S, 3H). MS (ESI) 429 (M + H) Y The following compounds are prepared using essentially the same procedure as the procedure used in Example 41 except that the aforementioned nitrile or the mentioned ester is used instead of. { 2-methyl-6- [3- (quinolin-2-ylaminomethyl) phenoxymethyl] -phenoxy} -acetonitrile. Example 41a Acid. { 2-methyl-6- [3- (2-quinolin-2-yl-vinyl) -phenoxymethyl] -phenoxy} -acetic XH NMR (300 MHz, DMSO) d 8.38 (d, 1H), 8.01 (d, 1H), 7.97 (d, 1H), 7.89 (d, 1H), 7.83 (d, 1H), 7.78 (dt, 1H), 7.59 (dt, 1H), 7.53 (d, 1H), 7.44 (d, 1H), 7.36 (m, 3H), 7.25 (bd, 1H), 7.11 (t, 1H), 7.02 (dt, 1H) ), 5.25 (s, 2H), 4.54 (s, 2H), 2.32 (s, 3H). MS (ESI) 426 (M + H) Y Prepared from. { 2-Methyl-6- [3- (2-quinolin-2-yl-vinyl) -phenoxymethyl] -phenoxy) -acetonitrile Example 35b). Example 41b Acid (2-methyl-1-6-. {3- [2- (pyridin-2-yloxy) -ethoxy] -phenoxymethyl] -phenoxy) -acetic acid XH NMR (300 MHz, DMSO) d 8.17 (dd) , 1H), 7.72 (m, 1H), 7.29 (dd, 1H), 7.20 (m, 2H), 7.07 (t, 1H), 6.99 (m, 1H), 6.85 (d, 1H), 6.60 (m, 3H), 5.13 (s, 2H), 4.57 (t, 2H), 4.49 (s, 2H), 4.30 (t, 2H), 2.28 (s, 3H). MS (ESI) 410 (M + H) *. Prepared from (2-methyl-6- { 3- [2-) pyridin-2-yloxy) ethoxy] -phenoxymethyl} -phenoxy) -acetonitrile (example 35c). Example 41 c Acid. { 2- [3- (7-Chloro-isoquinolin-3-ylmethoxy) -phenoxymethyl] -6-methyl-phenoxy) -acetic acid XH NMR (300 MHz, CDC13) d 9.13 (d, 1H), 7.96 (s, 1H) , 7.79 (s, 1H), 7.74 (d, 1H), 7.65 (d, 1H), 7.30 (d, 1H), 7.20 (d, 1H), 7.10 (m, 2H), 6.81 (s, 1H), 6.62 (d, 1H), 6.49 (d, 1H), 5.25 (s, 2H), 5.16 (s, 2H), 4.59 (s, 2H), 2.37 (s, 3H). MS (ESI) 464 (M + H, pattern C1) Y Prepared from. { 2- [3- (7-Chloro-isoquinolin-3-ylmethoxy) -phenoxymethyl] -6-methyl-phenoxy) -acetonitrile (example 39a). Example 4 Id Acid. { 2-methyl-6- [3- (naphthalen-2-ylmethoxy) -phenoxymethyl] -phenoxy} -acetic XH NMR (300 MHz, CDCl 3) d 8.00 (m, 3H), 7.48 (dd, 1H), 7.43 (m, 2H), 7.23 (m, 2H), 7.16 (m, 2H), 7.05 (t, 1H), 6.62 (m, 1H), 6.55 (m, 2H). M3 (ESI) 429 (M-rH) Y Prepared from. { 2-methyl-6- [3- (naphthalen-2-ylmethoxy) -phenoxymethyl] -phenoxy} acetonitrile (example 39b). Example 4le Acid. { 2- [3- (4-tert-Butyl-benzyloxy) -phenoxymethyl] -6-methyl-phenoxy} -acetic 1 H NMR (300 MHz, CDCl 3) d 7.38 (m, 3 H), 7.27 (m, 2 H), 7.24 (d, 1 H), 7.17 (d, 1 H), 7.10 (d, 1 H), 6.59 (m, 3H), 5.07 ís, 2H), 4.98 (s, 2H), 4.57 (s, 2H), 2.33 (s, 3H), 1.33 (s, 9H). M- (ESI) 435 (M + H) Y Prepared from. { 2- [3- (4- erc-butyl-benzyloxy) -phenoxymethyl] -6-methyl-phenoxy} -acetonitrile (example 39c). Example 41 f Acid. { 2-methyl-6- [3- (2-phenoxy-ethoxy) -phenoxymethyl] phenoxy} acetic XH NMR (300 MHZ, CDC13) d 7.03-7.33 (m, 6H), 6. 95 (m, 3H), 6. 57 (m, 3H), 5.07 (s, 2H), 4.55 (s, 2H), 4.29 (m, 4H), 2.33 (s, 3H). MS (ESI) 409 (M + H) +. Prepared from. { 2-methyl-6- [3- (2-phenoxy-ethoxy) -phenoxymethyl) -phenoxy} -acetonitrile (Example 39d). Example 41 g [2-Methyl-6- [3- (3-phenyl-propoxy) -phenoxymethyl) phenoxy] acid} -acetic 1H NMR (300 MHz, CDC13) d 7.07-7.41 (m, 9H), 6.54 (m, 3H), . 08 (s, 2H), 4.58 (s, 2H), 3.94 (t, 2H), 2.80 (t, 2H), 2.34 (s, 3H), 2.09 (qn, 2H). MS (ESI) 407 (M + H) Y Prepared from. { 2-methyl-6- [3- (3-phenyl-propoxy) -phenoxymethyl) phenoxy} acetonitrile (example 39e). Example 41h Acid. { 2-Methyl-6- [3- (3-phenoxy-benzyloxy) -phenoxymethyl] -phenoxy} -acetic XH NMR (300 MHz, CDC13) d 7.31 (m, 4H), 7.06-7.25 (m, 6H), 7.01 (m, 2H), 6.94 (m, 1H), 6.57 (m, 3H), 5.06 ( s, 2H), 4.99 (S, 2H), 4.56 (s, 2H), 2.33 (s, 3H). MS (ESI) 471 (M + H) *.

Prepared from. { 2-methyl-6- [3- (3-phenoxy-benzyloxy) phenoxymethyl) phenoxy} acetonitrile (example 39f). Example 41i [2- (3- (3-Methoxy-benzyloxy) -phenoxymethyl] -6-methyl-phenoxy) -acetic acid MS (ESI) 409 (M + H) +. Prepared from. { 2- [3- (3-methoxy-benzyloxy) -phenoxymethyl] -6-methyl-phenoxy} -acetic (example 39g). Example 41j Acid. { 2- [3- (3, 4-dichloro-benzyloxy) -phenoxymethyl] -6-methyl-phenoxy) -acetic XH NMR (300 MHz, CDC13) d 7.60 (d, 1H), 7.51 (d, 1H), 7.30- 7.38 (m, 2H), 7.28 (d, 1H), 7.23 (d, 1H), 7.17 (d, 1H), 6.66 (m, 3H), 5.16 (s, 2H), 5.05 (s, 2H), 4.65 (s, 2H), 2.42 (s, 3H). MS (ESI) 447 (M + H) *. Prepared from. { 2- [3- (3,4-dichloro-benzyloxy) -phenoxymethyl] -6-methyl-phenoxy} -acetonitrile (example 39h). Example 41k Acid. { 2- [3- (6,7-difluoroquinolin-2-ylmethoxy) phenoxymethyl] -6-methylphenoxy] acetic Melting point 94-95 ° C. XH NMR (300 MHz, CDC13): d 8.10 (d, 1H), 7.73 (m, 1H), 7.56 (d, 1H), 7.44 (d, 1H), 7.29 (s, 1H), 7.18 (m, 1H), 7.08 (m, 2H), 6.79 (s, 1H) ), 6.61 (d, 1H), 6.51 (m, 1H), 5.31 (s, 2H), 5.15 (s, 2H), 4.61 (s, 2H), 2.35 (s, 3H). MS (ESI) 466 (M + H) *. Prepared from. { 2- [3- (6,7-difluoroquinolin-2-ylmethoxy) phenoxymethyl] -6-methyl-phenoxy} acetonitrile (example 39i). Example 411 Acid. { 2- [3- (6,7-difluoroquinolin-2-ylmethoxy) phenoxymethyl) -6-methylphenoxy} acetic Melting point 137-141 ° C. XH NMR (300 MHz, CDC13): d 8.16 (d, 1H), 7.79 (d, 1H), 7.29-7.05 (m, 6H), 6.71 (s, 1H), 6.61 (m, 2H), 5.53 (s) , 2H), 5.10 (s, 2H), 4.57 (s, 2H), 2.33 (s, 3H). MS (ESI) 466 (M + H) Y Prepared from. { 2- [3- (6,8-difluoroquinolin-2-ylmethoxy) phenoxymethyl] -6-methylphenoxy} acetonitrile (example 39j). Example 41m Acid. { 2-methyl-6- [3- (l-oxyquinolin-2-ylmethoxy) phenoxymethyl] phenoxy} acetic Melting point 146-147 ° C. X H NMR (300 MHz, CDCl 3): d 8.73 (d, 1 H), 8.01 (m, 1 H), 7.93 (m, 1 H), 7.89 (m, 1 H), 7.70 (m, 1 H), 7.55 (d, 1 H) ), 7.26 (m, 2H), 7.01 (m, 2H), 6.75 (m, 3H), 5.69 (s, 2H), 5.26 (s, 2H), 4.47 (s, 2H), 2.24 (s, 3H) . MS (ESI) 446 (M + H). "Prepared from. {2-methyl-6- [3- (1-oxyquinolin-2-ylmethoxy) phenoxymethyl] phenoxy] -acetonitrile (Example 39k). Example 41n Acid { 2- [3- (6-fluoroquinolin-2-ylmethoxy) phenoxymethyl] -6-methylphenoxy) acetic Melting point 160-161 ° C. XH NM.R (300 MHz, CDCl 3): d 8.17 (m, 2H), 7.72 (d, 1H), 7.48 (_ ?, 2H), 7.27 (m, 1H), 7.19 (d, 1H), 7.08 (m, 2H), 6.63 (s, 1H), 6.62 (d, 1H), 6.53 (d, 1H), 5.35 (s, 2H), 5.14 (s, 2H), 4.61 (s, 2H), 2.34 (s, 3H), MS (ESI) 448 (M + H ) Y Prepared from. {2- [3- (6-fluoroquinolin-2-ylmethoxy) phenoxymethyl] -6-methylphenoxy} acetonitrile (Example 391) Example 41o Acid. {2-methyl-6-) [3- (1-methyl-4-oxo-l, 4-dihydroquinolin-2-ylmethoxy) phenoxymethyl] -phenoxy) acetic melting point 192-194 ° C. XH NMR (300 MHz, 1: 1 CDC13: CD. OD): d 8.29 (m, 1H), 7.76 (m, 2H), 7.41 25 (m, 1H), 7.25-6.92 (m, 4H), 6.81-6.41 (m, 4H), 5.11 (m, 4H) , 4.39 (s, 2H), 3.88 (s, 3H), 2.27 (s, 3H), MS (ESI) 460 (M + H ) *. Prepared from. { 2-methyl-6- [3- (l-methyl-4-oxo-l, 4-dihydroquinolin-2-ylmethoxy) phenoxymethyl] phenoxy-acetonitrile (example 39m). Example 41p Acid. { 4-Chloro-2- [3- (6-fluoroquinolin-2-ylmethoxy) phenoxymethyl] -6-methylphenoxy) acetic Melting point 140-141 ° C. XH NMR (300 MHz, 5: 1 CDC13: CD3OD): d 8.20 (d, 1H), 8.07 (m, 1H), 7.69 (d, 1H), 7.50 (m, 2H), 7.25 (s, 1H), 7.16 (m, 1H ), 7.11 (s, 1H), 6.67 (s, 1H), 6.60 (m, 2H), 5.30 (s, 2H), 5.07 (s, 2H), 4.24 (s, 2H), 2.25 (s, 3H) . MS (ESI) 482, 484 (M + H) +, Cl pattern. Prepared from. { 4-chloro-2- [3- (6-fluoroquinolin-2-ylmethoxy) phenoxymethyl] -6-methylphenoxy} acetonitrile (Example 40a). Example 41q Acid. { 2,4-dichloro-6- [3- (6-fluoroquinolin-2-ylmethoxy) phenoxymethyl] phenoxy} acetic melting point 189-190 ° C. XH NMR (300 MHz, 5: 1 CDC13: CD.OD): d 8.22 (d, 1H), 8.07 (m, 1H), 7.73 (d, 1H), 7.52 (m, 2H), 7.35 (m, 2H) ), 7.21 (m, 1H), 6.72 (s, 1H), 6.65 (m, 2H), 5.34 (s, 2H), 5.22 (s, 2H), 4.68 (s, 2H). MS (ESI) 502, 504, 506 (M + H) +, Cl 2 standard. Prepared from. { 2,4-dichloro-6- [3- (6-fluoroquinolin-2-yl-ethoxy) phenoxymethyl] phenoxy} acetonitrile (example 40b). Example 41r Acid. { 2-methyl-6- [3- (2-pyridin-2-yl-ethoxy) -phenoxymethyl] -phenoxy} -acetic XH NMR (300 MHz, DMSO) d 8.50 (d, 1H), 7.73 (dt, 1H), 7.36 (d, 1H), 7.20 (m, 4H), 7.04 (m, 1H), 6.58 (m, 2H), 6.50 (d, 1H, 5.77 (s, 2H), 5.15 (s, 2H), 4.35 (, 4H), 3.20 (t, 2H), 2.25 (s, 3H), MS (ESI) 394 (M + H) Y Prepared from. {2-methyl-6- [3- (2-pyridin-2-yl-ethoxy) -phenoxymethyl] -phenoxy} -acetonitrile (example 21) Example 41s Acid { 2- [3- (quinolin-2-ylmethoxy) phenoxymethyl] -6-methylphenoxy} -acetic melting point 154-157 ° C; XH NMR (300 MHz, CDCl.) D 8.25 (d, 1H), 8.19 (d, 1H). 7.81 (d, 1H), 7.77-7.70 (m, 2H), 7.60-7.55 (m, 1H), 7.27 (dd, 1H), 7.18 (d, 1H), 7.13-7.04 (m, 2H), 6.85 (t, 1H), 6.61 (dd, 1H), 6.53 (dd, 1H), 5.40 (s, 2H), 5.18 (s, 2H), 4.62 (s, 2H), 2.35 (s, 3H); MS (ESI) 430 (M + H) Y Prepared from. { 2- [3- (quinolin-2-ylmethoxy) phenoxymethyl] -6-methylphenoxy} acetonitrile (example ). Example 41t Acid. { 2-methyl-6- [3- (quinoxalin-2-ylmethoxy) -phenoxymethyl] -phenoxy} -acetic XH NMR (300 MHz, DMSO-d6) d 9.07 (s, 1H), 8.14-8.05 (m, 2H), 7. 87-7.82 (m, 2H), 7.19-7.05 (m, 3H), 6.97-6.92 (m, 1H), 6.77 (s, 1H), 6.67-6.57 (m, 2H), 5.41 (s, 2H), 5.19 (s, 2H), 4.10 (s, 2H), 2.21 (s, 3H); MS (ESI) 431 (M + H) *. Prepared from. { 2- [3- (Quinoxalin-2-ylmethoxy) -phenoxymethyl] -6-methylphenoxy} acetonitrile (example 39). Example 41u 2- Acid. { 2-methy1-6- [3- (quinolin-2-ylmethoxy) -phenoxymethyl] -phenoxy} -propionic XH NMR (300 MHz, DMSO-d, 3) d 8.40 (d, 1H), 7.99 (dd, 2H), 7.77 (dd, 1H), 7.67-7.58 (, 2H), 7.22-7.10 (m, 3H), 6.98 (dd, 1H), 6.73 (s, 1H), 6.60 (dd, 2H), 5.33 (s, 2H), 5.19 (dd, 2H), 4.40-4.34 (m, 1H), 2.24 (s, 3H), 1.35 (d, 3H); MS (ESI) 444 (M + H) *. Prepared from 2-. { 2-methyl-6- [3- (quinolin-2-ylmethoxy) -phenoxymethyl] -phenoxy} -Methyl propionate (example 36a). Example 41v Acid. { 2,4- [Dichloro-6- (3- (quinolin-2-ylmethoxy) -phenoxymethyl] -phenoxy] -acetic melting point 201-203 ° C; XHR NMR (300 MHz, DMS0-d6) d 8.38 (d, 1H), 7.98 (dd, 2H), 7.76 (dd, 1H), 7.66-7.57 (m, 2H), 7.54 (d, 1H), 7.39 (d, 1H), 7.18 (dd, 1H), 6.75 (s, 1H), 6.66-6.61 (m, 2H), 5.33 (s, 2H), 5.28 (s, 2H), 4.48 (s, 2H), MS (ESI) 484, 486 (M + H, C12 ) And prepared from. {2,4-dichloro-6- [3- (quinolin-2-ylmethoxy) -phenoxymethyl] -phenoxy] -acetonitrile (example 36b) Example 41w Acid. chloro-2-methyl-6- [3- (quinolin-2-ylmethoxy) phenoxymethyl) -phenoxy) -acetic acid NMR (300 MHz, CDC13) d 8.37 (d, 1H), 8.02 (d, 1H), 7.93 ( d, 1H), 7.78-7.70 (m, 2H), 7.60 (t, 1H), 7.24-7.15 (m, 3H), 6.73 (s, 1H), 6.66-6.61 (m, 2H), 5.34 (s, 2H), 5.14 (s, 2H), 4.27 (s, 2H), 2.29 (s, 3H); MS (ESI) 464 (M + H) Y Prepared from. { 4-Chloro-2-methyl-6- [3- (quinolin-2-ylmethoxy) -phenoxymethyl] -phenoxy} acetonitrile (example 36c). Example 41x Acid. { 2-tert-Butyl-6- [3- (quinolin-2-ylmethoxy) -phenoxymethyl] -phenoxy} -acetic XH NMR (300 MHZ, CD.OD) d 8.33 (d, 1H), 8.01 (d, 1H), 7.90 (d, 1H), 7.80-7.55 (m, 3H), 7.35-7.28 (m, 2H) ), 7.15-7.01 (m, 2H), 6.71 (s, 1H), 6.60 (d, 2H), 5.40 (s, 2H), 5.10 (s, 2H), 4.40 (s, 2H), 1.41 (s, 9H); MS (ESI) 472 (M + H) Y Prepared from. { 2-tert-Butyl-6- [3- (quinolin-2-ylmethoxy) -phenoxymethyl] -phenoxy-acetonitrile (example 36d).

Example 41 and Acid. { 4-Chloro-2-methoxy-6- [3- (quinolin-2-ylmethoxy) -phenoxymethyl] -phenoxy-acetic melting point. 185-190 ° C. XH NMR (300 MHZ, DMSO) d 8.45 (d, 1H), 8.04 (t, 2H), 7.82 (t, 1H), 7.71-7.76 (m, 2H), 7.23 (t, 1H), 7.13 (d, 1H), 7.02 (d, 1H), 6.77 (d, 1H), 6.71-6.67 (m, 2H), 5.38 (s, 2H), 5.28 (s, 2H), 4.62 (s, 2H), 3.86 (s) , 3H); MS (ESI) 480 (M + H) Y Prepared from. { 4-Chloro-2-methoxy-6- [3- (quinolin) 2-ylmethoxy) -phenoxymethyl] -phenoxy} -acetonitrile (example 36e). Example 41z 2- [3- (Quinolin-2-ylmethoxy) -phenoxymethyl] -benzoic acid XH NMR (300 MHz, CDC13) d 8.13 (d, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.70-7.41 (m, 5H), 7.10 (t, 1H), 6.67 (s, 1H), 6.58 (d, 2H), 5.51 (s, 2H), 5.36 (s, 2H); MS (ESI) 386 (M + H) Y Prepared from 2- [3- (quinolin-2-ylmethoxy) -phenoxymethyl] -benzonitrile (example 36f). Example 41aa 2- [3- (Quinolin-2-ylmethoxy) -phenoxymethyl] -thiophene-2-carboxylic acid XH NMR (300 MHz, CD3OD) d 8.36 (d, 1H), 8.04 (d, 1H), 7.94 (d , 1H), 7.78 (t, 1H), 7.70 (d, 1H), 7.61 (t, 1H), 7.48 (d, 1H), 7.13-7.19 (m, 2H), 6.70 (s, IH), 6.61 ( dt, 2H), 5.46 (s, 2H), 5.32 (s, 2H); MS (ESI) 392 (M + H) *. Prepared from methyl 2- [3- (quinolin-2-ylmethoxy) -phenoxymethyl] -thiophene-2-carboxylate (Example 36g). Example 4lab Acid. { 2- (3- (chiral-2-ylmethoxy) -phenoxymethyl] -phenyl} -acetic XH NMR (300 MHz, CDC13) d 8.20-8.11 (m, 2H), 7.83-7.52 (m, 4H), 7.40 -7.27 (m, 4H), 7.18-7.10 (m, 1H), 6.67-6.46 (m, 3H), 5.35 (s, 2H), 5.12 (s, 2H), 3.76 (s, 2H), MS 400 ( M + H) * .Prepared from. {2- [3- (quinolin-2-ylmethoxy) -phenoxymethyl] -phenyl} -acetonitrile (example 38) Example 41ac Acid. 2-Methyl-6- [3- (quinolin-2-ylmethoxy) -benzyloxymethyl] -phenoxy] -acetic acid XH NMR (300 MHz, CDC13) d 8.19 (d, 1H), 8.09 (d, 1H), 7.82 (d, 1H), 7.78-7.65 (m, 2H), 7.75 (dd, 1H), 7.31-26 (dd, 1H), 7.18 (dd, 1H), 7.05-6.92 (m, 4H), 5.20 (s) , 2H), 4.26 (s, 2H), 4.23 (s, 2H), 4.15 (s, 2H), 2.12 (s, 3H); MS (ESI) 478, 480 (M + H; C1) Y Prepared from (Example 52Y Example Lad. Acid. {2- 2- [3- (4-Chloro-quinolin-2-ylmethoxy) -phenoxymethyl] -6- methyl-phenoxy.) -acetic lE NMR (300 MHz, DMSO) d 8.20 (dd, 1H), 8.08 (d, 1H), 7.91-7.74 (m, 3H), 7.24-7.15 (m, 3H), 7.01 (t, 1H), 6.74 (t, 1H), 6.66-6.59 (m, 2H), 5.32 (s, 2H), 5.12 (s, 3H), 4.43 (s, 2H), 2.24 (s, 3H); MS (ESI) 464 (M + H) *. Prepared from. {2- [3- (4-chloro-quinolin-2-ylmethoxy) -phenoxymethyl] -6-methyl-phenoxy} -acetonitrile ( Example 39n) Example 41ae Acid. {2- [3- (7-Chloro-quinolin-2-ylmethoxy) -phenoxymethyl] -6-methyl-phenoxy} -acetic acid XH NMR (300 MHz, DMSO) d 8.42 (d, 1H), 8.03-8.00 (m, 2H), 7. 68-7.60 (m, 2H), 7.27-7.07 (m, 3H), 6.94 (t, 1H), 6.70 (d, 1H), 6.59 (dd, 2H), 5.31 (s, 2H), 5.18 (s, 2H), 2.20 (s, 3H); MS (ESI) 464 (M + H) *. Prepared from. { 2- [3- (7-chloro-quinolin-2-ylmethoxy) -phenoxymethyl] -6-methyl-1-phenoxy} acetonitrile (example 39o). Example 41af Acid. { 2- [3- [6-methoxy-quinolin-2-ylmethoxy) -phenoxymethyl] -6-methyl-phenoxy} -acetic XH NMR (300 MHz, CDC13) d 8.07 (t, 2H), 7.60 (d, 1H), 7.36 (d, 1H), 7.27-7.24 (m, 1H), 7.15 (d, 1H), 7.05- 7.00 (m, 3H), 6. 79 (s, 1H), 6.58 (d, 1H), 6.49 (dd, 1H), 5.31 (s, 2H), 5.14 (s, 2H), 4.54 (s, 2H). 3.90 (s, 3H), 2.30 (s, 3H); MS (ESI) 460 (M + H) Y Prepared from [2- [3- (6-methoxy-quinolin-2-ylmethoxy) -phenoxymethyl] -6-methyl-phenoxy} acetonitrile (example 39 p). Example 41ag Acid. { 2- [4-Bromo-3- (quinolin-2-ylmethoxy) -phenoxymethyl] -6-methyl-phenoxy} -acetic XH NMR (300 MHZ, DMSO) d 8.42 (d, 1H), 8.00-7.97 (m, 2H), 7.79-7.70 (m, 2H), 7.63-7.58 (m, 1H), 7.46 (d, 1H) ), 7.20-7.13 (m, 2H), 6.99-6.95 (m, 2H), 6.59 (dd, 1H), 5.42 (s, 2H), 5.17 (s, 2H), 4.30 (s, 2H), 2.22 ( s, 3H); MS (ion spray) 508 (M + H) *. Prepared from. { 2- [4-Bromo-3- (quinolin-2-ylmethoxy) -phenoxymethyl] -6-methyl) phenoxy} ethyl acetate (example 54). Example 41ah Acid. { 2- [2-Bromo-5- (quinolin-2-ylmethoxy) -phenoxymethyl] -6-me ti 1-f enoxy} -acetic XH NMR (300 MHZ, CDCl3) d 8.18-8.15 (m, 2H), 7.81-7.72 (m, 2H), 7.63-7.53 (m, 2H), 7.37 (d, 1H), 7.28 (d, 1H) ), 7.17-7.13 (m, 1H), 7.09-7.03 (m, 1H), 6.91 (d, 1H), 6.42 (dd, 2H), . 36 (s, 2H), 5.32 (s, 2H), 4.63 (s, 2H), 2.32 (s, 3H); MS (ion spray) 508 (M + H) Y Prepared from. { 2- [2-Bromo-5- (quinolin-2-ylmethoxy) -phenoxymethyl] -6-methyl-phenoxy) -acetic acid (example 54). Example 41ai Acid. { 2-Methyl-6- [3-methyl-5- (quinolin-2-ylmethoxy) phenoxymethyl) -phenoxy) -acetic acid XH NMR (300 MHz, CDCl3) d 8.21-8.14 (m, 2H), 7.82-7.66 (m , 3H), 7.58 (t, 1H), 7.27-7.24 (m, 1H), 7.17 (d, 1H), 7.04 (t, 1H), 6.60 (s, 1H), 6.43 (s, 1H), 6.37 (s, 1H), 5.24 (s, 2H), . 13 (s, 2H), 4.60 (s, 2H), 2.32 (s, 3H), 2.19 (s, 3H); MS (ion spray) 444 (M + H) Y Prepared from. { 2-Methyl-6- [3-methyl-5- (quinolin-2-ylmethoxy) -phenoxymethyl] -phenoxy) -acetic acid ethyl ester (example 36j).

Example 41aj Acid. { 2- [2-acetyl-5- (quinolin-2-ylmethoxy) -phenoxymethyl] -6-methyl-phenoxy} -acetic XH NMR (300 MHZ, DMSO) d 8.39 (d, 1H), 8.00-7.96 (m, 2H), 7.76 (t, 1H), 7.67-7.57 (m, 3H), 7.28 (d, 1H), 7.14 (d, 1H), 7.02-7.00 (m, 2H), 6.69 (d, 1H), 5.43 (s, 2H), 5.35 (s, 2H), 4.27 (s, 2H), 2.39 (s, 3H) . 2.23 (s, 3H); MS (ion spray) 472 (M + H) Y Prepared from. { 2- [2-acetyl-5- (quinolin-2-ylmethoxy) -phenoxymethyl]) -6-methyl) phenoxy} ethyl acetate (example 59). Example 41ak Acid. { 4-Chloro-2-methyl-6- [3- (2-pyridin-2-yl-ethoxy) -phenoxymethyl] -phenoxy) -acetic acid XH NMR (300 MHz, DMSO) d 8.52 (d, 1H), 7.73 ( m, 1H), 7.26 (m, 5H), 6.56 (m, 3H), '5.12 (s, 2H), 4.48 (s, 2H), 4.34 (t, 2H), 3.17 (t, 2H), 2.26 ( s, 3H). MS (ESI) 428 (M + H) *. Prepared from. { 4-Chloro-2-methyl-6- [3- (2-pyridin-2-yl-ethoxy) -phenoxymethyl] -phenoxy} -acetonitrile (example 36k). Example 41 to the acid. { 2- [3- (Benzooxazol-2-ylaminomethyl) -phenoxymethyl] -6-methy1-phenoxy} -acetic XH NMR (300 MHz, DMSO) d 8.48 (bs, 1H), 7.12 (m, 11H), 5.14 (s, 2H), 4.46 (m, 4H), 2.26 (s, 3H). MS (ESI) 419 (M + H) Y Prepared from. { 2- [3- (benzooxazol-2-ylaminomethyl) -phenoxymethyl] -6-methyl-phenoxy} acetonitrile (example 35d).

Example 4 lam Acid. { 2- [3- (Benzooxazol-2-ylaminomethyl) -phenoxymethyl] -4-chloro-6-methyl-phenoxy) -acetic XH NMR (300 MHz, DMSO) d 8.47 (bt, 1H), 7.28 (m, 5H) , 7.02 (m, 5H), 5.14 (s, 2H), 4.49 (d, 2H), 4.46 (s, 2H), 2.26 (s, 3H). MS (ESI) 453 (M + H) *. Prepared from. { 2- [3- (benzooxazol-2-ylaminomethyl) -phenoxymethyl] -4-chloro) 6-methyl-phenoxy} - acetonitrile (example 361). Example 41 Acid. { 2- [3- (4-Chloro-quinolin-2-ylmethoxymethyl) -phenoxymethyl] -6-methyl-1-phenoxy} -acetic XH NMR (300 MHz, DMSO) d 8.20 (d, 1H), 8.05 (d, 1H), 7.81 (m, 3H), 7.25 (m, 2H), 7.12 (m, 1H), 7.00 (m, 4H), 5.21 (s, 2H), 4. 77 (s, 2H), 4.62 (s, 2H), 4.15 (s, 2H), 2.24 (s, 3H). MS (ESI) 478 (M + H) Y Prepared from. { 2- [3- (4-chloro-quinolin-2-ylmethoxymethyl) -phenoxymethyl] -6-methyl-phenoxy} acetonitrile (example 35e). Example 4lao Acid. { 2- [3- (6-methoxy-quinolin-2-ylmethoxymethyl) -phenoxymethyl] -6-methyl-phenoxy} -acetic XH NMR (300 MHz, CDC13) d 8.18 (d, 1H), 8.10 (d, 1H), 7.64 (d, 1H), 7.36 (m, 2H), 7.26 (m, 3H), 7.12 (m, 2H), 6.98 (, 2H), . 24 (s, 2H), 4.73 (s, 2H), 4.69 (s, 2H), 4.62 (s, 2H), 3.93 (s, 3H), 2.38 (s, 3H). MS (ESI) 474 (M + H) *. Prepared from. { 2- [3- (6-methoxy-quinolin-ylmethoxymethyl) -phenoxymethyl] -6-methyl-phenoxy} acetonitrile (example 35f). Example 41ap Acid. { 2-methy1-6- [3- (quinolin-2-ylmethoxymethyl) -phenoxymethyl] phenoxy} -acetic XH NMR (300 MHz, CDC13) d 8.30 (d, 1H), 8.18 (d, 1H), 7.85 (d, 1H), 7.74 (m, 2H), 7.58 (m, 1H), 7.38 (d, 1H), 7.28 (m, 3H), 7. 12 (m, 1H), 6.99 (m, 2H), 5.24 (s, 2H), 4.78 (s, 2H), 4.71 (s, 2H), 4.63 (s, 2H), 2.39 (s, 3H). MS (ESI) 444 (M + H) Y Prepared from. { 2-methyl-6- [3- (quinolin-2-ylmethoxymethyl) phenoxymethyl] -phenoxy-acetonitrile (example 35g). Example 41aq Acid. { 2-methy1-6- [3- (pyridin-4-ylmethoxy) -phenoxymethyl] -phenoxy} -acetic XH NMR (300 MHz, DMSO) d 8.57 (s, 2H), 7.44 (m, 2H), 7.22 (m, 3H), 7.07 (m, 1H), 6.69 (m, 1H), 6.61 (, 2H), 5.15 (s, 2H), . 13 (s, 2H), 4.47 (s, 2H), 2.27 (s, 3H). MS (ESI) 380 (M + H) Y Prepared from. { 2- ethyl-6- [3- (pyridin-4-ylmethoxy) -phenoxymethyl] -phenoxy} acetonitrile (Example 39q). Example 4 Acid. { 2-Methyl-6- [3- (pyridin-2-ylmethoxy) -phenoxymethyl] phenoxy) acetic acid X H NMR (300 MHZ, DMSO) d 8.58 (bd, 1 H), 7.83 (m, 1 H), 7.50 (d, 1 H ), 7.34 (, 1H), 7.21 (m, 3H), 7.05 (m, IH), 6.64 (m, 3H), 5.14 (s, 4H), 4.38 (s, 2H), 2.26 (s, 3H) ). MS (ESI) 380 (M + H) Y Prepared from (2-methyl-6- [3- (pyridin-2-ylmethoxy) -phenoxymethyl] -phenoxy] -acetonitrile (Example 39r) Example 4 2-Methyl-6 [3-pyridin-3-ylmethoxy-phenoxymethyl-phenoxy] -acetic acid XH NMR (300 MHz, DMSO) d 8.67 (s, 1H) 8.55 (bd, 1H), 7.86 (d, 1H), 7.43 (m, 1H), 7.28 (m, 3H), 7.07 (m, 1H), 6.70 (s, 1H), 6.62 (m, 2H), 5.13 (s, 4H), 4.47 (s, 2H) ), 2.27 (s, 3H). MS (ESI) 380 (M + H) *. Prepared from. { 2-methyl-6- [3- (pyridin-3-ylmethoxy) -phenoxymethyl] -phenoxy} -acetonitrile (eg 39s). Example 41at Acid. { 2- [3- (6,7-dichloro-quinolin-2-ylmethoxy) phenoxymethyl] -6-ethyl-phenoxy] -acetic acid XH NMR (300 MHz, DMSO) d 8.44 (m, 2H), 8.30 (s, 1H ), 7.76 (d, 1 HOUR! , 7.22. { m, 3H), 7.04 (m, 1H), 6.72 (m, 1H), 6.63 (m, 2H), . 35 (s, 2H), 5.13 (s, 2H), 4.46 (s, 2H), 2.26 (s, 3H). MS (ESI) 498 (M + H) +. Prepared from. { 2- [3- (6,7-dichloro-quinolin-2-ylmethoxy) -phenoxymethyl] -methyl-1-phenoxy} -acetonitrile (example 39t). Example 4lau ethyl 4-benzyloxy-2- [3- (2-carboxymethoxy-3-methyl-benzyloxy) -benzyloxy) -6-methyl-benzoate XH NMR (300 MHZ, DMSO) d 7.31 (m, 5H), 7.06 (m, 2H), 6.96 (m, 2H), 6.65 (d, 1H), 6.54 (d, 1H), 5.12 (d, 6H), 4.48 (s, 2H), 4.22 (q, 2H), 2.28 ( s, 3H), 2.19 (s, 3H), 1.21 (t, 3H). MS (ESI) 571 (M + H) Y Prepared from ethyl 4-benzyloxy-2- [3- (2-cyanomethoxy-3-methylbenzyloxy) -benzyloxy] -6-methyl-benzoate (Example 64b). Example 41av 4-Benzyloxy-2- [3- (2-carboxymethoxy-3-methyl-benzyloxy) benzyloxy acid} -6-methyl-benzoic XH ™ MR (300 MHz, DMSO) d 7.32 (m, 5H), 7.02 (m, 4H), 6.64 (d, 1H), 6.52 (d, 1H), 5.13 (m, 6H) , 4.48 (s, 2H), 2.28 (s, 3H), 2.22 (s, 3H). MS (ESI) 543 (M + H) Y Prepared from ethyl 4-benzyloxy-2- (3- (2-carboxymethoxy-3-methyl-benzyloxy) -benzyloxy] -6-methyl-benzoate (example 41au) Example 4law 2-Methyl] -6- [3- (1,3,3-trimetho-l-2-oxo-2,3-dihydro-l H-indol-6-yloxymethyl) -phenoxymethyl] phenoxy) -acetic acid XH ™ MR (300 MHz, DMSO) d 7.21 (m, 5H), 6.99 (m, 3H), 6.75 (d, 1H), 6.64 (dd, 1H), 5.24 (s, 2H), 5.07 (s, 2H) ), 4.12 (s, 2H), 3.10 (s, 3H), 2.25 (s, 3H), 1.21 (s, 6H). MS (ESD476 (M + H) *. Prepared from. {2-methyl-6- [3- (1, 3, 3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6 -yloxymethyl) -phenoxymethyl] -phenoxy.) acetonitrile (example 64c) Example 411ax 7- [3- (quinolin-2-ylmethoxy) -phenoxymethyl] -benzofuran-2-carboxylic acid XH NMR (300 MHZ, CD3OD) d 8.36 (dd, 1H), 8.03 (dd, 1H), 7.94 (dd, IH), 7.61-7.78 (m, 4H), 7.45-7.49 (m, 2H), 7.16-7.29 (m, 2H), 6.77 (s, 1H), 6.67 (dt, 2H), 5.42 (s, 2H), 5.32 (s, 2H); MS (ESI) 426 (M + H) *. Prepared from ethyl 7- [3- (quinolin-2-ylmethoxy) -phenoxymethyl] -benzofuran-2-carboxylate (example 36i). Example 41a and Acid. { 2-methyl-6- [3- (2-phenyl-thiazol-4-ylmethoxy) -phenoxymethyl] -phenoxy) -acetic acid. X H NMR (300 MHz, DMSO): d 7.92 (m, 2 H), 7.77 (s, 1 H), 7.47 (m, 3 H), 7.20 (m, 1 H), 7.15 (m, 2 H), 6.98 (t, 1 H) ), 6.72 (t, 1H), 6.60 (m, 2H), 5.15 (s, 2H), 5.14 (s, 2H), 4.15 (s, 2H), 2.23 (s, 3H); MS (ESI) 462 (M + H) *. Prepared from. { 2-methyl-6- [3- (2-phenyl-thiazol-4-ylmethoxy) -phenoxymethyl] -phenoxy} -acetonitrile (Example 39u). Example 42 (4-Chloro-2,6-dimethyl-phenoxy) acetonitrile 4-Chloro-2,6-dimethylphenol (5.0 g, 32 mmol), bromoacetonitrile (2.2 mL, 32 mmol) and potassium carbonate (6.6 g, 48 mmol are combined with acetone (50 ml) and heated at reflux for 18 hours.The reaction is filtered, concentrated and the residue is partitioned between dichloromethane and water.The organic phase is washed with IN HCl and water, and is then dried over magnesium sulfate, concentrated and purified by column chromatography (silica), 10% ethyl acetate in hexanes) to give the title compound. MS (El) 195 (M) *, Cl pattern. Example 42a (2- tert -Butyl-6-methylphenoxy) -acetonitrile The title compound is prepared using essentially the same procedure as the procedure used in example 42, except that 2-erc-butyl-6-methylphenol is used instead of 4-chloro-2,6-dimethylphenol. MS (El) 203 (M +) Y Example 42b (2,6-dimethyl-phenoxy) -acetic acid ethyl ester The title compound is prepared using essentially the same procedure as the procedure used in example 42 except that 2, 6 -dimethylphenol in place of 4-chloro-2,6-dimethylphenol and ethyl bromoacetate in place of bromoacetonitrile. Example 43 (2-Bromomethyl-4-chloro-6-methyl-phenoxy) -acetonitrile (4-Chloro-2,6-dimethyl-phenoxy) -acetonitrile (700 mg, 3.6 mmol, Example 42), N-bromosuccinimide (510 mg, 2.9 mmol and benzoyl peroxide (72 mg, 0.29 mmol) are heated at reflux in carbon tetrachloride (10 mL) for 16 hours.The reaction is cooled, filtered and the filtrate is concentrated and purified by column chromatography (silica, acetate). of 5% ethyl in hexanes) to provide the title compound: MS (El) 273, 275 (M) +, Br standard.

The following compounds are prepared using essentially the same procedure as the procedure used in Example 43, except that the aforementioned methyl analog is used, instead of (4-chloro-2,6-dimethyl-phenoxy) -acetonitrile. Example 43a (2-Bromomethyl-1-6-tert-butyl-phenoxy) -acetonitrile MS (El) 281 (M +) Y Prepared from (2-erc-butyl-6-methylphenoxy) -acetonitrile (Example 42a). Example 43b 2-bromomethyl-6-methyl-phenoxy) -acetic acid ethyl ester Prepared from ethyl (2,6-dimethyl-phenoxy) -acetate (example 42b). Example 44 Chloro-2-hydroxy-3-methoxy-benzaldehyde A solution of sulfuryl chloride (15 ml, 190 mmol) in toluene (20 mL) is added dropwise over 1.5 hours to a solution of o-vaniline (25.0 g) , 164 mmol) in toluene (90 mL) and the reaction is then stirred for 16 hours. Water (30 ml) is added for 10 minutes with cooling in an ice bath. The solid is filtered, washed with water, and dried to provide the title compound. MS (El) 186 (M.) Y Example 45 4-Chloro-2-methyl-1-oxo-quinoline 70% pure mCPBA is added (6.9 g, 29 mmol) to a solution of 4-chlorokquinaldine (5.1 g, 29 mmol) in dichloroethane and heated to a temperature of 50 ° C for 4 hours. The solution is concentrated and divided between ethyl acetate and aqueous potassium carbonate. The organic phase is washed with additional aqueous potassium carbonate, water, water and then dried over magnesium sulfate. The solution is filtered and concentrated to provide the title compound which is used without further purification MS (ESI) 194 (M + H) *. The following compounds are prepared using essentially the same procedure as the procedure used in Example 45 except that quinaldine is used in place of 4-chloroquinaldine. Example 45a 7-Chloro-2-methyl-1-oxo-quinoline MS (ESI) 194 (M + H) +. Prepared from 7-chloroquinaldine.

Example 45b 6-methoxy-2-methyl-1-oxo-quinoline MS (ESI) 190 (M + H) *. Prepared from 6-methoxyquinoline. Example 45c 5-ethyl-2-methyl-pyridine 1-oxide MS (ESI) 138 (M + H) *. Prepared from 5-ethyl-2-ethylpyridine. EXAMPLE 46 4-Chloroquinolin-2-ylmethyl Chloride 4-Chloro-2-methyl-1-oxo-quinoline (4.3 g, 22 mmol) is dissolved in chloroform (200 mL) and p-toluenesulfonyl chloride (3.7 g) is added. , 20 mmol) and the reaction is heated to a temperature of 65 ° C for 24 hours. The reaction is allowed to cool and then the reaction is concentrated and partitioned between ethyl acetate and 10% aqueous potassium carbonate. The organic phase is dried over magnesium sulfate, concentrated and purified by column chromatography (silica, 60% dichloromethane in hexanes) to give the title compound MS (ESI) 212 (M + H) *. The following compounds are prepared using essentially the same procedure as the procedure used in Example 45 except that quinaldine is used in place of 4-chloroquinaldine. Example 46a 7-Chloroquinolin-2-ylmethyl chloride MS (ESI) 212 (M + H) +. Prepared from 7-chloro-2-methyl-1 -oxo-quinoline (example 45a). Example 46b 6-Methoxyquinolin-2-ylmethyl Chloride MS (ESI) 208 (M + H) *. Prepared from 6-methoxy-2-methyl-1-oxo-quinoline (example 45b). EXAMPLE 47 2- [3- [5-Chloro-3-methyl-2- (lH-tetrazol-5-ylmethoxy) -benzyloxy-phenoxymethyl) -quinoline Sodium azide (395 mg, 6.1 mmol) and ammonium chloride (325 mg) mg, 6.1 mmol) are added to a solution of [4-chloro-2-methyl-6- [3- (quinolin-2-ylmethoxy) -phenoxymethyl] -phenoxy]} acetonitrile (300 mg, 0.68 mmol, Example 36c) in DMF (2 mL) and heated at a temperature of 110 C for 2 hours. The reaction is then cooled and poured into a 1N sodium hydroxide solution (20 mL) with formation of a solid. This mixture is then washed with ether (4 times) and the ether is discarded. The remaining aqueous solution also contains a solid that is filtered. The solid is dissolved in 10% ethanol in water (250 mL) and the pH is lowered approximately (5 with 2N HCL) A solid precipitates which is filtered to provide the title compound Melting point 181-184 ° C; 1 H NMR (300 MHz, DMSO d 6) d 8.40 (d, 1 H), 8.01-7.97 (m, 2 H), 7.77 (d, 1 H), 7.66-7.60 (m, 2 H), 7.33 (d, 2 H), 7.18 (dd, 1H), 6.72 (dd, 1H), 6.65 (dd, 1H), 6.59 (dd, 1H), 5.33 (s, 2H), 5.27 (s, 2H), 5.07 (s, 2H), 2.24 (s, 3H); MS (ESI) 488, 490 (M + H; C1) Y Example 48 (3- (quinolin-2-ylmethoxy) -phenyl] -methanol 2-Chloromethylquinoline hydrochloride (11.6 g, 54 mmol) , 3-hydroxybenzyl alcohol (6.7 g, 54 mmol) and potassium carbonate (16 g, 116 mmol) are heated in DMF (45 mL) at a temperature of 50 ° C for 14 hours, the temperature is increased to 80 ° C. and heated for an additional 24 hours The reaction is cooled and added to water, filtered, and the solid is washed with water to give a semi-hard product. in ethyl acetate, dried over magnesium sulfate, filtered and concentrated. The sample is then recrystallized from ethyl acetate and hexanes to give the title compound. MS (ESI) 266 (M + H) *. Example 49 2- (3-Chloromethyl-phenoxymethyl) -quinoline hydrochloride Thionyl chloride (0.95 mL, 13 mmol) is added to a solution of [3- (quinolin-2-ylmethoxy) -phenyl) -methanol (2.9 g, 11 mmol, Example 48) in dichloromethane (30 mL) and allowed to stir for 18 hours. The reaction is concentrated in vacuo and subjected to azeotropia 2 times from chloroform in order to obtain the title compound which is used without further purification. Example 50 2- [3- (quinolin-2-ylmethoxy) -benzyloxy] -6-trifluoromethyl-benzaldehyde [3- (quinolin-2-ylmethoxy) -phenyl] -methanol (300 mg, 1.13 mmol, example 48) is dissolved in DMF (6 mL) and sodium hydride (60%, 60 mg, 1.5 mmol) is added and allowed to stir for 20 minutes. 2-Fluoro-6- (trifluoromethyl) benzaldehyde (0.30 mL, 2.2 mmol) and the reaction is heated to a temperature of 90 ° C for 5 hours. The reaction is partitioned between ethyl acetate (200 mL) and water (200 mL), dried over magnesium sulfate, filtered, concentrated in vacuo and purified by column chromatography (silica, 25% ethyl acetate in hexane) to provide the title compound. Example 51 2- [3- (Suinolin (n-2-ylmethoxy) -benzyloxy] -6-trifluoromethyl-benzoic acid A solution of 2- [3- (quinolin-2-ylmethoxy) -benzyloxy] -6-trifluoromethyl-benzaldehyde (46 mg, 10 0.1 mmol, Example 50) in 2-methyl-2-butene (1 mL), t-butanol (2 mL) and water (2 mL) is treated with sodium dihydrogen phosphate dihydrate (153 mg, 1.1 mmoles) and sodium chlorite (198 mg, 2.2 mmol) After 45 minutes, the reaction is partitioned between dichloromethane (50 mL) and water. { 50 mL). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo to provide the title compound: melting point 184-185 ° C; 1H NMR (300 MHz, CDC13) d 8.28 (d, 1H), 8.12 (d, 1H), 7.82-7.75 (m, 2H), 7.66-7.55 (m, 2H), 7.42 (dd, 1H), 7.30- 7.27 (m, 2H), 7.16 (d, 1H), 7.07 (dd, 1H), 6.88 (d, 1H), 6.77 (dd, 1H), 5.44 (s, 2H), 5.07 (s, 2H); MS (ESI) 454 (M + H) Y Example 52. { 4-Chloro-2-methyl-6- [3- (quinolin-2-ylmethoxy) -benzyloxymethyl] -phenoxy} acetonitrile [3- (quinolin-2-ylmethoxy) -phenyl) -methanol (190 mg, 0.72 mmol, Example 48) is dissolved in DMF (6 mL) and sodium hydride (60%, 30 mg, 0.75 mmol) is added. ) and allowed to stir for 10 minutes. (2-Bromomethyl-chloro-6-methyl-phenoxy) -acetonitrile (210 mg, 0.78 mmol, Example 43) is added and the reaction is allowed to stir for 6 hours. The reaction is partitioned between ethyl acetate and water and the organic phase is washed with additional water. The organic phase is dried, concentrated and purified by column chromatography (silica, 25% ethyl acetate in hexanes) to give the title compound. MS (ESI) 458 (M + H) +, Cl standard. EXAMPLE 53 Methyl 2-methyl-6- (3- (quinolin-2-ylmethoxy) -benzyloxymethyl] -benzoate The title compound is prepared using essentially the Same procedure as the procedure used in Example 52, except that methyl 2-bromomethyl-6-methyl-benzoate (Example 2) is used in place of (2-bromomethyl-4-chloro-6-methyl-phenoxy) -acetonitrile MS (ESI) 427 (M + H) *.

Example 54 [2-4-bromo-3- (quinolin-2-ylmethoxy) phenoxymethyl] -6-methyl-1-phenoxy) ethyl acetate [2-methyl-6- [3- (quinolin-2-ylmethoxy) phenoxymethyl] - phenoxy) ethyl acetate (350 mg, 0.76 10 mmol, Example 36h), NBS (150 mg, 0.84) and benzoyl peroxide (20 mg, 0.08 mmol) are dissolved / suspended in chloroform (7 ml) and heated to reflux for 2 hours. The reaction is cooled to room temperature, filtered, preabsorbed in silica gel by rotary evaporation. The crude material is purified by flash chromatography (silica, 15% ethyl acetate in hexanes) to give the title compound in a ratio of about 1: 1 regioisomers are determined from NMR NOE data. 537 (M + H) * for both compounds. Example 55 3-methyl-5- (quinolin-2-ylmethoxy) -phenol 2- (Chloromethyl) -quinoline hydrochloride (1.28 g, 6.0 mmol), orcinol (568 mg, 4.0 mmol), K_C0; (1.68 g, 12.0 mmol) and a catalytic amount of tetrabutylammonium iodide (approximately 10 mg) are dissolved / suspended in anhydrous. (10 mL) and -heated to a temperature of 50 C during the night. The reaction is cooled to room temperature and partitioned between water and ethyl ether (100 ml) the pH of the aqueous layer is adjusted to about 5 and further extracted with ethyl ether (100 ml). The organic reactions are combined and washed with brine (2x lOOml) dried in MgSO. filtered and preabsorbed in silica gel. The crude preabsorbed material is purified by flash chromatography (silica, 20% ethyl acetate in hexanes) to provide the title compound. This product (approximately 80% purity, the rest is 2-methylquinoline is used without further purification). MS (ESI) 266 (M + H) *. Example 56 2- (3- (quinolin-2-ylmethoxy) -benzyloxy-benzaldehyde 2- (3-Chloro-ethyl-phenoxymethyl) -quinoline (371 mg, 1.3 rimol, Example 49) and salicylaldehyde (133) L, 1.55 mmole) they are dissolved in acetone (10 mL). K_C03 (525 mg, 3.75 mmol) is added and the contents are heated to reflux for 16 hours. The reaction is cooled to room temperature, poured into water (100 mL) and the contents are heated to reflux for 16 hours. The reaction is cooled to room temperature, poured into water (100 ml) and extracted with ethyl ether (3x50 ml). The ether layers are combined and washed with brine (3 x 75 mL) and dried in MgSOj. The crude material is preadsorbed on silica gel and purified by flash chromatography (silica, 20-25% ethyl acetate in hexanes) to provide the title compound.

MS (ion spray) 370 (M + H) * Example 57 Acid 3-. { 2- [3- (quinolin-2-ylmethoxy) -benzyloxy] -phenyl) -acrylic. 2- [3- (quinolin-2-ylmethoxy) -benzyloxy] -benzaldehyde (110 mg, 0.3 mmol, Example 56) is dissolved in pyridine (1 mL). Malonic acid (63 mg, 0.6 mmol) and piperidine (10 mL, 0.1 mmol) are added and the contents are heated at a temperature of 85 ° C for 2 hrs, and then at 110 ° C for 2 hours and then at 110 ° C. C for 2 additional hours. The reaction is cooled and placed under a stream of nitrogen at a temperature of 40 ° "C in order to remove the pyrium. A small amount of toluene is added and the contents are again placed under a stream of nitrogen to a 40 ° C (repeat) temperature The crude material is purified on silica gel by flash chromatography (silica, 2.5% methanol in dichloromethane) to give the title compound.XH NMR (300 MHz, CDC13) d 8.33 (d, 1H), 8.21-8.16 (m, 2H), 7.81-7.70 (m, 3H), 7.56-7.50 (m, 2H), 7.37-7.25 (m, 3H), 7.03-6.93 (m, 4H), 6.50 ( d, 1H), 5.48 (s, 2H), 5.14 (s, 2H), MS (ion spray) 412 (M + H) * Example 58 1- [2-hydroxy-4- (quinolin-2-ylmethoxy ) -phenyl) -ethanone 2 4'-dihydroxy-acetophenone (912 mg, 6 mmol) and 2-chloromethyl-quinoline hydrochloride (856 mg, 4.0 mmol, Example 49) are dissolved in acetonitrile (20 mL). K2C03 is added (1.12 g, 8.0 mmol) and the contents are heated to a temperature of 5 0 ° C for 16 hours. The reaction is cooled to room temperature and the solvent is removed by rotary evaporation. The contents are divided between ethyl acetate (100 mL) and water (100 mL), the aqueous layer is acidified with 2N HCL to a pH of about 2 and further extracted with ethyl acetate (2 x 50 mL). All organic fractions are combined and washed with brine (3xl50ml), dried in MgSO- and concentrated. The crude material is preadsorbed on silica gel and purified by flash chromatography (silica, 15% ethyl acetate in hexanes) to give the title compound. MS (ion spray) 294 (M + H) Y Example 59. { 2- [2-acetyl-5- (quinolin-2-ylmethoxy) -phenoxymethyl] -6-methyl) phenoxy} ethyl acetate 1- [2-hydroxy-4- (quinolin-2-ylmethoxy) -phenyl) ethanone (185 mg, 0.63 mmol, Example 58) is dissolved in 2: 1 DMF / acetonitrile (6 mL). Ethyl (2-bromomethyl-6-methyl-phenoxy) -acetate (272 mg, 0.95 mmol, Example 43b) and K2C03 (177 mg, 1.26 mmol) are added and the contents are heated to a temperature of 50 ° C for 2 hours. days. The reaction is cooled to room temperature e and the volume reduced under a stream of nitrogen at 40 ° C. The contents are divided into ethyl acetate (50ml) and water (50ml). The aqueous layer is further extracted with ethyl acetate (2 x 50 mL). The organic fractions are combined and washed with brine (3 x 75 mL), dried in MgSO4 and concentrated. The crude material is dissolved in 1: 1 dichloromethane / methanol, preadsorbed on silica gel and purified by flash chromatography (silica, 20% ethyl acetate in hexanes) to give the title compound. MS (ion spray) 500 (M + H) +. EXAMPLE 60 Methyl 2- [3- (quinolin-2-ylmethoxy) -benzyloxy] -benzoate The hydrochloride free base of 2- (3-chloro-ii-phenoxymethyl) -quinoline (540 mg, 1.7 mmol, Example 49) is prepared by dividing the material between ethyl ether and sodium bicarbonate and by drying the organic phase with magnesium sulfate. This material is then dissolved with methyl salicylate (260 mg, 1.7 mmol) in DMF (10 ml) at a temperature of 0 ° C and sodium hydride (60%, 65 mg, 1.7 mmol) is added. The reaction is brought to room temperature for 15 minutes and then heated to a temperature of 60 ° C for 6 hours. The reaction is cooled and partitioned between ethyl acetate and a saturated solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered, concentrated in vacuo and purified by column chromatography (silica, 50 to 80% ether in hexanes) to provide the title compound.; MS (ESI) 400 (M + H) *. The following compounds are prepared using essentially the same procedure as the procedure employed in Example 60, except that the aforementioned salicylate is used in place of methyl salicylate. Example 60a methyl 3-methoxy-2- [3- (quinolin-2-ylmethoxy) -benzyloxy] -benzoate Prepared from 3-methoxysalicylate. Example 60b 4 -me oxy-2- [3- (o'uir.cIin-2-ylrr.e i) -benzyloxy-7-en o or Y methyl Prepared from methyl 4-methoxysalicylate. Example 60c methyl 5-methoxy-2- (3- (quinolin-2-ylmethoxy) -benzyloxy) -benzoate Prepared from methyl 5-methoxysalicylate. Example 60d Methyl 2-methoxy-6- [3- (quinolin-2-ylmethoxy) -benzyloxy) -benzoate Prepared from methyl 6-methoxysalicylate (Example 61). Example 60e ethyl 2-methy1-6- [3- (quinolin-2-ylmethoxy) -benzyloxy) -benzoate MS (ESI) 428 (M + H) *. Prepared from ethyl 6-methylsalicylate (see, Hauser, Frank M., Synthesi s 1980, 1 0, 814-15) Example 61 Methyl 6-methoxysalicylate A mixture of 6-methoxysalicylic acid (10.0 g, 59.5 mmole) in methanol (40 mL) and sulfuric acid (2 mL) is refluxed for 48 hours.Although a certain amount of acid remains, the reaction is concentrated to remove the methanol and divide it between ethyl acetate and a saturated carbonate solution. of sodium The organic phase is separated and washed with carbonated charcoal sata haeta which does not remain acidic by means of TLC analysis The organic phase is dried and concentrated in order to provide the title compound in the form of a solid with a low point of boiling Example 62 5- [3- (quinolin-2-ylmethoxy) -benzyloxy) methyl nicotinate To a solution of 5-hydroxy nicotinic acid methyl ester (200 mg, 1.3 mmol) in DMF (3 mL) is added a 60% sodium hydride emulsion (50 mg), 1.2 mmol and is The mixture is stirred for 30 minutes. The free base of 2- (3-chloromethyl-phenoxymethyl) -quinoline hydrochloride (350 mg, 1.2 mmol, Example 49) is prepared by dividing the material between ethyl ether and sodium bicarbonate and by drying the organic phase with magnesium sulphate. A solution of this free base in DMF (2 mL) is added to the alcohol and this mixture is stirred at a temperature of 25 ° C for 16 hours. The solvent is removed in vacuo, dichloromethane (10 mL) and water (5 mL) are added and the mixture is acidified to pH 6 with acetic acid. The organic layer is dried in magnesium sulfate and the solvent is removed in vacuo. The residue is purified by flash chromatography (silica, 4% methanol in dichloromethane) to give the title compound. MS (ESI) 401 (M + H) *. Example 63 Ethyl 4-benzyloxy-2-hydroxy-6-methyl-benzoate To a solution of 2, -dihi? Rox? - '-methyl benzoate ethyl ether (4.22 g, 22 mmol) in acetone (80 mL) is added potassium carbonate (3.0 g, 22 mmol) and benzyl bromide (2.6 mL, 22 mmol) and this mixture is heated to reflux overnight. The cooled reaction is diluted with ethyl acetate (100 mL) and water (100 mL) and the organic layer is washed with water (2 x 80 mL) and brine (2 X 80 mL). The organic layer is dried over magnesium sulfate and the solvent is removed to provide the title compound without further purification. MS (El) 286 (M) Y Example 63a Ethyl 2-hydroxy-4-methoxy-6-methylbenzoate The title compound was prepared using essentially the same procedure as the procedure used in Example 63, except that it was used iodomethane instead of benzyl bromide. Example 64 Ethyl 4-benzyloxy-2-methyl-6- [3- (quinolin-2-ylmethoxy) -benzyloxy] -benzoate To a solution of ethyl 4-benzyloxy-2-hydroxy-6-methyl-benzoate. { 5. 1 g, 16 mmol, Example 63) in DMF (100 mL), with cooling in a water bath at 25 ° C, a 60% sodium hydride emulsion (1.3 g, 32 mmol) is added over a period of time. of 2 minutes. This mixture is stirred for a period of 30 minutes with the removal of cooling bath. A hydrochloride solution of 3- (quinoiin-y-yl-fettoxy) -benzyl (5.1 g, 16 mmol, example 49) in DMF (55 mL) is added and the reaction is heated to a temperature of 60 ° C for 6 hours . The solvent is removed in vacuo and the residue purified by flash chromatography (silica, 0.5-2% methanol or in dichloromethane) to provide the title compound. MS (ESI) 534 (M + H) *. Example 64a Ethyl 4-methoxy-2-methyl-6- [3- (quinolin-2-ylmethoxy) -bezyloxy) -benzoate The title compound is prepared using essentially the same procedure as the procedure used in Example 64 except that ethyl 2-hydroxy-4-methoxy-6-methylbenzoate (Example 63a) is used in place of ethyl 4-benzyloxy-2-hydroxy-6-methyl-benzoate. MS (ESI) 458 (M + H) *. Example 64b Ethyl 4-benzyloxy-2- [3- (2-cyanomethoxy-3-methyl-benzyloxy) -benzyloxy] -6-methyl-benzoate. The title compound is prepared using essentially the same procedure as the procedure used in Example 64 except that [2- (3-bromomethylphenoxymethyl) -6-methyl-phenoxy] -acetonitrile (Example 76) is used instead of hydrochloride of 3- (quinolin-2-ylmethoxy) -benzyl chloride. XH NMR (300 MHz, CDCl3) d 7.30 (m, 8H), 7.12 (m, 1H), 7.06 (cs, 1H), 6.93 (or, 77), 6.93 Xc, 1H, 6.42 ís, 2HY 5.07 (s, 2H), 5.04 ( s, 2H), 5.02 (s, 2H), 4.71 (s, 2H), 4.33 (q, 2H), 2.39 (s, 3H), 2.30 (s, 3H), 1.31 (t, 3H). MS (ESI) 552 (M + H) *. Example 64c. { 2-Methyl-6- [3- (1, 3, 3-trimethyl-2-oxo-2,3-dihydro-lH-indol-6-yloxymethyl) -phenoxymethyl] -phenoxy} acetonitrile The title compound is prepared using essentially the same procedure as the procedure used in example 64, except that [2- (3-bromomethyl-phenoxymethyl) -6-methyl-phenoxy] -acetonitrile (Example 76) is used in place of 3 - (quinolin-2-ylmethoxy) -benzyl chloride hydrochloride and 6-hydroxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one (Example 80) instead of 4- ethyl benzyloxy-2-hydroxy-6-methyl-benzoate. XH NMR (300 MHz, CDC13) 6 7.32 (dd, 2H), 7.24 (s, 1H), 7.1) (m, 4H), 6.96 (dd, 1H), 6.62 (dd, 1H), 6.54 (d, 1H) ), 5.10 (s, 2H), 5.06 (s, 2H), 4.72 (s, 2H), 3.18 (s, 3H), 2.39 (s, 3H), 1.34 (s, 6H). MS (ESI) 457 (M + H) *. Example 65 Ethyl 2-hydroxy-6-methyl-4- [3- (quinolin-2-ylmethoxy) -benzyloxy] -benzoic acid 2,4-Dihydroxy-6-methyl-benzoic acid ethyl ester (315 mg, 1.6 mmol) with 2- (3-chloromethyl-phenoxymethyl) -quinoline hydrochloride (0.51 g, 1.6 mmol, Example 49), tetrabutylammonium iodide (55 mg, 0.15 mmol) and potassium carbonate (0.48 g, 3.5 mmol) in acetone (9 mL). The reaction is heated to reflux for 48 hours. The reaction is partitioned between ethyl acetate and saturated ammonium chloride. The organic phase is washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude product. This material is purified by column chromatography (silica, 3% ether in dichloromethane) to the title compound; mp 127-128 ° C, MS (ESI) 444 (M + H) *. EXAMPLE 66 Ethyl 2-methoxy-6-methyl-4-3- (quinolin-2-ylmethoxy) -benzyloxy-benzoate To a solution of 2-hydroxy-6-methyl4- [3- (quinolin-2-ylmethoxy) - ethyl benzyloxy] -benzoate (150 mg, 0.34 mmol, Example 65) in DMF (5 mL) is added sodium hydride (60%, 14 mg, 0.34 mmol) and the reaction is stirred 20 mm. It is added. iodine methane (0.03 mL, 0.5 mmol) and the reaction is heated to a temperature of 50 ° C for 7 hours. The reaction is concentrated in vacuo and the residue is partitioned between dichloromethane and aqueous ammonium chloride. The water layer is back-extracted with dichloromethane. The organic phases are combined, dried in sulfate and magnesium, filtered and concentrated to give a crude product. The residue is purified by column chromatography (silica, 10-20% ethyl acetate in hexanes to give the title compound: MS (ESI) 458 (M + H) Y Example 66a 2-benzyloxy-6-methyl-4- Ethyl [3- (quinolin-2-ylmethoxy) -benzyloxy] -benzoate The title compound is prepared using essentially the same procedure as the procedure used in Example 66 except that benzyl bromide is used in place of iodomethane. (ESI) 534 (M + H) + Example 67 4-Benzyloxy-2-methyl-6- [3- (quinolin-2-ylmethoxy) -benzyloxy) -benzoic acid 4-benzyloxy-2-methyl-6- [ Ethyl 3- (quinolin-2-ylmethoxy) -benzyloxy] -benzoate (2.4 g, 4.5 mmol, Example 64) is added to ethanol (50 ml) and 10 N sodium hydroxide (4.4 ml, 44 mmol) and subjected at reflux for 8 hours. The solvent is removed in vacuo and the residue is dissolved in dichloromethane with a small amount of water and acidified to pH 6 with IN HCl. The organic layer is dried in MgSO 4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica, 1% methanol in dichloromethane) to give the title compound. melting point 146-149 ° C; XH NMR (300 MHz, CD3OD) d 8.34 (d, 1H), 8.04 (d, 1H), 7.91 (d, 1H), 7.78-7.70 (m, 2H), 7.61 (t, H), 7.37-7.20 ( m, 7H), 7.05-6.91 (m, 2H), 6.51 (d, 1H), 6.47 (d, 1H), 5.35 (s, 2H), 5.09 (s, 2H), 5.03 (s, 2H), 2.29 (s, 3H); MS (ESI) 506 (M + H) *. The following compounds are prepared using essentially the same procedure as the procedure used in example 67 except that the mentioned ester is used in place of 4-benzyloxy-2-methyl-6- [3- (quinolin-2-ylmethoxy) -benzyloxy ] -ethylbenzoate. Example 67a 2-Methoxy-6-methyl-4- [3- (quinolin-2-ylmethoxy) -benzyloxy] -benzoic acid X H NMR (300 MHz, CDCl 3) 8.38 (d, 1 H), 8.03 (d, 1 H) , 7.79 (d, H), 7.70-7.67 (m, 2H), 7.61 (t, H), 7.28 (t, 1H), 7.14 (s, 1H), 7.01 (t, 2H), 6.35 (t, 2H) ), 5.37 (s, 2H), 5.03 (s, 2H), 3.71 (s, 3H), 2.26 (s, 3H); MS (ESI) 430 (M + H) +. Prepared from ethyl 2-methoxy-6-methyl-4- [3- (quinolin-2-ylmethoxy) -benzyloxy) -benzoate (Example 66). Example 67b 2-Benzyloxy-6-methyl-4- [3- (quinolin-2-ylmethoxy) -benzyloxy] -benzoic acid mp 125-127 ° C; XH NMR (300 MHz, CDC13) d 8.18 (d, 1H), 7.83 (d, 1H), 7.74-7.55 (m, 3H), 7.40 (s, 5H), 7.39-7.29 (m, 1H), 7.09 (s, 1H), 7.00 (m, 2H), 6.50 (s, 2H), 5.41 (s, 2H), 5.13 (s, 2H), 5.04 (s 2H), 2.58 (s, 3H); MS (ESI) 506 (M + H) *. Prepared from ethyl 2-benzyloxy-6-methyl-4- [3- (quinolin-2-ylmethoxy) -benzyloxy] -benzoate (Example 66a). Example 67c 4-Methoxy-2-methyl-6- [3- (quinolin-2-ylmethoxy) -benzyloxy] -benzoic acid XH NMR (300 MHz, DMSO) d 8.39 (d, 1H), 8.02-7.96 (m, 2H), 7.79-7.74 (m, 1H), 7.67-7.57 (m, 2H), 7.31-7.25 (m, 1H), 7.16 (s, 1H), 7.02-6.96 (m, 2H), 6.49 (s, 1H), 6.39 (s, 1H), 5.34 (s, 2H), 5.09 (s, 2H), 3.71 (s, 2H), 2.20 (s, 3H); MS (ESI) 429 (M + H) *. Prepared from ethyl 4-methoxy-2-methyl-6- [3- (quinolin-2-ylmethoxy) -benzyloxy] -benzoate. (Example 64a). Example 68 5-ethyl-2-chloromethyl-pyridine To a solution of 5-ethyl-2-methyl-pyridine-1-oxide (427 mg, 3.1) moles ,. Example 45c) in CH2D_ (2 mL) is added a solution (0.2 mL) of phosphorous trichloride oxide (v) (327 mL) in CH2D2 (2 mL). The remaining solution of phosphorus chloride oxide (v) and a solution of triethylamine (488 μL) in CH2C12 (2 mL) are added simultaneously at a rate such that reflux is maintained. After the addition is determined, the reaction mixture is allowed to cool to 20 ° C and diluted with EtOAc. The organic layer is washed with a saturated solution of NaHCO, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 10% ethyl acetate in dichloromethane) to give the title compound. ..3 (ESI) 157 (M + H) *. Example 69 2- (5-ethyl-pyridin-2-yl) -ethanol To a cooled solution (-10 ° C) of diisopropylamine (2.31 mL, 1 6.5 mL) in THF (45 mL) is added dropwise (2.5 M) n-butyllithium (6.6 mL, 16.5 mmol), allowed to stir for 10 minutes and then cooled to -78 ° C. To this mixture is added dropwise a solution of 5-ethyl-2-methylpyridine (1.98 mL, 15 mmol) in THF (3 mL) and allowed to stir for 10 minutes at a temperature of -78 ° C. The reaction mixture is added to paraformaldehyde (1.13 g, 37.5 mmol), the cold bath is removed and the stirring is continued for 1 hour. The reaction is quenched with H.O, diluted with EtOAc and the organic layer is washed with brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 0.5% ammonia / 5% methanol / dichloromethane) to give the title compound as a pale yellow oil. MS (El) 151 (M) Y Example 69a 2-quinoline-2-y1-ethanol The title compound is prepared using essentially the same procedure as the procedure used in example 69, except that 2-methy1-quinoline is used in place of 5-etii-2-met? ipyridine. MS (ESI) 174 7 -'- 71) Y Example 70 3- [2- (5-Ethyl-pyridin-2-yl) -ethoxy] -phenyl benzoic acid ester A solution of 2- (5-ethyl- pyridin-2-yl) -ethanol (480 mg, 3.17 mmol, example 69) in THF (11 mL) is added resorcinol monobenzoate (630 mg, 2.94 mmol), triphenylphosphine (850 mg, 3.24 mmol) and diethyl azodicarboxylate ( 510 mL, 3.24 mmol). The resulting mixture is stirred for 1 hour and then concentrated. The residue is purified by flash chromatography (silica, 35% ethyl acetate hexanes) to give the title compound as a yellow oil. MS (ESI) 348 (M + H) *. Example 70a 3- (2-pyridin-2-yl-ethoxy) -phenyl ester of benzoic acid The title compound is prepared using essentially the same procedure as the procedure used in example 70 except that 2- (2-hydroxyethyl) is used ) pyridine in place of 2- (5-ethyl-pyridin-2-yl) -ethanol. MS (ESI) 320 (M + H) *. Example 71 3- [2- (5-ethyl-pyridin-2-yl) -ethoxy] -phenol To a solution of 3- [2- (5-ethyl-pyridin-2-yl) -ethoxy] -phenyl ester of Benzoic acid (493 mg, 1.42 mmol, Example 70) in 1: 1 THF 1 CH.OK (5 L) is added a solution of 10 N NaOH (0.5 mL) and water (50 L). The reaction mixture is stirred for 15 minutes and then cooled to 5 ° C., adjust the pH to 7 with a 2N HCl solution, and dilute with EtOAc. The organic layer is washed sequentially with brine, a saturated solution of NaHCO 3, and then dried over MgSO 4 and concentrated. The residue is purified by several triturations with hexane to give the title compound as a crystalline solid. MS (ESI) 244 (M + H) Y Example 71a 3- (2-pyridin-2-yl-ethoxy) -phenol The title compound is prepared using essentially the same procedure as the procedure used in Example 71 except that used 3- (2-pyridin-2-yl-ethoxy) -phenyl ester of benzoic acid (Example 70a) in place of 3- [2- (5-ethyl-pyridin-2-yl) -ethoxy] -phenyl ester. MS (ESI) 216 (M + H) *. Example 72 [3- (2-methoxy-ethoxymethoxy) -phenyl] -methanol To a cooled (0 ° C) suspension of 60% NaOH (660 mg, 16.5 mmol) in THF (35 mL) is added dropwise a 3-hydroxybenzaldehyde solution (1.89 g, 15 mmol) in THF (15 mL) and the resulting mixture is stirred for 20 minutes. To the mixture is added 2-methoxyethoxymethyl chloride (1.88 mL, 16.5 mmol) and DMPU (5 mL). The cold bath is removed and stirred for 1 hour. The reaction mixture is cooled to a temperature of 0 ° C and then NaBH 2M (in triglyme) (3.75 mL, 7.5 mmol) is added slowly and allowed to stir for 1 hour. Quench slowly with a 2N HCl solution (3.9 mL) and the reaction mixture is diluted with ether. The organic layer is washed with brine, dried over MgSO and concentrated. The residue is purified by flash chromatography (silica, 60% ethyl acetate in hexanes) to give the title compound as a pale yellow oil. MS (El) 212 (M) Example 73 2- [3- (2-methoxy-ethoxymethoxy) -benzyloxymethyl] -pyridine To a cooled solution (0 ° C) of [3- (2-methoxy-ethoxymethoxy) -phenyl] -methanol (212 mg, 1 mmol, Example 72) in THF (3 mL) is added 60% NaH (80 mg, 2 mmol) and the mixture is stirred for 10 minutes. 2-Picolyl chloride hydrochloride (164 mg, 1 mmol) and DMPU (0.8 mL) are added, the cold bath is removed and the reaction mixture is allowed to stir for 2 hours. The reaction is quenched with a saturated solution of NH4C1 and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 70% ethyl acetate in hexanes) to give the title compound as a pale yellow oil. MS (ESI) 304 (M + H) * The following compounds are prepared using essentially the same procedure as the procedure used in Example 73 except that the aforementioned halide is used, instead of 2-picolyl chloride hydrochloride Example 73 a 2- [3- (2-methoxy-ethoxymethoxy) -benzyloxymethyl] -quinoline MS (ESI) 354 (M + H) *. Prepared from 2- (chloromethyl) quinoline hydrochloride. Example 73b 4-Chloro-2- [3- (2-methoxy-ethoxymethoxy) -benzyloxymethyl] quinoline MS (ESI) 338 (M + H) +. Prepared from 2-chloromethyl-4-chloroquinoline (example 46).

Example 73c 6-methoxy-2- [3- (2-methoxy-ethoxymethoxy) -benzyloxymethyl] -quinoline MS (ESI) 384 (M + H) Y Prepared from 2-chloromethyl-6-methoxyquinoline (example 46 b) ). Example 74 3- (Pyridin-2-ylmethoxymethyl) -phenol To a solution of 2- [3- (2-methoxy-ethoxymethoxy) -benzyloxymethyl] -pyridine (171 mg, 0.56 mmol, Example 73) in CH 3 OH (1.9 mL) p-Toluenesulfonic acid monohydrate (148 mg, 0.78 mmol) is added. The mixture is heated to a temperature of 60 ° C and stirred for 1.5 hours, then cooled to room temperature and diluted with EtOAc.

The organic layer is washed with a saturated solution of N-C03, brine, and then said layer is dried over MgSO4 and concentrated to give the title compound as a white crystalline solid. MS (ESI) 216 (M + H) *. The following compounds are prepared using essentially the same procedure as the procedure used in Example 74 except that the MEM ether is used instead of 2- [3- (2-methoxy-ethoxymethoxy) -benzyloxymethyl] -pyridine. Example 74a 3- (Quinolin-2-ylmethoxymethyl) -phenol MS (ESI) 266 (M + H) *. Prepared from 2- [3- (2-methoxy-ethoxymethoxy) -benzyloxymethyl] quinoline (example 73a). Example 74b 3- (4-Chloro-quinolin-2-ylmethoxymethyl) -phenol MS (ESI) 300 (M + H) +. Prepared from 4-chloro-2- [3- (2-methoxy-ethoxymethoxy) -benzyloxymethyl] -quinoline (example 73b).

Example 74c 3- (6-methoxy-quinolin-2-ylmethoxymethyl) -phenol MS (ESI) 296 (M + H) +. Prepared from 6-methoxy-2- [3- (2-methoxy-ethoxymethoxy) -benzyloxymethyl] -quinoline (example 73c).

Example 75 [2- (3-hydroxymethyl-phenoxymethyl) -6-methyl-phenoxy] -acetonitrile To a solution of 3-hydroxybenzyl alcohol (202 mg, 1.63 mmol) in DMF (5.4 mL) is added K; C03 (247 mg, 1.79 mmol, and (2-bromomethyl-6-methyl-phenoxy) -acetonitrile (430 mg 1.79 mmoles, Example 24) The resulting mixture is heated to 60 ° C and stirred for 3 hours, then cooled to room temperature and diluted with ether.The organic layer is washed with water, brine, dried in MgSO 4 and concentrated. The residue is purified by flash chromatography (silica, 30% ethyl acetate in hexanes) to give the title compound: MS (El) 283 (M) Y Example 76 [2- (3-Bromomethyl-phenoxymethyl) -6- methyl-phenoxy] -acetonitrile To a solution of [2- (3-hydroxymethyl-phenoxymethyl) -6-methyl-phenoxy] -acetonitrile (230 mg, 0.81 mmol, Example 75) in THF (3 mL) is added Ph3P (233 mg, 0.89 mmole) and stirred until homogeneous, the solution is cooled to 0 ° C and then NBS is added in portions (151 mg, 0.85 mmole) and the mixture is left to stir for 45 mm. The reaction is concentrated under reduced pressure. The residue is purified by flash chromatography (silica, 40% CH2C1_ in hexanes) to give the title compound as a white crystalline solid. MS (El) 345, 347 (M) +, Br standard. Example 77 6-methoxy-3-methyl-1,3-dihydro-indol-2-one To a cooled solution (-73"C) of 6- Methoxy-l, 3-dihydro-indol-2-one (840 mg, 5.2 mmol, see Qualich, Synthesis 1993, 51-53) in THF (20 mL) is added dropwise TMEDA (1.57 mL, 10.4 mL) followed by dropwise addition of n-Buli 2.5M (4.16 L, 10.4 mmol) The mixture is allowed to stir for 15 minutes and then warmed to -25 ° C. Iodomethane (405 μL, 6.5 mmol) is added dropwise and stirred for 20 minutes. The reaction is quenched with a saturated NH 4 Cl solution, warmed to room temperature and diluted with EtOAc. The organic layer is washed with a saturated solution of NH 4 Cl, brine, dried in MgSO 4 and concentrated. The residue is purified by flash chromatography (silica, 45% ethyl acetate in hexanes) to provide the title compound. MS (ESI) 178 (M + H) *. Example 78 6-methoxy-3, 3-dimethyl-1,3-dihydro-indol-2-one To a cooled solution (-78 ° C) of 6-methoxy-3-methyl-1,3-dihydro-indole 2-one (679 mg, 3.83 mmol, example 77) in THF (13 mL) is added TMEDA (1.16 mL, 7.66 mmol) followed by dropwise addition of n-BuLi 2.5M (3.06 mL)., 7.66 mmoles). The mixture is stirred for 15 minutes and then heated to -25 ° C. Iodomethane (275 mL, 4.40 mmol) is added dropwise and stirred for 30 minutes. The reaction is quenched with a saturated solution of NH-C1, warmed to room temperature and diluted with EtOAc. The organic layer is washed with a saturated solution of NHC1, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 35% ethyl acetate in hexanes) to give the title compound as a white crystalline solid. MS (ESI) 192 (M + H) *. Example 79 6-methoxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one To a cooled solution (-5C-0 ° C) of 6-methoxy-3, 3-dimethyl-1, 3-dihydro-indol-2-one (600 mg, 3.14 mmol, Example 78) in THF (10.5 mL) is added 60% NaH (132 mg, 3.30 mmol) and stirred for 15 minutes. Iodomethane (215 mL, 3.45 mmol) is added to the reaction mixture and stirred for 2 hours. The reaction is quenched with a saturated solution of NH4C1 and is diluted with EtOAc. The organic layer is washed with a saturated solution of NH4C1, brine, dried over MgSO. and concentrated. The residue is purified by flash chromatography (silica, 30% ethyl acetate in hexanes) to give the title compound as a white crystalline solid. MS (ESI) 206 (M + H) +. EXAMPLE 80 6-Hydroxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one To a solution of 6-methoxy-1,3,3-trimethyl-1,3-dihydro-indole-2 -one (601 mg, 2.93 mmol, Example 79) in acetic acid (880 mL) is added hydrobromic acid (48% in H20) (8.8 L). The resulting solution is heated to reflux (105 ° -110 ° C), stirred for 2 hrs, and then cooled to room temperature and concentrated under reduced pressure. The residue is dissolved in EtOAc and the organic layer is washed with water, brine, dried over MgSO4 and concentrated. The residue is purified by trituration with a small volume of ether in order to provide the title compound as an off-white solid. MS (ESI) 192 (M + H) Y Example 81 2- [3- (2-methoxy-ethoxymethoxy) -benzyloxy] -quinoline To a solution of 60% NaH (44 mg, 1.1 mmol) in DMSO (2 mL ) a solution of [3- (2-methoxy-ethoxymethoxy) -phenyl] -methanol (212 mg, 1.0 mmol, Example 72) in DMSO (1 mL) is added dropwise. Allow to stir for 20 minutes and then add 2-chloroquinoline (180 mg, 1.1 mmol) and heat at 100 ° C. For 1 hour, the reaction mixture is cooled to room temperature and diluted with EtOAc. The organic layer is washed with a saturated solution of NHC1, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 25% ethyl acetate in hexanes) to give the title compound as a colorless oil. MS (ESI) 340 (M + H) *. EXAMPLE 82 2-3- (Methoxy) -phenylsulfenylmethyl] -6-methyl-isobutyl benzoate A 10 N solution of sodium hydroxide (0.32 mL, 3.2 mmol) is added slowly to a solution of 3-methoxybenthiol (0.42 g, 3.0 mmol) in isobutanol (2 mL) followed by a solution of isobutyl 2-bromomethyl-6-methylbenzoate (0.96 g, 3.3 mmol, Example 2) in isobutanol (2 mL). The reaction is allowed to stir for 15 minutes and then divided between ethyl acetate and dilute aqueous HCl. The organic phase is washed with water, dried over magnesium sulfate, concentrated and purified by column chromatography (silica, 40% dichloromethane in hexanes) to give the title compound. MS (El) 344 (M) Y Example 83 2- [3- (Hydroxy) -phenylsulfanylmethyl] -6-methyl-isobutyl benzoate is added boron tribromide (1.3 mL, 1.0 M in dichloromethane, 1.3 mmol) to a solution of 2- [3- (methoxy) -phenylsulfanylmethyl] -6-methyl-isobutyl benzoate (194 mg, 0.56 mmol, Example 82) in dichloromethane (3 mL) at a temperature of 0 ° C and then the reaction is stirred at room temperature for 3 hours. The reaction is then divided between a solution of sodium bicarbonate and ethyl acetate. The organic phase is dried in magnesium sulfate, concentrated and purified by column chromatography (silica, 15% ethyl acetate in hexanes) to give the title compound. MS (El) 330 (M) Y Example 84 Isobutyl 2-methyl-6- [3- (quinolin-2-ylmethoxy) -phenylsulfanylmethyl] -benzoate. The free base of 2- (chloromethyl) quinoline hydrochloride (148 mg, 0.69 mmol) is prepared by dividing the material between ethyl ether and sodium bicarbonate and by drying the organic phase with magnesium sulfate. This material is then dissolved with isobutyl 2- [3- (hydroxy) -phenylsulfanylmethyl] -6-methyl-benzoate (220 mg, 0.67 mmol, Example 83) in DMF (2 mL) at a temperature of 0 ° C and add sodium hydride (60%, 27 mg, 0.67 mmol).

The reaction is allowed to stir for 16 hours and then divided between ethyl acetate and water. The organic phase is washed with water (3 times), dried over magnesium sulfate, concentrated and purified by column chromatography (silica, 10% ethyl acetate in hexanes) to give the title compound. XH NMR (300 MHz, CDC13) d 8.19 (d, 1H), 8.08 (d, 1H), 7.83 (d, 1H), 7.74 (t, 1H), 7.63 (d, 1H), 7.55 (t, 1H) , 7.18-7.07 (m, 4H), 6.99 (d, 1H), 6.89 (d, 1H), 6.82 (dd, 1H), 5.33 (s, 2H), 4.18 (s, 2H), 4.10 (d, 2H) ), 2.36 (s, 3H), 2.07-2.01 (m, 1H), 0.98 (d, 6H); MS (ESI) 472 (M + H) *. Example 85 2-Methy1-6- [3- (quinolin-2-ylmethoxy) -phenylsulfinylmethyl] -isobutylbenzoate is added m-chloroperbenzoic acid (< 86%, 34 mg, 0.17 mmol) to a 2-methyl solution -6- [3- (quinolin-2-ylmethoxy) -phenylsulfanylmethyl) -isobutylbenzoate (80 mg, 0.17 mmol, Example 84) in dichloromethane (1 mL) and the reaction is stirred overnight. The reaction is partitioned between ethyl acetate and sodium bicarbonate and the organic phase is washed with an additional solution of bicarbonate, dried over magnesium sulfate, concentrated and purified by column chromatography (silica, 4C ethyl acetate in hexanes). to provide the title compound. S (ESI) 488 (M + H) *.

EXAMPLE 86 Isobutyl 2-Methyl-6- [3- (quinolin-2-ylmethoxy) -phenylsulfonylmethyl] -benzoate M-chloroperbenzoic acid (< 86%, 62 mg, 0-31 mmol) is added to a solution of Isobutyl -methyl-6- [3- (quinolin-2-ylmethoxy) -phenylsulfanylmethyl] -benzoate (73 mg, 0.16 mmol, Example 85) in dichloromethane (1 mL) and the reaction is stirred overnight. The reaction is partitioned between ethyl acetate and sodium bicarbonate and the organic phase is washed with an additional solution of bicarbonate, dried over magnesium sulfate, concentrated and purified by column chromatography (silica, 30% ethyl acetate in hexanes). to provide the title compound. MS (ESI) 504 (M + H) "Example 87 (l-Quinolin-2-ylmethyl-1 H-imidazol-4-yl) -methanol and (3-quinolin-2-ylmethyl-3-H-imidazol-4-yl) -methanol 2-Chloromethyl-quinoline hydrochloride (2.24 g, 10.5 mmol), 4- (hydroxymethyl) -imidazole hydrochloride (1.35 g, 10 mmol) and K2CO3 (4.2 g, 30 mmol) are dissolved / suspended in anhydrous DMF (20 mL) ) and are heated to a temperature of 100 ° C with rapid stirring overnight.The reaction is cooled to room temperature and poured into water (400 mL) and extracted into chloroform (3 x 150 mL) .The organic fractions are combined and washed with brine (2 x 200 mL), dried in MgSO4, filtered and reduced in vacuo in an oil.The crude material is purified by flash chromatography (silica, 5% methanol in dichloromethane) to provide (3-quinolin-2-ylmethyl-3H-imidazol-4-yl) -methanol and (1-quinolin-2-ylmethyl-1H-imidazol-4-yl) -methanol in the proportion 2: 3 The identity of each isomeric region was determined by NMR NOE experiments. MS (ESI) 240 (M + H) * found for both regioisomers. Example 88 Isobutyl 2-methyl-6- (1-quinolin-2-ylmethyl-1H-imidazol-4-ylmethoxymethyl) -benzoate (l-quinolin-2-ylmethyl-1H-imidazol-4-yl) -methanol (350 mg, 1.46 mmole, Example 87) is dissolved in 20% DMPU in THF (5 mL) and cooled to 0 ° C. Sodium hydride (60%, 60 mg, 1.50 mmol) is added in portions and the contents are stirred for 15 minutes. Isobutyl 2-bromomethyl-6-methyl-benzoate (57%, 730 mg, 1.46 mmol, Example 2) is added, the reaction is allowed to come to room temperature and is stirred overnight. The contents are poured into water (200 ml) and extracted with dichloromethane (3 x 75 ml). The organic fractions are combined and washed with brine (3 x 100 mL), dried in MGSO4, filtered and reduced under vacuum in an oil. The crude material is purified by flash chromatography (silica, 3% methanol in dichloromethane) to provide the title compound. MS (ESI) 443 (M + H) *.

Example 88a 2-Methyl-6- (3-quinolin-2-ylmethyl-3H-imidazol-4-ylmethoxymethyl) isobutylbenzoate The title compound is prepared using essentially the same procedure used in Example 88 except that it uses (3-quinolin-2-ylmethyl-3H-imidazol-4-yl) -methanol in place of (l-quinolin -2-ylmethyl-lH-imidazol-4-yl) -methanol. MS (ESI) 443 (M + H) *. EXAMPLE 89 2-Methyl-6- (1-quinolin-2-ylmethyl-1H-imidazol-4-ylmethoxymethyl) -benzoic acid 2-methyl-6- (1-quinolin-2-ylmethyl-1H-imidazol-4-ylmethoxymethyl) - isobutyl benzoate (300 mg, 0.68 mmol, Example 88) is dissolved in ethanol (5 ml). NaOH ION (680 mL, 6.8 mmol) is added and the contents are heated to a temperature of 90 ° C overnight. The reaction is cooled to room temperature, 2N HCL (3.4 mL, 6.8 mmol) is added and the pH adjusted to about 5-7. The contents are drained in water (100 mL) and extracted with chloroform (3 x 75 mL). The organic fractions are combined, washed with brine (3 x 100 mL), dried in MgSO 4, filtered and reduced under vacuum in an oil. The crude material is purified by HPLC (C-18, 25-50% acetonitrile in water for 15 minutes) to provide the title compound in the form of the TFA salt. XH NMR (300 MHz, CDCl.) D 8.93- (s, 1H), 8.31 (d, 1H), 8.07 (d, 1H), 7.86 (d, 1H), 7.78 (t, 1H), 7.63 (t, 1H), 7.51 (d, 1H), 7.44 (s, 1H), 7.17-7.12 (m, 1H), 7.06-7.01 (m, 2H), 5.64 (s, 2H), 4.66 (s, 2H), 4.48 (s, 2H), 2.29 (s, 3H). MS (ESI) 388 (M + H) +. Example 89a 2-Methyl-6- (3-quinolin-2-ylmethyl-3H-imidazol-4-ylmethoxymethyl) -benzoic acid The title compound is prepared using essentially the same procedure used in example 89 except that 2- is used. Methyl-6- (3-quinolin-2-ylmethyl-3H-imidazol-4-ylmethoxymethyl) -isobutylbenzoate in place of 2-methyl-6- (l -quinolin-2-ylmethyl-lH-imidazol-4-ylmethoxymethyl) ) -isobutylbenzoate. XH NMR (300 MHz, CDC13) d 8.95 (s, 1H), 8.27 (d, 1H), 8.05 (d, 1H), 7.82-7.76 (m, 2H), 7.64-7.59 (m, 1H), 7.46 ( s, 1H), 7.38 (d, 1H), 7.10-6.99 (m, 2H), 6.92 (d, 1H), 5.91 (s, 2H), 4.52 (s, 2H), 4.49 (s, 2H), 2.23 (s, 3H). MS (ESI) 388 (M + H) *. Example 90 2- [3- (lH-Indol-3-ylmethyl) -phenoxymethyl] -quinoline In indole (230 mg, 2.0 mmol) is dissolved in tetrahydrofuran (3 mL) and ethylmagnesium bromide (1M, 2.0 mL, 2.0 is added. mmoles) and The reaction is heated for 2 hours at a temperature of 65 ° C. The free base of 2- (3-chloromethyl-phenoxymethyl) -quinoline hydrochloride (400 mg, 1.2 mmol, Example 49) is prepared by dividing the material between ethyl ether and sodium bicarbonate and drying the organic phase with magnesium sulfate. . This free base is dissolved in tetrahydrofuran (2 ml) and added to the cooled solution of indole / Grignard, together with catalytic tetrabutylammonium iodide. This mixture is heated for 6 hours at a temperature of 65 ° C. The reaction is then cooled and partitioned between ethyl ether and ammonium chloride. The organic phase is washed with brine, dried over magnesium sulfate, concentrated and purified column chromatography (silica, dichloromethane) to give the title compound. MS (ESI) 365 (M + H) *. EXAMPLE 91 3- (3- (Quinolin-2-ylmethoxy) -benzyl) -indol-yl acid} -acetic Sodium hydride (60%, 22 mg, 0.55 mmol) is added to a solution of 2- [3- (lH-indol-3-ylmethyl) -phenoxymethyl) -quinoline (90 mg, 0.25 mmol, Example 90) in DMF (2.5 mL). After stirring for 5 minutes, ethyl bromoacetate (0.1 mL, 0.9 mmol) is added and the reaction is stirred for 2 hours. The reaction is partitioned between ethyl acetate and ammonium chloride and the organic phase is washed with water. The organic phase is dried over magnesium sulfate, concentrated and then the solid is triturated with ether-ether and ethyl acetate to give the title compound as a solid. Melting point 151-159 IJC; : H NMR (300 MHz, CDC13) d 8.20 (t, 2H), 7.83-7.80 (m, 1H), 7.77-7.71 (m, 1H), 7.67 (d, 1H5, 7.61-7.53 (m, 1H), 7.45-7.42 (m, 1H), 7.29-7.14 (m, 3H), 7.05-6.99 (m, 2H), 6.94 (s, 1H), 6.85 (m, 2H), 5.16 (s, 2H), 4.84 ( 5, 2H), 4.1 (s, 2H), MS (ESI) 423 (M + H) *, Example 92 (2-formyl-6-methyl-2-phenoxy) -ethyl ethyl bromoacetate (4.5 mL, 40 mmol), 2-hydroxy-3-methyl-benzaldehyde (5 g, 37 mmol) and potassium carbonate (8.1 g, 59 mmol) are combined in acetone (60 mL) and refluxed overnight. it is filtered and the solvent is removed from the filtrate under reduced pressure to provide the title compound MS (GC-MS) 222 (M) Y Example 93 7-methyl-benzofuran-2-ethyl carboxylate Sodium is dissolved (0.52 g, 23 mmol) in ethanol (60 mL) and (2-formyl-6-methyl-2-phenoxy) -acetic acid ethyl ester (5 g, 23 mmol, Example 92) is added, this mixture is refluxed for 3 hours and The solvent is removed in a vacuum, the residue is dissolved in dichloromethane-water and acidified with IN HCl. The organic layer is washed with water and brine and then dried over magnesium sulfate and the solvent is removed in vacuo. The residue is purified by flash chromatography (silica, 1% methanol in dichloromethane) to give the title compound. MS (GC-E1) 176 (M) Y Example 94 Ethyl 7-bromomethyl-benzofuran-2-carboxylate 7-methyl-benzofuran-2-carboxylic acid ethyl ester (0.5 g, 2.4 mmol, Example 93), N-bromosuccimide ( 0.48 g, 2.7 mmol) and benzoyl peroxide (0.06 g, 2.4 mmol) are combined in carbon tetrachloride (10 mL) and heated in an oil bath at 90 ° C overnight. The reaction is filtered and the filtrate solvent is removed in vacuo. The residue is purified by flash chromatography (silica, 5-10% ethyl acetate in hexanes) to provide the title compound. MS (GC-E1) 360, 362 (M *, Br pattern). Example 95 Ethyl 2-methyl-6-trifluoromethanesulfonyloxy benzoate ethyl 6-methylsalicylate (2.5 g, 14 mmol, see, Rauser, Frank M., Synthesis 1980, 10, 814-15) is dissolved in TRF (20 mL) under a nitrogen atmosphere and cooled in an ice bath. Sodium hydride (60%, 0.56 g, 14 mmol) is added and the mixture is stirred for 15 minutes. Then DMPU (0.20 mL) and N-phenyl-trifluoromethanesulfunimide (5.0 g, 14 mmol) are added and the reaction is stirred and stirred with cooling for 2 hours. The solvent is removed in vacuo and ether is added and the organic substances are washed with water, then dried in magnesium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (silica, dichloromethane) to give the title compound. Example 96 3- (2-Methoxy-ethoxymethoxy) -phenyl Yodide To a suspension of 60% sodium hydride (1.76 g, 44 mmol) in THF (10 mL), cooled to 0 ° C, 3-iodophenol is added. (8.8 g, 40 mmol) and methoxyethoxy ethyl (5 mL, 44 mmol) in THF (50 mL). After DMPU (10 mL) is added, the cooling bath is removed and the reaction is stirred for one hour. The reaction is diluted with ether, washed with water and brine and the organic layer is dried over magnesium sulfate. The solvent is removed in vacuo to provide the title compound. Example 97 [3- (2-methoxy-ethoxymethoxy) -phenylethynyl] -trimethylsilane 3- (2-methoxy-ethoxymethoxy-phenyl) iodide (12.1 g, 39 mmol, 96) and tetrakis (triphenylphosphine) palladium (1.2 g, 1.0 mmol) and cuprous iodide (0.096 g, 0.5 mmol) are dissolved in THF (120 mL) and to this is added piperidine (12 mL) and (trimethylsilyl) acetylene (8 mL, 57 mmol). This mixture is degassed and then stirred for 2 hours. The reaction is then diluted with ether and washed 2 times with water and brine and the organic layer is dried over magnesium sulfate. The solvent is removed in vacuo to provide the title compound. MS (El) 206 (M) Y Example 98 Ethyl 2- [3- (2-methoxy-ethoxymethoxy) -phenylethynyl) -6-methyl-benzoate [3- (2-methoxy-ethoxymethoxy) -phenylethynyl] -trimethylsilane ( 0.57 g, 2 mmol, Example 97) and tetrabutylammonium fluoride 10 M (2.1 mL, 2 mmol) are added to THF (10 mL) and acetic acid (0.13 g, 2 mmol) is added and this mixture is stirred at 20". C, under a nitrogen atmosphere After 15 minutes, in solvent it is removed under vacuum and the residue is subjected to azeotropy with benzene and purified by flash chromatography (silica, 20% ethyl acetate, 30% dichloromethane in hexanes) to provide l-ethynyl-3- (2-methoxy-ethoxymethoxy) -benzene (0.28 g, 1.4 mmol) which is dissolved in THF (8 mL), cooled to -78 ° C, under a nitrogen atmosphere and this solution is add 2.5M n-butyllithium (0.56 mL, 1.4 mmol) dropwise for 30 seconds.After stirring for 15 minutes, 1.0 M zinc chloride in ether (1.4 mL, 1.4 mmol) is added dropwise over 3 minutes. 0 seconds and this mixture is stirred for 30 minutes. Bis- (dibenzylidenacetone) palladium (0.04 g, 0.07 mmol) and bis are added. { diphenylphosphino) ferrocene (0.04 g, 0.07 mmol) and ethyl 2-methyl-6-trifluoromethanesulfonyloxy benzoate (0.44 g, 1.4 mmol, 95) in THF (2 ml) is added to this mixture. The cooling bath is removed and allows the heating of the reaction at room temperature. The reaction mixture is then heated in an oil bath at a temperature of 65 ° C overnight. The reaction is then diluted with ethyl acetate (50 ml), washed with ammonium chloride and brine and then dried over magnesium sulfate. The solvent is removed in vacuo and the residue is purified by flash chromatography (silica, 10% ethyl acetate, 25% dichloromethane in hexanes) to give the title compound. MS (ESI) 369 (M + H) *. Example 99 (3-Methyl-4-oxo-3,4-dihydro-quinazolin-2-yl) -methyl chloride. To a suspension of isatoic anhydride (1.63g, 10 mmol) in dioxane (40 mL) is added a solution of methylamine (5 mL, 2M in THF). The resulting solution is stirred for 1 hour and then concentrated in vacuo. The residue is taken up in toluene (30 mL) and then pyridine (5.5 mL) is added followed by a solution of chloroacetyl chloride (2.7 mL, 34 mmol) in toluene (15 mL). The resulting mixture is stirred for 15 hours. The solid product is filtered, washed with water, and then dried in vacuo to give 2. lg of a tan solid. A portion of this product (452 mg, 2 mmol) is suspended in benzene (10 mL) and then p-toluenesulfonic acid monohydrate (394 mg, 2 mmol) is added. This mixture is heated to 70 ° C and stirred at this temperature for 10 hours. The mixture is then cooled to room temperature and the benzene solution is decanted. The residual solid is mixed with the sodium bicarbonate solution (saturated) and this mixture is extracted with ethyl acetate / methanol / dichloromethane. The combined extracts are washed with brine, dried over MgSO4 and concentrated to provide the title compound as a tan solid. XH NMR (300 MHz, CDC15): d 8.28 (d, 1H), 7.75 (t, 1H), 7.67 (d, 1H), 7.51 (t, 1H), 4.62 (s, 3H), 3.76 (s, 3H) ). Example 100 3- (2-hydroxymethyl-3-methyl-benzyloxy) -phenol To a cooled (0 ° C) solution of methyl 2-methyl-6- [(3-hydroxy-phenoxy) -methyl] -benzoate (220 mg, 0.76 mmol, Example 5) in TRF (2 mL) is added a solution of lithium aluminum hydride (1.5 mL, 1M in THF). The resulting solution is stirred for 10 minutes and then heated to room temperature and stirred for 40 minutes. This solution is then cooled to 0, JC and water (75 ml) is added dropwise, followed by a solution of sodium hydroxide (75 ml, 5N) and water (75 ml). The resulting suspension is diluted with ether, filtered through Celite and the solid is washed completely with methanol (until the solid is free of product with TLC analysis). The combined filtrates are concentrated in vacuo to provide the title compound as a white solid. MS (El) 244 (M) +.

EXAMPLE 101 2- [3- (2-Hydroxymethyl-3-methyl-benzyloxy) -phenoxymethyl] -3-methyl-3H-quinazol-4-one To a solution of 3- (2-hydroxymethyl-3-methyl-benzyloxy) phenol (87 mg, 0.38 mmol, example 100) and (3-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl) methyl chloride (94 mg, 0.45 mmol, example 99) in DMF ( 1 ml) is added K2C03 powder (78 mg, 0.5 mmol). The resulting mixture is heated to a temperature of 60 ° C and stirred at this temperature for 5 hours. This mixture is cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 40% ethyl acetate / dichloromethane in hexanes) to give the title compound as a foam. MS (ESI) 417 (M + H) *. Example 101a. { 2- (3- (5-Cyclobutyl- [1,2,4] oxadiazol-3-ylmethoxy) -phenoxymethyl] -6-methyl-phenyl} -methanol The title compound is prepared using essentially the same procedure as the procedure used in Example 101 except that 3-chloromethyl-5-cyclobutyl- [1, 2, 4] oxadiazole is used in place of (3-methyl-4-oxo-3,4-dihydro-quinazolin-2-) chloride il) -methyl MS (ESI) 381 (M + H) * Example 102 2-methyl-6- [3- (3-methyl-4-oxo-3,4-dihydro-quinazolin-2-ylmethoxy) -phenoxymethyl) ] -benzaldehyde To a cooled solution (-78 ° C) of oxalyl chloride (2.5 ml, 1.75 M in CH2D2) is added, dropwise, DMSO (80 ml). Solution of 2- [3- (2-hydroxymethyl-3-methyl-benzyloxy) -phenoxymethyl] -3-methyl-3H-quinazolin-4-one (120 mg, 0.28 mmol, Example 101) in dichloromethane (1 ml) is The solution is stirred for 5 minutes and then triethylamine (276 ml, 2 mmol) is added in one portion.The cold bath is removed and stirring continues for 10 minutes. The mixture is then diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated to give the title compound as a solid. MS (ESI) 415 (M + H) *. Example 102a 2- [3- (5-Cyclobutyl- [1,2,4] oxadiazol-3-ylmethoxy) -phenoxymethyl] -6-methyl-benzaldehyde The title compound is prepared using essentially the same procedure used in Example 102 except that it is used. { 2- [3- (5-Cyclobutyl- [1, 2, 4] oxadiazol-3-yl-ethoxy) -phenoxymethyl) -6-methyl-phenyl} -methanol (example 101 a) instead of 2- [3- (2-hydroxymethyl-3-methyl-benzyloxy) -phenoxymethyl] -3-methyl-3H-quinazolin-4-one. MS (ESI) 379 (M + H) *. Example 103 2-Methyl-6- [3- (3-methyl-4-oxo-3,4-dihydro-quinazolin-2-ylmethoxy) -phenoxymethyl) -benzoic acid To a suspension of 2-methyl-6- [3 - (3-Methyl-4-oxo-3,4-dihydro-quinazolin-2-ylmethoxy) -phenoxymethyl] -benzaldehyde (120 mg, 0.28 mmol, example 102) in t-butanol (1.5 mL) is added isobutene (0.5 mL) followed by NaC102 (220 mg, technical grade 1.6 mmol) in water (1.5 mL) and NaH2P04.H20 (220 mg, 1.6 mmol) in water (1.5 mL). This mixture is stirred for 1 hour (during this time the solids dissolve) and then diluted with ethyl acetate, washed with water and brine, dried over MgSOc and concentrated. The residue is purified by flash chromatography (10% methanol in dichloromethane). This product was suspended in chloroform and filtered through Celite. The filtrate is concentrated under reduced pressure to provide the title compound as an amorphous solid. XH NMR (300 MHz, CDC13): d 8.41 (d, 1H), 7.84 (m, 2H), 7.62 (m, 1H), 7.33 (m, 2H), 7.20 (m, 1H), 7.14 (t, 1H) ), 6.81 (m, 1H), 6.70 (m, 2H), 5.29 (s, 2H), 5.25 (s, 2H), 3.80 (s, 2H), 2.52 (s, 3H). MS (ESI) 430 (M + H) +. Example 103a 2- [3- (5-Cyclobutyl- [1,2,4] oxadiazol-3-ylmethoxy) -phenoxymethyl] -6-methyl-benzoic acid The title compound is prepared using essentially the same procedure as the procedure used in Example 103, except that 2- [3- (5-cyclobutyl- [1,2,4] oxadiazol-3-ylmethoxy) -phenoxymethyl] -6-methyl-benzaldehyde (example 102a) is used instead of 2- methyl-6- [3- (3-methyl-4-oxo-3, 4-dihydro-quinazolin-2-ylmethoxy) -phenoxymethyl] -benzaldehyde. XH NMR (300MHz, DMSO) d: 7.10 (m, 4H), 6.68 (s, 1H), 6.60 (m, 2H), 5.19 (s, 2H), 5.13 (s, 2H), 3.86 (m, 1H) , 2.36 (m, 4H), 2.28 (s, 3H), 2.08 (m, 1H), 1.96 (m, 1H). MS (ESI) 395 (M + H) *. Example 104 5-phenyl-2-methylpyridine To a cooled solution (-70 ° C) of 3-phenylpyridine (1.43 L, 10.0 mmol) in diethyl ether (Y5 mL) is added dropwise methyllithium (LiBr complex, 1.5 M in diethyl ether, 7.33 mL, 11.0 mmol). After heating at room temperature for 16 hours the reaction is cooled (0 ° C) and quenched with distilled water (5 mL). The reaction is then extracted with methylene chloride, the crust layer is isolated and concentrated, and the resulting residue is purified by column chromatography (silica, 3: 1 hexane: EtOAc) to give the title compound as an oil. pale yellow. MS (ESI) 170 (M + H) *. Synthesis of a compound of the formula (VI) A compound of the formula (VI) is prepared in a multi-step synthesis illustrated in the scheme presented below. The key initial material is quinaldine. In the first stage, it is chlorinated to form 2-chloromethylquinoline, which without isolation, reacts with hydroquinone to form the intermediate 4- (quinolin-2-yl-methoxy) phenol (VIII). This intermediate then reacts with a, a'-dichloro-o-xylene to form 2- (4-quinolin-2-yl-methoxy) phenoxymethyl] benzyl chloride, which is converted in situ to 2- [4-quinoline- 2-yl-pietoxy) phenoxymethyl] phenylacetonitrile (IX), the penultimate precursor for (VI). (IX) is converted to crude (VI), in a reaction with sodium azide and ammonium chloride which transforms the nitrile group into the tetrazole ring. The purification of the final product is achieved by recrystallization of the crude material from methanol to provide pure (VI). 1) a, a '-diclcrc-? Iler.c l) C? _ # 1,2, 4-tricioroDer.ceno ri.O or a MeOH, i re cquir.cr.a, (VI) (Cru.c) Solid phase synthesis of a compound of the formula: 1. Carsa de Aciao: DMF A round-bottomed flask of IS is loaded with 4- (bromomethyl) benzoic acid (32.36 g, 150.0 mmol) and dichloromethane (650 mL). A stirring bar is carefully added and the reaction bottle is immersed in an ice-water bath.

After about 15 minutes, oxalyl chloride (15.7 mL, 180 moles) is added. After about 15 minutes, N, N-dimethylformamide (500 mL, cat) is added. The reaction begins to bubble. After stirring for 1.5 hours, the ice-water bath is removed. After stirring for 3 hours at room temperature, the effervescence ends. At the end of this period, the stirring bar is removed from the reaction mixture and the solvent of the reaction is removed in vacuum. After removal of the solvent, more dichloromethane is added to the reaction flask and this is also removed under vacuum. A 3-L three-neck round bottom flask is loaded with dry N, N-dimethylformamide (1.3L), N, N-diisopropylethylamine (39.19 mL, 225 mmol), 4-N, -di-ethylaminopyridine (3.67 g, mmoles) and MicroKANS [14? 6, 15 mg Wang resin (1.7 mmoles / g charge) by MicroKANS 25.5 micromoles / microKAN, 37.1 mmoles]. The bottle is equipped with an overhead shaker. After stirring for about 15 minutes, a solution of the acid chloride in accordance with that prepared above in dry N, N-dimethylformamide (200 mL) is transferred to the reaction bottle. After 14 hours, the reaction solvent is removed. DMF (1.5 L) is added to the reaction bottle. The agitation of the flask is allowed for approximately 15 minutes and the solvent is drained. The MicroKANs are washed, stirred for 20 minutes and drained in the following sequence, repeatedly: DMF (2 x 6 L), THF (3 x 6 L), dichloromethane (3 x 6 L) and ether (2 x 6 L). After final washing, the MicroKANs are dried by welding a stream of nitrogen through the flask with intermittent stirring. After sufficient drying, the MicroKANs are classified for the next reaction. 2. Displacement of phenol: A 3-L three-neck round bottom flask is loaded with 3-chloro-4-hydroxybenzaldehyde (21.9 g, 140 mmol) and DMF (1.5 L). The reaction bottle is equipped with an agitator at the top and immersed in an ice-water bath. After approximately 15 minutes, sodium hydride is carefully added (60% dispersion in oil, 6.48 g, 180 mmol). After about 30 minutes, the ice-water bath is removed and the reaction is allowed to stir at room temperature for one hour. At the end of this period, the microKANs [1274, 25.5 micromoles / microKAN, 32.5 mmoles] and potassium iodide (1.0 g) are added to the reaction mixture. The reaction bottle is immersed in an oil bath that is heated to 60 ° C. After 14 hours, the reaction bottle is removed from the oil bath and allowed to cool to room temperature. The solvent is removed from the reaction. DMF (1.2 L) is added to the reaction bottle. The agitation of the bottle is allowed for about 15 minutes and the solvent is drained. DMF: water (1: 1, 1.2 L) is added to the reaction flask. The agitation of the bottle is allowed for about 15 minutes and the solvent is drained. This sequence is repeated at least three times or until the washing effluent becomes clear. The reaction flasks are washed repeatedly in the following sequence: THF (2 x 4 L), dichloromethane (1 x 4 L) and then methanol (1 x 4 L), dichloromethane (1 x 4 L) then methanol (1 x 4) L), dichloromethane (1 x 4 L) then methanol (1 x 4 L), dichloromethane (1 x 4 L) and ether (1 x 4 L). After the final wash, the MicroKANs are dried by blowing a stream of nitrogen through the flask with intermittent stirring. After sufficient drying, the MicroKANs are classified for the next reaction. 3. Reducing amination: A 2 L round neck flask with three necks is loaded with the microKANs [784, 25.5 micromoles / microKAN, 20.0 mmol], trimethylorthoformate '(850 mL) and 2- (2-aminoethyl) pyridine 20.79 g, 170 mmol). The reaction bottle is equipped with an agitator at the top. After 2 hours, sodium cyanoborohydride (21.37 g, 340 mmol) is added. After about 10 minutes, acetic acid (17.0 mL, 297 mmol) is added. After stirring for an additional 1 hour, the reaction bottle is drained. Methanol (800 mL) is added to the flask. After stirring for approximately 10 minutes, the flask is then drained. The reaction bottle is washed repeatedly in the following sequence: DMF (3 x 4 L), dichloromethane (1 x 4 L) then methanol (1 x 4 L), dichloromethane (1 x 4 L) then methanol (1 x 4) L), dichloromethane (1 x 4 L) then methanol (1 x 4 L), dichloromethane (1 x 4 L) and ether (1 x 4 L). After the final wash, the microKANS are dried by blowing a stream of nitrogen through the flask with intermittent stirring. After sufficient drying, the icrcKANs are classified for the next reaction. 4. Acylation: CH_C1: A 2-L three-neck round bottom flask is loaded with MicroKANs [784, 15 mg resin (1.7 mmoles / g loading) by MicroKAN, 25.5 micromoles / microKAN, 20.0 mmoles], and dichloromethane (800 mL). The reaction bottle is equipped with an agitator at the top. Add N, N-diisopropylethylamine (20.9 mL, 120 mmol) and 4-N, N-imethylaminopyridine (195 mg, 1.6 mmol). After about 15 minutes, c-cyclopentanecarbonyl chloride (10.6 g, 80.0 rimol) is added. The reaction is allowed to stir for 61 hours, the reaction bottle is drained. Dichloromethane (800 mL) is added to the reaction flask. After stirring for approximately 10 minutes, the bottle is drained. This is repeated. The MicroKANs from all the acylation reactions are combined in a random manner in two large separate bottles and washed repeatedly in the following sequence: dichloromethane (1 x 4 L), THF (2 x 4 L), dichloromethane (1 x 4 L) then methanol (1 x 4 L), dichloromethane (1 x 4 L) then methanol (1 x 4 L), dichloromethane (1 x 4 L) then methanol (1 x 4 L), dichloromethane (1 x 4 L) and ether (1 x 4 L).

. Dissociation: The MicroKAN is classified in individual wells of an IRORI AccuClave 96 dissociation station. The well is charged with dichloromethane (600 mL) and then with a mixture of TFA: dichloromethane (1: 1, 600 mL). After stirring for approximately forty minutes, the reaction well is drained in 2 mL microtubes in a 96-well format. The reaction well is again charged with dichloromethane (600 mL). After manual agitation, it is also drained in the 2 mL microtube in a 96-well format. The dissociation mixture is removed in vacuum using a Savant Speedvac. The products concentrated from the dissociation mother plates are reconstituted with THF and transferred onto two daughter plates using a Packard MultiProbe liquid handler. The daughter plates are concentrated in vacuum using a Ger.ie Vac. Analytical: MS: m / z 493 (M *). The methods described above are employed to prepare the following compounds of this invention. 5- [2- (4- (2-quinolinylmethoxy) phenoxymethyl) benzyl] tetrazole (mp 108-111 ° C) CALCULATED: C, 59.87; H, 5.96; N, 13.96 FOUND: C, 59.67, 60.01; H, 5.62, 5.63; N,. 13.73, 13.77 5- [4-methoxy-3- (3- (2-quinolinylmethoxy) phenoxymethyl) phenyl] tetrazole (mp 184-87 ° C) CALCULATED: C, 67.63; H, 4.88; N, 15.78 FOUND: C, 67.18; H, 5.13; N, 15.40 5- [3- (4- (2-quinolinylmethyloxy) phenoxymethyl) phenyl) tetrazole (FUSION POINT 176-177 ° C) CALCULATED: C, 69.63; H, 4.75; N, 16.92 FOUND: C, 69.58, 69.64; H, 5.00, 4.98; N, 16.66, 16.63 - (3-methoxy-4- (4- (2-quinolinylmethyloxy) benzyloxy) phenyl] tetrazole (FUSION POINT 195-97 ° C) CALCULATED: C, 67.63; H, 4.88; N, 15.77 FOUND: C, 67.27; H, 4.89; N, 15.41, 5- [4- (3- (2-quino-1, I-methyl-oxy) phenoxymethyl) -3-methoxyphenyl] -tetrazole (FUSION POINT 189-91 ° C) CALCULATED: C, 66.95; H, 4.95; N, 15.61 FOUND: C, 66.48; H, 5.14; N, 14.93 5- [3- (4- (2-quinolinylmethyloxy) phenoxymethyl) benzyl) tetrazole (FUSION POINT: 139-44 ° C) CALCULATED: C, 70.53; H, 5.03; N, 16.45 FOUND: C, 70.33, 70.54; H, 5.25, 5.36; N, 16.38, 16.41 - [4- (4- (2-quinolinylmethyloxy) phenoxymethyl) benzyl) tetrazole (POINT OF FUSION 167-71 ° C) CALCULATED: C, 67.33; H, 5.31; N, 15.70 FOUND: C, 67. 54, 67. 67,; H, 5. 33, 5. 33; N, 15. 48, 15. 52 5- [4-met? Xi-3- (4- (2-quinolinylmethyloxy) phenylmethyloxy) phenyl] tetrazole (POINT OF FUSION 210-13 ° C) CALCULATED: C, 68.33; H, 4.82; N, 4.90 FOUND: C, 68.32; H, 4.90; N, 14.79 4- [3- (2-quinolinylmethyloxy) phenoxymethyl] phenoxyacetic acid (POINT OF FUSION 164 (decomposition)) CALCULATED: C, 69.27; H, 5.35; N, 3.23 FOUND: C, 69.53, 69.65; H, 5.11, 5.05; N, 3.21, 3.12 - [2- (4- (2-quinolinylmethyloxy) phenoxymethyl) phenoxymethyl] tetrazole (POINT OF FUSION 183-85 ° C) CALCULATED: C, 65.63; H, 5.08; N, 15.31 FOUND: C, 65.77, 65.52; H, 4.99, 5.03; N, 14.92, 15.03 4- [4- (2-quinolinylmethyloxy) phenoxymethyl) phenoxyacetic acid (176 ° C (dec)) CALCULATED: C, 71.50; H, 5.16; N, 3.34 FOUND: C, 71.10, 71.17; H, 5.27, 5.33; N, 3.37, 3.34 4- [3- (2-quinolinylmethyloxy) phenoxymethyl] phenylacetic acid (POINT OF FUSION 158-60 ° C) CALCULATED: C, 75.17; H, 5.30; N, 3.51 FOUND: C, 74.89; H, 5.36; N, 3.37 2- [3- (3- (2-quinolinylmethyloxy) phenoxymethyl) phenoxy] pentanoic acid (POINT OF FUSION 133-35 ° C) CALCULATED: C, 73.51; H, 5.95; N, 3.06 FOUND: C, 73.35, 73.60; H, 5.95, 5.98; N, 3.08, 3.05 2- [3- (2-quinolinylmethyloxy) phenoxymethyl] phenoxyacetic acid (FUSION POINT 169-172 ° C) CALCULATED: C, 72.28; H, 5.10; N, 3.37 FOUND: C, 69.34, 69.69; H, 5.10, 5.13; N, 3.00, 3.08 CALCULATED: C, 69.27; H, 5.35; N. 3.23 (as hydrate) 2- [4- (2-quinolinylmethyloxy) phenoxymethyl] cinnamic acid (FUSION POINT 175-178 ° C) CALCULATED: C, 75.90; H, 5.14; N. 3.40 FOUND: C, 73.92; H, 5.20; N. 3.01 CALCULATED: C, 74.27; H, 5.27; N, 3.33 (as hydrate) 6-acetyl-2-propyl-3- [3- (2-quinolinylmethyloxy) -benzyloxy] phenoxyacetic acid (POINT OF FUSION 153-58 ° C) CALCULATED: C, 72.13; H, 5.85; N, 2.90 FOUND: C, 71.68, 72.08; H, 5.88, 5.83; N, 2.65, 2.70 2- [2- (4- (7-Chloroquinolin-2-ylmethyloxy) -phenoxymethyl) phenoxy] propionic acid (FUSION POINT 169-173 ° C) CALCULATED: C, 67.32; H, 4.78; N, 3.02; Cl, 7.64 FOUND: C, 65.18; H, 4.90; N, 2.84; Cl, 8.33 CALCULATED: C, 65.41; H, 4.96; N, 2.93; Cl, 7.42 (as HYDRATE) 2- [4- (2-quinolinylmethyloxy) phenoxymethyl] phenylacetic acid (POINT OF FUSION 181-83 ° C) CALCULATED: C, 75.17; H, 5.30; N, 3.51 FOUND: C, 75.12, 74.96; H, 5.50, 5.49; N, 3.16, 3.16 3- [3- (2-quinolinylmethyloxy) phenoxymethyl) phenoxyacetic acid (POINT OF FUSION 146-51 ° C) CALCULATED: C, 72.28; H, 5.10; N. 3.37 FOUND: C, 71.82, 71.80; H. 5.24, 5.23; N, 2.98, 3.00 CALCULATED: C, 71.50; H, 5.16; N, 3.34 (as HYDRATE) 2- [4- (2-quinolinylmethyloxy) phenoxymethyl] phenoxyacetic acid (POINT OF FUSION 153-57 ° C) CALCULATED: C, 72.28; H, 5.10; N, 3.37 FOUND: C, 72.30, 71.72; H, 5.39, 5.30; N, 2.94, 2.89, 5- [2- (4- (7-chloroquinolin-2-ylmethyloxy) -phenoxymethyl) benzyl] tetrazole (FUSION POINT 159-63 ° C) CALCULATED: C, 65.57; H, 4.40; N, 15.29 FOUND: C, 64.16; H, 4.72; N, 14.98 CALCULATED: C, 64.30; H, 4.53; N, 14.99 (as HYDRATE) 2-carbomethoxy-5- [3- (2-quinolinylmethyloxy) -phenoxymethyl] phenoxyacetic acid (POINT OF FUSION 187-89 ° C) CALCULATED: C, 68.49; H, 4.90; N, 2.95 FOUND: C, 66.71; H, 4.96; N, 2.70 CALCULATED: C, 66.59; H, 5.07; N, 2.87 (as HYDRATE) 2- [3- (2-quinolinylmethyloxy) phenoxymethyl] -6-methylphenoxyacetic acid (POINT OF FUSION 149-53 ° C) CALCULATED; C, 72.71; H, 5.40; N, 3.26 FOUND: C, 71.23; H, 5.46; N, 3.08 CALCULATED: C, 71.22; H, 5.51; N, 3.19 (as HYDRATE) 2- [3- (3- (2-quinolinylmethyloxy) phenoxymethyl) phenoxy] glutaric acid (POINT OF FUSION 129-30 ° C) CALCULATED: C, 69.00; H, 5.17; N, 2.87 FOUND: C, 58.19; H, 4.93; N, 2.23 CALCULATED: C, 58.23; H, 5.17; N, 2.43 (as HYDRATE) 2- [3- (2-quinolinylmethyloxy) phenoxymethyl] benzylmalonic acid (POINT OF FUSION 164-65 ° C) CALCULATED: C, 70.89; H, 4.08; N, 3.06 FOUND: C, 70.51, 70.61; H, 5.03, 5.24; N, 3.03, 2.90 2- [2- (3- (2-quinolinylmethyloxy) phenoxymethyl) phenoxy] pentanoic acid (POINT OF FUSION 118-20 ° C) CALCULATED: C, 73.51; H, 5.95; N, 3.06 FOUND: C, 73.26; H, 6.07; N, 2.79 2- [4- (2-quinolinylmethyloxy) phenoxymethyl) -6-methylphenoxy acetic acid (POINT OF FUSION 151-53 ° C) CALCULATED: C, 72.71; H, 5.40; N, 3.26 FOUND: C, 71.41; H, 5.58; N, 3.03 CALCULATED: C, 71.22; H, 5.51; N, 3.19 (as HYDRATE) 2- (2- (4- (2-quinolinylmethyloxy) phenoxymethyl) phenoxy) pentanoic acid (POINT OF FUSION 85-92 ° C) CALCULATED: C, 73.51; H, 5.95; N, 3.06 FOUND: C, 71.73, 71.79; H, 5.96, 5.91; N, 3.06, 2.83 CALCULATED: C, 72.09; H, 6.05; N, 3.00 (as HYDRATE) 2-carbomethoxy-5- [4- (2-quinolinylmethyloxy) -phenoxymethyl] phenoxyacetic acid (FUSION POINT 149-51 ° C) CALCULATED: C, 68. 49; H, 4 90; N, 2 95 FOUND: C, 68.00, 68.08; H, 4.98, 5.04; N, 2.90, 2.90 2- [2- (4- (2-quinolinylmethyloxy) phenoxymethylphenoxy) propionic acid (POINT OF FUSION 161 -64 ° C) CALCULATED: C, 72.71; H, 5.40; N, 3.26 FOUND: C, 70.96, 71.10; H, 5.51, 5.58; N, 3.08, 3.10 CALCULATED: C, 71.22; H, 5.52; N, 3.19 (as HYDRATE) [2- (3- (2-quinolinylmethyloxy) phenoxymethyl) phenoxy] glutaric acid (POINT OF FJ IOM 83 ° C decomposition) CALCULATED: C, 68.98; H, 5.17; N, 2.87 FOUND: C, 64.10, 63.75; H, 4.89, 4.92; N, 2.64, 2.69 CALCULATED: C, 63.74; H, 5.63: N, 2.65 (as HYDRATE) 2- (3- [2-quinolinylmethyloxy] benzyloxy) phenoxyacetic acid (POINT OF FUSION 153-55 ° C) CALCULATED: C, 72.28; H, 5.10; N. 3.37 FOUND: C, 71.75; H, 5.14; N. 3.38 CALCULATED: C, 71.50; H, 5.16; N. 3.34 (as HYDRATE) 2- (2- [4- (2-quinolinylmethyloxy) phenoxymethyl] -4-chlorophenoxy) propionic acid (FUSION POINT 196-99 ° C) CALCULATED: C, 67.32; H, 4.78; N, 3.02 FOUND: C, 67.40, 67.43; H, 4.89, 4.94; N, 3.01, 3.13 2- (2- [3- (2-quinolinylmethyloxy) phenoxymethyl] -4-chlorophenoxy) propionic acid (FUSION POINT 169-71 ° C) CALCULATED: C, 67.32; H, 4.78; N, 3.02 FOUND: C, 65.47; H, 5.31; N, 2.78 CALCULATED: C, 65.41; H, 4.96; N, 2.93 (as HYDRATE) 2- (2- [3- (2-quinolinylmethyloxy) phenoxymethyl] -4-chlorophenoxy) pentanoic acid (POINT OF FUSION 144-45 ° C) CALCULATED: C, 68.36; H, 5.33; N, 2.85 FOUND: C, 67.74, 67.86; H, 5.39, 5.47; N, 2.91, 2.84 CALCULATED: C, 67.74; H, 5.38; N, 2.82 (as HYDRATE) 2- (2- [4- (2-quinolinylmethyloxy) phenoxymethyl] -4-chlorophenoxy) pentanoic acid (FUSION POINT 155-56 ° C) CALCULATED: C, 68.36; H, 5.33; N, 2.85 FOUND: C, 65.96; H, 5.59; N, 2.66 CALCULATED: C, 65.95; H, 5.53; N, 2.75 (as HYDRATE) 2- (2- [4- (2-quinolinylmethyloxy) phenoxymethyl] -4-chlorophenoxy) pentanoic acid (FUSION POINT 155-56 ° C) CALCULATED: C, 68.36; H, 5.33; N, 2.85 FOUND: C, 66.15; H, 5.58; N, 2.68 CALCULATED: C, 65.95; H, 5.53; N, 2.75 (as HYDRATE) 2- (2- [4- (2-quinolinylmethyloxy) phenoxymethyl] -6-chlorophenoxy) pentanoic acid (MELTING POINT 161-62 ° C) CALCULATED: C, 68.36; H, 5.33; N, 2.85 FOUND: C, 68.15; H, 5.36; N, 2.72, 2- (2- [3- (2-quinolinylmethoxy) phenoxymethyl] -6-chlorophenoxy) pentanoic acid (FUSION POINT 169-70 ° C) CALCULATED: C, 68.36; H, 5.33; N, 2.85 FOUND: C, 68.10; H, 5.39; N, 2.72 2- (2- [3- (2-quinolinylmethyloxy) phenoxymethyl) -6-chlorophenoxy) -4-methylpentanoic acid (FUSION POINT 164-66 ° C) CALCULATED: C, 68.84; H, 5.58; N, 2.77 FOUND: C, 68.84; H, 5.70; N, 2.69 2- (2- [4- (2-quinolinylmethyloxy) phenoxymethyl] -6-chlorophenoxy) -4-methylpentanoic acid (167-69 ° C FUSION POINT) CALCULATED: C, 68.84; H, 5.58; N, 2.77 FOUND: C, 68.78; H, 5.67; N, 2.68 5- [3- (3- (2-quinolinylmethyloxy) benzyloxy) -4-methoxypheni] tetrazole 'FUSION POINT 204-07 ° C) CALCULATED: C, 67.63; H, 4.88; N, 15.78 FOUND: C, 67.11; H, 5.15; N, 15.86 N- [3-methoxy-4- (3- (2-quinolinylmethyloxy) benzyloxy) benzoyl) benzenesulfonamide hydrochloride (POINT) FUSION decomposition 88) CALCULATED: C, 62.99; H, 4.60; N, 4.74 FOUND: C, 63.88; H, 5.13; N, 4.80 5-carboxy-2- (3- (2-quinolinylmethyloxy) phenoxymethyl) phenoxyacetic acid (FUSION POINT) 226-28 ° C) CALCULATED: C, 61.90; H, 5.18; N, 2.77 FOUND: C, 61.62; H, 5.11; N, 2.67 5- [3-methoxy-4- (3- (2-quinolinylmethyloxy) benzyloxy) phenyl) tetrazole (FUSION POINT) 204-05 ° C) CALCULATED: C, 67.67; H, 5.14; N, 15.87 FOUND: C, 67.63; H, 4.88; N, 15.78, 5- (4- (3- (2-quinolinylmethyloxy) benzyloxy) phenyl) tetrazole (POINT OF FUSION 233-36 ° C) CALCULATED: C, 69.58; H, 4.73; N, 16.91 FOUND: C, 69.59; H, 4.89; N, 16.91 y ^ N N-N $ 4-156'C 166-170'C or 1 w ~ -y / ^ .N .f ^ / OW . < ? and ^ 161-162 * C V '173-4 * C (dec) ^ / * lß2-184 * C OR : .96 find or C 3.9-? H 6.31, N 2.89 Using a combination of the above examples, various compounds can be made within the scope of the present invention. Compounds in accordance with the present invention exhibit remarkable pharmacological activities in accordance with tests described in the literature, said test results are correlated as believed with pharmacological activity in humans and other mammals. The following results of pharmacological tests are typical characteristics of compounds of the present invention. The compounds of the present invention have a potent activity as PPAR ligand receptor linkers and possess an antidiabetic, antilipidemic, antihypertensive, antiarteriosclerotic activity and are also anticipated to be effective for the treatment of diabetes, obesity and other diseases. related HPPARa binding assay The activity of the compounds of the invention as modulators of PPARa can be examined in several relevant and in vitro and in vivo clinical trials, for example, by comparing with a PPARa modulator known as, for example, [3H] -GW2331 (2- (4- (3- [2, 4-difluorofenyl] -1- heptylureido) -ethyl] phenoxy) -2-methylbutyric acid). (S. Kliewer, et al., Proc. Natl. Acad. Sci. USA 94 (1997).

Ligand binding domain of a human peroxime proliferator activated receptor (hPPARa-LBD): A binding assay for PPARa could be performed through the following procedure: cDNA encoding the putative ligand binding domain of human PPARa (amino acids 167 -468) (Sher, T., Yi, HF., McBride, OW &Gonzalez, FJ (1993) Biochemistry 32, 5598-5604) are amplified by PCR (polymerase chain reaction) and inserted into the BamHI site of the Plasmid pGEX-2T (Pharmacia). The soluble fraction of the fusion proteins GST-hPPARa or glutathione-S-transferase (GST) alone are overexpressed in BL21 (DE3) pLysS cells of E. coli and purified from bacterial extracts in accordance with that described in (S) Kliewer, et al., Proc. Natl. Acad. Sci. USA 94 (1997), 4318-4323). Gel filtration assay: 30 ml of 90 nM GST-hPPARa-LBD are mixed with 20 ml of 50 nM 'H-GW2331 with or without 5 ml of 10 mM test compounds in the linker buffer containing 10 mL Tris, 50 mM KCl, 0.05% Tween 20 and 10 mM DTT. The reaction mixtures are incubated in 96-well plates for 2 hours at room temperature. 50 ml of the reaction mixtures are then charged to a 96-well gel filtration block (following the manufacturer's instructions) (EdgeBioSystems). The block placed on top of a clean 96-well plate is centrifuged at 1000 revolutions per minute for 2 minutes. The block is discarded. 100 ml of scintillation fluid is added to each well of the 96-well plate. After equilibration during the night, the plate is counted in the Microbeta counter (Wallac). Homogeneous scintillation proximity link test. For the Scarchard analysis, SPA beads coated with glutathione (1.5 mg / ml) (Amersham) are mixed with GST-hPPARa-LBD (10 mg / ml) in the binding buffer. The resulting paste is incubated at room temperature with stirring for 15 minutes. 20 ml of the paste is then added in 30 ml of the linker buffer containing various amounts of 3H-GW2331 (10 to 500 nM). The non-specific binding is determined in the presence of 100 mM of GW2331. For the competition link test, 20 ml of the paste are then added in 30 ml of the binding buffer containing 75 nM of 3H-GW2331 and 0.03-20 mM of the test compounds. For control experiments, the SPA beads coated with glutathione (1.5 mg / ml) are coated with GST proteins (10 mg / ml). 20 ml of the paste is mixed with 30 ml of 75 nM of 3H-GW2331 with or without 10 mM of GW2331. The above experiments are all performed in a 96-well plate. The plates sealed with the reaction mixtures are allowed to equilibrate for 2 hours and counted in the Microbeta counter (Wallac).

Link assay of hPPAR? The activity of the compounds of the invention as modulators of PPAR? can it be examined in several relevant in vitro and in vivo preclinical assays, for example, by comparing with a PPAR modulator? known, for example, [3H] -BRL 49853 (Lehman LJ et al, J Biol. Chem. 270, 12953-12956; Lehman LJ et al, J. Biol. Chem. 272, 3406-3410 (1997), and Nichols , JS; et al Analytical 'Biochemistry 257, 112-119 (1998)). Ligand binding domain of human peroxime proliferator activated receptor (hPPAR? -LBD) A binding assay for PPAR? it can be done through the following procedure: cDNA encoding the putative ligand binding domain of PPAR? Human (amino acids 176-477 (Green, ME et al, Gene expression 281-299 (1995)) are amplified by PCR (polymerase chain reaction) and inserted in four in the Ba Hl site of the plasmid pGEX-2T (Pharmacia) The soluble fraction of the GST-hPPARα or glutathione-S-transferase (GST) fusion proteins alone are overexpressed in E. coli BL21 (DE3) pLysS cells and purified from bacterial extracts. of fusion, GST-PPAR? -LBD in PBS (5 mg / 100 ml / well) are incubated in the 96-well plates coated with glutathione for 4 hours.The unbound proteins are then discarded and the plates are washed twice. with the wash buffer (10 mM Tris, 50 M KCl and 0.05% Tween 20) 100 ml of the reaction mixtures containing 60 nM of 3H-BRL-49853 and 10 mM of the test compounds (10 ml of compounds 0.1 mM for each well of the plates) in the binding buffer (10 mM Tris, 50 M KCl and 10 mM DTT) are added after s and incubate at room temperature for 2.5 hours. The reaction mixtures are discarded and the plates are washed twice with the wash buffer. 100 ml of scintillation fluid is added to each well and the plates are counted in a β-counter. HPPARd binding assay The activity of the compounds of the invention as PPARd modulators can be examined in several relevant in vitro and in vivo preclinical assays (see references).

WO 97/28149; Brown P. et al Chemistry & Biology, 4, 909-18, (1997)), for example comparison with a modulator of PPARd known, for example [JH;] GW2433 or [JH:] compound X Compound X The hPPARd binding assay comprises the steps of: (a) preparing multiple test samples by incubating separate aliquots of the hPPARd receptor with a test compound in TEGM containing 5-10% cytoplasmic lysate from COS cells. 1 and 2.5 nM labeled ([JH] compound X, 17 Ci / mmol) for a minimum of 12 hours, and preferably of approximately 16 hours at a temperature of 4o C, wherein the concentration of the test compound in each test sample is different, and preparing a control sample by incubating a separate additional aliquot of the hPPARd receptor under the same conditions but without the test compound; then (b) remove the unbound ligand by adding dextran / gelatin-coated carbon to each sample while maintaining the samples at a temperature of 4 ° C and allowing it to pass at least 10 minutes, then (c) submit each of the test samples and control sample from step (b) to centrifugation at a temperature of 4 ° C until the carbon forms pellets; then (d) counting a portion of the supernatant fraction from each of the test samples and the control sample from step (c) in a liquid scintillation counter and analyzing the results to determine the IC5 of the test compound. In the hPPARd binding assay, preferably at least four test samples of various concentrations of a single test compound are prepared in order to determine the IC50. The compounds useful according to the present invention can be administered to a patient in various forms adapted for the selected administration route, i.e., orally, or parenterally. Parenteral administration in this regard includes administration through the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transeptalial including transdermal, ophthalmic, sublingual and buccal administration; topical administration including ophthalmic, dermal, ocular, rectal and nasal inhalation through insufflation and aerosol and rectal systemic administration. The active compound can be administered orally, for example, with an inert diluent or with an edible assimilable carrier, or it can be enclosed in soft or hard-shell gelatin capsules, or it can be compressed into tablets, or it can be Incorporate directly with the diet food. In the case of an oral therapeutic administration, the active compound can be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, pills, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and preparations should contain at least 0.1% active compound. The percentage of the compositions and preparations can obviously vary and can comfortably be from about 2% to about 61 weight of the unit. The amount of active compound in such therapeutically useful compositions is such that adequate dosage is obtained. Preferred compositions or preparations according to the present invention are prepared in such a way that a unit dosage form oral contains between about 50 and 300 mg of active compound. The tablets, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as for example dicalcium phosphate; a disintegrating agent such as, for example, corn starch, potato starch, alginic acid and the like; a lubricant such as, for example, magnesium stearate; and a sweetener such as for example sucrose, lactose or saccharin can be added either a flavoring agent such as mint flavor, oil of wintergreen, or cherry flavor. When the unit dosage form is a capsule, it may contain, in addition to materials of the type described above, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For example, tablets, pills or capsules can be coated with lacquer, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as, for example, cherry or orange flavor. Obviously, any material used for the preparation of a unit dosage form must be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound can be incorporated into sustained release preparations and formulations. The active compound can also be administered parenterally or intraperitoneally. Solutions of the active compound as a free base or a pharmaceutically acceptable salt can be prepared in water suitably mixed with a surfactant such as for example hydroxypropylcellulose. The dispersion can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injections include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must present fluidity in such a way that there is an ease of handling with a syringe. It can be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or a dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol and the like), suitable mixtures thereof and vegetable oils. Proper fluidity can be maintained, for example, through the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be obtained through various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosan, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be achieved through agents that retard absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compound in the amount required in the appropriate solvent with several of the other ingredients mentioned above, as required, followed by filtered sterilization. In general, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing the basic dispersion medium, and the other ingredients required from those mentioned above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and lyophilization technique which provide a powder of the active ingredient plus any additional desired ingredients from a previously filtered sterile solution. The therapeutic compounds useful in accordance with the present invention can be administered to a patient alone or in combination with pharmaceutically acceptable carriers, in accordance with the above, the ratio is determined by the solubility and chemical nature of the compound, the route of selected administration and standard pharmaceutical practice. The physician will determine the dosage of the therapeutic agents present that will be most suitable for prophylaxis or treatment and said dosage will vary with the form of administration and the particular compound selected and will also vary with the particular patient being treated. Usually the doctor will want to start the treatment with small dosages for small increments until the optimal effect is reached under the circumstances. The therapeutic dosage will generally be from 0.1 to 100 mM / day or from approximately 0.1 mg to approximately 50 mg / kg of body weight per day, or from 10 mg to approximately 50 mg / kg of body weight, or more preferably from 30 mg to approximately 50 mg / kg of body weight per day, and more, although it can be administered in several different dosage units. Higher dosages are required for oral administration. The compounds useful according to the present invention can be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond quickly to a higher or lower dose and may find adequate weaker maintenance doses. For other patients, it may be necessary to have long-term treatments in a regimen of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. In general, the active product will be administered orally 1 to 4 times a day. It is evident that for other patients it will be necessary to prescribe no more than one or two doses per day. One skilled in the art will readily appreciate that the present invention is well suited to achieve the objects of the present invention and achieve the purposes and advantages mentioned, as well as those inherent therein. The compounds, compositions and methods described herein are presented as representative of the preferred embodiments, or are considered as exemplary but not limiting of the scope of the present invention.

Claims (88)

1. A compound of the formula I where Arl), Aryl) and are independently, fused aryl, arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, or fused heteroarylheterocyclyl; A is -0-, -S-, -SO-, -S02-, -NR13, ~ C (0) -, -N (Ri.) C (O) -, -C (0) N (R15) - , -N (R ..) C (0) N (R15) -, -C (R14) = N-, a chemical bond, B is -O-, -S-, -SO-, -S02-, -NR.-7-, a chemical bond, ethynylene, -C (0) -, -N (R_8) C (0) -, or good -C (0) NR.6-; D is -0-, -S-, -NR19-, a chemical bond, ethynylene, N (R20) C (0) -, -C (0) -, or -C (0) N (R20) -; E is a chemical bond or an ethylene group; a is 0-4, b is 0-4, c is 0-4, d is 0-5; e is 0-4, f is 0-6; g is 1-4, h is 1-4, R :, R3, Rs,?, R9, and R? -_, are independently hydrogen, halogen, alkyl, carboxyl, alkoxycarbonyl or aralkyl; R 2 R 4, R 6, Re, Rio, and R 12 are independently - (CH 2) q-X; q is 0-3; X is hydrogen, halogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, aralkoxy, heteroaralkoxy, carboxyl, alkoxycarbonyl, tetrazolyl, acyl, acyl HNSO? -, - SR23, YXY2N- O YY4NCO -; Y1 and Y2 are independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl, one of Y1 and Y2 is hydrogen, or alkyl and the other of Y1 and Y: is acyl or aroyl; Y3 and Y4 are independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl; Z is R2_02C-, R_? OC, cycloimide, -CN, R210_SHNCO-, R2_02SHN-, (R2_) 2NCO-, R2? O-, 2,4-thiazolidinedione, or tetrazolyl; Y R19 and R2? are independently hydrogen, alkyl, aryl, cycloalkyl, or aralkyl; R13, i7, R19 and R23 are independently R22OC-, R22NHOC-, hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroaralkyl, or aralkyl; R14, R15, Rie, Rie and R6 are independently hydrogen, alkyl, aralkyl, carbonyl, or alkoxycarbonyl; or R-, and RI together with the carbon and nitrogen atoms through which they are attached form a 5 or 6 membered azaheterocyclyl group; or when a is 2-4, then neighboring radicals R_ together with the carbon atoms on which the Ri radicals are attached form an ethylene group; or when b is 2-4, then neighboring radicals R3 together with the carbon atoms on which the radicals R3 are attached form an ethylene group; or when c is 2-4, then radicals Rs neighboring with the carbon atoms on which the radicals R5 are attached form an ethylene group; or when d is 2-5, then neighboring R7 radicals together with the carbon atoms on which the RT radicals are bonded form an ethylene group; or when e is 2-4, then radicals Ra adjacent together with the carbon atoms on which the radicals R9 are attached form an ethylene group; or when f is 2-6, then neighboring radicals R__ together with the carbon atoms on which the Rp radicals are attached form an ethylene group; and R22 is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroaralkyl, or aralkyl; or a pharmaceutically acceptable salt, an N-oxide thereof, a hydrate thereof or a solvate thereof.

2. A compound according to formula 1 wherein J is optionally substituted aryl, optionally substituted azaheteroaryl, or optionally substituted fused arylheterocyclenyl; (Arll) is optionally aryl, optionally substituted heteroaryl, or optionally substituted fused arylheterocyclenyl, and "ArlIIJ is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted fused arylheterocyclic alkyl or optionally substituted fused arylheterocyclenyl

3. A compound according to claim 1 where a = 1 or 2, R_ and R2 are hydrogen, A is a chemical bond, and b = 0.

4. A compound according to claim 1 wherein a = 0; A is

R1 and R16 are hydrogen; g is 1, 2, or 3; and b = 0. 5. A compound according to claim 1 wherein a = 0; A is -NR ..-, b = 1, R3 and R ^ are hydrogen.

6. A compound according to claim 1 wherein a = 2; neighboring radicals R_ together with the carbon atoms with which the radicals R_ are bonded to form an ethylene group; R2 is hydrogen; A is a chemical bond; and b = 0.

7. A compound according to claim 1 wherein a = 1, 2 or 3; R_ and R2 are hydrogen; A is - O-; and b = 0.

8. A compound according to claim 1 wherein a = 1; R_, R2 R_ and R are hydrogen; A is -0-; and b = 1.

9. A compound according to claim 1 wherein c = 1 or 2; R5 and R6 are hydrogen or alkyl; B is a chemical bond; and d = 0.

10. A compound according to claim 1 wherein c = 2; Radicals Rs neighboring together with the carbon atoms on which the R5 radicals are bonded form an ethylene group; R6 is hydrogen; B is a chemical bond; and d = 0.

11. A compound according to claim 1 wherein c = 0 or 1; R and Re are hydrogen; B is -0-; and d = 0 or 1.

12. A compound according to claim 1 wherein c = 0; B is -C (0) - or -S (0) 2-; d = 1 and R7 and R8 sen, independently hydrogen or alkyl.

13. A compound according to claim 1 wherein e = 0; f = 0; D and E are a chemical bond; Z is R2? 02SHNCO-, and R2i is phenyl.

14. A compound according to claim 1 wherein e = 0; f = 0 or 1; D and E is a chemical bond; Z is tetrazolyl, NH2C0- or -C02R2 ?; and R: _ is hydrogene or lower alkyl.

15. A compound according to claim 1 wherein e = 0; f = 0 or 1; D is -0- or a chemical bond; E is a chemical bond; and Z is tetrazolyl, NH_CO- or -C02R2 ?; and R_? it is hydrogen or lower alkyl.

16. A compound according to claim 1 wherein e = 0; f = 1; D is -0- or a chemical bond; E is a chemical bond; R__ and R_2 are hydrogen or alkyl; and Z is tetrazolyl, NH2CO- or -C02R2 ?; and R.i is hydrogen or lower alkyl.

17. A compound according to claim 1 wherein e = 2, then neighboring R9 radicals together with the carbon atoms on which the R9 radicals are bonded form an ethylene group; f = 0; D and E is a chemical bond; and Z is -CO.R.i; and R2? It is hydrogen.

18. A compound according to claim 1 wherein e = 0; f = 3; D is -0-; E is a chemical bond; R p and R 2 are hydrogen or alkyl, or at least one of R n is carboxyl or alkoxycarbonyl; Z is tetrazolyl, or -CO.R.i, * and R2_ is hydrogen or lower alkyl.

19. A compound according to claim 1 wherein e = 0; f = l, 2, or 3; D is -C (O) -; E is a chemical bond; p and R 2 are hydrogen or alkyl; Z is tetrazolyl or -C02R2 ?; and R2? it is hydrogen or lower alkyl.

20. A compound according to claim 1 wherein (Arl j is a quinolinyl, quinoxalinyl, quinazolinyl, isoquinolinyl, N-alkyl-quinolin-4-onyl, quinazolin-4-onyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, benzothiophenyl, indolinyl, oxazolyl, thiazolyl, oxadiazolyl isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, triazolyl, pyridylpyrimidinyl, pyrazinyl, pyridazinyl, phenyl, or optionally substituted naphthalenyl, wherein the substituent is a ring system substituent as defined herein , more preferably a substituent selected from the group consisting of phenyl, substituted phenyl, thienyl, substituted thienyl, cycloalkyl, lower alkyl, branched alkyl, fluoro, chloro, alkoxy, aralkyloxy, trifluoromethyl, and trifluoromethyloxy

21. A compound in accordance with claim 1 wherein i Arl] is unsubstituted quinolin-2-yl, quinolin-2-yl substituted in 3-position, quino lin-2-yl substituted in position 4, quinolin-2-yl substituted in position 6 or quinolin-2-yl substituted in position 7; an unsubstituted quinozalin-2-yl, quinozalin-2-yl substituted in position 3, quinozalin-2-yl substituted in position 6 or quinozalin-2-yl disubstituted in positions 3,6; unsubstituted quinazolin-2-yl, quinazolin-2-yl substituted in position 4 or quinazolin-2-yl substituted in position 6; unsubstituted isoquinolin-3-yl, isoquinolin-3-yl substituted in position 6 or isoquinolin-3-yl substituted in position 7; quinazolin-4-on-2-yl substituted in position 3; N-substituted quinolin-4-on-2-yl; oxazol-4-yl substituted in position 2 or oxazol-4-yl disubstituted in positions 2,5; oxazol-2-yl substituted in position 4 or oxazol-2-yl disubstituted in positions 4,5; thiazol-4-yl substituted in position 2 or thiazol-4-yl disubstituted in positions 2,5; thiazol-2-yl substituted in position 4 or thiazol-2-yl disubstituted in positions 4,5; [1, 2, 4] oxadiazol-3-yl substituted in position 5; [1, 2, 4] oxadiazol-5-yl substituted in position 3, imidazol-2-yl substituted in position 5 or imidazol-2-yl disubstituted in positions 3,5; imidazol-5-yl substituted in position 2 or imidazol-5-yl disubstituted in positions 2,3; isoxazol-5-yl substituted in position 3; isoxazol-3-yl substituted in position 5; [1, 2, 4] thiadiazol-3-yl substituted in position 5; [1, 2, 4] -thiadiazol-5-yl substituted in position 3; [1, 3, 4] -thiadiazol-5-yl substituted in position 2; [1,3,4] -oxadiazol-5-yl substituted in position 2; pyrazol-3-yl substituted in position 1; pyrazol-5-yl substituted in position 3; [1, 2, 4] -triazol-5-yl substituted in position 3; [1, 2, 4] -triazol-5-yl substituted in position 1; pyridin-2-yl substituted in position 3; pyridin-2-yl substituted in position 5; pyridin-2-yl substituted in position 6 or pyridin-2-yl disubstituted in positions 3,5; pyrazin-2-yl substituted in position 3, pyrazyl-2-yl substituted in position 5, pyrazin-2-yl substituted in position 6 or pyrazin-2-yl disubstituted in positions 3,5; substituted pyrimidin-2-yl in position 5 or pyrimidin-2-yl substituted in position 6; pyridazin-3-yl substituted in position 6 or pyridazin-3-yl disubstituted in positions 4,6; unsubstituted naphthalene-2-yl, naphthalene-2-yl substituted in the 3-position, naphthalene-2-yl substituted in the 4-position, naphthalene-2-yl substituted in the 6-position or naphthalene-2-yl substituted in the 7-position; phenyl substituted in position 2, phenyl substituted in position 4, phenyl disubstituted in positions 2,4; unsubstituted benzothiazol-2-yl or benzothiazol-2-yl substituted in position 5; unsubstituted benzoxazol-2-yl or benzoxazol-2-yl substituted in position 5; unsubstituted benzimidazol-2-yl or benzimidazol-2-yl substituted in the 5-position; unsubstituted thiophen-2-yl, thiophen-2-yl substituted in position 3, thiophen-2-yl substituted in position 6 or thiophen-2-yl disubstituted in positions 3,6; unsubstituted benzofuran-2-yl, benzofuran-2-yl substituted in position 3, benzofuran-2-yl substituted in position 6 or benzofuran-2-yl disubstituted in positions 3, 6; benzofuran-6-yl substituted in position 3 or benzofuran-6-yl disubstituted in positions 3,7, wherein the substituent is a substituent of the ring system.

22. A compound according to claim 21, wherein (Ar1 j is substituted by a substituent selected from the group consisting of phenyl, substituted phenyl, thienyl, substituted thienyl, cycloalkyl, lower alkyl, branched alkyl, fluoro, chloro, alkoxy, aralkyloxy, trifluoromethyl and trifluoromethyloxy

23. A compound according to claim 1 wherein R_ and R: are hydrogen, a = 1, A is -0-, and b = 0.

24. A compound according to claim 1. Wherein R_ and R_ are hydrogen, a = 2, A is -0-, and b = 0.

25. A compound according to claim 1 wherein a = 0; A is -O- or -NR_3-; R3 is hydrogen or alkyl, R3 and R are both independently hydrogen, and b = 1.

26. A compound according to claim 1 wherein a = 0; A is -O- or -NR? 3-; R_3 is hydrogen or alkyl; R3 and R4 are both independently hydrogen; b = 1; and (Arl) is quinolin-2-yl substituted in position 3, quinolin-2-yl substituted in position 4, quinolin-2-yl substituted in position 6, quinolin-2-yl substituted in position 7, quinoxalin-2-yl unsubstituted, quinoxalin-2-yl substituted in position 3, quinoxalin-2-yl substituted in position 6, quinoxalin-2-yl disubstituted in positions 3,6, quinazolin-2-yl unsubstituted, quinazolin-2-yl substituted in position 4 , substituted quinazolin-2-yl in position 6, unsubstituted isoquinolin-3-yl, isoquinolin-3-yl substituted in position 6, isoquinolin-3-yl substituted in position 7, oxazol-2-yl substituted in position 4, oxazol- 2-disubstituted ilo in positions 4,5, thiazol-2-yl substituted in position 4, thiazol-2-yl disubstituted in positions 4,5, imidazol-2-yl substituted in position 5, imidazol-2-yl disubstituted in positions 3.5, pyrazole-3-yl substituted in position 1, pyrazol-5-yl substituted in position 3, pyridin-2-yl substituted in position 3, pyridin-2-yl substituted in position 5, pyridin-2-yl substituted in position 6 or pyridin-2-yl disubstituted in positions 3,5, pyrazin-2-yl substituted in position 3, pyrazin-2-yl substituted in position 5, pyrazin-2 ilo substituted in position 6, disubstituted pyrazin-2-yl in positions 3,5, pyrimidin-2-yl substituted in position 5, pyrimidin-2-yl substituted in position 6, pyridazin-3-yl substituted in position 6, pyridazin- 3-disubstituted ilo in positions 4,6, unsubstituted benzothiazol-2-yl, benzothiazol-2-yl substituted in position 5, unsubstituted benzoxazol-2-yl, benzoxazol-2-yl substituted in position 5, unsubstituted benzimidazol-2-yl , benzimidazol-2-yl substituted in position 5, benzofuran-6-yl substituted in position 3 or benzofuran-6-yl disubstituted in positions 3,7.

27. A compound of the formula (la) in on T and f Arll are independently, aryl, fused aryl or fused, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl, or fused heteroarylheterocyclyl; A is -0-, -S-, -SO-, -S02-, -NR? _, -C (0) -, -N (R14) C (0) -, -C (0) N (R15) -, -N (R14) C (0) N (R15) -, -C (R _ ") = N-, a chemical bond, B is -0-, -S-, -SO-, -SO; -, -NR.7-, a chemical bond, ethynylene, -C (0) -, -N (R? 8) C (0) - , or -C (0) NR_8-; D is -0-, -S-, -NR-.Q-, a chemical bond, etinilenc, N (R; :) C (0) -, -C (0) -, or -C (0) N (R: o) -; E is a chemical bond or an ethylene group; a is 0-4, b is 0-4 c is 0-4 d is 0-5 e is 0-4 f is 0-6 g is 1-4; h is 1-4; Ri, R3, R5, R7, R9, and R11 are independently hydrogen, halogen, alkyl, carboxyl, alkoxycarbonyl or aralkyl; R2, R., Re, R8, Rio, and R12 are independently - (CH2) q-X; q is 0-3; X is hydrogen, halogen, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, aralkoxy, heteroaralkoxy, carboxyl, alkoxycarbonyl, tetrazolyl, acyl, acyl HNS02-, - SR: 3, YXY2N- O and Y Y4NCO -; "..." and Y2 are independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl, one of Y "and Y2 is hydrogen, or alkyl and the other of Y" and Y 'is acyl or aroyl; YJ and Y4 are independently , hydrogen, alkyl, aryl, aralkyl or heteroaralkyl: Z is R21O2C-, R.iOC, cycloimide, -CN, R__0, SHNCO-, R_? O_SHN-, (R _?) 2NCO-, R_? O ~, 2,4-thiazolidinedione, or tetrazolyl; R_. and R21 are independently hydrogen, alkyl, aryl, cycloalkyl, or aralkyl; Ri3, R17, Ri9 and R2s are independently R22OC-, R;; NH0C-, hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroaralkyl, or aralkyl; Ri, R15, Rie, Rie and R20 are independently hydrogen, alkyl, aralkyl, carbonyl, or alkoxycarbonyl; or R14, and R15 together with the carbon and nitrogen atoms through which they are attached form a 5- or 6-membered azaheterocyclyl group; or when a is 2-4, then radicals Ri, which are neighbors together with the carbon atoms on which the radicals R_ are attached, form an ethylene group; or when b is 2-4, then neighboring radicals R3 together with the carbon atoms on which the radicals R3 are attached form an ethylene group; or when c is 2-4, then neighboring radicals R5 together with the carbon atoms on which the radicals Rs are attached form an ethylene group; or when d is 2-5, then radicals R? neighbors together with the carbon atoms on which the Ri radicals are attached form an ethylene group; or when e is 2-4, then neighboring R9 radicals together with the carbon atoms on which the radicals R are attached form an ethylene group; or when f is 2-6, then radicals Rp neighboring with the carbon atoms on which the Rp radicals are bonded form an ethylene group; and R22 is hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, heteroaralkyl, or aralkyl; or a pharmaceutically acceptable salt, an N-oxide thereof, a hydrate thereof or a solvate thereof.

28. A compound according to claim 27 wherein (ArIJy (Arll) are independently fused aryl, arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl or fused heteroarylheterocyclyl; d = 1 or 2, B is -0-, R £, R6, Ri, Rd are independently hydrogen, e = 0, f = 0, D and E are a chemical bond, Z is R21O2C-, R.iOC- , cycloimide, -CN, R_? 02SHNC0-, R2? 02SHN-, (R2i) 2NCO-, R 2? 0-2, -thiazolidinedione, or tetrazolyl; R 'is lower alkyl, halo, alkoxy, aryloxy or aralkyl; Y R "is lower alkyl or halo

29. A compound according to claim 27 in the Arljy (ArlI) are independently aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylheterocyclenyl. or fused heteroarylheterocyclyl, c + d = 1 or 2, B is -0-, Rs, R6, R7, R8 are independently hydrogen, e = 0, f = 0, D and E are a chemical bond, Z is - CO.H; R 'is lower alkyl, halo, alkoxy, aryloxy or aralkyl, and R "is lower alkyl or halo.

30. A compound according to claim 27 wherein a = 0-2; b = 0-1; A is -O- or -NR?; -; c + d = 1 or 2; B is -O-; R_, R2, R3, R4, R =, R6, R and Re are independently hydrogen; R13 is hydrogen, R_: 0C-, or alkyl; e = 0; f = 0; D and E are a chemical bond; Z is -CO.H; R 'is lower alkyl, halo, alkoxy, aryloxy or aralkyl; and R "is lower alkyl or halo

31. A compound according to claim 27 wherein a = 1 or 2; A is -0- b = 0; Ri,?, R7 and R8 are independently hydrogen; optionally substituted, B is -O-, d = 1, e-0, f-0, D and E are a chemical bond, R 'is hydrogen, halo or benzyloxy, R "is lower alkyl, preferably methyl, Z is -C02H

32. A compound according to claim 27 wherein: a = 1 or 2; A is -0- b = 0; Ri, 2, Rs and e are independently hydrogen; (Arll) is optionally substituted phenyl; c = 1; B is -O-; d = 0; e = 0, f = 0, D and E are a chemical bond; R 'is hydrogen, halo or benzyloxy; R "is lower alkyl, preferably methyl Z is -C02H

33. A compound according to claim 27 wherein: a = 1 or 2; A is -0- b = 0; Ri, R2, Ri, R8 , Rp and Ri are independently hydrogen, (ArlIJ is optionally substituted phenyl, c = 0, B is -0-, d = 1, e = 0, f = 1, D and E are a chemical bond, R 'is halo R "is lower alkyl, preferably methyl, Z is -C02H.

34. A compound according to claim 27 wherein: a = 1; A is -0-b = 0; c = 0-1; B is -0-; d = 0 or 1, where c + d = 1 or 2; e = 0; f = 0; D and E are a chemical bond; R 'is hydrogen, aralkoxy, or halo; R "is lower alkyl, preferably methyl, Z is -C02H 35. A compound according to claim 27 wherein: a = 1; A is -0-b = 0; c = 0; B is -0- d = 1, e = 0, f = 0, D and E are a chemical bond;

R 'is hydrogen; R "is lower alkyl, Z is -C02H,

36. A compound according to claim 27 wherein: (Arl) and (ArIl) are aryl or heteroaryl, a = 1; A is -0- b = 0; = 0, B is -O-, d = 1, _ ^ • f = 0, D and E are a chemical bond, R 'is hydrogen, R "is lower alkyl; Z is -C02H.

37. A compound according to claim 27 wherein: (optionally substituted azaheteroaryl aryl; Pyrolyl optionally substituted; a = 1; A is -0-; b = 0; c = 0; B is -O-; d = 1. e = 0; f = 0; D and E are a chemical bond; R 'is hydrogen; R "is lower alkyl Z is C02H

38. A compound according to claim 27 wherein: (Arl) is optionally substituted quinolinyl, or a 5-membered heteroaryl group wherein the heteroaryl group is substituted by optionally substituted phenyl or optionally substituted cyclohexyl; (optionally substituted phenyl aryl; a = 1; A is -O-; b = 0; c = 0; B is -O-; d = 1, e = 0, f = 0, D and E are a chemical bond; R 'is hydrogen; R "is lower alkyl, Z is C02H,

39. A compound according to claim 1 selected within the group 25 OR 0 \ * 0 HO '~ ^ _ / 0 ^ y ..- ^ ~. or ^ -y - ~ -y ^^ -.- 0. -y * - OH O O N, 0 - \ _- > O OH OH cu and Cl. -o "^ 1 / OH Ko ' N '^ = 5- HO'V cuc? R-2: * "s * £ .cc V- £ ^ \ a . " Y

40. A compound according to claim 1 selected from the group consisting of and * -yy?

41. A compound according to claim 1 selected from the group consisting of

42. A compound according to claim 1 selected from the group consisting of CA ix? and

43. A compound according to claim 1, selected within the group consisting of ..le and

44. A compound according to claim 1 selected from the group consisting of

45. A compound according to claim 1 selected from the group consisting of sX-oAs; ayy X; and

46. A compound according to claim 1 selected from the group consisting of

47. A compound according to claim 1 selected from the group consisting of

48. A compound according to claim 1 of the formula

49. A pharmaceutical composition comprising a pharmaceutically acceptable amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.

50. A method for the treatment of a patient suffering from a physiological disorder that can be modulated by a compound according to claim 1 having a ligand binding activity of PPAR, comprising administering a pharmaceutically amount to the patient. effective of the compound, or a pharmaceutically acceptable salt thereof.

51. A method according to claim 50 wherein the disease is associated with a physiologically damaging blood level of insulin, glucose, free fatty acids (FFA), or triglycerides.

52. The method according to claim 51, wherein the physiological disorder is hyperglycemia.

53. The method according to claim 52, wherein the hyperglycemia is diabetes.

54. The method according to claim 52, wherein the hyperglycemia is type II diabetes.

55. The method according to claim 51, wherein the physiological disorder is hyperinsulinism.

56. The method according to claim 55, wherein hyperinsulinism is Syndrome X.

57. The method according to claim 51, wherein the physiological disorder is insulin resistance.

58. The method according to claim 51, wherein the physiological disorder is a cardiovascular condition.

59. The method according to claim 58, wherein the cardiovascular condition is atherosclerosis.

60. The method according to claim 51, wherein the physiological disorder is hyperlipidemia.

61. The method according to claim 51, wherein the physiological disorder is hypertension. '

62. The method according to claim 51, wherein the physiological disorder is a disorder of the feg.

63. The method according to claim 50, wherein the mtion is agonist.

64. The method according to claim 50, wherein the mtion is antagonistic.

65. A method for mting PPAR-? Receptor activity which comprises contacting said PPAR- receptor? with a compound according to claim 1.

66. A pharmaceutical composition comprising a pharmaceutically acceptable amount of the compound according to claim 27 and a pharmaceutically acceptable carrier.

67. A method for the treatment of a patient suffering from a physiological disorder that can be modulated by a compound according to claim 27 having a PPAR ligand binding activity, comprising administering a pharmaceutically amount to the patient. effective of the compound, or a pharmaceutically acceptable salt thereof.

68. A method according to claim 67 wherein the disease is associated with a physiologically damaging blood level of insulin, glucose, free fatty acids (FFA) or triglycerides.

69. The method according to claim 67, wherein the physiological disorder is hyperglycemia.

70. The method according to claim 69, wherein the hyperglycemia is diabetes.

71. The method according to claim 69, wherein the hyperglycemia is type II diabetes.

72. The method according to claim 67, wherein the physiological disorder is hyperinsulinism.

73. The method according to claim 72, wherein hyperinsulinism is Syndrome X.

74. The method according to claim 67, wherein the physiological disorder is insulin resistance.

75. The method according to claim 67, wherein the physiological disorder is a cardiovascular disorder.

76. The method according to claim 75, wherein the cardiovascular disorder is atherosclerosis.

77. The method according to claim 67, wherein the physiological disorder is hyperlipidemia.

78. The method according to claim 67, wherein the physiological disorder is hypertension.

79. The method according to claim 67, wherein the physiological disorder is a disorder of the diet.

80. The method according to claim 67, wherein the mediation is agonist.

81. The method according to claim 67, wherein the mediation is antagonistic.

82. A method for mediating PPAR receptor activity, comprising contacting said PPAR receptor with a compound according to claim 27.

83. A method for treating a patient suffering from a physiological disease that can be modulated by a compound having a ligand binding activity of PPARa and PPAR ?, which comprises administering to the patient a pharmaceutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, wherein said compound is of the formula

84. A method for the treatment of a patient suffering from a physiological disease that can be modulated by a compound having PPARα ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, wherein said compound is selected within the group consisting of

85. A method for the treatment of a patient suffering from a physiological disease which can be modulated by a compound having a ligand binding activity of PPARd, comprising administering to the patient a pharmaceutically effective amount of the compound, or a pharmaceutically salt acceptable thereof, wherein said compound is of the formula:

86. A method for the treatment of a patient suffering from a physiological disease that can be modulated by a compound having a ligand binding activity of PPARa and PPARd, comprising administering to the patient a pharmaceutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of

87. A method for the treatment of a patient suffering from a physiological disease that can be modulated by a compound having a ligand binding activity of PPARd and PPAR ?, which comprises administering to the patient a. pharmaceutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of

88. A method for the treatment of a patient suffering from a physiological disease that can be modulated by a compound having a PPARα ligand binding activity, comprising administering to the patient a pharmaceutically effective amount of the compound, or a salt pharmaceutically acceptable thereof, wherein said compound is selected from the group consisting of